High volume ECMO centers have developed mobile ECMO programs in recent years to facilitate implementation of ECMO support at hospitals with lower capabilities, and transfer these patients for further care. We report a case of mobile ECMO on patient with COVID-19 related ARDS, and discuss the potential application in current SARS-CoV-2 pandemic.

Dear editor,Given time, drug discovery programmes will undoubtedly yield highly potent drugs to form the basis of optimised COVID-19 regimens. However, if efficacious therapies can be identified from current medicines, repurposing represents the fastest route to establish deployable interventions and buy time for vaccine and novel drug development. It is important to note that effective medicines were rigorously optimised for the treatment of specific indications. Route of administration, dosage and schedules for existing therapies were optimised to provide adequate plasma/tissue pharmacokinetics and safety for their target disease or condition. These cannot be assumed to be optimal for COVID-19 but are often highly predictable from pre-existing data and clinical experience. For example, hydroxychloroquine and lopinavir/ritonavir recently failed to deliver benefits in RCTs for mild/moderate and severe disease,1, 2 but the clear disconnect between reportedin vitro antiviral activity and known human pharmacokinetics after administration of approved doses was predictable.3Interpretation of laboratory-based antiviral activity assessments is complicated by current uncertainty regarding the appropriateness of the existing model systems. The majority of in vitro antiviral screening assays have utilised Vero cells, which were derived from the kidney of African Green Monkey in the 1970s, and the lack of clinical evidence for which to validate the exposure-response relationship in humans is problematic. Evidence is emerging that the anti-SARS-CoV-2 activity of drugs may be higher in cells derived from humans. However, the question of which cell types are most representative of in vivo performance is yet to be addressed, and all that can really be concluded from current knowledge is that the susceptibility of SARS-CoV-2 to antivirals is cell-type-dependent. The consequences of this in terms of the variety of cell types known to be infected and/or sustain productive infection in vivo is equally uncertain, and further exacerbated by the lack of robustly validated animal models. However, repurposed drugs cannot be assumed to be active against SARS-CoV-2 at a dose that was optimised on the basis of potency for and accumulation at their initial therapeutic target.Nucleoside/nucleotide polymerase inhibitors have proven highly successful for other viruses, but usually require combination with another drug class. Remdesivir and favipiravir have in vitro anti-SARS-CoV-2 activity across multiple studies, and the unprecedented speed at which they have transitioned through COVID-19 RCTs can only be commended.4, 5, 6 Daily IV infusion may make inherent sense for severely ill patients, but a transformational impact for COVID-19 can only be realised if wide compatibility with global healthcare systems and equitable access across all country contexts is achieved. While reduction in symptom duration may mitigate healthcare saturation in high-income countries, the absence of a clear benefit for mortality diminishes game-changing potential. However, the clinical validation of the antiviral activity of such drugs will make them clear candidates for implementation as part of community-based interventions if other challenges are addressed. Importantly, the combination of nucleoside analogues with a secondary target such as the protease has stood the test of time in antiviral pharmacology. The recent reports of low-dose dexamethasone leading to an impact on mortality7 is a significant step forward but long-term mitigation of viral transmission, with subsequent economic and social restrictions, requires antiviral treatment or prevention to minimise hospitalisation through a community-targeted approach.Focussing on existing single drugs, and not appropriately formulated medicines, will require the rethinking of a number of medicine development parameters such as posology, reformulation and therapeutic index (Figure 1); current HIV medicines, for example, are formulated for chronic (life-long) dosing to moderate and control disease but a successful COVID-19 therapy will likely require only a short term acute administration to rapidly cure the patient. Conversely, different considerations are required for longer-term applications in COVID-19 chemoprophylaxis, which could have a dramatic effect on control of the pandemic.Many advanced drug delivery technologies have emerged in recent years. Long-acting drug delivery involving injectable, implantable or microarray patch mediated delivery have attracted enormous recent interest for prevention of other infectious diseases,8, 9 and the ability to deliver potent antiviral combinations for a period of months could play a transformational role in the absence of a safe and efficacious vaccine. The physicochemistry and activity of the polymerase inhibitors, and other drugs with known anti SARS-Cov-2 activity, also warrants investigation of pulmonary delivery via nebuliser or metered dose inhaler for direct dosing to the upper airways to supplement systemic drug delivery as pre- or post-exposure prophylaxis. Several advanced drug delivery strategies can be applied rapidly and do not need to be prohibitively expensive for global community programmes. It seems unlikely that a global pandemic can be ended if effective medicines are only available to the few and equitable access is therefore of benefit to all. Importantly, relying solely upon pre-existing formulations and posologies optimised for other diseases carries inherent risk of rejecting drug candidates with an otherwise high potential for global impact.

Sir, We read with interests the article by Kate F Walker and colleagues, entitled ”Maternal transmission of SARS-COV-2 to the neonate, and possible routes for such transmission: A systematic review and critical analysis”. In the article, the authors systematically analyzed the mode of delivery on the infection rates of COVID-19 in the newborn. Despite the limitations, especially the retrospective nature of studies examined, this study provided important information about the selection of mode of delivery of women with COVID-19. It suggests that neonatal infection rates are not different after Caesarean birth or vaginal delivery. However, the severity of the COVID-19 infection of the mothers was not considered. Clinically, pregnant women with the more severe COVID-19 infection appear to prefer delivery by Caesarean delivery rather than vaginal birth. Therefore, it is possible that any beneficial effects of Caesarean birth in reducing transmission of COVID-19 might not be apparent because the severity of COVID-19 infection was greater in these women. This selective bias would weaken the conclusions of current studies. We feel that prospective evaluation the safety of mode of delivery with COVID-19 is required.Rui-hong Xue11Department of Obstetrics and Gynecology, International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China

Through this case, we present the thought process, team-based strategy and sequel of managing a complex, critically ill pregnant with ARDS and COVID-19 pneumonia. This case also confirms the feasibility of using convalescent plasma and ECMO during early postnatal period in acutely ill parturient with respiratory failure.

As the world learned about Covid-19, the application of ECMO also evolved as health systems in the United States had some time to prepare. We report our initial experience using extracorporeal support for Covid-19 patients with the resource challenges that attend a worldwide pandemic.

Experience and training in field work is a critical component of undergraduate education in ecology, and many university courses incorporate field-based or experiential components into the curriculum in order to provide students hands-on experience. Due to the onset of the COVID-19 pandemic and the sudden shift to remote instruction in the spring of 2020, many instructors of such courses found themselves struggling to identify strategies for developing rigorous field activities that could be completed online, solo, and from a student’s backyard. This case study illustrates the process by which one field-based course, a UC California Naturalist certification course offered at the University of California, Davis, transitioned to fully remote instruction. The transition relied on established, publicly available, online participatory science platforms (e.g., iNaturalist) to which the students contributed data and observations remotely. Student feedback on the course and voluntary continued engagement with the participatory science platforms indicates that the student perspective of the experience was on par with previous traditional offerings of the course. This case study also includes topics and participatory science resources for consideration by other faculty facing a similar transition from group field activities to remote, individual field-based experiences.

COVID-19 created a host of challenges for science education; in our case, the pandemic halted our in-person elementary school outreach project on bird biology. This project was designed as a year-long program to teach fifth grade students in Ithaca, New York, USA about bird ecology and biodiversity, using outdoor demonstrations and in-person games and activities to engage students in nature. As a central part of this effort, we set up nest boxes on school property and had planned to monitor them with students during bird breeding in the spring. Here, we describe our experiences transitioning this program online: we live streamed nest boxes to students’ virtual classrooms and used them as starting points for virtual lessons on bird breeding and nestling development. We suggest that instituting similar programs at local schools can promote equitable learning opportunities for students across geographical locations and with various living situations. In an era of social distancing and isolation, we propose that nest box live streaming and virtual lessons can support local communities by providing access to the outdoors and unconventional science learning opportunities for all students.

