Investigating mental defeat in individuals with chronic pain: Protocol for a longitudinal experience sampling study.

INTRODUCTION: Previous qualitative and cross-sectional research has identified a strong sense of mental defeat in people with chronic pain who also experience the greatest levels of distress and disability. This study will adopt a longitudinal experience sampling design to examine the within-person link between the sense of mental defeat and distress and disability associated with chronic pain. METHODS AND ANALYSIS: We aim to recruit 198 participants (aged 18-65 years) with chronic pain, to complete two waves of experience sampling over 1 week, 6 months apart (time 1 and time 2). During each wave of experience sampling, the participants are asked to complete three short online surveys per day, to provide in-the-moment ratings of mental defeat, pain, medication usage, physical and social activity, stress, mood, self-compassion, and attention using visual analogue scales. Sleep and physical activity will be measured using a daily diary as well as with wrist actigraphy worn continuously by participants throughout each wave. Linear mixed models and Gaussian graphical models will be fit to the data to: (1) examine the within-person, day-to-day association of mental defeat with outcomes (ie, pain, physical/social activity, medication use and sleep), (2) examine the dynamic temporal and contemporaneous networks of mental defeat with all outcomes and the hypothesised mechanisms of outcomes (ie, perceived stress, mood, attention and self-compassion). ETHICS AND DISSEMINATION: The current protocol has been approved by the Health Research Authority and West Midlands-Solihull Research Ethics Committee (Reference Number: 17/WM0053). The study is being conducted in adherence with the Declaration of Helsinki, Warwick Standard Operating Procedures and applicable UK legislation.

The Relationship between Intolerance of Uncertainty and Problematic Social Media Use during the COVID-19 Pandemic: A Serial Mediation Model.

The COVID-19 pandemic has brought significant interruptions to life certainty, and there has been a lack of research on the influence of uncertainty. The present research aimed to explore how intolerance of uncertainty, maladaptive coping strategies, and fear of missing out affect social media use in a Chinese community sample (N = 311) during the pandemic. Serial mediation analysis was applied, integrating the mediating role of maladaptive coping strategy and fear of missing out. Intolerance of uncertainty, maladaptive coping strategies, and fear of missing out was positively related to PSMU. Based on the mediation analysis, when age and gender were controlled, the direct effect of intolerance of uncertainty on PSMU was significant. The total indirect effect was also significant. The effect of intolerance of uncertainty on PSMU was mediated by maladaptive coping strategies and fear of missing out. Taken together, maladaptive coping strategies and fear of missing out played a serial mediating role between intolerance of uncertainty and PSMU. The findings imply that strategies to improve the tolerance of uncertainty, reduce fear of missing out, and relevant coping strategies could be potentially helpful in mitigating problematic social media use, especially during the COVID-19 pandemic.

Protein Kinase C-Mediated Hyperphosphorylation and Lateralization of Connexin 43 Are Involved in Autoimmune Myocarditis-Induced Prolongation of QRS Complex.

Myocarditis is a serious and potentially life-threatening disease, which leads to cardiac dysfunction and sudden cardiac death. An increasing number of evidence suggests that myocarditis is also a malignant complication of coronavirus pneumonia, associated with heart failure and sudden cardiac death. Prolonged QRS complexes that are related to malignant arrhythmias caused by myocarditis significantly increase the risk of sudden cardiac death in patients. However, the molecular mechanisms are not fully known at present. In this study, we identify protein kinase C (PKC) as a new regulator of the QRS complex. In isolated hearts of normal rats, the PKC agonist, phorbol-12-myristate-13-acetate (PMA), induced prolongation of the QRS complex. Mechanistically, hyperphosphorylation and lateralization of connexin 43 (Cx43) by PKC induced depolymerization and internalization of Cx43 gap junction channels and prolongation of the QRS duration. Conversely, administration of the PKC inhibitor, Ro-32-0432, in experimental autoimmune myocarditis (EAM) rats after the most severe inflammation period still significantly rescued the stability of the Cx43 gap junction and alleviated prolongation of the QRS complex. Ro-32-0432 reduced phosphorylation and blocked translocation of Cx43 in EAM rat heart but did not regulate the mRNA expression level of ventricular ion channels and the other regulatory proteins, which indicates that the inhibition of PKC might have no protective effect on ion channels that generate ventricular action potential in EAM rats. These results suggest that the pharmacological inhibition of PKC ameliorates the prolongation of the QRS complex via suppression of Cx43 hyperphosphorylation, lateralization, and depolymerization of Cx43 gap junction channels in EAM rats, which provides a potential therapeutic strategy for myocarditis-induced arrhythmias.

