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.

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.

Development and Assessment of Two Highly Pathogenic Avian Influenza (HPAI) H5N6 Candidate Vaccine Viruses for Pandemic Preparedness.

OBJECTIVE: In China, 24 cases of human infection with highly pathogenic avian influenza (HPAI) H5N6 virus have been confirmed since the first confirmed case in 2014. Therefore, we developed and assessed two H5N6 candidate vaccine viruses (CVVs). METHODS: In accordance with the World Health Organization (WHO) recommendations, we constructed two reassortant viruses using reverse genetics (RG) technology to match the two different epidemic H5N6 viruses. We performed complete genome sequencing to determine the genetic stability. We assessed the growth ability of the studied viruses in MDCK cells and conducted a hemagglutination inhibition assay to analyze their antigenicity. Pathogenicity attenuation was also evaluated in vitro and in vivo. RESULTS: The results showed that no mutations occurred in hemagglutinin or neuraminidase, and both CVVs retained their original antigenicity. The replication capacity of the two CVVs reached a level similar to that of A/Puerto Rico/8/34 in MDCK cells. The two CVVs showed low pathogenicity in vitro and in vivo, which are in line with the WHO requirements for CVVs. CONCLUSION: We obtained two genetically stable CVVs of HPAI H5N6 with high growth characteristics, which may aid in our preparedness for a potential H5N6 pandemic.

Profile and generation of reduced neuraminidase inhibitor susceptibility in highly pathogenic avian influenza H7N9 virus from human cases in Mainland of China, 2016-2019.

Human infections with highly pathogenic avian influenza (HPAI) H7N9 virus were detected in late 2016. We examined the drug resistance profile of 30 HPAI H7N9 isolates from Mainland of China (2016-2019). Altogether, 23% (7/30) carried neuraminidase inhibitors (NAIs) - resistance mutations, and 13% (4/30) displayed reduced susceptibility to NAIs in neuraminidase (NA) inhibition test. An HPAI H7N9 reassortment virus we prepared was passaged with NAIs for 10 passages. Passage with zanamivir induced an E119G substitution in NA, whereas passage with oseltamivir induced R292K and E119V substitutions that simulated that seen in oseltamivir -treated HPAI H7N9 cases, indicating that the high frequency of resistant strains in the HPAI H7N9 isolates is related to NAIs use. In presence of NAIs, R238I, A146E, G151E and G234T substitutions were found in HA1 region of HA. No amino acid mutations were found in the internal genes of the recombinant virus.

Cross-neutralizing Anti-hemagglutinin Antibodies Isolated from Patients Infected with Avian Influenza A (H5N1) Virus.

OBJECTIVE: To recover broad-neutralizing monoclonal antibodies (BnAbs) from avian influenza A (H5N1) virus infection cases and investigate their genetic and functional features. METHODS: We screened the Abs repertoires of expanded B cells circulating in the peripheral blood of H5N1 patients. The genetic basis, biological functions, and epitopes of the obtained BnAbs were assessed and modeled. RESULTS: Two BnAbs, 2-12D5, and 3-37G7.1, were respectively obtained from two human H5N1 cases on days 12 and 21 after disease onset. Both Abs demonstrated cross-neutralizing and Ab-dependent cellular cytotoxicity (ADCC) activity. Albeit derived from distinct Ab lineages, i.e., V H1-69-D2-15-J H4 (2-12D5) and V H1-2-D3-9-J H5 (3-32G7.1), the BnAbs were directed toward CR6261-like epitopes in the HA stem, and HA 2 I45 in the hydrophobic pocket was the critical residue for their binding. Signature motifs for binding with the HA stem, namely, IFY in V H1-69-encoded Abs and LXYFXW in D3-9-encoded Abs, were also observed in 2-12D5 and 3-32G7.1, respectively. CONCLUSIONS: Cross-reactive B cells of different germline origins could be activated and re-circulated by avian influenza virus. The HA stem epitopes targeted by the BnAbs, and the two Ab-encoding genes usage implied the VH1-69 and D3-9 are the ideal candidates triggered by influenza virus for vaccine development.

Epidemiology of Sepsis-3 in a sub-district of Beijing: secondary analysis of a population-based database.

