Porcine Epidemic Diarrhea Virus Antagonizes Host IFN-λ-Mediated Responses by Tilting Transcription Factor STAT1 toward Acetylation over Phosphorylation To Block Its Activation.

Porcine epidemic diarrhea virus (PEDV) is the main etiologic agent causing acute swine epidemic diarrhea, leading to severe economic losses to the pig industry. PEDV has evolved to deploy complicated antagonistic strategies to escape from host antiviral innate immunity. Our previous study demonstrated that PEDV downregulates histone deacetylase 1 (HDAC1) expression by binding viral nucleocapsid (N) protein to the transcription factor Sp1, inducing enhanced protein acetylation. We hypothesized that PEDV inhibition of HDAC1 expression would enhance acetylation of the molecules critical in innate immune signaling. Signal transducer and activator of transcription 1 (STAT1) is a crucial transcription factor regulating expression of interferon (IFN)-stimulated genes (ISGs) and anti-PEDV immune responses, as shown by overexpression, chemical inhibition, and gene knockdown in IPEC-J2 cells. We further show that PEDV infection and its N protein overexpression, although they upregulated STAT1 transcription level, could significantly block poly(I·C) and IFN-λ3-induced STAT1 phosphorylation and nuclear localization. Western blotting revealed that PEDV and its N protein promote STAT1 acetylation via downregulation of HDAC1. Enhanced STAT1 acetylation due to HDAC1 inhibition by PEDV or MS-275 (an HDAC1 inhibitor) impaired STAT1 phosphorylation, indicating that STAT1 acetylation negatively regulated its activation. These results, together with our recent report on PEDV N-mediated inhibition of Sp1, clearly indicate that PEDV manipulates the Sp1-HDAC1-STAT1 signaling axis to inhibit transcription of OAS1 and ISG15 in favor of its replication. This novel immune evasion mechanism is realized by suppression of STAT1 activation through preferential modulation of STAT1 acetylation over phosphorylation as a result of HDAC1 expression inhibition. IMPORTANCE PEDV has developed sophisticated evasion mechanisms to escape host IFN signaling via its structural and nonstructural proteins. STAT1 is one of the key transcription factors in regulating expression of ISGs. We found that PEDV and its N protein inhibit STAT1 phosphorylation and nuclear localization via inducing STAT1 acetylation as a result of HDAC1 downregulation, which, in turn, dampens the host IFN signaling activation. Our study demonstrates a novel mechanism that PEDV evades host antiviral innate immunity through manipulating the reciprocal relationship of STAT1 acetylation and phosphorylation. This provides new insights into the pathogenetic mechanisms of PEDV and even other coronaviruses.

Effectiveness of massage therapy on anxiety and depression of COVID-19 convalescent: A protocol for systematic review and meta-analysis

Background: Novel coronavirus pneumonia was first detected in Wuhan, China, in late December 2019. Its widespread infectivity and strong pathogenicity has posed a great threat to public health, seriously affecting social production and life. The disease caused by this virus has been officially named COVID-19 (coronavirus disease 2019) by the World Health Organization (WHO). Tuina (massage) therapy is 1 of the widely employed complementary and alternative medicine interventions in the world. As a useful therapy implemented on human’s skin, muscles and joints, tuina (massage) has unique advantages in the field of medicine. This systematic review and meta-analysis will summarize the current evidence of tuina (massage) used as an intervention for COVID-19. Methods: We will search the following electronic databases for randomized controlled trials to evaluate the effectiveness and safety of massage therapy in treating all patients recovering from COVID-19: Wanfang and Pubmed Database, china national knowledge infrastructure database, cochrane central register of controlled trials, cumulative index of nursing and allied health literature and excerpta medica database. Each database will be searched from inception to October 2022. The entire process will include study selection, data extraction, risk of bias assessment and meta-analyses. Results: This proposed study will evaluate the effectiveness and safety of massage therapy for patients recovering from COVID-19. Conclusions: This proposed systematic review will evaluate the existing evidence on the effectiveness and safety of massage therapy for patients recovering from COVID-19.

