Model Integration in Computational Biology: The Role of Reproducibility, Credibility and Utility

During the COVID-19 pandemic, mathematical modeling of disease transmission has become a cornerstone of key state decisions. To advance the state-of-the-art host viral modeling to handle future pandemics, many scientists working on related issues assembled to discuss the topics. These discussions exposed the reproducibility crisis that leads to inability to reuse and integrate models. This document summarizes these discussions, presents difficulties, and mentions existing efforts towards future solutions that will allow future model utility and integration. We argue that without addressing these challenges, scientists will have diminished ability to build, disseminate, and implement high-impact multi-scale modeling that is needed to understand the health crises we face.

Clinical characteristics of 290 foreign-imported cases infected with SARS-CoV-2 in Chengdu, China

Objective: To analyze the epidemiological and clinical characteristics of foreign-imported patients infected with SARS-CoV-2 in Chengdu City.

A one-year follow-up study on dynamic changes of leukocyte subsets and virus-specific antibodies of patients with COVID-19 in Sichuan, China.

Background: SARS-CoV-2 infection causes immune response and produces protective antibodies, and these changes may persist after patients discharged from hospital. Methods: This study conducted a one-year follow-up study on patients with COVID-19 to observe the dynamic changes of circulating leukocyte subsets and virus-specific antibodies. Results: A total of 66 patients with COVID-19 and 213 healthy patients with inactivated SARS-CoV-2 vaccination were included. The virus-specific total antibody, IgG and IgM antibody of patients after one year of recovery were higher than those of healthy vaccinated participants (94.13 vs 4.65, 2.67 vs 0.44, 0.09 vs 0.06, respectively) (P < 0.001). Neutrophil count (OR = 1.73, 95% CI: 1.10-2.70, P = 0.016) and neutrophil-to-lymphocyte ratio (OR = 1.59, 95% CI: 1.05-2.41, P = 0.030) at discharge were the influencing factors for the positivity of virus-specific IgG antibody in patients after one year of recovery. The counts of CD4+ and CD8+ T, B and NK cells increased with the time of recovery, and remained basically stable from 9 to 12 months after discharge. After 12 months, the positivity of IgG antibody was 85.3% and IgM was 11.8%, while the virus-specific antibody changed dynamically in patients within one year after discharge. Conclusions: The SARS-CoV-2 specific antibody of recovered patients showed dynamic fluctuation after discharge, while the leukocyte subsets gradually increased and basically stabilized after 9 months.

Small molecule therapeutics to destabilize the ACE2-RBD complex: A molecular dynamics study.

The ongoing coronavirus disease 19 (COVID-19) pandemic has infected millions of people, claimed hundreds of thousands of lives, and made a worldwide health emergency. Understanding the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mechanism of infection is crucial in the development of potential therapeutics and vaccines. The infection process is triggered by direct binding of the SARS-CoV-2 receptor-binding domain (RBD) to the host-cell receptor angiotensin-converting enzyme 2 (ACE2). Many efforts have been made to design or repurpose therapeutics to deactivate the RBD or ACE2 and prevent the initial binding. In addition to direct inhibition strategies, small chemical compounds might be able to interfere and destabilize the metastable, prefusion complex of ACE2-RBD. This approach can be employed to prevent the further progress of virus infection at its early stages. In this study, molecular docking was employed to analyze the binding of two chemical compounds, SSAA09E2 and Nilotinib, with the druggable pocket of the ACE2-RBD complex. The structural changes as a result of the interference with the ACE2-RBD complex were analyzed by molecular dynamics simulations. Results show that both Nilotinib and SSAA09E2 can induce significant conformational changes in the ACE2-RBD complex, intervene with the hydrogen bonds, and influence the flexibility of proteins. Moreover, essential dynamics analysis suggests that the presence of small molecules can trigger large-scale conformational changes that may destabilize the ACE2-RBD complex.

Follow-Up Study of the Cardiopulmonary and Psychological Outcomes of COVID-19 Survivors Six Months After Discharge in Sichuan, China.