Abstract Background Differentiating viral from bacterial acute respiratory infections (ARIs) remains challenging, due to the non-specific clinical manifestations. The COVID-19 pandemic is putting extraordinary strain on healthcare resources. To date, molecular testing is available but has a long turnaround time and therefore cannot provide results at the point-of-care (POC) thereby exposing COVID-19/Non-COVID-19 patients to each other while awaiting diagnosis. Methods This observational study prospectively evaluated the utility of a triage strategy including FebriDx, a POC fingerstick blood test that differentiates viral from bacterial ARIs through simultaneous detection of Myxovirus-resistance protein A (MxA) and C-reactive protein (CRP), in rapidly determining viral cases requiring immediate isolation and confirmatory molecular testing, from non-infectious patients or bacterial infections requiring antibiotics. Results 75 consecutive patients were screened, 48 eligible cases were tested with FebriDx, 36 were confirmed viral infection and 35/36 had COVID-19. 31/35 COVID-19 cases tested positive for SARS-CoV-2 via rRT-PCR and (4/35) had a clinical diagnosis of probable COVID-19 based on symptoms, epidemiological history, and chest imaging (PPV 100% (35/35)). 13 cases were FebriDx viral negative and rRT-PCR was also negative. In one case, it was not possible to determine the exact cause of infection, although a viral infection could not be excluded. Including this patient, FebriDx NPV was 92.3% (12/13), exceeding the NPV of rRT-PCR a 68.3% (13/19), and diagnostic sensitivity was conservatively calculated at 97% (35/36) compared to 82.9% (29/35) for initial rRT-PCR. The diagnostic specificity of both FebriDx and rRT-PCR was 100%. Conclusions: FebriDx could be deployed as part of a reliable triage strategy for identifying possible COVID-19 patients with symptomatic ARI in the COVID-19 pandemic. Key words: Pandemic; COVID-19; SARS-CoV-2; pneumonia; viral; point of care; infection