Chest computed tomography and pulmonary function analysis of coronavirus disease 2019 survivors in 1 month follow-up period after cure and discharge

OBJECTIVE: The objective is to explore the chest computed tomography (CT) and pulmonary function findings of coronavirus disease 2019 (COVID-19) survivors 1 month after discharge. METHODS: We retrospectively analyzed the chest CT and pulmonary function findings of 158 (COVID-19) survivors who were discharged and followed up at Wuhan Red Cross Hospital from April 9 to May 10, 2020. RESULTS: Follow-up chest CT revealed that pulmonary lesions in all patients were clearly absorbed and dissipated. One month after discharge, 125 (79.1%) patients had residual imaging abnormalities, mainly light ground-glass opacities (44.9%) and light patchy shadows (38.6%). Other features included fibrous cord lesions in 90 cases (57.0%), pulmonary nodules in 46 cases (29.1%), pleural thickening in 44 cases (27.8%), and mediastinal lymphadenopathy in 81 cases (51.3%). Among 158 COVID-19 survivors, 124 were tested for pulmonary function. Pulmonary function tests revealed pulmonary function impairment in 10 patients (8.1%), restrictive ventilation dysfunction in 16 (12.9%), and pulmonary diffusion dysfunction in 48 (38.7%). Residual lung lesions and pleural thickening were negatively correlated with DLCO% (P < 0.05). CONCLUSION: COVID-19 patients have characteristic findings on chest CT and pulmonary function testing. Identifying these findings is helpful to dynamically monitor the disease prognosis.

DNAJA3 Interacts with PEDV S1 Protein and Inhibits Virus Replication by Affecting Virus Adsorption to Host Cells.

Porcine epidemic diarrhea virus (PEDV) infection causes huge economic losses to the pig industry worldwide. DNAJA3, a member of the Hsp40 family proteins, is known to play an important role in the replication of several viruses. However, it remains unknown if it interacts with PEDV. We found that DNAJA3 interacted with PEDV S1, initially with yeast two-hybrid screening and later with Co-IP, GST pull-down, and confocal imaging. Further experiments showed the functional relationship between DNAJA3 and PEDV in the infected IPEC-J2 cells. DNAJA3 overexpression significantly inhibited PEDV replication while its knockdown had the opposite effect, suggesting that it is a negative regulator of PEDV replication. In addition, DNAJA3 expression could be downregulated by PEDV infection possibly as the viral strategy to evade the suppressive role of DNAJA3. By gene silencing and overexpression, we were able to show that DNAJA3 inhibited PEDV adsorption to IPEC-J2 cells but did not affect virus invasion. In conclusion, our study provides clear evidence that DNAJA3 mediates PEDV adsorption to host cells and plays an antiviral role in IPEC-J2 cells.

Development and Validation of Algorithms to Identify COVID-19 Patients Using a US Electronic Health Records Database: A Retrospective Cohort Study.

Introduction: In order to identify and evaluate candidate algorithms to detect COVID-19 cases in an electronic health record (EHR) database, this study examined and compared the utilization of acute respiratory disease codes from February to August 2020 versus the corresponding time period in the 3 years preceding. Methods: De-identified EHR data were used to identify codes of interest for candidate algorithms to identify COVID-19 patients. The number and proportion of patients who received a SARS-CoV-2 reverse transcriptase polymerase chain reaction (RT-PCR) within ±10 days of the occurrence of the diagnosis code and patients who tested positive among those with a test result were calculated, resulting in 11 candidate algorithms. Sensitivity, specificity, and likelihood ratios assessed the candidate algorithms by clinical setting and time period. We adjusted for potential verification bias by weighting by the reciprocal of the estimated probability of verification. Results: From January to March 2020, the most commonly used diagnosis codes related to COVID-19 diagnosis were R06 (dyspnea) and R05 (cough). On or after April 1, 2020, the code with highest sensitivity for COVID-19, U07.1, had near perfect adjusted sensitivity (1.00 [95% CI 1.00, 1.00]) but low adjusted specificity (0.32 [95% CI 0.31, 0.33]) in hospitalized patients. Discussion: Algorithms based on the U07.1 code had high sensitivity among hospitalized patients, but low specificity, especially after April 2020. None of the combinations of ICD-10-CM codes assessed performed with a satisfactory combination of high sensitivity and high specificity when using the SARS-CoV-2 RT-PCR as the reference standard.