BACKGROUND: With the publication of Sepsis-3 definition, epidemiological data based on Sepsis-3 definition from middle-income countries including China are scarce, which prohibits understanding of the disease burden of this newly defined syndrome in these settings. The purpose of this study was to describe incidence and outcome of Sepsis-3 in Yuetan sub-district of Beijing and to estimate the incidence rate of Sepsis-3 in China. METHODS: The medical records of all adult residents hospitalized from July 1, 2012 to June 30, 2014 in Yuetan sub-district of Beijing were reviewed. Patients with sepsis-3 and severe sepsis/septic shock were identified. The incidence rates and mortality rate of sepsis-3 and sepsis/septic shock were calculated, incidence rates and in-hospital mortality rates were normalized to the population distribution in the 2010 National Census. Population incidence rate and case fatality rate between sexes were compared with the Z test, as the data conformed to Poisson distribution. RESULTS: Of the 21,191 hospitalized patients, 935 patients were diagnosed with Sepsis-3, and 498 cases met severe sepsis/septic shock criteria. The crude annual incidence rate of Sepsis-3 in Yuetan sub-district was 363 cases per 100,000 population, corresponding to standardized incidence rates of 236 cases per 100,000 population per year, respectively. The overall case fatality rate of Sepsis-3 was 32.0%, the crude population mortality rates of Sepsis-3 was 116 cases per 100,000 population per year, the standardized mortality rate was 67 cases per 100,000 population per year, corresponding to a speculative extrapolation of 700,437 deaths in China. The incidence rate and mortality rate of Sepsis-3 were significantly higher in males, elderly people, and patients with more comorbidities. The 62.1% of patients with Sepsis-3 had community-acquired infections, compared with 75.3% of infected patients without Sepsis-3 (P < 0.001). The most common infection in patients with Sepsis-3 was lower respiratory tract infection. When compared with patients with Sepsis-3, patients diagnosed as severe sepsis/septic shock were more likely to have higher case fatality rate (53.4% vs. 32.0%, P < 0.001) CONCLUSIONS:: This study found the standardized incidence rate of 236 cases per 100,000 person-year for Sepsis-3, which was more common in males and elderly population. This corresponded to about 2.5 million new cases of Sepsis-3 per year, resulting in more than 700,000 deaths in China. CLINICAL TRIAL REGISTRATION: NCT02285257, https://clinicaltrials.gov/ct2/show/record/NCT02285257.

Synaptic modifications driven by spike-timing-dependent plasticity in weakly coupled bursting neurons.

In the course of development, sleep, or mental disorders, certain neurons in the brain display spontaneous spike-burst activity. The synaptic plasticity evoked by such activity is here studied in the presence of spike-timing-dependent plasticity (STDP). In two chemically coupled bursting model neurons, the spike-burst activity can translate the STDP related to pre- and postsynaptic spike activity into burst-timing-dependent plasticity (BTDP), based on the timing of bursts of pre- and postsynaptic neurons. The resulting BTDP exhibits exponential decays with the same time scales as those of STDP. In weakly coupled bursting neuron networks, the synaptic modification driven by the spike-burst activity obeys a power-law distribution. The model can also produce a power-law distribution of synaptic weights. Here, the considered bursting behavior is made of stereotypical groups of spikes, and bursting is evenly spaced by long intervals.

Adaptive control of dynamical synchronization on evolving networks with noise disturbances.

In real-world networked systems, the underlying structure is often affected by external and internal unforeseen factors, making its evolution typically inaccessible. An adaptive strategy was introduced for maintaining synchronization on unpredictably evolving networks [Sorrentino and Ott, Phys. Rev. Lett. 100, 114101 (2008)PRLTAO0031-900710.1103/PhysRevLett.100.114101], which yet does not consider the noise disturbances widely existing in networks' environments. We provide here strategies to control dynamical synchronization on slowly and unpredictably evolving networks subjected to noise disturbances which are observed at the node and at the communication channel level. With our strategy, the nodes' coupling strength is adaptively adjusted with the aim of controlling synchronization, and according only to their received signal and noise disturbances. We first provide a theoretical analysis of the control scheme by introducing an error potential function to seek for the minimization of the synchronization error. Then, we show numerical experiments which verify our theoretical results. In particular, it is found that our adaptive strategy is effective even for the case in which the dynamics of the uncontrolled network would be explosive (i.e., the states of all the nodes would diverge to infinity).

Clinical Features and Peripheral Blood T Lymphocyte Subsets in Hand, Foot, and Mouth Disease According to Different Pathogens.

OBJECTIVE: To investigate the changes in lymphocyte subsets that are caused by infection with different pathogens in children with hand, foot, and mouth disease. METHODS: T lymphocyte subsets were measured in the patients' peripheral blood, and serum, throat swab, and fecal samples were tested for enterovirus. RESULTS: Fecal and throat swab samples exhibited similar positive detection rates, and were significantly more likely to be positive, compared to serum samples (P < 0.01). The EV71-positive group exhibited significantly lower CD4 + TM cell counts (QR: 1.058), compared to the CD4 + TM cell counts in the CoxA16-positive group (QR: 1.391; P < 0.05). CONCLUSIONS: Throat swab and fecal samples exhibited significantly higher positive detection rates, compared to serum samples. In addition, EV71-infected children exhibited significantly lower CD4+ T-cell counts, compared to CoxA16-infected children, which suggests that EV71 infection may be associated with a poorer prognosis.