  Changes of serum IL-10, IL-1β, IL-6, MCP-1, TNF-α, IP-10 and IL-4 in COVID-19 patientsQingqing Lu1，Zhenhua Zhu2，Chaochao Tan3, Hui Zhou2，Yan Hu2，Ge Shen4，Pan Zhu4，Gang Yang4，Xiaobing Xie2△（1. Hunan University of Chinese Medicine, Changsha Hunan  Postal Code: 410208； 2. The First Hospital of Hunan University of Chinese Medicine, Changsha Hunan  Postal Code: 410007； 3. Hunan Provincial People’s Hospital, Changsha Hunan  Postal Code: 410005; 4.Loudi Center for Disease Control and Prevention，Loudi Hunan Postal Code: 417000）△ Correspondence author, E-mail：xxiaobing888@163.com Abstract: Background and purpose: Studies have shown that some cytokines in COVID-19 patients were elevated. This study aims to assess whether IL-10, IL-1β, IL-6, MCP-1, TNF-α, IP-10 and IL-4 serve as potential diagnostic biomarkers of COVID-19. Methods: The above serum cytokines in COVID-19 patients and non COVID-19 patients were detected by ELISA, SARS-CoV-2 IgM and IgG were detected by chemiluminescence method. Data were analyzed by independent-samples Mann-Whitney U-test, Levene T-test, T’-test or Spearman Correlation test as appropriate. Results: Serum levels of IL-10, IL-1β, MCP-1, TNF-α and IL-4 in COVID-19 patients were significantly higher than those in non-COVID-19 patients, while IL-6 were only significantly higher than in healthy people, IP-10 were significantly lower than in other diseases patients. AUCs of COVID-19 diagnosed by IL-10, IL-1β, IL-6, MCP-1, TNF-α, IP-10 and IL-4 were 0.735, 0.775, 0.595, 0.821, 0.848, 0.387 and 0.682, respectively. In COVID-19 patients’ serum, the levels of IL-10 and MCP-1 of male had noticeably higher than those of female, and all cytokines were significantly positively correlated with age, IL-1β and IL-4 were significantly negatively correlated with IgM, while IL-10, IL-1β, IL-6, TNF-α and IP-10 were significantly negatively correlated with IgG. IL-10 on 43-56 days were significantly lower than at 29-42 days, TNF-α at 15-42 days were significantly higher than at 0-14 days, IP-10 at 0-14 days were the highest, IL-4 at 29-42 days were significant higher than on 0-14 days. Conclusions: The detection of IL-10, IL-1 β, IL-6, MCP-1, TNF-α and IL-4 would assist the clinical study of COVID-19, and targeted inhibition of IP-10 in the early stage may be the key to future treatment of COVID-19.Keywords: cytokine; COVID-19; clinical value; course of disease;Q: What’s already known about this topic?A: Symptoms of COVID-19 patients, infection pathways of SARS-CoV-2, and the COVID-19 patients have higher cytokines.Q: What does this article add?A: What kinds of cytokines in COVID-19 patients were increased, whether they were potential diagnostic biomarkers of COVID-19 and offer prognostic insight upon initial presentation to help guide treatment, their relationship with age, gender，antibody concentration and course of the disease were also discussed.IntroductionNovel coronavirus (SARS-CoV-2) has high infectivity[1,2], the main methods for diagnosing it were nucleic acid detection and serological antibody detection [3]. Inflammatory factors are often increased in severe and critical patients [4], including interleukin (IL), colony-stimulating factor (CSF), chemokine, interferon (IFN), tumor necrosis factor (TNF), chemokine and growth factor (GF) [5]. Most of cytokines are produced by T lymphocytes, fibroblasts and mononuclear macrophages, and can in turn act on these cells, for example, IL-1β can activate vascular endothelial cells and lymphocytes, IL-6 can activate T lymphocytes and induce macrophage activation, MCP-1 can activate mononuclear macrophages, TNF-α can activate fibroblasts, IP-10 can recruit neutrophils and promote the secretion of multiple cytokines, thus, these cytokines could promote each other and jointly mediate inflammation; however, IL-10 can inhibit the inflammatory process. The early symptoms of Coronavirus disease 19 (COVID-19) patients were fever, dry cough and fatigue [6], but severe patients may develop even multiple organ failure [4], which may be related to the levels of cytokines [7-9]. In addition, overactivation of T cells was found in COVID-19 patients [10]. The production of cytokines is related to the individual immune function, so we assumed that the severity of COVID-19 can be predicted according to their levels. Our study aims to reveal the changes of serum levels in IL-10, IL-1β, IL-6, monocyte chemoattractant protein (MCP)-1, TNF-α, interferon-inducible protein (IP)-10 and IL-4 in COVID-19 patients, and assist clinical treatment of COVID-19. Materials and methods2.1 Specimens77 serum samples from male patients and 43 serum samples from female patients were collected from 48 COVID-19 patients in Loudi Center for Disease Control and Prevention, some of who were repeatedly sampled two to four times, and their ages ranged from 8 to 78 years old. The demographic and characteristics of the study participants have been showed in Table 1. Throat swab samples of these patients, including 2 dead patients and 17 asymptomatic infected patients, were detected by real-time PCR (test kits were purchased from Hunan Shengxiang Biotechnology Company), and the positive results of SARs-CoV-2 nucleic acid were confirmed. The COVID-19 is diagnosed according COVID-19 diagnosis and treatment guideline (Seventh Edition)[4]. Brief description is as follows: with epidemiological history and in line with the relevant clinical manifestations, as well as with new coronavirus etiology or serological evidence can be diagnosed. According COVID-19 diagnosis and treatment guideline (Seventh Edition), most of COVID-19 patients only received general treatment, including bed rest, timely effective oxygen therapy and antiviral treatment. Severe and critical patients generally need to be transferred to ICU for treatment including above treatment and timely organ function support treatment. The patients in this study received antiviral drugs such as interferon alpha, ritonavir, ribavirin and some traditional Chinese medicine, such as Qingfei Paidu decoction. In addition, we also collected the serum of non COVID-19 patients from The First Hospital of Hunan University of Chinese medicine. Among these patients, 53 patients suffered from the malignant tumor, hematological disease, rheumatic immune system disease and other diseases that increase the level of inflammatory factors, and 35 healthy people. All patients and their families had informed consent to the inclusion of the study and authorized to use their test results for the study. 2.2 Methods2.2.1 cytokine detectionThe 120 serum contents of IL-10, IL-1β, IL-6, MCP-1, TNF-α, IP-10 and IL-4 were detected by ELISA reader at 450 nm, the test kits and their standard were purchased from Beijing Human Diagnostics Company (double-antibody sandwich ELISA ), TECAN 200-8 were purchased from Shanghai TECAN Trading Company. Sensitivity: the minimal detectable concentrations for they were 0.0225, 0.0355, 0.0600, 0.0655, 0.0386, 0.0102 and 0.0180 pg/mL; specificity: when 50 ng / ml (100 ng / ml for IL-4) was used for specificity test, they did not react with common interfering cytokines and proteins. For statistical analysis: count the results which lower than the minimum detectable concentrations as half of the minimum detectable concentrations. A hole was added as a blank control. The samples whose OD value exceeds the linear range should be diluted before detection. The experiment was conducted in strict accordance with the instructions in the kit. All the reagents had their own standard. Both the repeatability (coefficient of variation between plates and within plates were less than 10%) and specificity were good. The kit has fixed value quality control and negative and positive control to ensure the accuracy of test results.2.2.2 SAS-COV-2 IgM and IgG antibody detectionThe serum samples of all cases were venous blood of 12 hours fasting without hemolysis or hyperlipidemia. The serum was obtained by centrifugation at 4000 RPM for 10 minutes, the contents of IgG and IgM in these serums were detected by magnetic particle chemiluminescence method, the SAS-COV-2 IgM and IgG test kits were purchased from Shenzhen Yahuilong Biotechnology Company, and 10.00AU/mL was taken as the positive judgment value, patients with results of 8-10AU/mL were retested 3-5 days later. Sensitivity and specificity were 98.5% and 100% when the cut-off value was 10.06 AU/mL; the HOOK effect would not appear when the antibody concentration was lower than 8000AU/mL. The experiment was carried out in strict accordance with the instructions in the kits. All the kits were provided with calibration information and quality control materials, and the repeatability (intra assay coefficient of variation was no more than 8%, and the inter assay coefficient of variation was no more than 15%) and specificity was good.2.2.3 Statistical analysisAll datas were processed by IBM SPSS statistic 21 and were drawn by GraphPad Prism 7. According to the characteristics of data distribution, independent-samples Mann-Whitney U-test was utilized to compare the serum levels of IL-10, IL-1 β, IL-6, MCP-1, TNF - α, IP-10 and IL-4 in different groups (COVID-19 patients, other diseases patients and healthy people) and course; Independent-samples Levene T-test or T’-test was utilized to compare COVID-19 patients in different genders; Spearman Correlation test was utilized to analyze the correlation between the levels of cytokines with ages, IgG and IgM. The difference was statistically significant with bilateral P-value < 0.05.3 Results3.1 Detection of IL-10, IL-1β, IL-6, MCP-1, TNF-α, IP-10 and IL-4 in serum samples of COVID-19 patients, other diseases patients and healthy people by ELISAAfter statistical analysis, as Figure 1 and Table 2 shows, it was found that the levels of IL-10, IL-1β, IL-6, MCP-1, TNF-α and IL-4 in the serum of COVID-19 patients were significantly higher than that in the serum of healthy people (PIL-10=0.000, PIL-1β==0.000,  PIL-6=0.000, PMCP-1=0.000, PTNF-α=0.000, PIL-4=0.002, respectively), while the serum levels of IP-10 between COVID-19 patients and healthy people were not significant different (P = 0.310); the serum levels of IL-10, IL-1β, MCP-1, TNF-α and IL-4 in COVID-19 patients were significantly higher than those in other diseases patients ( PIL-10=0.000, PIL-1β,=0.000, PMCP-1=0.000, PTNF-α=0.000, PIL-4=0.000, respectively), IP-10 in COVID-19 patients were significantly lower than those in other diseases patients (P=0.004), while the serum levels of IL-6 between COVID-19 patients and other diseases patients were not significant different (P = 0.078). In addition, IL-10, IL-6, MCP-1, and IL-4 in other diseases patients were significantly higher than those in healthy people (PIL-10=0.000, PIL-6,=0.000, PMCP-1=0.023, PIL-4=0.002, respectively), while the serum levels of IL-1β, TNF-α and IP-10 between COVID-19 patients and other diseases patients were not significant different (PIL-1β=0.453, PTNF-α=0.147, PIP-10=0.073, respectively).3.2 Diagnostic efficacy of detection of the IL-10, IL-1β, IL-6, MCP-1, TNF-α, IP-10 and IL-4 on COVID-19 by ELISA The abilities of prediction of IL-10, IL-1β, IL-6, MCP-1, TNF-α, IP-10 and IL-4 on COVID-19 were assessed by ROC curve, as Figure 2 shows, the COVID-19 patients were positive, and the other diseases patients and healthy people were negative, and select the tangent point with the largest Youden’s index as the cut-off value. When choose 2.621, 4.898, 1.730, 19.948, 0.110, 7.083 and 4.015 pg/mL respectively as their cut-off value, AUCs of COVID-19 diagnose by IL-10, IL-1β, IL-6, MCP-1, TNF-α, IP-10 and IL-4 were 0.735, 0.775, 0.595, 0.821, 0.848, 0.387 and 0.682, respectively, which means that IL-10, IL-1β, IL-6, MCP-1, TNF-α and IL-4 have potential diagnostic value for COVID-19, and TNF-α and MCP-1 have the best predictive effect. The sensitivities of diagnosis of TNF-α, MCP-1, IL-1β, IL-10, IL-4 and IL-6 were 81.2%, 84.6%, 63.2 %, 65.8 %, 67.5% and 72.6%, and the specificities of they were 93.0%, 69.8%, 95.3%, 89.5%, 100% and 64.0%; the sensitivity (parallel experiment) and specificity (series experiment) of combined diagnosis of TNF-α and MCP-1 were 97.1% and 97.9%, respectively. 