Short-Term Exposure to Ambient Air Pollution and Influenza: A Multicity Study in China.

BACKGROUND: Air pollution is a major risk factor for planetary health and has long been suspected of predisposing humans to respiratory diseases induced by pathogens like influenza viruses. However, epidemiological evidence remains elusive due to lack of longitudinal data from large cohorts. OBJECTIVE: Our aim is to quantify the short-term association of influenza incidence with exposure to ambient air pollutants in Chinese cities. METHODS: Based on air pollutant data and influenza surveillance data from 82 cities in China over a period of 5 years, we applied a two-stage time series analysis to assess the association of daily incidence of reported influenza cases with six common air pollutants [particulate matter with aerodynamic diameter ≤2.5µm (PM2.5), particulate matter with aerodynamic diameter ≤10µm (PM10), NO2, SO2, CO, and O3], while adjusting for potential confounders including temperature, relative humidity, seasonality, and holiday effects. We built a distributed lag Poisson model for one or multiple pollutants in each individual city in the first stage and conducted a meta-analysis to pool city-specific estimates in the second stage. RESULTS: A total of 3,735,934 influenza cases were reported in 82 cities from 2015 to 2019, accounting for 72.71% of the overall case number reported in the mainland of China. The time series models for each pollutant alone showed that the daily incidence of reported influenza cases was positively associated with almost all air pollutants except for ozone. The most prominent short-term associations were found for SO2 and NO2 with cumulative risk ratios of 1.094 [95% confidence interval (CI): 1.054, 1.136] and 1.093 (95% CI: 1.067, 1.119), respectively, for each 10 µg/m3 increase in the concentration at each of the lags of 1-7 d. Only NO2 showed a significant association with the daily incidence of influenza cases in the multipollutant model that adjusts all six air pollutants together. The impact of air pollutants on influenza was generally found to be greater in children, in subtropical cities, and during cold months. DISCUSSION: Increased exposure to ambient air pollutants, particularly NO2, is associated with a higher risk of influenza-associated illness. Policies on reducing air pollution levels may help alleviate the disease burden due to influenza infection. https://doi.org/10.1289/EHP12146.

A study on inhibition of the Aß1-42-induced inflammatory response by the Huatuo Zaizao pill through the NF-κB signaling pathway.

Introduction: The pathology of Alzheimer's disease (AD) includes ß-amyloid (Aß) (plaques) and neurofibrillary tangles (NFTs). This study aimed to explore the efficacy of Huatuo Zaizao pill (HTZP) in an AD mouse model induced by injecting Aß1-42, and the neuroprotective mechanism of HTZP in AD. Material and methods: C57BL/6 (B6) mice were randomly divided into 4 groups (n = 10, per group): control group, AD model group, and 2 different doses of HTZP treated groups. The Morris water maze test was carried out on AD mice to assess the learning ability after treatment with HTZP for 15 day. The levels of inflammatory factors and the nuclear factor-κB (NF-κB) pathway were examined by western blot and real-time polymerase chain reaction (PCR). The content of microglia was investigated by immunofluorescence. Results: This study revealed that a cognitive disorder could be mitigated when the AD mice were treated with HTZP, which might be associated with the decreased level of pro-inflammatory factors, and the inhibitory activities of microglia. Additionally, phosphorylation of IκB and NF-κB p65 could be reduced by prohibiting the neuroinflammation of NF-κB activation in the hippocampus of AD mice. Conclusions: These results showed that HTZP could mitigate a cognitive disorder, diminish the activation of microglia, and inhibit the content of inflammatory factors through the NF-κB pathway in Aß1-42-induced AD mice. HTZP may be an appropriate agent for AD treatment in the future.

Comparative study on epidemiological and etiological characteristics of patients with acute diarrhea with febrile or non-febrile symptoms in China.