Treatment of MDA5-positive dermatomyositis complicated by gangrenous cholecystitis with tofacitinib.

BACKGROUND: Dermatomyositis is a rare idiopathic inflammatory disease with diverse presentations that can have varying degrees of cutaneous and systemic involvement. This phenotypic heterogeneity makes DM a therapeutic challenge. Some therapeutic drugs, such as hormones and immunosuppressants, have poor therapeutic effects. In recent years, tofacitinib has been reported to be effective in the treatment of dermatomyositis. CASE PRESENTATION: We report a case of anti-MDA5 antibody-positive dermatomyositis that was relieved after treatment with tofacitinib, during which gallbladder gangrene and suppurative cholecystitis occurred. After cholecystectomy, we continued to use tofacitinib and achieved a good therapeutic effect. CONCLUSIONS: Tofacitinib is effective in the treatment of anti-MDA5 antibody-positive dermatomyositis, but the risk of infection is increased. It can still be used after infection control. Close follow-up should be performed during the use of tofacitinib.

Trends in characteristics and outcomes among US adults hospitalised with COVID-19 throughout 2020: an observational cohort study.

OBJECTIVES: To examine the temporal patterns of patient characteristics, treatments used and outcomes associated with COVID-19 in patients who were hospitalised for the disease between January and 15 November 2020. DESIGN: Observational cohort study. SETTING: COVID-19 subset of the Optum deidentified electronic health records, including more than 1.8 million patients from across the USA. PARTICIPANTS: There were 51 510 hospitalised patients who met the COVID-19 definition, with 37 617 in the laboratory positive cohort and 13 893 in the clinical cohort. PRIMARY AND SECONDARY OUTCOME MEASURES: Incident acute clinical outcomes, including in-hospital all-cause mortality. RESULTS: Respectively, 48% and 49% of the laboratory positive and clinical cohorts were women. The 50- 65 age group was the median age group for both cohorts. The use of antivirals and dexamethasone increased over time, fivefold and twofold, respectively, while the use of hydroxychloroquine declined by 98%. Among adult patients in the laboratory positive cohort, absolute age/sex standardised incidence proportion for in-hospital death changed by -0.036 per month (95% CI -0.042 to -0.031) from March to June 2020, but remained fairly flat from June to November, 2020 (0.001 (95% CI -0.001 to 0.003), 17.5% (660 deaths /3986 persons) in March and 10.2% (580/5137) in October); in the clinical cohort, the corresponding changes were -0.024 (95% CI -0.032 to -0.015) and 0.011 (95% CI 0.007 0.014), respectively (14.8% (175/1252) in March, 15.3% (189/1203) in October). Declines in the cumulative incidence of most acute clinical outcomes were observed in the laboratory positive cohort, but not for the clinical cohort. CONCLUSION: The incidence of adverse clinical outcomes remains high among COVID-19 patients with clinical diagnosis only. Patients with COVID-19 entering the hospital are at elevated risk of adverse outcomes.

Emergent Virus Reactivation in SARS-CoV-2-Negative Community Acquired Pneumonia Patients During the COVID-19 Pandemic

Emergent viruses (namely, HSV-1, CMV, and EBV) reactivation were common in critically ill patients and/or immunosuppressed patients. This study aimed to understand the clinical manifestations and reactivation of the emergent viruses in SARS-CoV-2-Negative community acquired pneumonia (CAP) patients during the COVID-19 pandemic. We retrospectively reviewed the medical records of CAP patients from January to March 2020, in our university hospital in China. The patients were divided into two groups based on the presence or absence of emergent viruses. In all patients, the positive rates of EBV, HSV, and CMV were 23.43% (15/64), 22.06% (15/68), and 12.50% (8/64), respectively. The most common presenting symptoms were fever (98, 57.99%) and dry cough (55, 32.54%). The levels of albumin, hemoglobin, lymphocyte count, and CD4 + T lymphocyte count in emergent viruses positive group were lower than those of viruses negative group (P < 0.05). The initial chest CT features of these patients were diverse. The most common manifestations were ground-glass opacity (91/169, 53.85%) and pulmonary nodule (88/169, 52.07%). More emergent viruses positive patients have bilateral upper lobes involvement than emergent viruses negative patients (P < 0.05). A total of 80.47% patients (136/169) received empirical antimicrobial treatment. The most commonly used antibiotic regimen was fluoroquinolone monotherapy (80/169, 47.34%). The emergent viruses positive patients have poorer clinical outcome (P < 0.05). In conclusion, emergent viruses reactivation was common in SARS-CoV-2-Negative CAP patients. Emergent viruses positive patients have poorer cellular immune function, more severer conditions and poorer prognosis. Fluoroquinolones may be a therapeutic option for CAP patients.