3.3 The relationship between serum levels of IL-10, IL-1β, IL-6, MCP-1, TNF-α, IP-10 and IL-4 with gender and age in COVID-19 patients According to the statistical analysis, as Table 3 shows, it was found that the serum levels of IL-10 and MCP-1 in male COVID-19 patients were markebly higher than those in female patients (PIL-10=0.038, PMCP-1=0.031, respectively), while the differences of serum levels of IL-1β, IL-6, IP-10, TNF-α and IL-4 between male COVID-19 patients and female patients were not markebly significant (PIL-1β=0.611, PIL-6=0.354, PTNF-α=0.152, PIP-10=0.208, PIL-4=0.225, respectively).Ages of the owners of 7 serum samples were not clearly, the relationship between levels of cytokines and age in the other 113 serum samples of COVID-19 patients were show in Figure 3. According to the statistical analysis, the levels of all cytokines in COVID-19 patients were significant positively correlated with their ages (rIL-10=0.403, PIL-10=0.000; rIL-1β=0.200, PIL-1β=0.034; rIL-6=0.320, PIL-6=0.001; rMCP-1=0.431, PMCP-1=0.000; rTNF-α=0.246, PTNF-α=0.009; rIP-10=0.397, PIP-10=0.000; rIL-4=0.283, PIL-4=0.002, respectively).3.4 The relationship between serum levels of IL-10, IL-1β, IL-6, MCP-1, TNF-α, IP-10 and IL-4 and SAS-COV-2 IgM and IgG SARS-Cov-2 IgM and IgG concentrations in COVID-19 patientsThe correlation analysis of levels of IL-10, IL-1β, IL-6, MCP-1, TNF-α, IP-10, IL-4 and antibody concentration in serum samples of COVID-19 patients were shown in Figure 4. It was found that the levels of IL-1β and IL-4 in COVID-19 patients were negatively correlated with the level of IgM (rIL-1β=-0.206, PIL-1β=0.024; rIL-4=-0.208, PIL-4=0.023, respectively), while there were no significant correlation between the levels of IL-10, IL-6, MCP-1, TNF-α and IP-10 and the concentrations of IgM(PIL-10=0.416, PIL-6=0.056, PMCP-1=0.675, PTNF-α=0.301, PIP-10=0.622, respectively); the levels of IL-10, IL-1β, IL-6, TNF-α and IP-10 were negatively correlated with the level of IgG (rIL-10=-0.222, PIL-10=0.015; rIL-1β=-0.212, PIL-1β=0.020; rIL-6=-0.372, PIL-6=0.000; rTNF-α=-0.185, PTNF-α=0.043; rIP-10=-0.273, PIP-10=0.003, respectively), but there were no significant correlation between the levels of MCP-1 and IL-4 and the concentrations of IgG (PMCP-1=0.082, PIL-4=0.067, respectively).3.5 Changes in serum IL-10, IL-1β, IL-6, MCP-1, TNF-α, IP-10 and IL-4 in COVID-19 patients 47 serum are from patients who eventually died, or asymptomatic infected patients, 3 serum are from whose onset time are unknown, the other 70 serum were be divided into five groups according to the acquisition time from onset: a. 0-14 days, b. 15-28 days, c. 29-42 days, d. 43-56 days and e. 57-70 days. As it was shown in Table 4, IL-10 on 43-56 days were significant lower than those on 29-42 days (P=0.049), TNF-α on 15-42 days were significant higher than those on 0-14 days (Pab=0.030, Pac=0.027), IP-10 on 0-14 days were significant higher than those on 43-56 days, IP-10 on 0-14 days were highest and were significant higher than those on43-56 days (P=0.018), and IL-4 on 29-42 days were significant higher than those on 0-14 days (P=0.018).4 DiscussionWe measured the serum levels of these cytokines in COVID-19 patients and non COVID-19 patients by ELISA, the results showed that the serum levels of IL-10, IL-1β, MCP-1, TNF-α and IL-4 in COVID-19 patients were significantly higher than those in non COVID-19 patients, while IL-6 were only significantly higher than in healthy people, IP-10 in COVID-19 patients were significantly lower than those in other diseases patients. IL-10, IL-1β, IL-6, MCP-1, TNF-α and IL-4 have potential study value for COVID-19, and TNF-α and MCP-1 have the best predictive effect. It should be noted that the serum levels of IL-10 and MCP-1 in male COVID-19 patients were significantly higher than those in the female patients. The serum levels of all cytokines in patients were significantly positively correlated with age. IL-1β and IL-4 were significantly negatively correlated with IgM, while IL-10, IL-1β, IL-6, TNF-α and IP-10 were significantly negatively correlated with IgG. The continuous monitoring of the cured COVID-19 patients showed that the levels of TNF-α on 15-42 days were significant higher than those on 0-14 days, and IL-4 on 29-42 days were significant higher than those on 0-14 days, study shows that ICU patients had higher plasma levels of cytokines than non-ICU patients[1], which suggested that levels of cytokines may related to the severity of the disease, so we assume that the reason for this change is that the disease on 0-14 days is light; IL-10 on 43-56 days were significant lower than those on 29-42 days, which may because on 43-56 days, the immune system secreted more IL-10 to induce excessive apoptosis of immune cells in order to avoid damaging its normal tissues in the late stage of inflammation; IP-10 on 0-14 days were highest and were significant higher than those on 43-56 days, the finding that IP-10 rose sharply in the early stages of COVID-19 suggested that targeted inhibition of IP-10 in the early stage might be the key to future treatment of COVID-19. 5 ConclusionTo sum up, we found that the serum levels of IL-1β, MCP-1, IL-6 and IP-10 in patients with COVID-19 were rise, which was same as Severe Acute Respiratory Syndrome (SARS)[11-13], this similarity may be related to the fact that both SARS-CoV-2 and SARS viruses attack Angiotensin-Converting Enzyme 2 (ACE2)[14,15] and produce similar inflammatory processes; TNF-α in patients with COVID-19 were also rise, which was same as Middle East Respiratory Syndrome Coronavirus (MERS)[12,16,17]; what's interesting is that the level of IL-4 and IL-10 also rise in patients with COVID-19, which was different with the another two high pathogenic coronavirus diseases [11-13,16,17]. IL-10, IL-1 β, IL-6, MCP-1, TNF-α and IL-4 would assist the clinical study of COVID-19. In COVID-19 patients, the serum levels of all cytokines were significant positively correlated with age, the poor prognosis of the elderly may be related to this; some of they have relationships with the gender or antibody, the former may be related to the high level of ACE2 in  male reproductive system [18-20]; the levels of cytokines would change with the course of disease, and we assumed that targeted inhibition of IP-10 in the early stage may be the key to future treatment of COVID-19. Due to the limited number of samples and enrollment, neither the levels of cytokines between mild and severe patients, were be compared. It has been reported that there are high levels of Pro-inflammatory cytokines in severe COVID-19 patients serum [1,16,21]. To make it clear that whether the cytokine level can predict the course of disease development of COVID-19 patients, the follow-up research will continue.Data Availability Statements: The datas that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.REFERENCES [1] Chaolin Huang，Yeming Wang，Xingwang Li，Lili Ren，Jianping Zhao，Yi Hu，et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China [J]. Lancet, 2020; 395: 497-506.[2] Hongzhou Lu, Charles W. Stratton, Yi‐Wei Tang. Outbreak of pneumonia of unknown etiology in Wuhan, China: The mystery and the miracle [J]. J Med Virol, 2020; 92: 401-402.[3] Yu Chen, Qianyun Liu, Deyin Guo. Emerging coronaviruses：genome structure，replication，and pathogenesis [J]. J Med Virol，2020; 92（4）：418-423.[4] The national health and Health Committee and the office of the State, Administration of traditional Chinese medicine (TCM).Diagnosis and Treatment Protocol for COVID-19 (Trial version 7)(state health office Medical Letter No.184 (2020). [EB/OL].(2020-03-04) [2020-03-05] http://www.nhc.gov.cn/yzygj/s7653p/202003/46c9294a7dfe4cef80dc7f5912eb1989.shtml.[5] Chousterman Benjamin G, Swirski Filip K, Weber Georg F. Cytokine storm and sepsis disease pathogenesis. [J]. Seminars in immunopathology,2017; 39(5):517-528.[6] Jasper Fuk-WooChan, Shuofeng Yuan, Kin-Hang Kok, Kelvin Kai-Wang To, Hin Chu, Jin Yang, et al. A familial cluster of pneumonia associated with the 2019 novel corona virus indicating person to person transmission: a study of a family cluster [J]. Lancet, 2020; 395: 514-523．[7] Shimabukuro-Vornhagen Alexander, Gödel Philipp, Subklewe Marion, Stemmler Hans Joachim, Schlößer Hans Anton, Schlaak Max, et al. Cytokine release syndrome. [J].Journal for immunotherapy of cancer,2018; 6(1):56-56.[8] Xue-Qin Meng, Xin-Hua Chen, Zayd Sahebally, Yu-Ning Xu, Sheng-Yong Yin, Li-Ming Wu, et al. Cytokines are early diagnostic biomarkers of graft-versus-host disease in liver recipients [J]. Hepatobiliary &amp; Pancreatic Diseases International,2017; 16(01):45-51.[9] Anne-Britt E Dekker, Pieta Krijnen, Inger B Schipper. Predictive value of cytokines for developing complications after polytrauma [J]. World Journal of Critical Care Medicine,2016; 5(03):187-200.[10] Zhe Xu, Lei Shi, Yijin Wang, Jiyuan Zhang, Lei Huang, Chao Zhang, et al. Pathological findings of COVID-19 associated with acute respiratory distress syndrome [J]. Lancet Respir Med, 2020; 8(4)：420-422.[11] Channappanavar Rudragouda, Perlman Stanley. Pathogenic human coronavirus infections: causes and consequences of cytokine storm and immunopathology. [J].Seminars in immunopathology, 2017; 39(5):529-539.[12] Kindler, E., V. Thiel, and F. Weber, Interaction of SARS and MERS Coronaviruses with the Antiviral Interferon Response[J]. Adv Virus Res, 2016. 96: 219-243.[13] Rudragouda Channappanavar, Anthony R. Fehr, Rahul Vijay, Matthias Mack, Jincun Zhao, David K. Meyerholz, et al. Dysregulated Type I Interferon and Inflammatory Monocyte-Macrophage Responses Cause Lethal Pneumonia in SARS-CoV-Infected Mice. Cell Host Microbe, 2016, 19(2): 181-193.[14] Yu Zhao, Zixian Zhao, Yujia Wang, Yueqing Zhou, Yu Ma, Wei Zuo. Single-cell RNA expression profiling of ACE2, the receptor of SARS-CoV-2 [J]. Am J Respir Crit Care Med, 2020, 202(5): 756-759. [15] Yushun Wan, Jian Shang, Rachel Graham, Ralph S. Baric, Fang Li. Receptor Recognition by the Novel Coronavirus from Wuhan: an Analysis Based on Decade-Long Structural Studies of SARS Coronavirus [J]. Journal of virology, 2020; 94(7): e00127-20.[16] Kim Eu Suk, Choe Pyoeng Gyun, Park Wan Beom, Oh Hong Sang, Kim Eun Jung, Nam Eun Young, et al. Clinical Progression and Cytokine Profiles of Middle East Respiratory Syndrome Coronavirus Infection [J].Journal of Korean Medical Science,2016; 31(11):1717-1725. [17] Dianna L. Ng, Farida Al Hosani, M. Kelly Keating, Susan I. Gerber, Tara L. Jones, Maureen G. Metcalfe, et al. Clinicopathologic, immunohistochemical, and ultrastructural findings of a fatal case of Middle East respiratory syndrome coronavirus infection in the United Arab Emirates[J]. Am J Pathol. 2016; 186:652-658.[18] Zhenyu Fan, Liping Chen, Jun Li. Clinical Features of COVID-19-Related Liver Functional Abnormality [J]. Clinical Gastroenterology and Hepatology,2020; 18(7):1561-1566.[19] Caibin Fan, Kai Li, Yanhong Ding, Wei Lu Lu, Jianqing Wang. ACE2 Expression in Kidney and Testis May Cause Kidney and Testis Damage After 2019-nCoV Infection  [J/OL]. https://www.medrxiv.org/content/10.1101/2020.02.12.20022418v1, 2020-02-13.[20] Iziah E Sama, Alice Ravera, Bernadet T Santema, Harry van Goor, Jozine M ter Maaten,  John G F Cleland, et al. Circulating plasma concentrations of angiotensin-converting enzyme 2 in men and women with heart failure and effects of renin–angiotensin–aldosterone inhibitors[J].Eur Heart J, 2020; 41(19):1810-1817.[21] Lingxi Guo, Dong Wei, Xinxin Zhang, Yurong Wu, Qingyun Li, Min Zhou. Clinical Features Predicting Mortality Risk in Patients With Viral Pneumonia: The MuLBSTA Score. [J]. Frontiers in microbiology,2019; 10:2752.AcknowledgementThe authors promise that all the data are from the clinical, and genuine and believable. The authors report no commercial associations that could be a conflict of interest. Novel Coronavirus Pneumonia Emergency Project of Hunan Province Science and Technology Department (2020SK3009, 2020SK3018, 2020SK3042) and the First-class Discipline Open Fund Project of Hunan University of Chinese Medicine (2018YXJS02) were received in support of this article.

