Current understanding on long non-coding RNAs in immune response to COVID-19.

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a global pandemic threatening the lives and health of people worldwide. Currently, there are no effective therapies or available vaccines for COVID-19. The molecular mechanism causing acute immunopathological diseases in severe COVID-19 is being investigated. Long noncoding RNAs (lncRNAs) have been proven to be involved in many viral infections, such as hepatitis, influenza and acquired immune deficiency syndrome. Many lncRNAs present differential expression between normal tissue and virus-infected tissue. However, the role of lncRNAs in SARS-CoV-2 infection has not been fully elucidated. This study aimed to review the relationship between lncRNAs and viral infection, interferon and cytokine storms in COVID-19, hoping to provide novel insights into promising targets for COVID-19 treatment.

A highly efficient needle-free-injection delivery system for mRNA-LNP vaccination against SARS-CoV-2.

Despite the various vaccines that have been developed to combat the coronavirus disease 2019 (COVID-19) pandemic, the persistent and unpredictable mutations of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) require innovative and unremitting solutions to cope with the resultant immune evasion and establish a sustainable immune barrier. Here we introduce a vaccine-delivery system with a combination of a needle-free injection (NFI) device and a SARS-CoV-2-Spike-specific mRNA-Lipid Nanoparticle (LNP) vaccine. The benefits are duller pain and a significant increase of immunogenicity compared to the canonical needle injection (NI). From physicochemical and bioactivity analyses, the structure of the mRNA-LNP maintains stability upon NFI, contradictory to the belief that LNPs are inclined towards destruction under the high-pressure conditions of NFI. Moreover, mRNA-LNP vaccine delivered by NFI induces significantly more binding and neutralizing antibodies against SARS-CoV-2 variants than the same vaccine delivered by NI. Heterogeneous vaccination of BA.5-LNP vaccine with NFI enhanced the generation of neutralizing antibodies against Omicron BA.5 variants in rabbits previously vaccinated with non-BA.5-specific mRNA-LNP or other COVID-19 vaccines. NFI parameters can be adjusted to deliver mRNA-LNP subcutaneously or intramuscularly. Taken together, our results suggest that NFI-based mRNA-LNP vaccination is an effective substitute for the traditional NI-based mRNA-LNP vaccination.

Metformin in therapeutic applications in human diseases: its mechanism of action and clinical study.

Metformin, a biguanide drug, is the most commonly used first-line medication for type 2 diabetes mellites due to its outstanding glucose-lowering ability. After oral administration of 1 g, metformin peaked plasma concentration of approximately 20-30 µM in 3 h, and then it mainly accumulated in the gastrointestinal tract, liver and kidney. Substantial studies have indicated that metformin exerts its beneficial or deleterious effect by multiple mechanisms, apart from AMPK-dependent mechanism, also including several AMPK-independent mechanisms, such as restoring of redox balance, affecting mitochondrial function, modulating gut microbiome and regulating several other signals, such as FBP1, PP2A, FGF21, SIRT1 and mTOR. On the basis of these multiple mechanisms, researchers tried to repurpose this old drug and further explored the possible indications and adverse effects of metformin. Through investigating with clinical studies, researchers concluded that in addition to decreasing cardiovascular events and anti-obesity, metformin is also beneficial for neurodegenerative disease, polycystic ovary syndrome, aging, cancer and COVID-19, however, it also induces some adverse effects, such as gastrointestinal complaints, lactic acidosis, vitamin B12 deficiency, neurodegenerative disease and offspring impairment. Of note, the dose of metformin used in most studies is much higher than its clinically relevant dose, which may cast doubt on the actual effects of metformin on these disease in the clinic. This review summarizes these research developments on the mechanism of action and clinical evidence of metformin and discusses its therapeutic potential and clinical safety.

Current understanding on long non-coding RNAs in immune response to COVID-19

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a global pandemic threatening the lives and health of people worldwide. Currently, there are no effective therapies or available vaccines for COVID-19. The molecular mechanism causing acute immunopathological diseases in severe COVID-19 is being investigated. Long noncoding RNAs (lncRNAs) have been proven to be involved in many viral infections, such as hepatitis, influenza and acquired immune deficiency syndrome. Many lncRNAs present differential expression between normal tissue and virus-infected tissue. However, the role of lncRNAs in SARS-CoV-2 infection has not been fully elucidated. This study aimed to review the relationship between lncRNAs and viral infection, interferon and cytokine storms in COVID-19, hoping to provide novel insights into promising targets for COVID-19 treatment.

