Nuclear Sensor Interferon-Inducible Protein 16 Inhibits the Function of Hepatitis B Virus Covalently Closed Circular DNA by Integrating Innate Immune Activation and Epigenetic Suppression.

BACKGROUND AND AIMS: Nuclear-located covalently closed circular DNA (cccDNA) of hepatitis B virus (HBV) is a determining factor for HBV persistence and the key obstacle for a cure of chronic hepatitis B. However, it remains unclear whether and how the host immune system senses HBV cccDNA and its biological consequences. APPROACH AND RESULTS: Here, we demonstrated that interferon-inducible protein 16 (IFI16) could serve as a unique innate sensor to recognize and bind to HBV cccDNA in hepatic nuclei, leading to the inhibition of cccDNA transcription and HBV replication. Mechanistically, our data showed that IFI16 promoted the epigenetic suppression of HBV cccDNA by targeting an interferon-stimulated response element (ISRE) present in cccDNA. It is of interest that this ISRE was also revealed to play an important role in IFI16-activated type I interferon responses. Furthermore, our data revealed that HBV could down-regulate the expression level of IFI16 in hepatocytes, and there was a negative correlation between IFI16 and HBV transcripts in liver biopsies, suggesting the possible role of IFI16 in suppressing cccDNA function under physiological conditions. CONCLUSIONS: The nuclear sensor IFI16 suppresses cccDNA function by integrating innate immune activation and epigenetic regulation by targeting the ISRE of cccDNA, and IFI16 may present as a therapeutic target against HBV infection.

Investigation of the Possible Causes of NRBC in ICU Patients and the Dynamic Trend of NRBC Count in Survival and Death Patients or with Different Underlying Diseases: A Retrospective Study.

Background: The mortality of intensive care unit (ICU) patients ranges from 5% to 30%, and nucleated red blood cells (NRBCs) were revealed to be related to mortality. However, few studies have discussed the causes of NRBC or compared the dynamic count among patients with underlying diseases. Aim: To explore the possible causes of NRBC in ICU patients and the dynamic trends between survival and death groups and underlying disease subgroups. Methods: A total of 177 ICU patients were retrospectively included. The possible causes of NRBC in ICU patients were discussed. The relationship between NRBC and in-hospital mortality and the dynamic trend of NRBC during hospitalization between the survival and death groups and underlying disease subgroups were compared. Results: The Acute Physiology and Chronic Health Evaluation II (APACHE II) score and Sequential Organ Failure Assessment (SOFA) score in the NRBC-positive group were higher (23.52 ± 9.39 vs. 19.62 ± 7.59; 13.50 (9.00-17.50) vs. 8.00 (6.00-12.00)). Red blood cell count (RBC), hemoglobin (Hb) level, oxygen saturation (SO2), oxygenation index (OI), and serum protein level were lower in the NRBC-positive group. However, D-dimer (D-D), liver and kidney function indices, lactate dehydrogenase (LDH), C-reactive protein (CRP), and procalcitonin (PCT) were higher than those in the NRBC-negative group. Correlation analysis showed that NRBC count was positively correlated with alkaline phosphatase (ALP) and red blood cell distribution width (RDW) and negatively correlated with SO2 (r = 0.431, P < 0.05; r = 0.363, P < 0.05; r = -0.335, P < 0.05). The mortality rate in the NRBC-positive group was higher, and the median survival time was shorter than that in the NRBC-negative group (77.9% vs. 95.7%, P < 0.001; 15 days vs. 8.5 days, P < 0.01). Univariate and multivariate Cox regression analyses showed that NRBC was an independent risk factor for in-hospital mortality (HR: 1.12 (1.03-1.22), P < 0.01). The NRBC count had different hazard ratios (HRs) for in-hospital mortality in the subgroups. Locally weighted scatterplot smoothing (LOWESS) analysis revealed that the NRBC count in the death group was higher and had a sharp upward trend before death, whereas that in the survival group was negative or stayed at a low level. The changing trend of the NRBC count was different in patients with different underlying diseases. Conclusion: The possible cause of NRBC in ICU patients was related to inflammation and hypoxia. The persistently high level and rapid upward trend of NRBC counts are risk factors for in-hospital mortality in ICU patients. The changing trend of the NRBC count varied in patients with different underlying diseases.

Parameters and Morphological Changes of Erythrocytes and Platelets of COVID-19 Subjects: A Longitudinal Cohort Study.