Scientific activities including university classes, wet lab research activities, fieldwork, and seminars/conferences have been cancelled in response to the ongoing COVID-19 pandemics. While the public health priority was to contain and mitigate the outbreak, the science sector swiftly adopted technologies to stay connected and continue the scientific activities as much as possible. Creativity, ingenuity, and resilience abound in the science community manifested in successful examples of truly global activities such as seminar series and conferences. While these platforms were initially concerned with maintaining the continuum of science education and dissemination, they attracted participants beyond the boundaries of their respective institutions and countries and thereby increased the equity. While the communities and countries are easing the societal restrictions and the scientific community returns to on-site work, it is important to learn the lessons and ensure equity in science education and dissemination moving forward.

Education in ecology and evolution often utilizes field instruction to teach key learning outcomes. Remote teaching of learning outcomes that have been traditionally taught in the field, necessitated by the COVID-19 pandemic, presents unique challenges for students, instructors, and institutions. A survey of 117 faculty conducted during spring 2020 revealed substantial reduction of learning outcomes typically taught in the field, and frequent substitutions of less active and more instructor-centered remote activities for field activities. The survey revealed generally negative instructor views on many remote teaching substitutions, yet also showed several approaches that instructors regarded as more effective, despite potential challenges with equitably teaching them. I suggest several models of remote substitutions for traditional field teaching of identification, field techniques, data collection, and study design in the context of the results of this survey.

The coronavirus disease of 2019 (COVID-19) pandemic has impacted educational systems worldwide, in particular primary and secondary schooling. To enable students of the local secondary school in Brisbane, Queensland, to continue with their practical agricultural science learning and facilitate online learning, a small-scale citizen science project was designed and rapidly implemented as a collaboration between the school and a multidisciplinary university research group focused on pollen allergy. Here we reflect on the process of developing and implementing this project from the perspective of the school and the university. A learning package including modules on pollen identification, tracking grass species, measuring field greenness, using a citizen science data entry platform, forensic palynology, as well as video guides, risk assessment and feedback forms were generated. Junior agriculture science students participated in the learning via online lessons and independent data collection in their own local neighborhood and/or school grounds situated within urban environments. The project provided useful data on local distribution and flowering of grass species. The experience allowed two-way knowledge exchange between the secondary and tertiary education sectors. The unique context of restrictions imposed by the social isolation policies as well as Public Health and Department of Education directives, allowed the team to respond by adapting teaching and research activity to develop and trial learning modules and citizen science tools. The project provided a focus to motivate and connect teachers, academic staff, and school students during a difficult circumstance. Extension of this citizen project for the purposes of research and secondary school learning, has the potential to offer ongoing benefits for grassland ecology data acquisition and student exposure to real-world science.