Impact of Heat Inactivation of Blood Samples on Therapeutic Drug Monitoring of 5 Second-Generation Antipsychotics and Their Metabolites.

BACKGROUND: The severe acute respiratory syndrome coronavirus 2 outbreak has been classified as a pandemic. Because many coronaviruses are heat sensitive, heat inactivation of patient samples at 56°C before testing reduces the risk of transmission. The aim of this study is to assess the impact of heat inactivation of patient blood samples on plasma concentrations of 5 second-generation antipsychotics and their metabolites. METHODS: Blood samples were collected during routine clinical therapeutic drug monitoring examination between April 3, 2021, and April 19, 2021. Samples were divided into 2 groups: group A, noninactivated raw sample, and group B, inactivated samples. Inactivation was performed by a 30-minute incubation at 56°C. The levels of the 5 drugs and their metabolites before and after sample heat inactivation were measured using liquid chromatography-tandem mass spectrometry and compared. Furthermore, correlation and Bland-Altman analyses were conducted. RESULTS: No statistically significant difference was observed between the levels of the 5 drugs and their metabolites (ie, risperidone, 9-OH-risperidone, aripiprazole, dehydroaripiprazole, olanzapine, quetiapine, norquetiapine, clozapine, and norclozapine) in the noninactivated group A and the inactivated group B ( P > 0.05). Each drug's concentration values in inactivated and noninactivated treatments correlated (Spearman rs > 0.98; P < 0.001). The results of the noninactivated treatment methods and samples alone showed good consistency via Bland-Altman analysis. CONCLUSIONS: Blood sample heat inactivation had no significant effect on the therapeutic drug monitoring of 5 second-generation antipsychotics and their metabolites. This inactivated treatment method should be recommended to effectively protect laboratory staff from virus contamination.

Randomised parallel trial on the effectiveness and cost-effectiveness in screening gait disorder of silent cerebrovascular disease assisted by artificial intelligent system versus clinical doctors (ACCURATE-1): study protocol.

IntroductionSilent cerebrovascular disease (SCD), which is a common disease in the elderly, leads to cognitive decline, gait disorders, depression and urination dysfunction, and increases the risk of cerebrovascular events. Our study aims to compare the accuracy of the diagnosis of SCD-related gait disorders between the intelligent system and the clinician. Our team have developed an intelligent evaluation system for gait. This study will evaluate whether the intelligent system can help doctors make clinical decisions and predictions, which aids the early prevention and treatment of SCD. METHODS AND ANALYSIS: This study is a multi-centred, prospective, randomised and controlled trial.SCD subjects aged 60-85 years in Shanghai and Guizhou will be recruited continuously. All subjects will randomly be divided into a doctor with intelligence assistance group or a doctor group, at a 1:1 ratio. The doctor and intelligent assistant group will accept the intelligent system evaluation. The intelligent system obtains gait parameters by an Red-Green-Blue-depth camera and computer vision algorithm. The doctor group will accept the clinicians' routine treatment procedures. Meanwhile, all subjects will accept the panel's gait assessment and recognition rating scale as the gold standard. The primary outcome is the sensitivity of the intelligent system and clinicians to screen for gait disorders. The secondary outcomes include the healthcare costs and the incremental cost effectiveness ratio of intelligent systems and clinicians to screen for gait disorders. ETHICS AND DISSEMINATION: Approval was granted by the Ethics Committee of Zhongshan Hospital affiliated with Fudan University on 26 November 2019. The approval number is B2019-027(2) R. All subjects will sign an informed consent form before enrolment. Serious adverse events will be reported to the main researchers and ethics committees. The subjects' data will be kept strictly confidential. The results will be disseminated in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT04457908.

Possible posttraumatic stress disorder in Chinese frontline healthcare workers who survived COVID-19 6 months after the COVID-19 outbreak: prevalence, correlates, and symptoms.