BACKGROUND: Acute diarrhea with fever can potentially represent a more severe form of the disease compared to non-febrile diarrhea. This study was to investigate the epidemiological characteristics and enteric pathogen composition of febrile-diarrheal patients, and to explore factors including pathogens associated with fever by age group. METHODS: A nationwide surveillance study of acute diarrheal patients of all ages was conducted in 217 sentinel hospitals from 31 provinces (autonomous regions or municipalities) in China between 2011 and 2020. Seventeen diarrhea-related pathogens, including seven viruses and ten bacteria, were investigated and their association with occurrence of fever symptoms was assessed using multivariate logistic analysis. RESULTS: A total of 146,296 patients with acute diarrhea (18.6% with fever) were tested. Th diarrheal children below 5 years had the highest frequency of fever (24.2%), and related to significantly higher prevalence of viral enteropathogens (40.2%) as compared with other age groups (P < 0.001). Within each age group, the febrile-diarrheal patients were associated with a significantly higher prevalence of bacterial pathogens than afebrile-diarrheal patients (all P < 0.01). There was discrepancy when each pathogen was compared, i.e., nontyphoidal Salmonella (NTS) was overrepresented in febrile vs non-febrile patients of all age groups, while the febrile vs non-febrile difference for diarrheagenic Escherichia coli (DEC) was only significant for adult groups. The multivariate analysis revealed significant association between fever and infection with rotavirus A among children [odds ratio (OR) = 1.60], for DEC in adult groups (OR = 1.64), for NTS in both children (OR = 2.95) and adults (OR = 3.59). CONCLUSIONS: There are significant discrepancy of the infected enteric pathogens in patients with acute diarrhea with fever between age groups, and it is valuable for priority detection of NTS and rotavirus A in patients with children < 5 years old and NTS and DEC in adult patients. The results may be useful in identifying dominant pathogen candidates for the application of diagnostic assays and prevention control.

Broad Impacts of Coronavirus Disease 2019 (COVID-19) Pandemic on Acute Respiratory Infections in China: An Observational Study.

BACKGROUND: To combat the coronavirus disease 2019 (COVID-19) pandemic, nonpharmaceutical interventions (NPIs) were implemented worldwide, which impacted a broad spectrum of acute respiratory infections (ARIs). METHODS: Etiologically diagnostic data from 142 559 cases with ARIs, who were tested for 8 viral pathogens (influenza virus [IFV], respiratory syncytial virus [RSV], human parainfluenza virus [HPIV], human adenovirus [HAdV], human metapneumovirus [HMPV], human coronavirus [HCoV], human bocavirus [HBoV], and human rhinovirus [HRV]) between 2012 and 2021, were analyzed to assess the changes in respiratory infections in China during the first COVID-19 pandemic year compared with pre-pandemic years. RESULTS: Test-positive rates of all respiratory viruses decreased during 2020, compared to the average levels during 2012-2019, with changes ranging from -17.2% for RSV to -87.6% for IFV. Sharp decreases mostly occurred between February and August when massive NPIs remained active, although HRV rebounded to the historical level during the summer. While IFV and HMPV were consistently suppressed year-round, RSV, HPIV, HCoV, HRV, and HBoV resurged and went beyond historical levels during September 2020-January 2021, after NPIs were largely relaxed and schools reopened. Resurgence was more prominent among children <18 years and in northern China. These observations remain valid after accounting for seasonality and long-term trend of each virus. CONCLUSIONS: Activities of respiratory viral infections were reduced substantially in the early phases of the COVID-19 pandemic, and massive NPIs were likely the main driver. Lifting of NPIs can lead to resurgence of viral infections, particularly in children.

Imperatorin inhibits mitogen-activated protein kinase and nuclear factor kappa-B signaling pathways and alleviates neuroinflammation in ischemic stroke.