Spatiotemporal properties of microsaccades: Model predictions and experimental tests.

Microsaccades are involuntary and very small eye movements during fixation. Recently, the microsaccade-related neural dynamics have been extensively investigated both in experiments and by constructing neural network models. Experimentally, microsaccades also exhibit many behavioral properties. It's well known that the behavior properties imply the underlying neural dynamical mechanisms, and so are determined by neural dynamics. The behavioral properties resulted from neural responses to microsaccades, however, are not yet understood and are rarely studied theoretically. Linking neural dynamics to behavior is one of the central goals of neuroscience. In this paper, we provide behavior predictions on spatiotemporal properties of microsaccades according to microsaccade-induced neural dynamics in a cascading network model, which includes both retinal adaptation and short-term depression (STD) at thalamocortical synapses. We also successfully give experimental tests in the statistical sense. Our results provide the first behavior description of microsaccades based on neural dynamics induced by behaving activity, and so firstly link neural dynamics to behavior of microsaccades. These results indicate strongly that the cascading adaptations play an important role in the study of microsaccades. Our work may be useful for further investigations of the microsaccadic behavioral properties and of the underlying neural dynamical mechanisms responsible for the behavioral properties.

Fast response and high sensitivity to microsaccades in a cascading-adaptation neural network with short-term synaptic depression.

Microsaccades are very small eye movements during fixation. Experimentally, they have been found to play an important role in visual information processing. However, neural responses induced by microsaccades are not yet well understood and are rarely studied theoretically. Here we propose a network model with a cascading adaptation including both retinal adaptation and short-term depression (STD) at thalamocortical synapses. In the neural network model, we compare the microsaccade-induced neural responses in the presence of STD and those without STD. It is found that the cascading with STD can give rise to faster and sharper responses to microsaccades. Moreover, STD can enhance response effectiveness and sensitivity to microsaccadic spatiotemporal changes, suggesting improved detection of small eye movements (or moving visual objects). We also explore the mechanism of the response properties in the model. Our studies strongly indicate that STD plays an important role in neural responses to microsaccades. Our model considers simultaneously retinal adaptation and STD at thalamocortical synapses in the study of microsaccade-induced neural activity, and may be useful for further investigation of the functional roles of microsaccades in visual information processing.

Model predictions of features in microsaccade-related neural responses in a feedforward network with short-term synaptic depression.

Recently, the significant microsaccade-induced neural responses have been extensively observed in experiments. To explore the underlying mechanisms of the observed neural responses, a feedforward network model with short-term synaptic depression has been proposed [Yuan, W.-J., Dimigen, O., Sommer, W. and Zhou, C. Front. Comput. Neurosci. 7, 47 (2013)]. The depression model not only gave an explanation for microsaccades in counteracting visual fading, but also successfully reproduced several microsaccade-related features in experimental findings. These results strongly suggest that, the depression model is very useful to investigate microsaccade-related neural responses. In this paper, by using the model, we extensively study and predict the dependance of microsaccade-related neural responses on several key parameters, which could be tuned in experiments. Particularly, we provide a significant prediction that microsaccade-related neural response also complies with the property "sharper is better" observed in many contexts in neuroscience. Importantly, the property exhibits a power-law relationship between the width of input signal and the responsive effectiveness, which is robust against many parameters in the model. By using mean field theory, we analytically investigate the robust power-law property. Our predictions would give theoretical guidance for further experimental investigations of the functional role of microsaccades in visual information processing.

[Advances in research and development of universal influenza vaccines].

Vaccination is the primary strategy for the prevention and control of pandemic influenza. Because influenza virus is highly variable across strains, universal influenza vaccines need to be developed to address this problem. This review describes the research progress in conserved epitopes of influenza virus, the advances in the research and development of universal influenza vaccines based on the relatively conserved sequences of NP, M2e, HA2, and headless HA, the mechanisms of cross-protection, and the methods to improve cross-protection.

[Preliminary study of a universal vaccine based on the HA2 protein of the H5N1 influenza virus].

Fragments encoding amino acids 76-130 in the linear conserved region (LCR) of A/Hubei/1/2010 (H5N1) HA2 was fused to hepatitis B core antigen (HBc) to generate a LCR-HBe virus-like particle (VLP). Results showed that the fusion protein of LCR-HBc was highly expressed in this prokaryotic expression system. The purified LCR-HBc particle stimulated high levels of IgG production in mice with a titer of > 1:12 800, and provided 50% cross-protection against lethal challenge by H1N1 viruses.

Spontaneous scale-free structure in adaptive networks with synchronously dynamical linking.