Protein Kinase C-Mediated Hyperphosphorylation and Lateralization of Connexin 43 Are Involved in Autoimmune Myocarditis-Induced Prolongation of QRS Complex

Myocarditis is a serious and potentially life-threatening disease, which leads to cardiac dysfunction and sudden cardiac death. An increasing number of evidence suggests that myocarditis is also a malignant complication of coronavirus pneumonia, associated with heart failure and sudden cardiac death. Prolonged QRS complexes that are related to malignant arrhythmias caused by myocarditis significantly increase the risk of sudden cardiac death in patients. However, the molecular mechanisms are not fully known at present. In this study, we identify protein kinase C (PKC) as a new regulator of the QRS complex. In isolated hearts of normal rats, the PKC agonist, phorbol-12-myristate-13-acetate (PMA), induced prolongation of the QRS complex. Mechanistically, hyperphosphorylation and lateralization of connexin 43 (Cx43) by PKC induced depolymerization and internalization of Cx43 gap junction channels and prolongation of the QRS duration. Conversely, administration of the PKC inhibitor, Ro-32-0432, in experimental autoimmune myocarditis (EAM) rats after the most severe inflammation period still significantly rescued the stability of the Cx43 gap junction and alleviated prolongation of the QRS complex. Ro-32-0432 reduced phosphorylation and blocked translocation of Cx43 in EAM rat heart but did not regulate the mRNA expression level of ventricular ion channels and the other regulatory proteins, which indicates that the inhibition of PKC might have no protective effect on ion channels that generate ventricular action potential in EAM rats. These results suggest that the pharmacological inhibition of PKC ameliorates the prolongation of the QRS complex via suppression of Cx43 hyperphosphorylation, lateralization, and depolymerization of Cx43 gap junction channels in EAM rats, which provides a potential therapeutic strategy for myocarditis-induced arrhythmias.

Harnessing reactive oxygen/nitrogen species and inflammation: Nanodrugs for liver injury.

Overall, 12% of the global population (800 million) suffers from liver disease, which causes 2 million deaths every year. Liver injury involving characteristic reactive oxygen/nitrogen species (RONS) and inflammation plays a key role in progression of liver disease. As a key metabolic organ of the human body, the liver is susceptible to injury from various sources, including COVID-19 infection. Owing to unique structural features and functions of the liver, most current antioxidants and anti-inflammatory drugs are limited against liver injury. However, the characteristics of the liver could be utilized in the development of nanodrugs to achieve specific enrichment in the liver and consequently targeted treatment. Nanodrugs have shown significant potential in eliminating RONS and regulating inflammation, presenting an attractive therapeutic tool for liver disease through controlling liver injury. Therefore, the main aim of the current review is to provide a comprehensive summary of the latest developments contributing to our understanding of the mechanisms underlying nanodrugs in the treatment of liver injury via harnessing RONS and inflammation. Meanwhile, the prospects of nanodrugs for liver injury therapy are systematically discussed, which provides a sound platform for novel therapeutic insights and inspiration for design of nanodrugs to treat liver disease.

Inflammatory Profiles and Clinical Features of Coronavirus 2019 Survivors 3 Months After Discharge in Wuhan, China.

BACKGROUND: Postdischarge immunity and its correlation with clinical features among patients recovered from coronavirus disease 2019(COVID-19) are poorly described. This prospective cross-sectional study explored the inflammatory profiles and clinical recovery of patients with COVID-19 at 3 months after hospital discharge. METHODS: Patients with COVID-19 discharged from 4 hospitals in Wuhan, recovered asymptomatic patients (APs) from an isolation hotel, and uninfected healthy controls (HCs) were recruited. Viral nucleic acid and antibody detection, laboratory examination, computed tomography, pulmonary function assessment, multiplex cytokine assay, and flow cytometry were performed. RESULTS: The72 age-, sex- and body mass index-matched participants included 19 patients with severe/critical COVID-19 (SPs), 20 patients with mild/moderate COVID-19 (MPs), 16 APs, and 17 HCs. At 3 months after discharge, levels of proinflammatory cytokines and factors related to vascular injury/repair in patients recovered from COVID-19 had not returned to those of the HCs, especially among recovered SPs compared with recovered MPs and APs. These cytokines were significantly correlated with impaired pulmonary function and chest computed tomographic abnormalities. However, levels of immune cells had returned to nearly normal levels and were not significantly correlated with abnormal clinical features. CONCLUSION: Vascular injury, inflammation, and chemotaxis persisted in patients with COVID-19 and were correlated with abnormal clinical features 3 months after discharge, especially in recovered SPs.