AIMS: Microglia-mediated neuroinflammation plays an important role in the pathological process of ischemic stroke, and the effect of imperatorin on post-stroke neuroinflammation is not fully understood. METHODS: Primary microglia were treated with imperatorin for 2 h followed by LPS (100 ng/ml) for 24 h. The expression of inflammatory cytokines was detected by RT-PCR, ELISA, and Western blot. The activation of MAPK and NF-κB signaling pathways were analyzed by Western blot. The ischemic insult was determined using a transient middle cerebral artery occlusion (tMCAO) model in C57BL/6J mice. Behavior tests were used to assess the neurological deficits of MCAO mice. TTC staining was applied to measure infract volume. RESULTS: Imperatorin suppressed LPS-induced activation of microglia and pro-inflammatory cytokines release and attenuated ischemic injury in MCAO mice. The results of transcriptome sequencing and Western blot revealed that downregulation of MAPK and NF-κB pathways might contribute to the protective effects of imperatorin. CONCLUSIONS: Imperatorin downregulated MAPK and NF-κB signaling pathways and exerted anti-inflammatory effects in ischemic stroke, which indicated that imperatorin might be a potential compound for the treatment of stroke.

Changes in notifiable infectious disease incidence in China during the COVID-19 pandemic.

Nationwide nonpharmaceutical interventions (NPIs) have been effective at mitigating the spread of the novel coronavirus disease (COVID-19), but their broad impact on other diseases remains under-investigated. Here we report an ecological analysis comparing the incidence of 31 major notifiable infectious diseases in China in 2020 to the average level during 2014-2019, controlling for temporal phases defined by NPI intensity levels. Respiratory diseases and gastrointestinal or enteroviral diseases declined more than sexually transmitted or bloodborne diseases and vector-borne or zoonotic diseases. Early pandemic phases with more stringent NPIs were associated with greater reductions in disease incidence. Non-respiratory diseases, such as hand, foot and mouth disease, rebounded substantially towards the end of the year 2020 as the NPIs were relaxed. Statistical modeling analyses confirm that strong NPIs were associated with a broad mitigation effect on communicable diseases, but resurgence of non-respiratory diseases should be expected when the NPIs, especially restrictions of human movement and gathering, become less stringent.

The changing pattern of enteric pathogen infections in China during the COVID-19 pandemic: a nation-wide observational study.

BACKGROUND: Non pharmaceutical interventions (NPI) including hand washing directives were implemented in China and worldwide to combat the COVID-19 pandemic, which are likely to have had impacted a broad spectrum of enteric pathogen infections. METHODS: Etiologically diagnostic data from 45 937 and 67 395 patients with acute diarrhea between 2012 and 2020, who were tested for seven viral pathogens and 13 bacteria respectively, were analyzed to assess the changes of enteric pathogen infections in China during the first COVID-19 pandemic year compared to pre-pandemic years. FINDINGS: Test positive rates of all enteric viruses decreased during 2020, compared to the average levels during 2012-2019, with a relative decrease of 71•75% for adenovirus, 58•76% for norovirus, 53•50% for rotavirus A, and 72•07% for the combination of other four uncommon viruses. In general, a larger reduction of positive rate in viruses was seen among adults than pediatric patients. A rebound of rotavirus A was seen after September 2020 in North China rather than South China. Test positive rates of bacteria decreased during 2020, compared to the average levels during 2012-2019, excepting for nontyphoidal Salmonella and Campylobacter coli with 66•53% and 90•48% increase respectively. This increase was larger for pediatric patients than for adult patients. INTERPRETATION: The activity of enteric pathogens changed profoundly alongside the NPIs implemented during the COVID-19 pandemic in China. Greater reductions of the test positive rates were found for almost all enteric viruses than for bacteria among acute diarrhea patients, with further large differences by age and geography. Lifting of NPIs will lead to resurgence of enteric pathogen infections, particularly in children whose immunity may not have been developed and/or waned. FUNDING: China Mega-Project on Infectious Disease Prevention; National Natural Science Funds.

Province-specific alcohol-attributable cancer deaths and years of potential life lost in China.