The current COVID-19 pandemic has forced the global higher education community to rapidly adapt to partially- or fully-online course offerings. For field- or lab-based courses in ecological curricula, this presents unique challenges. Fortunately, a diverse set of active learning techniques exist, and these techniques translate well to online settings. However, limited guidance and resources exist for developing, implementing, and evaluating active learning assignments that fulfil specific objectives of ecology-focused courses. To address these informational gaps, we (1) identify broad learning objectives across a variety of ecology-focused courses, (2) provide examples, based on our collective online teaching experience, of active learning activities that are relevant to the identified ecological learning goals, and (3) provide guidelines for successful implementation of active learning assignments in online courses. Using The Wildlife Society’s list of online higher education ecology-focused courses as a guide, we obtained syllabi from 45 ecology-focused courses, comprising a total of 321 course-specific learning objectives. We classified all course-specific learning objectives into at least one of five categories: (1) Identification, (2) Application of Concepts/Hypotheses/Theories, (3) Management of Natural Resources, (4) Development of Professional Skills, or (5) Evaluation of Concepts/Practices. We then provided two examples of active learning activities for each of the five categories, along with guidance on their implementation in online settings. We suggest that, when based on sound pedagogy, active learning techniques can enhance the online student’s experience by activating ecological knowledge; moreover, active learning techniques should also be incorporated into in-person offerings once the current COVID-19 crisis has abated.

Now, we know that the first report of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) was in December 2019 in Wuhan, China. In January, the existence of a disease caused by a virus with respiratory tropism for humans was announced, and in February it was already named SARS-Cov-2. The World Health Organization (WHO) 1 gave it the name of COVID-19, on February 11. One month later, WHO declared that the disease caused by this virus was already a pandemic (WHO, 2020)1. The virus started in China, then affected other Asian countries such as Japan, South Korea, etc., and later spread to Europe, then America.As this pandemic progresses, the reports of this six-month period show that this SARS-CoV-2 coronavirus not only targets the respiratory system, its effect on the cardiovascular, digestive, and renal apparatus has also been described. In addition, recent reports have described a set of neurological symptoms 2-4. Furthermore, the presence of this virus in the neurons and the capillary endothelium of the frontal cortex was seen in a patient who died of SARS-CoV-24. Moreover, other reports have shown its presence in the brainstem and in the cerebrospinal fluid (CSF) of other patients with SARS-CoV-2 5-6. Recent reports suggested that the cells with the expression of the angiotensin-converting enzyme 2 (ACE-2) may be a target for this coronavirus, since ACE 2 is a suggested cellular receptor for this coronavirus 4,7-8. Interestingly, various reports have demonstrated the presence of ACE-2, in both neurons and glial cells 7,9-11. Consequently, the evidence suggests that central nervous system (CNS) may be a target organ for this virus. It is known that the presence of this virus is responsible for the inflammatory process, which causes damage not only at the pulmonary level, but also at the cardiovascular, renal, and digestive system levels. All of these structures have a great regenerative capacity and thus reduce the damage in the long term. However, an inflammatory process at the CNS level could leave sequelae that, with age, could favor the early appearance of neurodegenerative processes, such as Alzheimer’s disease, Parkinson’s disease, vascular type dementia, multiple sclerosis etc., 12-13. Consequently, preventive measures should be taken to avoid the CNS from suffering future damage.Autopsy of patients with COVID-19 has shown that the brain tissue is hyperemic, edematous, and has degenerated neurons 2,7. However, it is necessary to know the percentage of cases in which there were changes in the nervous tissue caused by SARS-CoV-2, the types of modifications and the CNS regions most affected by COVID\sout-19. Data can help us know the impact on the brain tissue of this viral infection. In addition to supporting the neuroinvasive effect on the CNS and peripheral nervous system (PNS) of this coronavirus, there are the reported cases of meningitis, encephalitis, and Guillain-Barré syndrome associated with SARS-CoV-2 7,14-17.The clinical picture of SARS-CoV-2 is very wide, with symptoms and signs that involve the respiratory, cardiovascular, renal, digestive, and hepatic systems. However, there are also symptoms in which the CNS and PNS could be involved 2,3. Neurological manifestations have been classified as non-specific and specific by various authors2,15,18-20. Among the non-specific ones are headache, fatigue, dyspnea, etc. While the specific ones imply clear CNS or PNS affection data, such as loss of smell and reduction of taste and vision, neural pain, epileptic seizures, acute cerebrovascular disease, and deterioration of the state of consciousness have also been reported3,14,15,17,19,20.The way in which the SARS-CoV-2 can reach neurons and glial cells is through the blood crossing the blood-brain barrier or by retrograde transport through peripheral nerves. There is evidence for both hypotheses. At the beginning of the disease, patients with COVID-19 may have alterations or loss of smell and taste, probably because the virus may damage this pathway, which has been reported to recover, in some cases at the end of the disease and in others up to several weeks after the patient recovered 20. The virus can pass through the olfactory pathway, which enters the brain through the cribiform plate (transcribial route) 5,7,21. This route has been reported for other viruses, including SARS-CoV7,18,22. In addition, various reports have detected various viruses with respiratory tropism, including some coronaviruses, can reach the brain by retrograde transport, due to their neurotropic properties 5,7,21,22.Moreover, there is a percentage of patients who enter the ICU and require ventilatory assistance, since they do not breathe spontaneously7,21,23. Consequently, it is necessary to study whether this effect of COVID-19 is due to direct action on lung tissue or due to its neurotoxicity at the level of the brainstem, by affecting the respiratory center, which responds to changes in blood pH and CO2 levels 24.In summary, more studies are required to obtain additional information on the neurotoxic effects of COVID-19. However, with the aforementioned data, we can suggest that this coronavirus has neurotropic properties with neuroinvasive activity, which should be investigated, looking for therapeutic tools to reduce the damage that could be left at the nervous tissue level.ReferencesWorld Health Organization, Novel Coronavirus (2019-nCoV) Situation Report – 22, 2020Mao L, Jin H, Wang M, Hu Y, Chen S, He Q, Chang J, et al., Neurologic manifestations of hospitalized patients with coronavirus disease 2019 in Wuhan, China. JAMA Neurol . 2020;77;1–9.Helms J, Kremer S, Merdji H, Clere-Jehl R, Schenck M, Kummerlen C, Collange O, et al., Neurologic Features in Severe SARS-CoV-2 Infection. N Engl J Med . 2020;382;2268-2270.Paniz-Mondolfi A, Bryce C, Grimes Z, Gordon RE, Reidy J, Lednicky J, Sordillo EM, Fowkes M. Central nervous system involvement by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). J Med Virol . 2020;92;699-702.Bulfamante G, Chiumello D, Canevini MP, Priori A, Mazzanti M, Centanni S, Felisati G. First ultrastructural autoptic findings of SARS-Cov-2 in olfactory pathways and brainstem. Minerva Anestesiol . 2020.Moriguchi T, Harii N, Goto J, Harada D, Sugawara H, Takamino J, Ueno M, et al., A first case of meningitis/encephalitis associated with SARS-Coronavirus-2. Int J Infect Dis . 2020;94;55-58.Baig AM, Khaleeq A, Ali U, Syeda H. Evidence of the COVID-19 Virus Targeting the CNS: Tissue Distribution, Host-Virus Interaction, and Proposed Neurotropic Mechanisms. ACS Chem Neurosci . 2020;11;995-998.Yan R, Zhang Y, Li Y, Xia L, Guo Y, Zhou Q. Structural basis for the recognition of SARS-CoV-2 by full-length human ACE2. Science . 2020;367;1444-1448.Yamagata R, Nemoto W, Nakagawasai O, Takahashi K, Tan-No K. Downregulation of spinal angiotensin converting enzyme 2 is involved in neuropathic pain associated with type 2 diabetes mellitus in mice.Biochem Pharmacol . 2020;174;113825.Mukerjee S, Gao H, Xu J, Sato R, Zsombok A, Lazartigues E. ACE2 and ADAM17 Interaction Regulates the Activity of Presympathetic Neurons.Hypertension. 2020;74;1181-1191.Kehoe PG, Al Mulhim N, Zetterberg H, Blennow K, Miners JS. Cerebrospinal Fluid Changes in the Renin-Angiotensin System in Alzheimer’s Disease. J Alzheimers Dis. 2019;72(2):525-535.Cairns DM, Rouleau N, Parker RN, Walsh KG, Gehrke L, Kaplan DL. A 3D human brain-like tissue model of herpes-induced Alzheimer’s disease.Sci Adv. 2020;6;eaay8828.. Flores G, Flores-Gómez GD, Gomez-Villalobos MJ. Neuronal changes after chronic high blood pressure in animal models and its implication for vascular dementia. Synapse. 2016;70;198-205.Dalakas MC. Guillain-Barré syndrome: The first documented COVID-19-triggered autoimmune neurologic disease: More to come with myositis in the offing. Neurol Neuroimmunol Neuroinflamm . 2020;7; e781.Faucher A, Rey PA, Aguadisch E, Degos B.Isolated post SARS-CoV-2 diplopia. J Neurol. 2020;1–2.Joob B, Wiwanitkit V. COVID-19 and Guillain-Barré syndrome. Rev Neurol (Paris), 2020.Wang L, Shen Y, Li M, Chuang H, Ye Y, Zhao H, Wang H. Clinical manifestations and evidence of neurological involvement in 2019 novel coronavirus SARS-CoV-2: a systematic review and meta-analysis. J Neurol . 2020;1–13.Asadi-Pooya AA, Simani L Central nervous system manifestations of COVID-19: A systematic review. J Neurol Sci . 413,116832..Kanwar D, Baig AM, Wasay M. Neurological manifestations of COVID-19. J Pak Med Assoc. 2020;70(Suppl 3), S101-S103.Kosugi EM, Lavinsky J, Romano FR, Fornazieri MA, Luz-Matsumoto GR, Lessa MM, Piltcher O, Sant’Anna GD. Incomplete and late recovery of sudden olfactory dysfunction in COVID-19. Braz J Otorhinolaryngol , 2020;S1808-8694, 30059-30068.Baig, A.M. Neurological manifestations in COVID-19 caused by SARS-CoV-2. CNS Neurosci Ther . 2020;26;499-501.Bohmwald K, Gálvez NMS, Ríos M, Kalergis AM. Neurologic Alterations Due to Respiratory Virus Infections. Front Cell Neurosci . 2018;12;386.Li YC, Bai WZ, Hashikawa T. The neuroinvasive potential of SARS-CoV2 may play a role in the respiratory failure of COVID-19 patients.J Med Virol . 2020;92;552-555.Guyenet PG, Bayliss DA. Neural Control of Breathing and CO2 Homeostasis. Neuron. 2015;87;946-961.