Plasma Metabolomic Profiles in Recovered COVID-19 Patients without Previous Underlying Diseases 3 Months After Discharge.

BACKGROUND: It remains unclear whether discharged COVID-19 patients have fully recovered from severe complications, including the differences in the post-infection metabolomic profiles of patients with different disease severities. METHODS: COVID-19-recovered patients, who had no previous underlying diseases and were discharged from Wuhan Union Hospital for 3 months, and matched healthy controls (HCs) were recruited in this prospective cohort study. We examined the blood biochemical indicators, cytokines, lung computed tomography scans, including 39 HCs, 18 recovered asymptomatic (RAs), 34 recovered moderate (RMs), and 44 recovered severe/ critical patients (RCs). A liquid chromatography-mass spectrometry-based metabolomics approach was employed to profile the global metabolites of fasting plasma of these participants. RESULTS: Clinical data and metabolomic profiles suggested that RAs recovered well, but some clinical indicators and plasma metabolites in RMs and RCs were still abnormal as compared with HCs, such as decreased taurine, succinic acid, hippuric acid, some indoles, and lipid species. The disturbed metabolic pathway mainly involved the tricarboxylic cycle, purine, and glycerophospholipid metabolism. Moreover, metabolite alterations differ between RMs and RCs when compared with HCs. Correlation analysis revealed that many differential metabolites were closely associated with inflammation and the renal, pulmonary, heart, hepatic, and coagulation system functions. CONCLUSION: We uncovered metabolite clusters pathologically relevant to the recovery state in discharged COVID-19 patients which may provide new insights into the pathogenesis of potential organ damage in recovered patients.

Latent profiles of the comorbidity of the symptoms for posttraumatic stress disorder and generalized anxiety disorder among children and adolescents who are susceptible to COVID-19.

The present study aims to examine the comorbidity patterns of the symptoms (intrusion and avoidance) for posttraumatic stress disorder (PTSD) and generalized anxiety disorder (GAD) and the role of perceived threat and courtesy stigma in distinguishing specific patterns of the symptoms for PTSD and GAD among children and adolescents who are susceptible to coronavirus disease 2019 (COVID-19) in Hubei, China. A total of 1172 (683 female and 489 male) children and adolescents aged 8-18 years were involved in completing the measurements of PTSD, GAD, perceived threat of COVID-19, and COVID-19-related courtesy stigma. The Latent Profile Analysis identified the three profiles of the symptoms for PTSD and GAD which were labeled as Moderate PTSD, Mild Comorbidity, and Severe Comorbidity. The scores of the symptoms for PTSD, GAD, perceived threat, and stigma were different among the three profiles. The risk factors (i.e., perceived threat and stigma) that are related to comorbidity patterns were examined through a three-step method. The possibility of entry into the Severe Comorbidity Profile increased with increasing perceived threat and stigma. The mental health care interventions for children and adolescents who are susceptible to COVID-19 can be developed to reduce perceived threat and stigma.

Efficacy and safety of OM-85 in paediatric recurrent respiratory tract infections which could have a possible protective effect on COVID-19 pandemic: A meta-analysis.

INTRODUCTION: The OM-85 (Broncho-Vaxom) consumption has drawn considerable attention in the prevention of recurrent respiratory tract infections. However, it has been reported that the relationship between OM-85 consumption and recurrent respiratory tract infections is variable. This meta-analysis was performed to evaluate this relationship. METHODS: A systematic literature search up-to May 2020 was performed and 14 studies were detected with 1859 paediatric subjects, of them 890 consumed OM-85. They were reporting relationships between OM-85 consumption and recurrent respiratory tract infections. Odds ratio (OR) or mean differences (MD) with 95% confidence intervals (CIs) was calculated to evaluate the prognostic role of OM-85 consumption and recurrent respiratory tract infections using the dichotomous or continuous method with a random or fixed-effect model. RESULTS: OM-85 consumption was significantly related to lower frequency of respiratory tract infections (MD, -1.16; 95% CI, -1.66 to -0.65, P < .001); lower total duration of respiratory tract infections (MD, -19.51; 95% CI, -23.00 to -16.01, P < .001); lower incidence of respiratory tract infections (OR, 0.40; 95% CI, 0.21-0.77, P = .006); lower number of antibiotic courses (MD, -1.40; 95% CI, -2.63 to 0.17, P = .03); and lower antibiotic use (OR, 0.38; 95% CI, 0.29-0.52, P < .001). However, OM-85 consumption was not significantly related to adverse event rate (OR, 1.02; 95% CI, 0.52-2.03, P = .94); or to wheezing attacks frequency (MD, -0.25; 95% CI, -0.59 to 0.08, P = .14). CONCLUSIONS: The impact of OM-85 consumption on recurrent respiratory tract infections may have a great effect as a tool to improve subjects' immunity against recurrent respiratory tract infections, which could be helpful in crucial situations, eg, COVID-19 pandemic. OM-85 non-consumers had an independent risk relationship with recurrent respiratory tract infections. This relationship forces us to recommend OM-85 consumption with those with a high risk of recurrent respiratory tract infections to avoid any possible complications.