OBJECTIVE: Cancer is a major cause of death in China. As alcohol drinking, a risk factor of cancer, is common in China, we aimed to estimate the alcohol-attributable cancer deaths and years of potential life lost (YPLL) across all provinces in China. METHODS: We estimated the proportion of cancer deaths and YPLL attributable to alcohol consumption at the province level. Population attributable fraction (PAF) was calculated based on: 1) prevalence of alcohol consumption, obtained from the China National Nutrition and Health Survey 2002; 2) dose-response relative risks (RRs) of alcohol consumption and site-specific cancer, extracted from published meta-analyses; 3) cancer mortality data, originated from the National Program of Cancer Registry 2013. RESULTS: We estimated that 98,306 cancer deaths were attributable to alcohol consumption and accounted for 4.56 % of the total cancer deaths in China in 2013. Of these deaths, a total of 919,741.57 person-years premature loss of life was caused. Both overall PAF and average YPLL per 100,000 individuals were much higher in men than that in women (7.01 % vs. 0.33 % and 130.55 vs. 4.45, respectively). At the province level, overall PAF ranged from 2.14 % (95 % CI: 1.40 %-2.87 %) in Shanghai to 6.56 % (95 % CI: 4.06 %-9.05 %) in Anhui and the average YPLL per 100,000 individuals ranged from 10.97 in Tibet to 106.52 in Shandong. CONCLUSIONS: Cancer burden attributable to alcohol consumption varied across provinces in China. Province-level approaches are warranted to decrease alcohol consumption and reduce the alcohol-related cancer burden.

Neuroprotective effects of ZL006 in Aß1-42-treated neuronal cells.

Amyloid beta (Aß)-induced neurotoxicity and oxidative stress plays an important role in the pathogenesis of Alzheimer's disease (AD). ZL006 is shown to reduce over-produced nitric oxide and oxidative stress in ischemic stroke by interrupting the interaction of neuronal nitric oxide synthase and postsynaptic density protein 95. However, few studies are reported on the role of ZL006 in AD. To investigate whether ZL006 exerted neuroprotective effects in AD, we used Aß1-42 to treat primary cortical neurons and N2a neuroblastoma cells as an in vitro model of AD. Cortical neurons were incubated with ZL006 or dimethyl sulfoxide for 2 hours and treated with Aß1-42 or NH3•H2O for another 24 hours. The results of cell counting Kit-8 (CCK-8) assay and calcein-acetoxymethylester/propidium iodide staining showed that ZL006 pretreatment rescued the neuronal death induced by Aß1-42. Fluorescence and western blot assay were used to detect oxidative stress and apoptosis-related proteins in each group of cells. Results showed that ZL006 pretreatment decreased neuronal apoptosis and oxidative stress induced by Aß1-42. The results of CCK8 assay showed that inhibition of Akt or NF-E2-related factor 2 (Nrf2) in cortical neurons abolished the protective effects of ZL006. Moreover, similar results were also observed in N2a neuroblastoma cells. ZL006 inhibited N2a cell death and oxidative stress induced by Aß1-42, while inhibition of Akt or Nrf2 abolished the protective effect of ZL006. These results demonstrated that ZL006 reduced Aß1-42-induced neuronal damage and oxidative stress, and the mechanisms might be associated with the activation of Akt/Nrf2/heme oxygenase-1 signaling pathways.

LncRNA-1810034E14Rik reduces microglia activation in experimental ischemic stroke.

BACKGROUND: Activation of microglial cells plays an important role in neuroinflammation after ischemic stroke. Inhibiting the activation of microglial cells has been suggested as a potential therapeutic approach in the treatment of ischemic stroke. METHODS: Oxygen-glucose deprivation in primary microglial cells and transient middle cerebral artery occlusion (MCAO) in C57BL/6 mice were used as the in vitro and in vivo ischemic stroke models. Microarray analysis was performed to investigate the overall impact of long non-coding RNAs (lncRNAs) on the inflammation status of microglial cells. RT-qPCR was used to evaluate the lncRNA levels and mRNA levels of cytokines and microglial cell markers. ELISA was taken to measure the level of cytokines. Immunofluorescence was used to observe the activation of microglial cells. Western blotting was performed to test the p65 phosphorylation. RESULTS: In this study, we showed that LncRNA-1810034E14Rik was significantly decreased in LPS-treated or oxygen-glucose deprivation-induced microglial cells. Overexpression of 1810034E14Rik decreased the infarct volume and alleviated brain damage in MCAO mice. 1810034E14Rik overexpression reduced the expression of inflammatory cytokines not only in ischemic stroke mice but also in oxygen-glucose deprivation-induced microglial cells. Moreover, 1810034E14Rik overexpression could suppress the activation of microglial cells and inhibit the phosphorylation of p65. CONCLUSIONS: LncRNA-1810034E14Rik plays an anti-inflammatory role in ischemic stroke and regulates p65 phosphorylation, making it a potential target for stroke treatment.

