Nafamostat reduces systemic inflammation in TLR7-mediated virus-like illness.

BACKGROUND: The serine protease inhibitor nafamostat has been proposed as a treatment for COVID-19, by inhibiting TMPRSS2-mediated viral cell entry. Nafamostat has been shown to have other, immunomodulatory effects, which may be beneficial for treatment, however animal models of ssRNA virus infection are lacking. In this study, we examined the potential of the dual TLR7/8 agonist R848 to mimic the host response to an ssRNA virus infection and the associated behavioural response. In addition, we evaluated the anti-inflammatory effects of nafamostat in this model. METHODS: CD-1 mice received an intraperitoneal injection of R848 (200 µg, prepared in DMSO, diluted 1:10 in saline) or diluted DMSO alone, and an intravenous injection of either nafamostat (100 µL, 3 mg/kg in 5% dextrose) or 5% dextrose alone. Sickness behaviour was determined by temperature, food intake, sucrose preference test, open field and forced swim test. Blood and fresh liver, lung and brain were collected 6 h post-challenge to measure markers of peripheral and central inflammation by blood analysis, immunohistochemistry and qPCR. RESULTS: R848 induced a robust inflammatory response, as evidenced by increased expression of TNF, IFN-γ, CXCL1 and CXCL10 in the liver, lung and brain, as well as a sickness behaviour phenotype. Exogenous administration of nafamostat suppressed the hepatic inflammatory response, significantly reducing TNF and IFN-γ expression, but had no effect on lung or brain cytokine production. R848 administration depleted circulating leukocytes, which was restored by nafamostat treatment. CONCLUSIONS: Our data indicate that R848 administration provides a useful model of ssRNA virus infection, which induces inflammation in the periphery and CNS, and virus infection-like illness. In turn, we show that nafamostat has a systemic anti-inflammatory effect in the presence of the TLR7/8 agonist. Therefore, the results indicate that nafamostat has anti-inflammatory actions, beyond its ability to inhibit TMPRSS2, that might potentiate its anti-viral actions in pathologies such as COVID-19.

Double stranded RNA drives anti-viral innate immune responses, sickness behavior and cognitive dysfunction dependent on dsRNA length, IFNAR1 expression and age.

Double stranded RNA is generated during viral replication. The synthetic analogue poly I:C is frequently used to mimic anti-viral innate immune responses in models of psychiatric and neurodegenerative disorders including schizophrenia, autism, Parkinson's disease and Alzheimer's disease. Many studies perform limited analysis of innate immunity despite these responses potentially differing as a function of dsRNA molecular weight and age. Therefore fundamental questions relevant to impacts of systemic viral infection on brain function and integrity remain. Here, we studied innate immune-inducing properties of poly I:C preparations of different lengths and responses in adult and aged mice. High molecular weight (HMW) poly I:C (1-6 kb, 12 mg/kg) produced more robust sickness behavior and more robust IL-6, IFN-I and TNF-α responses than poly I:C of < 500 bases (low MW) preparations. This was partly overcome with higher doses of LMW (up to 80 mg/kg), but neither circulating IFNß nor brain transcription of Irf7 were significantly induced by LMW poly I:C, despite brain Ifnb transcription, suggesting that brain IFN-dependent gene expression is predominantly triggered by circulating IFNß binding of IFNAR1. In aged animals, poly I:C induced exaggerated IL-6, IL-1ß and IFN-I in the plasma and similar exaggerated brain cytokine responses. This was associated with acute working memory deficits selectively in aged mice. Thus, we demonstrate dsRNA length-, IFNAR1- and age-dependent effects on anti-viral inflammation and cognitive function. The data have implications for CNS symptoms of acute systemic viral infection such as those with SARS-CoV-2 and for models of maternal immune activation.