PURPOSE: Some studies have shown that patients with coronavirus disease 2019 (COVID-19) still have sequelae after discharge. However, little is known about the long-term physical and psychological sequelae of patients, especially factors that influenced the prognosis. PATIENTS AND METHODS: Patients with COVID-19 were followed up for 6 months. The psychological status of patients was evaluated by DASS-21 questionnaire, while physical functions were determined using medical history, laboratory examination, thoracic computed tomography (CT), and echocardiography. RESULTS: Fifty patients infected with COVID-19 were enrolled, and 11 (22%) patients still showed symptoms related to COVID-19. The mean contents (cells/ul) of CD3+ cells, CD4+ and CD8+ T, B lymphocytes and NK cells of the survivors elevated significantly after 6-month discharge (P < 0.001). The frequency of ground-glass opacities and consolidations decreased from 90% to 42% (P < 0.001), and 54% to 20%, (P = 0.001), respectively, while the changes of reticulation and bronchiectasis were insignificant (P > 0.05). The frequency of left ventricular diastolic dysfunction decreased from 40% to 15% (P = 0.002). Depression was observed in 5 (12.5%) participants, stress in 3 (7.5%), anxiety in 6 (15%), and among them 1 (2.5%) showed extremely severe anxiety. Covariation analysis elucidated age might be a risk factor (OR: 1.09, 95% CI: 1.01-1.18, P = 0.038), while NK cell was a good prognostic factor for pulmonary recovery. The comorbidities were significantly positive correlated with persist pulmonary damage (r = 0.33, P = 0.020). Compared with patients with antiviral therapy, patients without antiviral therapy had higher anxiety score (3 vs 0, P = 0.033). CONCLUSION: After 6-month discharge, the persisting cardiopulmonary damage was observed in recovery patients, and psychological implications should not be ignored. Age, comorbidities, NK cell and antiviral therapy might be associated with the prognosis of COVID-19.

Clinical analysis of the effect of thymalfasin on common type patients with COVID-19

Objective We observed the effect of thymalfasin on common type patients with COVID-19. Methods A total of 26 cases of common type COVID-19 patients with had reduced cellular immune function (CD4+T counts<410 cells/L) in the Public and Health Clinical Center of Chengdu and discharged from January 29, 2020 to March 20, 2020 were included as research objects, and they were divided into control group and observation group, depending on whether or not the thymalfasin method is used. The patients in control group used recombinant human interferon a-2beta, abidor or lopinavir/ritonavir, and traditional Chinese medicine, the observation group extra added thymalfasin. Then the treatment effect were compared between the two groups. Results There were no significant difference in age, gender, condition and the baseline CD4+T and CD8+T counts between the two groups, the cases were all followed up at our hospital after discharge. There was no significant difference in time of SARS-CoV-2 nucleic acid turning negative, hospital stay, nucleic acid re-positive rate, C-reactive protein and serum amyloid protein (SAA) at discharge between the two groups (P > 0.05). The CD4+T count and CD8+T count at discharge in two groups were both higher than those on admission (P < 0.05), there were no statistical significances in the degree of elevation between the two groups(P > 0.05). Conclusion The study does not show that common type COVID-19 patients who had reduced cellular immune function can obtain definite clinical benefits by using the thymalfasin according to the instructions.

Analysis of the results of follow-up COVID-19 patients half a year after discharge in Chengdu

Objective: To summarize the follow-up results of COVID-19 patients half a year after discharge in Chengdu.

Diagnosis, treatment and the reasons for re-detectable positive RNA test of one case of imported COVID-19 in Chengdu

Summarizing the clinical characteristics and the process of two times of nucleic acid turning re-positive after discharge of an imported COVID-19 case in Chengdu in order to provide experience for clinical management of such cases. A retrospective research method was used to analyze the diagnosis and treatment process, as well as the clinical symptoms and examination results 15 days after discharge of an imported COVID-19 case in Chengdu. The case was tested positive for SARS-CoV-2 nucleic acid in Thailand on March 7, 2020. After arriving in Chengdu on March 10, 2020, he was sent to Chengdu Public Health Clinical Medical Center for isolation treatment. On March 11, the SARS-CoV-2 nucleic acid test of nasopharyngeal swab was suspiciously positive and the result of anal swab was positive. The case was admitted to the hospital as an asymptomatic accompanied by a decline in cellular immune function, his physical examination showed no positive signs. Then he was converted to a confirmed case after 22 days of hospitalization. After the case was discharged 15 days from the hospital, his virus nucleic acid had returned re-positive for 2 times. He was accompanied by neurological symptoms and was diagnosed as anxious and depressive when nucleic acid returned re-positive for the second time, and his symptoms resolved after treatment with psychiatric drugs. Asymptomatic patients of COVID-19 can be converted to confirmed cases. Nucleic acid returning re-positive does not mean that the patient's condition has relapsed or worsened. Patients with COVID-19 may have mental disorder, medical staff need to find it out in time and provide psychological intervention or necessary medication.

Differences in Immune Responses between Children and Adults with COVID-19.

Over 85 590 000 individuals have been infected with severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2). Although there have been an increasing number of reports on coronavirus disease 2019 (COVID-19), it is unclear why infected children show milder symptoms than adults. A retrospective case study was performed at two designated hospitals for COVID-19. Patients (56 children and 63 adults) with confirmed SARS-CoV-2 infection and mild pneumonia were randomly enrolled in this study. The median age of the children was 7.0 years, and 51.79% of them were boys. The median age of the adults was 57 years, and 47.62% were men. The most common symptoms were fever, cough, sputum and diarrhoea. There were no significant differences in symptoms between children and adult patients. In terms of immunological indices on admission, adult patients displayed typical leukopenia and markedly higher levels of IL-2, IL-4, and IL-6 than child patients. The elevation of IL-2, IL-4 and IL-6 in adults induced more extensive lung injury. The effective and non-aggressive immune response successfully resisted SARS-CoV-2 invasion and maintained mild symptoms in child patients. The correlation of higher IL-2, IL-4, and IL-6 with the lung injury might be evidence that preventing excessive cytokine production can avoid further lung damage in these patients.