Huatuo Zaizao pill ameliorates cognitive impairment of APP/PS1 transgenic mice by improving synaptic plasticity and reducing Aß deposition.

BACKGROUND: It is well known that Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by memory deficits and cognitive decline. Amyloid-ß (Aß) deposition and synaptic dysfunction play important roles in the pathophysiology of Alzheimer's disease (AD). The Huatuo Zaizao pill (HT) is a Traditional Chinese Medicine (TCM) that has been used clinically for many years in China, mainly for post-stroke rehabilitation and cognitive decline; however, the mechanism of cognitive function is not clear. In this study, we investigated the effect of HT on hippocampal synaptic function, Amyloid-ß (Aß) deposition in APP/PS1 AD transgenic mice. METHOD: Six-month-old APP/PS1 transgenic (Tg) mice were randomly divided into control, HT-treated, and memantine (MEM)-treated groups. Then, these groups were orally administered vehicle (for the control), HT (0.25 g/kg) and MEM (5 mg/kg) respectively for 4 weeks. The Morris water maze, Novel Object Recognition, and Open field tests were used to assess cognitive behavioral changes. We evaluated the effects of HT on neuronal excitability, membrane ion channel activity, and synaptic plasticity in acute hippocampal slices by combining electrophysiological extracellular tests. Synaptic morphology in the hippocampus was investigated by electron microscopy. Western blotting was used to assess synaptic-associated protein and Aß production and degrading levels. Immunofluorescence staining was used to determine the relative integrated density. RESULTS: HT can ameliorate hippocampus-dependent memory deficits and improve synaptic dysfunction by reversing LTP impairment in APP/PS1 transgenic mice. Moreover, HT reduces amyloid plaque deposition by regulating α-secretase and γ-secretase levels. CONCLUSION: HT can improve the learning and memory function of APP/PS1 transgenic mice by improving synaptic function and reducing amyloid plaque deposition.

In Situ Analysis of Oxygen Vacancies and Band Alignment in HfO2/TiN Structure for CMOS Applications.

The density of oxygen vacancies characterization in high-k/metal gate is significant for semiconductor device fabrication. In this work, a new approach was demonstrated to detect the density of oxygen vacancies by in situ x-ray photoelectron spectroscopy (XPS) and ultraviolet photoelectron spectroscopy (UPS) measurement. Moreover, the band alignment of the structure with optical band gap measured by spectroscopic ellipsometry (SE) and valence band offset by UPS were reported. The specific areal density of oxygen vacancies in high-k dielectric of HfO2/TiN was obtained by fitting the experiment data to be 8.202 × 1010cm- 2. This study would provide an effective approach to characterize the oxygen vacancies based defects which cause threshold voltage shifts and enormous gate leakage in modern MOSFET devices.

Panaxatriol saponins promotes angiogenesis and enhances cerebral perfusion after ischemic stroke in rats.