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disease (COVID-19) in China at the end of 2019 brought with it uncertainty as to whether it would bring an increase in maternal, fetal and neonatal morbidity and mortality. This uncertainty drove fear; understandable given the high case fatality rate associated with previous severe respiratory illness causing coronaviruses.Given the novel nature of SARS-CoV-2, clinicians and women and their families rely primarily on limited information from case reports and case series to inform their decisions about pregnancy management. Early evidence from these sources demonstrated a tendency toward preterm delivery mainly as a consequence of elective interventions (Della Gatta et al. Am J Obstet Gynecol, 2020, Vol.223, p36-41), which are likely to have been exacerbated by the uncertainty of COVID-19 on pregnancy and neonatal outcomes.The reliance on research reports, case series and case reports continues. However, such reports are at higher risk of bias, including publication bias. Concerns have also been expressed about the potential of reporting of same people with COVID-19 across different reports (Bauchner et al. JAMA, 2020, Vol.323, p1256). Such reporting leads to inaccurate estimates of the impact of the disease on outcomes, which is aggravated when an evidence base is relatively small, evolving and critical to informing good care decisions.In this issue, Thornton et al. report a review of case reports and case series of the risk of the neonate becoming infected with SARS-COV-2 by mode of birth, type of infant feeding and mother-infant interaction (BJOG 2020 xxxx). Their findings lead them to conclude that vaginal delivery, breast and are safe in the context of COVID-19 disease. But, what interests me equally in this paper is their approach to reducing the risk of duplicate reports in estimating disease impact.First, their data sources included a daily PubMed search supplemented by alerts from experts on social media; daily searches of three electronic databases including the Maternity and Infant Care Database and citation tracking. Second, geo-coding of data to unique distinct locations. Here, in response to reviewer feedback, which the authors refreshingly acknowledge, the team invited a native speaker of Chinese familiar with health institutes in Wuhan to provide contextual information to maximise the likelihood of correct site identification (which did result in some geo-coding revisions). Third, they attempted to identify sites unnamed in reports using author affiliations, which ultimately did not provide the assurances they needed to be confident in retaining some reports.The accuracy of inferences drawn from research reports, case series and case reports is enhanced when authors report clearly if and when any patients are reported in other reports and when processes to minimise erroneous repeated inclusion of the same patients. Thornton et al.’s paper is informative clinically but is equally interesting in its flexing of methods to iteratively address an evolving evidence base and minimise uncertainty. Such approaches may lack the sophistication of techniques applied to larger evidence bases yet are critical to informing decisions early in an evolving evidence base. Further development of the processes may inform future pandemic readiness.No disclosures: A completed disclosure of interest form is available to view online as supporting information.

Barriers to fieldwork exist for many reasons such as physical ability, financial cost, and time availability. Unfortunately, these barriers disproportionately affect minority communities and create a disparity in access to fieldwork experience in the natural science community. Travel restrictions and the global lockdown has extended this barrier to fieldwork across the community and led to increased anxiety about gaps in productivity, especially for graduate students and early-career researchers. In this paper, we discuss Agent-Based Modeling as an open-source, accessible, and inclusive resource to substitute for lost fieldwork during COVID-19 and future scenarios of travel restrictions such as climate change. We detail the process of model development with a plethora of examples from the literature on how Agent-Based Models can be applied broadly across life-science research. We aim to amplify awareness and adoption of this technique to broaden the diversity and size of the Agent-Based Modeling community in ecology and evolutionary research. We also describe the benefits of Agent-Based models as a teaching and training resource for students across education levels. Finally, we discuss the current challenges facing Agent-Based Modeling and discuss how the field of quantitative ecology can work in tandem with traditional field ecology to improve both methods.

Background: Lung ultrasound (LUS) has been successfully used in the diagnosis of different pulmonary diseases. Present study design to determine the diagnostic value of LUS in the evaluation of children with COVID-19, and to compare chest X-ray and LUS results with tomography (CT).   Method and objectives: In this prospective multi-center study, 40 children with confirmed COVID-19 were included. LUS was performed to all patients at admission. The chest X‐ray and CT were performed according to the decision of the primary physicians. LUS results were compared with chest X-ray and CT. The sensitivity and specificity and diagnostic performance was determined. Results: Of the 40 children median (range) was 10.5 (0.4-17.8) years. Chest X-ray and LUS were performed on all and chest CT was performed on 28 (70%) patients at the time of diagnosis. Sixteen (40%) patients had no apparent chest CT abnormalities suggestive of COVID-19, whereas 12 (30%) had abnormalities. LUS confirmed the diagnosis of pulmonary involvement in 10 out of 12 patients with positive CT findings. LUS demonstrated normal lung patterns among 15 patients out of 16 who had normal CT features. The sensitivity identified by the chest X-ray and LUS tests was comparedand statistically significantly different (p=0.016). Chest X-ray displayed false-negative results for pulmonary involvement in 75% whereas for LUS it was 16.7%. Conclusions: LUS might be a useful tool in the diagnostic steps of children with COVID-19. A reduction in chest CT assessments may be possible when LUS is used in the initial diagnostic steps for these children.