Suffering from COVID-19 and witnessing the suffering and deaths of patients with COVID-19 may place frontline healthcare workers (HCWs) at particularly high risk for posttraumatic stress disorder (PTSD); however, few data are available on the clinical characteristics of PTSD among frontline HCWs who survived COVID-19 ("surviving HCWs" hereafter). The present study examined the prevalence, correlates, and clinical symptoms of possible PTSD in surviving HCWs 6 months after the COVID-19 outbreak in China. A total of 291 surviving HCWs and 42 age- and gender-matched COVID-19-free frontline HCWs (control group) were recruited and administered the Chinese Essen Trauma Inventory, which was used to assess the presence of possible PTSD according to DSM-IV-TR criteria. Survivors' clinical data and characteristics of exposure to COVID-19 were collected via self-report questionnaires. Surviving HCWs had significantly higher rates of possible PTSD than controls (19.9% vs. 4.8%, P = 0.017). Correlates of PTSD in survivors were ICU admission (OR = 8.73, P = 0.003), >10 respiratory symptoms during the most symptomatic period of COVID-19 (OR = 3.08, P = 0.006), the residual symptom of dizziness (OR = 2.43, P = 0.013), the residual symptom of difficult breathing (OR = 2.23, P = 0.027), life in danger due to COVID-19 (OR = 16.59, P = 0.006), and exposure to other traumatic events (OR = 2.94, P = 0.035). Less commonly seen PTSD symptoms in survivors were having nightmares about the event (34.5%), suddenly feeling like they were living through the event suddenly (25.9%), being unable to remember an important part of the event (32.8%), and overalertness (31.0%). Nearly one-fifth of the surviving HCWs had possible PTSD 6 months after the COVID-19 outbreak. Mental health services for this vulnerable population should include periodic screening for PTSD, expanded social support, and, when necessary, psychotherapy and psychopharmacological treatment.

Haze episodes before and during the COVID-19 shutdown in Tianjin, China: Contribution of fireworks and residential burning.

Potential health benefits from improved ambient air quality during the COVID-19 shutdown have been recently reported and discussed. Despite the shutdown measures being in place, northern China still suffered severe haze episodes (HE) that are not yet fully understood, particularly how the source emissions changed. Thus, the meteorological conditions and source emissions in processing five HEs occurred in Beijing-Tianjin-Hebei area were investigated by analyzing a comprehensive real-time measurement dataset including air quality data, particle physics, optical properties, chemistry, aerosol lidar remote sensing, and meteorology. Three HEs recorded before the shutdown began were related to accumulated primary pollutants and secondary aerosol formation under unfavorable dispersion conditions. The common "business as usual" emissions from local primary sources in this highly polluted area exceeded the wintertime atmospheric diffusive capacity to disperse them. Thus, an intensive haze formed under these adverse meteorological conditions such as in the first HE, with coal combustion to be the predominant source. Positive responses to the shutdown measures were demonstrated by reduced contributions from traffic and dust during the final two HEs that overlapped the Spring and Lantern Festivals, respectively. Local meteorological dispersion during the Spring Festival was the poorest among the five HEs. Increased residential burning plus fireworks emissions contributed to the elevated PM2.5 with the potential of enhancing the HEs. Our results highlight that reductions from shutdown measures alone do not prevent the occurrence of HEs. To further reduce air pollution and thus improve public health, abatement strategies with an emphasis on residential burning are needed.

Impact of meteorological condition changes on air quality and particulate chemical composition during the COVID-19 lockdown.

Stringent quarantine measures during the Coronavirus Disease 2019 (COVID-19) lockdown period (January 23, 2020 to March 15, 2020) have resulted in a distinct decrease in anthropogenic source emissions in North China Plain compared to the paralleled period of 2019. Particularly, 22.7% decrease in NO2 and 3.0% increase of O3 was observed in Tianjin, nonlinear relationship between O3 generation and NO2 implied that synergetic control of NOx and VOCs is needed. Deteriorating meteorological condition during the COVID-19 lockdown obscured the actual PM2.5 reduction. Fireworks transport in 2020 Spring Festival (SF) triggered regional haze pollution. PM2.5 during the COVID-19 lockdown only reduced by 5.6% in Tianjin. Here we used the dispersion coefficient to normalize the measured PM2.5 (DN-PM2.5), aiming to eliminate the adverse meteorological impact and roughly estimate the actual PM2.5 reduction, which reduced by 17.7% during the COVID-19 lockdown. In terms of PM2.5 chemical composition, significant NO3- increase was observed during the COVID-19 lockdown. However, as a tracer of atmospheric oxidation capacity, odd oxygen (Ox = NO2 + O3) was observed to reduce during the COVID-19 lockdown, whereas relative humidity (RH), specific humidity and aerosol liquid water content (ALWC) were observed with noticeable enhancement. Nitrogen oxidation rate (NOR) was observed to increase at higher specific humidity and ALWC, especially in the haze episode occurred during 2020SF, high air humidity and obvious nitrate generation was observed. Anomalously enhanced air humidity may response for the nitrate increase during the COVID-19 lockdown period.