BACKGROUND: Panaxatriol saponins (PTS), an extract from the traditional Chinese herb Panax notoginseng, which has been used to treat ischemic stroke for many years in China. However, the mechanism underlying the effects of PTS remains unclear. This study aimed to determine whether PTS can protect against ischemic brain injury by promoting angiogenesis and to explore the possible mechanism by which it promotes angiogenesis. METHODS: Middle cerebral artery occlusion (MCAO) was induced in rats, and neurological deficit scores and brain infarct volumes were assessed. Micro-Positron emission tomography (PET) was adopted to assess cerebral perfusion, and real-time PCR and western blotting were used to evaluate vascular growth factor and Sonic hedgehog (Shh) pathway component levels. Immunofluorescence staining was used to determine capillary densities in ischemic penumbrae. RESULTS: We showed that PTS improved neurological function and reduced infarct volumes in MCAO rats. Micro-PET indicated that PTS can significantly increase 18F-fluorodeoxyglucose (18F-PDG) uptake by ischemic brain tissue and enhance cerebral perfusion after MCAO surgery. Moreover, PTS was able to increase capillary densities and enhance angiogenesis in ischemic boundary zones and up-regulate vascular endothelial growth factor (VEGF) and Angiopoietin-1 (Ang-1) expression by activating the Shh signaling pathway. CONCLUSION: These findings indicate that PTS exerts protective effects against cerebral ischemic injury by enhancing angiogenesis and improving microperfusion.

Neuronal Soluble Fas Ligand Drives M1-Microglia Polarization after Cerebral Ischemia.

AIMS: This study explored sFasL expression in neurons and the potential role of neuronal sFasL in modulating the microglial phenotypes. METHODS: In vivo, middle cerebral artery occlusion (MCAO) was induced in both FasL-mutant (gld) and wild-type (wt) mice. In vitro, primary cortical neuron or microglia or coculture from wt/gld mice was subjected to oxygen glucose deprivation (OGD). sFasL level in the supernatant was evaluated by ELISA. Neuronal-conditioned medium (NCM) or exogenous sFasL was applied to primary microglia with or without FasL neutralizing antibody. Protein expression of JAK2/STAT3 and NF-κB pathways were determined by Western blot. The effect of microglia phenotype from wt/gld mice on the fate of ischemic neurons was further elucidated. RESULTS: In vivo, compared with wild-type mice, M1 markers (CD16, CD32 and iNOS) were attenuated in gld mice after MCAO. In vitro, post-OGD neuron released more sFasL. Both post-OGD NCM and exogenous sFasL could trigger M1-microglial polarization. However, this M1 phenotype shift was partially blocked by utilization of FasL neutralizing antibody or gld NCM. Consistently, JAK2/STAT3 and NF-κB signal pathways were both activated in microglia after exogenous sFasL treatment. Compared with wild-type mice, M1-conditioned medium prepared from gld mice protected neuron against OGD injury. CONCLUSIONS: Ischemic neurons release sFasL, which contributes to M1-microglial polarization. The underlying mechanisms may involve the activation of JAK2/STAT3 and NF-κB signaling pathways.

Hydroxy-safflor yellow A attenuates Aß1₋42-induced inflammation by modulating the JAK2/STAT3/NF-κB pathway.

Beta-amyloid (Aß)-mediated inflammation plays a critical role in the initiation and progression of Alzheimer׳s disease (AD). Anti-inflammatory treatment may provide therapeutic benefits. In this study, the effect of hydroxy-safflor yellow A (HSYA) on Aß1-42-induced inflammation in AD mice was investigated and the underlying mechanisms were explored. Aß1-42 was injected into bilateral hippocampi of mice to induce AD models in vivo. Spatial learning and memory of mice were investigated by the Morris water maze test. Activated microglia and astrocytes were examined by immunofluorescence staining for ionized calcium-binding adapter molecule-1 (Iba-1) and glial fibrillary acidic protein (GFAP). The mRNA of inflammatory cytokines were measured using real-time PCR. NF-κB p65 translocation was analyzed by western blotting and immunostaining. IκB and phosphorylation of JAK2 and STAT3 were tested by western blotting. The results showed that HSYA ameliorated the memory deficits in Aß1-42-induced AD mice. HSYA suppressed Aß1-42-induced activation of microglia and astrocytes and reduced the mRNA expression of pro-inflammatory mediators. HSYA up-regulated the JAK2/STAT3 pathway and inhibits the activation of NF-κB signaling pathways. Pharmacological inhibition of STAT3 by AG490 reversed the inactivation of p65 and anti-inflammatory effects of HSYA. In conclusion, these results suggest that HSYA protects Aß1-42-induced AD model through inhibiting inflammatory response, which may involve the JAK2/STAT3/NF-κB pathway.