A potential ex vivo infection model of human induced pluripotent stem cell-3D organoids beyond coronavirus disease 2019.

The novel coronavirus disease 2019 (COVID-19) outbreak began in the city of Wuhan, whereupon it rapidly spread throughout China and subsequently across the world. Rapid transmission of COVID-19 has caused wide-spread panic. Many established medications have been used to treat the disease symptoms; however, no specific drugs or vaccines have been developed. Organoids derived from human induced pluripotent stem cells (iPSCs) may serve as suitable infection models for ex vivo mimicking of the viral life cycle and drug screening. Human iPSC-3D organoids, self-organised tissues with multiple cell environments, have a similar structure and function as real human organs; hence, these organoids allow greater viral infection efficiency, mimic the natural host-virus interactions, and are suitable for long-term experimentation. Here, we suggest the use of a functional human iPSC-organoid that could act as a reliable and feasible ex vivo infection model for investigation of the virus. This approach will provide much needed insight into the underlying molecular dynamics of COVID-19 for the development of novel treatment and prevention strategies.

Why do we lack a specific magic anti-COVID-19 drug? Analyses and solutions.

The Coronavirus 2019 (COVID-19) pandemic represents the greatest worldwide public health crisis of recent times. The lack of proven effective therapies means that COVID-19 rages relatively unchecked. Current anti-COVID-19 pharmacotherapies are drugs originally designed for other diseases, and administered orally or intravascularly. Thus, they can have various adverse effects. A specific anti-Coronavirus drug should not only target the virus per se, but also treat the related respiratory and cardiovascular symptoms. Here, we examine the advantages and disadvantages of current anti-COVID-19 pharmacotherapies, and analyze the reasons why in the era of big data we have not yet established specific coronavirus therapies and related technical bottlenecks. Finally, we present our design of a novel nebulized S-nitrosocaptopril that is under development for targeting both coronaviruses and their related symptoms.

Is oseltamivir suitable for fighting against COVID-19: In silico assessment, in vitro and retrospective study.

BACKGROUND: Oseltamivir is a first-line antiviral drug, especially in primary hospitals. During the ongoing outbreak of coronavirus disease 2019 (COVID-19), most patients with COVID-19 who are symptomatic have used oseltamivir. Considering its popular and important role as an antiviral drug, it is necessary to evaluate oseltamivir in the treatment of COVID-19. OBJECTIVE: To evaluate the effect of oseltamivir against COVID-19. METHODS: Swiss-model was used to construct the structure of the N-terminal RNA-binding domain (NRBD) of the nucleoprotein (NC), papain-like protease (PLpro), and RNA-directed RNA polymerase (RdRp) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). TM-align program was performed to compare the structure of the viral proteins with the structure of the neuraminidase of influenza A. Molecular docking was used to analyze the theoretical possibility of effective binding of oseltamivir with the active centers of the viral proteins. In vitro study was used to evaluate the antiviral efficiency of oseltamivir against SARS-CoV-2. By clinical case analysis, we statistically evaluated whether the history of oseltamivir use influenced the progression of the disease. RESULTS: The structures of NRBD, PLpro, and RdRp were built successfully. The results from TM-align suggested that the S protein, NRBD, 3C-like protease (3CLpro), PLPrO, and RdRp were structurally similar to the influenza A neuraminidase, with TM-scores of 0.30077, 0.19254, 0.28766, 0.30666, and 0.34047, respectively. Interestingly, the active center of 3CL pro was found to be similar to the active center from the neuraminidase of influenza A. Through an analysis of molecular docking, we discovered that oseltamivir carboxylic acid was more favorable to bind to the active site of 3CLpro effectively, but its inhibitory effect was not strong compared with the positive group. Finally, we used in vitro study and retrospective case analysis to verify our speculations. We found that oseltamivir is ineffective against SARS-CoV-2 in vitro study and the clinical use of oseltamivir did not improve the patients' symptoms and signs and did not slow the disease progression. CONCLUSIONS: We consider that oseltamivir isn't suitable for the treatment of COVID-19. During the outbreak of novel coronavirus, when oseltamivir is not effective for the patients after they take it, health workers should be highly vigilant about the possibility of COVID-19.