Overall reduced lymphocyte especially T and B subsets closely related to the poor prognosis and the disease severity in severe patients with COVID-19 and diabetes mellitus.

BACKGROUND: A dysregulated host immune response is common in patients with COVID-19. AIM: In this study, we aimed to define the characteristics of lymphocyte subsets and their relationship with disease progression in COVID-19 patients with or without diabetes mellitus (DM). METHODS: The baseline peripheral lymphocyte subsets were compared between 55 healthy controls and 95 patients with confirmed COVID-19, and between severe and non-severe COVID-19 patients with or without DM. RESULTS: The prevalence of DM in the COVID-19 group was 20%, and patients with severe COVID-19 had a higher prevalence of DM than those with non-severe disease (P = 0.006). Moreover, a significantly poor prognosis and a higher rate of severity were found in those with DM relative to those without DM (P = 0.001, 0.003). Generally, all lymphocytes and subsets of lymphocytes, especially B and T cells, were significant reduced in COVID-19 patients, particularly in those with DM. Patients with severe COVID-19 and DM had the lowest lymphocyte counts compared with those with severe COVID-19 without DM, and those with non-severe COVID-19 with or without DM. Partially decreased lymphocyte subsets, age and DM were closely related to disease progression and prognosis. CONCLUSIONS: These findings provide a reference for clinicians that immunomodulatory treatment may improve disease progression and prognosis of COVID-19 patients, especially those with severe disease with DM. Trial registration Chinese Clinical Trial Register ChiCTR2000034563.

Lymphocyte subsets with the lowest decline at baseline and the slow lowest rise during recovery in COVID-19 critical illness patients with diabetes mellitus.

BACKGROUND: Host dysregulation of immune response was highly involved in the pathological process of Coronavirus disease 2019 (COVID-19), especially COVID-19 severe cases with DM. AIM: In this study we aimed at the dynamic change of peripheral lymphocyte and subsets during COVID-19 covery. METHODS: The peripheral lymphocyte and subsets of 95 confirmed cases with COVID-19 from baseline to four weeks were compared between critical illness and non-critical illness cases with or without DM. RESULTS: The dynamic characteristics of lymphocyte and subsets in COVID-19 patients was that it reduced significantly at one week, rapidly elevated to the peak at two weeks after onset, then gradually declined during recovery. The COVID-19 critical illness patients with DM had the lowest decline at one week and the slow lowest rise at two weeks after onset, while COVID-19 non-critical illness patients with DM had the rapid highest rise at two weeks after onset, both of them had similar lymphocyte and subsets at five weeks after onset and lower than those patients without DM. CONCLUSIONS: These findings provide a reference for clinicians that for COVID-19 patients with DM and the lowest decline of lymphocyte and subsets, immunomodulatory therapy as soon as possible might avoid or slow down disease progression; moreover for COVID-19 critical illness patients with or without DM and non-critical illness patients with DM, continuous immunomodulatory therapy in later stages of disease might speed up virus clearance, shorten hospital stay, improve disease prognosis in COVID-19 critical illness patients with DM.

Continuous thrombocytopenia after SARS-CoV-2 nucleic acid negative in a non-severe COVID-19 patient for several months.

BACKGROUND: Thrombocytopenia was common in the coronavirus disease (Covid-19) patients during the infection, especially in severe COVID-19 patients, but was less in the non-severe Covid-19 patients. However, the platelet count would be restored after antivirus treatment. In this paper, we report continuous thrombocytopenia in a non-severe Covid-19 case after a negative nucleic acid test for Covid-19. CASE PRESENTATION: A non-severe COVID-19 patient had the platelet continuous decrease for several months after the SARS-CoV-2 nucleic acid turning negative, and without well response to the glucocorticoid. The dynamic change of platelet count followed that of the lymphocyte count. After excluding the medicines possibility, immune system disorders, other specific virus infection and specific antibody of platelet, the thrombocytopenia continuously lasted for several months. The upward trend did not begin until June 2020 and she took the tapering dose of prednisone under the instruction of the hematologist. CONCLUSION: Excluding other potentialities inducing thrombocytopenia, we highly hypothesized the SARS-CoV-2 may cause thrombocytopenia by disturbing the immune system to induce the thrombocytopenia in our report,, which needs longer time to restore the immune system and platelet count via the glucocorticoid. We firstly reported this case in order to contribute the clinician to better deal with the patients like this.