Cellular and molecular atlas of the placenta from a COVID-19 pregnant woman infected at midgestation highlights the defective impacts on foetal health.

OBJECTIVES: The impacts of the current COVID-19 pandemic on maternal and foetal health are enormous and of serious concern. However, the influence of SARS-CoV-2 infection at early-to-mid gestation on maternal and foetal health remains unclear. MATERIALS AND METHODS: Here, we report the follow-up study of a pregnant woman of her whole infective course of SARS-CoV-2, from asymptomatic infection at gestational week 20 to mild and then severe illness state, and finally cured at Week 24. Following caesarean section due to incomplete uterine rupture at Week 28, histological examinations on the placenta and foetal tissues as well as single-cell RNA sequencing (scRNA-seq) for the placenta were performed. RESULTS: Compared with the gestational age-matched control placentas, the placenta from this COVID-19 case exhibited more syncytial knots and lowered expression of syncytiotrophoblast-related genes. The scRNA-seq analysis demonstrated impaired trophoblast differentiation, activation of antiviral and inflammatory CD8 T cells, as well as the tight association of increased inflammatory responses in the placenta with complement over-activation in macrophages. In addition, levels of several inflammatory factors increased in the placenta and foetal blood. CONCLUSION: These findings illustrate a systematic cellular and molecular signature of placental insufficiency and immune activation at the maternal-foetal interface that may be attributed to SARS-CoV-2 infection at the midgestation stage, which highly suggests the extensive care for maternal and foetal outcomes in pregnant women suffering from COVID-19.

Bacteriostatic Potential of Melatonin: Therapeutic Standing and Mechanistic Insights.

Diseases caused by pathogenic bacteria in animals (e.g., bacterial pneumonia, meningitis and sepsis) and plants (e.g., bacterial wilt, angular spot and canker) lead to high prevalence and mortality, and decomposition of plant leaves, respectively. Melatonin, an endogenous molecule, is highly pleiotropic, and accumulating evidence supports the notion that melatonin's actions in bacterial infection deserve particular attention. Here, we summarize the antibacterial effects of melatonin in vitro, in animals as well as plants, and discuss the potential mechanisms. Melatonin exerts antibacterial activities not only on classic gram-negative and -positive bacteria, but also on members of other bacterial groups, such as Mycobacterium tuberculosis. Protective actions against bacterial infections can occur at different levels. Direct actions of melatonin may occur only at very high concentrations, which is at the borderline of practical applicability. However, various indirect functions comprise activation of hosts' defense mechanisms or, in sepsis, attenuation of bacterially induced inflammation. In plants, its antibacterial functions involve the mitogen-activated protein kinase (MAPK) pathway; in animals, protection by melatonin against bacterially induced damage is associated with inhibition or activation of various signaling pathways, including key regulators such as NF-κB, STAT-1, Nrf2, NLRP3 inflammasome, MAPK and TLR-2/4. Moreover, melatonin can reduce formation of reactive oxygen and nitrogen species (ROS, RNS), promote detoxification and protect mitochondrial damage. Altogether, we propose that melatonin could be an effective approach against various pathogenic bacterial infections.

Pediatric BMI changes during COVID-19 pandemic: An electronic health record-based retrospective cohort study.