Inspired by the anti-Hebbian learning rule in neural systems, we study how the feedback from dynamical synchronization shapes network structure by adding new links. Through extensive numerical simulations, we find that an adaptive network spontaneously forms scale-free structure, as confirmed in many real systems. Moreover, the adaptive process produces two nontrivial power-law behaviors of deviation strength from mean activity of the network and negative degree correlation, which exists widely in technological and biological networks. Importantly, these scalings are robust to variation of the adaptive network parameters, which may have meaningful implications in the scale-free formation and manipulation of dynamical networks. Our study thus suggests an alternative adaptive mechanism for the formation of scale-free structure with negative degree correlation, which means that nodes of high degree tend to connect, on average, with others of low degree and vice versa. The relevance of the results to structure formation and dynamical property in neural networks is briefly discussed as well.

[Evaluation of influenza A virus nucleoprotein based on baculovirus surface-display technology].

Nucleoprotein (NP) of influenza virus is highly conserved and type-specific. NP can trigger strong cell-mediated immune responses in host and is involved in the protection against the challenges with different subtype influenza viruses. Here, NP of an avian H5N1 (A/Hubei/1/2010, HB) was expressed by baculovirus surface-display technology and its immunogenicity as well as protective mechanism was investigated in mice infection model. Western blot and immunolabeled electron microscopy assay showed NP was displayed on baculovirus surface. ELISA results showed NP could induce high level of anti-NP IgG in the sera from NP-Bac-inoculated mice. Two cellular immune peptides (NP57-74 IQNSITIERMVLSAFDER and NP441-458 RTEIIKMMESARPEDLSF) were identified by IFN-gamma ELISPOT assay. NP57-66 and NP441-450 and NP protein could be able to trigger the activation of CD4+ and CD8+ T cells, and the response of CD8+ T was more predominant. The challenge study of mice-adapted virus A/PR/8/34 (H1N1) showed that NP-Bac could reduce viral load and attenuate the damage to lung tissue. 50% protection ratio against the virus could be detected.

[Accessing the features of surface neuraminidase (N1) of influenza A virus presenting on the platforms for anti-NA Abs screening].

OBJECTIVE: To understand if the Neuraminidase (N1) of Influenza A virus at the surface of yeast-displaying system, eukaryotic expression system and the infected cells could be used for anti-NA Abs screening, their activities and bindings to five candidate Abs were assayed. METHODS: The surface NA expression was obtained by transfecting by recombinant NA constructors with specific tag-labels or live virus infection. The functional activity was measured by the fluorescent assay. Their bindings to the Abs were detected by flow cytometry. RESULTS: The surface NAs presenting on the yeast-displaying system and eukaryotic expression system exhibited functional NA activities as the NA at the surface of virus-infected cells which showed affinities to Ab1, 4, and 5. The same bindings to Abl and 5 were found in the surface NA expressed by eukaryotic expression system while minor binding was observed in the yeast displayed-NA. CONCLUSION: The epitopes of yeast-displayed NA may be different from the NAs present at eukaryotic expression system and the infected cells which more likely suitable for the screening of anti-NA Abs.

Network evolution induced by asynchronous stimuli through spike-timing-dependent plasticity.

In sensory neural system, external asynchronous stimuli play an important role in perceptual learning, associative memory and map development. However, the organization of structure and dynamics of neural networks induced by external asynchronous stimuli are not well understood. Spike-timing-dependent plasticity (STDP) is a typical synaptic plasticity that has been extensively found in the sensory systems and that has received much theoretical attention. This synaptic plasticity is highly sensitive to correlations between pre- and postsynaptic firings. Thus, STDP is expected to play an important role in response to external asynchronous stimuli, which can induce segregative pre- and postsynaptic firings. In this paper, we study the impact of external asynchronous stimuli on the organization of structure and dynamics of neural networks through STDP. We construct a two-dimensional spatial neural network model with local connectivity and sparseness, and use external currents to stimulate alternately on different spatial layers. The adopted external currents imposed alternately on spatial layers can be here regarded as external asynchronous stimuli. Through extensive numerical simulations, we focus on the effects of stimulus number and inter-stimulus timing on synaptic connecting weights and the property of propagation dynamics in the resulting network structure. Interestingly, the resulting feedforward structure induced by stimulus-dependent asynchronous firings and its propagation dynamics reflect both the underlying property of STDP. The results imply a possible important role of STDP in generating feedforward structure and collective propagation activity required for experience-dependent map plasticity in developing in vivo sensory pathways and cortices. The relevance of the results to cue-triggered recall of learned temporal sequences, an important cognitive function, is briefly discussed as well. Furthermore, this finding suggests a potential application for examining STDP by measuring neural population activity in a cultured neural network.