What Is the Impact of the COVID-19 Pandemic on Quality of Life and Other Patient-reported Outcomes? An Analysis of the Hand-Wrist Study Cohort.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic, and its associated lockdowns in many parts of the world, have changed our daily lives and may have a psychological impact on around the globe. However, it is unknown how this influences the patient-reported outcome measures (PROMs) of patients involved in ongoing clinical research and medical care. For both the current and potential future lockdowns, it is important to determine if PROMs collected during such a period can be interpreted with confidence. QUESTIONS/PURPOSES: (1) Is there a difference in quality of life between patients in the COVID-19 period group (March 23, 2020 to May 4, 2020) and patients in a reference period group (from the same period in 2018 or 2019)? (2) Is there a difference in pain, hand function, anxiety, depression, and illness perception between patients in the COVID-19 period group and patients in the reference period group? METHODS: This study was part of a large cohort study with routine outcome measures of patients with hand and wrist conditions. To answer our research questions, we analyzed two samples because not all PROMs were sent to participants at the same time points after treatment. The first sample consisted of all participants who completed PROMs on quality of life (QoL), pain, and hand function at their final follow-up time point, which was either 3, 6, or 12 months post-treatment. The second sample consisted of participants who completed PROMs 3 months post-treatment on anxiety, depression, and illness perception. Each sample consisted of two groups: a COVID-19 period group and a reference period group. We included 1613 participants in the first sample (COVID-19 period group: n = 616; reference period group: n = 997) and 535 participants in the second sample (COVID-19 period group: n = 313; reference period group: n = 222). The primary outcome was QoL, expressed in the EuroQol 5-Dimensions questionnaire (EQ-5D) index score. Secondary outcomes were the other domains on the EQ-5D, as well as pain, hand function, anxiety, depression, and illness perception. RESULTS: We found no between-group differences in the EQ-5D index score (standardized mean difference 0.035; p = 0.98). Furthermore, there were no between-group differences in PROM scores for hand function, anxiety, or depression. There were, however, a few small differences in subdomain items regarding pain and illness perception, but we believe in aggregate that these are unlikely to make a clinically important difference in our main finding. CONCLUSION: The COVID-19 pandemic and its associated lockdown had no influence on QoL and had little influence on secondary outcomes in participants who were part of the Hand-Wrist Study Cohort. This finding implies that PROMs data collected during this period can be used with confidence in clinical research. Our findings indicate that when a pandemic like this occurs again, we can continue to use PROMs for analysis in clinical research or routine outcome measures. LEVEL OF EVIDENCE: Level III, therapeutic study.

Mainstream reintegration of COVID-19 survivors and its implications for mental health care in Africa.

The novel coronavirus pandemic has undoubtedly emerged as a serious public health threat in many societies across the world. Due to the sporadic and unpredictable nature of the pandemic, it is important to admit that the virus can cause psychological distress and emotional instability that might impact on people in diverse ways at the individual, community and national levels, with serious mental health implications (e.g. depression, mood disorders, obsessive-compulsive disorder, other anxiety disorders). Due to the weak healthcare challenges inherent in Africa, these mental health challenges require urgent redress to ensure mental health well-being for all, especially COVID-19-positive patients who have recovered (i.e. survivors). This essay outlines some of these challenges and offers strategies to address them. Broader mental health training for facility and community-based health workers are urgently required and should be coordinated within countries with specific guidelines for psychosocial support during outbreaks such as the current pandemic. A framework that promotes reintegration for COVID-19 survivors could also be designed based on context-specific needs through individualized protocols such as the "RAPID-Psychological First Aid [PFA]". This tool kit, if effectively employed, would help facilitate optimal well-being of the people devoid of any psychological challenges created by the pandemic.

Post-COVID-19 Epidemic: Allostatic Load among Medical and Nonmedical Workers in China.

BACKGROUND: As the fight against the COVID-19 epidemic continues, medical workers may have allostatic load. OBJECTIVE: During the reopening of society, medical and nonmedical workers were compared in terms of allostatic load. METHODS: An online study was performed; 3,590 Chinese subjects were analyzed. Socio-demographic variables, allostatic load, stress, abnormal illness behavior, global well-being, mental status, and social support were assessed. RESULTS: There was no difference in allostatic load in medical workers compared to nonmedical workers (15.8 vs. 17.8%; p = 0.22). Multivariate conditional logistic regression revealed that anxiety (OR = 1.24; 95% CI 1.18-1.31; p < 0.01), depression (OR = 1.23; 95% CI 1.17-1.29; p < 0.01), somatization (OR = 1.20; 95% CI 1.14-1.25; p < 0.01), hostility (OR = 1.24; 95% CI 1.18-1.30; p < 0.01), and abnormal illness behavior (OR = 1.49; 95% CI 1.34-1.66; p < 0.01) were positively associated with allostatic load, while objective support (OR = 0.84; 95% CI 0.78-0.89; p < 0.01), subjective support (OR = 0.84; 95% CI 0.80-0.88; p < 0.01), utilization of support (OR = 0.80; 95% CI 0.72-0.88; p < 0.01), social support (OR = 0.90; 95% CI 0.87-0.93; p < 0.01), and global well-being (OR = 0.30; 95% CI 0.22-0.41; p < 0.01) were negatively associated. CONCLUSIONS: In the post-COVID-19 epidemic time, medical and nonmedical workers had similar allostatic load. Psychological distress and abnormal illness behavior were risk factors for it, while social support could relieve it.