Changes in source contributions to particle number concentrations after the COVID-19 outbreak: Insights from a dispersion normalized PMF.

Factor analysis models use the covariance of measured variables to identify and apportion sources. These models, particularly positive matrix factorization (PMF), have been extensively used for analyzing particle number concentrations (PNCs) datasets. However, the variation of observed PNCs and particle size distribution are driven by both the source emission rates and atmospheric dispersion as well as chemical and physical transformation processes. This variation in the observation data caused by meteorologically induced dilution reduces the ability to obtain accurate source apportionment results. To reduce the influence of dilution on quantitative source estimates, a methodology for improving the accuracy of source apportionment results by incorporating a measure of dispersion, the ventilation coefficient, into the PMF analysis (called dispersion normalized PMF, DN-PMF) was applied to a PNC dataset measured from a field campaign that includes the Spring Festival event and the start of the COVID-19 lockdown in Tianjin, China. The data also included gaseous pollutants and hourly PM2.5 compositional data. Eight factors were resolved and interpreted as municipal incinerator, traffic nucleation, secondary inorganic aerosol (SIA), traffic emissions, photonucleation, coal combustion, residential heating and festival emissions. The DN-PMF enhanced the diel patterns of photonucleation and the two traffic factors by enlarging the differences between daytime peak values and nighttime concentrations. The municipal incinerator plant, traffic emissions, and coal combustion have cleaner and more clearly defined directionalities after dispersion normalization. Thus, dispersion normalized PMF is capable of enhancing the source emission patterns. After the COVID-19 lockdown began, PNC of traffic nucleation and traffic emissions decreased by 41% and 44%, respectively, while photonucleation produced more particles likely due to the reduction in the condensation sink. The significant changes in source emissions indicate a substantially reduced traffic volume after the implement of lockdown measures.

Novel insight from the first lung transplant of a COVID-19 patient.

BACKGROUND: To reveal detailed histopathological changes, virus distributions, immunologic properties and multi-omic features caused by SARS-CoV-2 in the explanted lungs from the world's first successful lung transplantation of a COVID-19 patient. MATERIALS AND METHODS: A total of 36 samples were collected from the lungs. Histopathological features and virus distribution were observed by optical microscope and transmission electron microscope (TEM). Immune cells were detected by flow cytometry and immunohistochemistry. Transcriptome and proteome approaches were used to investigate main biological processes involved in COVID-19-associated pulmonary fibrosis. RESULTS: The histopathological changes of the lung tissues were characterized by extensive pulmonary interstitial fibrosis and haemorrhage. Viral particles were observed in the cytoplasm of macrophages. CD3+ CD4- T cells, neutrophils, NK cells, γ/δ T cells and monocytes, but not B cells, were abundant in the lungs. Higher levels of proinflammatory cytokines iNOS, IL-1ß and IL-6 were in the area of mild fibrosis. Multi-omics analyses revealed a total of 126 out of 20,356 significant different transcription and 114 out of 8,493 protein expression in lung samples with mild and severe fibrosis, most of which were related to fibrosis and inflammation. CONCLUSIONS: Our results provide novel insight that the significant neutrophil/ CD3+ CD4- T cell/ macrophage activation leads to cytokine storm and severe fibrosis in the lungs of COVID-19 patient and may contribute to a better understanding of COVID-19 pathogenesis.

Managing Close Contacts of COVID-19 Confirmed Cases in Metropolitan Areas in China.

The novel coronavirus (COVID-19) outbreak has rapidly spread across the world. As medical systems continue to develop vaccines and treatments, it is crucial for the public health community to establish nonpharmaceutical interventions (NPIs) that can effectively mitigate the rate of SARS-Coronavirus-2 (SARS-CoV-2) spread across highly populated residential areas, especially among individuals who have close contact with confirmed cases. A community-driven preparedness strategy has been implemented in metropolitan areas in China. The Chinese Center for Disease Control and Prevention (CCDC) has required that all COVID-19 confirmed cases be recorded and documented in a national notifiable disease surveillance system (NDSS). After receiving reports of newly confirmed cases, an epidemiological services team at the CCDC or trained medical professionals at local clinical facilities start a case-contact investigation. A task force performs home visits to infected individuals. Persons under investigation (PUIs) can stay in designated quarantine facilities for 14 days or in special circumstances can be quarantined at home. This community-based approach involved all stakeholders including local public health departments, public safety authorities, neighborhood councils, and community health centers.