BACKGROUND: Beginning March 2020, the COVID-19 pandemic has disrupted different aspects of life. The impact on children's rate of weight gain has not been analysed. METHODS: In this retrospective cohort study, we used United States (US) Electronic Health Record (EHR) data from Optum® to calculate the age- and sex- adjusted change in BMI (∆BMIadj) in individual 6-to-17-year-old children between two well child checks (WCCs). The mean of individual ∆BMIadj during 2017-2020 was calculated by month. For September-December WCCs, the mean of individual ∆BMIadj (overall and by subgroup) was reported for 2020 and 2017-2019, and the impact of 2020 vs 2017-2019 was tested by multivariable linear regression. FINDINGS: The mean [95% Confidence Interval - CI] ∆BMIadj in September-December of 2020 was 0·62 [0·59,0·64] kg/m2, compared to 0·31 [0·29, 0·32] kg/m2 in previous years. The increase was most prominent in children with pre-existing obesity (1·16 [1·07,1·24] kg/m2 in 2020 versus 0·56 [0·52,0·61] kg/m2 in previous years), Hispanic children (0·93 [0·84,1·02] kg/m2 in 2020 versus 0·41 [0·36,0·46] kg/m2 in previous years), and children who lack commercial insurance (0·88 [0·81,0·95] kg/m2 in 2020 compared to 0·43 [0·39,0·47] kg/m2 in previous years). ∆BMIadj accelerated most in ages 8-12 and least in ages 15-17. INTERPRETATION: Children's rate of unhealthy weight gain increased notably during the COVID-19 pandemic across demographic groups, and most prominently in children already vulnerable to unhealthy weight gain. This data can inform policy decisions critical to child development and health as the pandemic continues to unfold. FUNDING: Amgen, Inc.

Dynamic governance decisions on multi-modal inter-city travel during a large-scale epidemic spreading.

Within half a year, COVID-19 spreads to most countries in the world, as well as posed a great threat to the public health of human beings. The implementation of non-pharmaceutical intervention (NPI), including travel ban, proved to be an effective way for controlling the epidemic spreading, e.g., the ban of inter-city transportation stops transporting virus through passengers between cities. However, travel ban could significantly impact many industries, e.g. tourism and logistics, thus jeopardizing the regional economy. This paper focus on assisting the national or regional government to make dynamic decisions on restricting and recovering intercity multi-modal travel services. Our model can characterize impacts of inter-city traffic on the spread of the COVID-19, as well as on the regional economy. By applying a reinforcement learning approach, we develop an online optimization model to identify the modal-specific travel banning strategy that can balance the epidemic control as well as the negative impacts on regional economy. The numerical study based on a network of multiple cities in China shows that the proposed approach can generate better strategies compared with some existing methods.

Nearly One In Five Skilled Nursing Facilities Awarded Positive Incentives Under Value-Based Purchasing.

Medicare's Skilled Nursing Facility Value-Based Purchasing Program, which awards value-based incentive payments based on hospital readmissions, distributed its first two rounds of incentives during fiscal years 2019 and 2020. Incentive payments were based on achievement or improvement scores-whichever was better. Incentive payments were as low as -2.0 percent in both program years and as high as +1.6 percent in FY 2019 and +3.1 percent in FY 2020. In FY 2019, 26 percent of facilities earned positive incentives and 72 percent earned negative incentives, compared with 19 percent positive and 65 percent negative incentives in FY 2020. Larger, rural, and not-for-profit facilities were more likely to earn positive incentives, as were those with the highest registered nurse staffing levels. Although these findings indicate the potential to reward high-quality care at skilled nursing facilities, intended and unintended outcomes of this new value-based purchasing program should be monitored closely for possible program refinements, particularly in light of the disproportionate impacts of coronavirus disease 2019 (COVID-19) on nursing facilities.

Comparative Analysis of 95 Patients with Different Severity in the Early Outbreak of COVID-19 in Wuhan, China.