Purpose: Information about dynamic changes occurring in the parameters and morphology of erythrocytes and platelets during the coronavirus disease 2019 (COVID-19) infection and convalescence is scarce. To explore potential associations between dynamic erythrocyte and platelet parameters, morphological changes, and the course or severity of the disease is essential. Patients and Methods: From January 17th, 2020, to February 20th, 2022, we followed up on 35 patients with non-severe and 11 patients with severe COVID-19 following their discharge. We collected clinical features, dynamic complete blood count (CBC), and peripheral blood smears (PBS) and analyzed parameter and morphological changes of erythrocytes and platelets depending on the course or severity of the disease. The course of the disease included four periods, namely onset (T1), discharge (T2), 1-year follow-up (T3), and 2-year follow-up (T4). Results: Red blood cell (RBC) counts and hemoglobin were the lowest in T2, followed by T1, and lower in T1 and T2 than in T3 and T4. Inversely, the red blood cell distribution width (RDW) was the highest in T2, followed by T1, and higher than in T3 and T4. Compared to non-severe patients, the platelet of severe patients was lower in T1 and T2. In contrast, the mean platelet volume (MPV) and platelet distribution width (PDW) tended to be higher in severe patients. Similarly, anisocytosis was more common in peripheral blood smears at early stages and in severe patients. Finally, large platelets were more common in severe patients. Conclusion: Anisocytosis of erythrocytes and large platelets are found in patients with severe COVID-19, these changes may help primary hospitals to identify patients with a high risk of severe COVID-19 at an early stage.

Longitudinal observation of viral load in patients infected with Omicron variant and its relationship with clinical symptoms.

Objective: In 2022, a new coronavirus variant (Omicron) infection epidemic broke out in Shanghai, China. However, it is unclear whether the duration of this omicron variant is different from that of the prototype strain. Methods: We retrospectively analyzed 157 cases of Omicron variant infection in Taizhou Public Health Center from March 29, 2022, to April 18, 2022, and observed the dynamics of nucleic acid Ct values during the admission and discharge of patients. Clinical and laboratory indicators of these patients were also obtained. Results: Compared to the prototype strain, the Omicron variant showed a broad population susceptibility in infected individuals (regardless of age and presence of underlying disease) and had slight damage to the immune system and renal function; the viral loads peaked was 2-3 days from disease onset; the median duration of omicron variant was 15-18 days; the nucleic acid Ct value of nasopharyngeal swabs of infected patients is lower than that of throat swabs, and the Ct value of oropharyngeal swabs is unstable during the recovery period. Conclusion: Therefore, we found that the time to peak viral load of this Omicron variant was 2-3 days after the onset of the disease, and the duration was 15-18 days; symptomatic patients had higher viral load and longer hospitalization time. This finding will provide a basis for understanding omicron variants and formulating the national prevention and control strategy.

Physical condition, psychological status, and posttraumatic stress disorder among recovered COVID-19 subjects: A mediation analysis.

The physical condition of individuals who contracted COVID-19 had a profound influence on mitigating the physical and psychological impact of the disease and the symptoms of posttraumatic stress disorder (PTSD). Little attention has been focused on the influence of physical condition on PTSD among recovered COVID-19 subjects. This study explored the relationship between physical and psychological status and PTSD and the potential mechanisms. Questionnaires were completed by 73 (50.7%, 73/144) COVID-19 recovered subjects who were diagnosed in Taizhou, Zhejiang, China. We conducted a face-to-face survey from January 17 to March 10, 2020. The mediation analysis approach was applied in this research. Our data show that recovered COVID-19 subjects who were in better physical condition exhibited fewer psychological problems [B (95%CI), (-1.65 -3.04, -0.26)] and lower PTSD [B (95%CI), -6.13 (-9.43, -2.83)]. In addition, the worse the psychological status of recovered COVID-19 subjects was, the stronger the PTSD (B [95%CI], 0.58 [0.02, 1.14]). Moreover, psychological status could significantly mediate the impact of physical condition on PTSD (ß1θ2 = -0.87). Together, COVID-19 recovered subjects who have better physical condition could decrease their PTSD, and the worse the physical condition of COVID-19 recovered subjects would increase their psychological problems. Our finding about psychological status could significantly mediate the impact of the physical condition on PTSD might be useful for medical institutions and the government seeking to help with the follow-up rehabilitation training of recovered COVID-19 subjects.