OBJECTIVE: To explore the clinical characteristics of patients with different severity in the early outbreak of COVID-19, hoping to provide reference for clinical diagnosis and treatment. METHODS: We retrospectively analyzed the clinical data of 95 COVID-19 patients in Wuhan Red Cross Hospital of China from January 17 to February 13, 2020. All patients were investigated with epidemiological questionnaires. Outcomes were followed up until April 1, 2020. RESULTS: There were 53 males and 42 females, aged 22-84 years (mean 57.3 years). Clinical classification included 54 cases of common type, 27 cases of severe type, and 14 cases of critical type. Six patients had been exposed to the local Huanan seafood market. There were 38 clusters of COVID-19, including 27 family clusters and 11 work unit clusters. Common symptoms included fever (86 (90.5%) of 95), cough (73 (76.8%)), and fatigue (50 (52.6%)). Laboratory findings showed that the most common abnormalities were lymphopenia (75 (78.9%)), elevated D-dimer (60 (63.2%)), and elevated C-reactive protein (56 (58.9%)) on admission. All patients had abnormal chest computed tomography, showing patchy shadows or ground-glass opacities. Severe and critical cases were older, more likely to have shortness of breath, more likely to have underlying comorbidities, and more likely to have abnormal laboratory findings than common cases. The prognosis of patients with different degrees of severity was significantly different. All common and severe patients (100%) were cured and discharged from the hospital, while 10 (71.4%) of 14 critical patients died. CONCLUSIONS: COVID-19 has fast transmission speed and high pathogenicity. We must assess the severity of the disease and take corresponding treatment measures as early as possible.

The Recommendations for the Management of Chinese Children With Epilepsy During the COVID-19 Outbreak.

The coronavirus disease (COVID-19) is the most severe public health problem facing the world currently. Social distancing and avoidance of unnecessary movements are preventive strategies that are being advocated to prevent the spread of the causative virus [severe acute respiratory syndrome (SARS)-CoV2]. It is known that epileptic children need long term treatments (antiepileptic drugs and/or immunosuppressive agents) as well as close follow up due to the nature of the disease. In addition, it is clear that epilepsy can concur with other chronic illnesses which can lower body immunity. As a result, epileptic children have high risk of acquiring this novel disease due to weak/immature immune system. Of concern, the management of children with epilepsy has become more challenging during this outbreak due to the prevention measures that are being taken. Although children with controlled seizures can be managed at home, it is challenging for pediatricians when it comes to cases with uncontrolled seizures/severe cases. To this end, we provide recommendations for the management of epileptic children at home, outpatient and inpatient settings.

The Scientific Foundation of Chinese Herbal Medicine against COVID-19.

The recent coronavirus disease 2019 (COVID-19) pandemic outbreak has caused a serious global health emergency. Supporting evidence shows that COVID-19 shares a genomic similarity with other coronaviruses, such as severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV), and that the pathogenesis and treatment strategies that were applied 17 years ago in combating SARS-CoV and other viral infections could be taken as references in today's antiviral battle. According to the clinical pathological features of COVID-19 patients, patients can suffer from five steps of progression, starting with severe viral infection and suppression of the immune system and eventually progressing to cytokine storm, multi-organ damage, and lung fibrosis, which is the cause of mortality. Therefore, early prevention of disease progression is important. However, no specific effective drugs and vaccination are currently available, and the World Health Organization is urging the development of novel prevention and treatment strategies. Traditional Chinese medicine could be used as an alternative treatment option or in combination with Western medicine to treat COVID-19, due to its basis on historical experience and holistic pharmacological action. Here, we summarize the potential uses and therapeutic mechanisms of Chinese herbal formulas (CHFs) from the reported literature, along with patent drugs that have been recommended by institutions at the national and provincial levels in China, in order to verify their scientific foundations for treating COVID-19. In perspective, more basic and clinical studies with multiple high-tech and translational technologies are suggested to further confirm the therapeutic efficacies of CHFs.

Expert consensus for managing pregnant women and neonates born to mothers with suspected or confirmed novel coronavirus (COVID-19) infection.

OBJECTIVE: To provide clinical management guidelines for novel coronavirus (COVID-19) in pregnancy. METHODS: On February 5, 2020, a multidisciplinary teleconference comprising Chinese physicians and researchers was held and medical management strategies of COVID-19 infection in pregnancy were discussed. RESULTS: Ten key recommendations were provided for the management of COVID-19 infections in pregnancy. CONCLUSION: Currently, there is no clear evidence regarding optimal delivery timing, the safety of vaginal delivery, or whether cesarean delivery prevents vertical transmission at the time of delivery; therefore, route of delivery and delivery timing should be individualized based on obstetrical indications and maternal-fetal status.