Aims: The storm-like nature of the health crises caused by COVID-19 has led to unconventional clinical trial practices such as the relaxation of exclusion criteria. The question remains: how can we conduct diverse trials without exposing sub-groups of populations to potentially higher drug exposure levels? The aim of this study was to build an extensive knowledge-base of the effect of intrinsic and extrinsic factors on the disposition of several repurposed COVID-19 drugs. Methods: Verified physiologically‐based pharmacokinetic (PBPK) models were used study the effect of COVID-19 drugs PK in geriatric patients, race, organ impairment, DDI risks, disease-drug interaction for repurposed COVID-19 drugs. Furthermore, these models were used to predict epithelial lining fluid (ELF) exposure which is relevant for COVID-19 patients by accounting for the interplay between cytokines and metabolic disposition. Results: The simulated PK profiles suggest no dose adjustments are required based on age and race for COVID-19 drugs; however, sometimes dose adjustments are warranted for patients exhibiting hepatic/renal impairment in addition to COVID-19 co-morbidity. PBPK model simulations suggest ELF exposure to attain a target concentration was adequate for most drugs except azithromycin, atazanavir and lopinavir/ritonavir. Conclusion: We demonstrate that systematically collated data on the ADME, human PK parameters, DDIs, and organ impairment has enabled verification of simulated plasma and lung tissue exposure of many repurposed COVID-19 drugs to justify broader recruitment criteria for patients. In addition, developed PBPK model helped to assess the correlation between target site exposure to relevant potency values from in vitro studies for SARS-CoV-2.

To the Editor, Severe asthma (SA) is a chronic disease affecting around 3-8% of adult asthma population in Europe, with the refractory form estimated to occur in 0.1% of the general population (1,2). SA is characterized by increased use of healthcare resources (i.e. emergency room/hospital admissions, access to intensive care units (ICU), use of biologics) due to exacerbations compared to the less severe form. In the current SARS-CoV-2 pandemic, there is an ongoing debate on the role of asthma and use of immunomodulating drugs, like corticosteroids and biologics, on COVID-19 outcomes. According to available data on COVID-19 hospitalizations, asthma seems to play little role on the clinical severity or access to health resources, unlike other chronic conditions such as hypertension, obesity and chronic obstructive pulmonary disease (3). However, to date, no information is available on the burden of SA on COVID-19 severity and hospitalization rates.A questionnaire was submitted to the Italian Registry of Severe Asthma (IRSA) network (4), assessing the prevalence and clinical characteristics of patients with SA who contracted COVID-19 during the outbreak in Italy (February 24th - May 18th 2020), and 41 out of 78 centers distributed evenly among different Italian regions participated to the survey (Figure 1a).Among the 558 subjects surveyed, 7 subjects contracted COVID-19 (1.25% of the national sample), with an average age of 54.5 years: 5 isolated at home/received home care (71.5%), while 2 subjects were admitted to the hospital (28.5%), none required accessed to ICU and no deaths were reported. All COVID-19 subjects with SA came from 2 regions of Northern Italy (6 Lombardy, 1 Emilia-Romagna, 3.7% of the regional population), all showing one or more comorbidities, and were treated with high-dose inhaled corticosteroids plus long-acting beta-2 agonists (ICS-LABA) and biologics (see Table 1).We then compared our results with data provided by the Italian Department for Civil Protection in the same time period from the affected geographic areas (5), and we observed that the frequency of COVID-19 among subjects referred to IRSA centers strongly correlated with the prevalence of SARS-CoV-2 infection in the corresponding province (Figure 1b). Furthermore, the hospitalization rate in COVID-19-SA subjects was not significantly different from the general population (24.1%, 23.6-24.6 95% C.I.; p=0.25, Chi-squared test). Lastly, we could not observe a significantly increased COVID-19 frequency in subjects undergoing high-dose ICS-LABA and biologics compared to SA treated with ICS-LABA alone (p=0.09, Fisher exact test).These findings from the IRSA registry offer some insights on the susceptibility to SARS-CoV-2 infection, access to healthcare resources and mortality by SA patients.Given the low prevalence of SA in Italy (2), we expected less COVID-19-SA cases per region than what reported by the IRSA survey. However, we observed that the geographic location of COVID-19-SA patients mostly reflected the bimodal distribution of the COVID-19 outbreak in Italy, mainly clustered in Lombardy and neighboring regions, where the highest cumulative COVID-19 cases were recorded (>500/100000 cases per inhabitants) (5). In these areas, the prevalence of positive cases by province also strongly correlated with the frequency of COVID-19-SA patients observed in each IRSA center (Figure 1b), suggesting that patients with SA most likely contract the infection when high circulation of the virus within the area of residence is present. The lack of positive cases reported in Southern regions further proves this hypothesis, and demonstrates the efficacy of the lockdown measures adopted to contain the further spread of the virus.Our results also suggest no increased risk of contracting COVID-19 in SA treated with biologics compared to ICS-LABA alone. Although there is currently no strong evidence that biologics used in asthma might affect the risk of contracting COVID-19, new evidence suggests a protective effect of inhaled corticosteroids against viral entry by ACE2 receptor downregulation, that are usually prescribed at a high dose in SA (6), thus a possible explanation to the lack of observed differences in our cohort.Despite the severity of asthma and reported comorbidities, no ICU admissions were reported, and hospital admissions in COVID-19-SA subjects did not differ from the median rate observed in the same geographic areas (5). Furthermore, we could observe no difference in the median monthly hospitalization rate of SA patients in 2019 compared to 2020 in Lombardy region where both hospital-admitted subjects reside (0.97 vs 0.9%, IRSA data).Our result is consistent with recent literature, showing that asthma in Western countries was not associated with an increased hospitalization rate and ICU admissions due to COVID-19 (3,8). It is still debated if a protective effect of Th2-inflammation in a significant proportion of asthma sufferers (7), or concomitant anti-inflammatory therapy could be the reasons for such outcomes (6). However, if asthma patients with COVID-19 require intubation, the duration of hospitalization was shown to be longer than average (8).As for the role of biologics in COVID-19 disease progression, we could not observe an increase in hospital admissions in patients with SA treated with biologics compared to the general population, with the majority isolating at home and requiring no additional treatment. Considering that, in areas with high prevalence of SARS-CoV-2 infection, 68.2% of SA subjects were treated with either omalizumab or mepolizumab, our observations further prove the safety of biologics during the COVID-19 pandemic.Lastly, we did not observe any deaths in our cohort, but we speculate that this outcome is most likely due to the small sample size and younger average age. In fact, advanced age seems to be the most determining risk factor on mortality due to COVID-19 compared to other causes. (9)Taken together, our results point at a neutral role of SA in the COVID-19 disease course and hospital admissions. One major strengths of our study is that, by using a fast and inexpensive tool, we could outline the salient features of severe asthma and COVID-19 at a national level, while the major weakness is the limited number of SA subjects diagnosed with COVID-19, that could lead to sampling bias and low accuracy. Further confirmation of these results with an increased sample size is therefore warranted

To the Editor Since the end of February 2020 Italy, first non- Asian Country, has reported an ever increasing number of COronaVIrus Disease 19 (COVID-19) patients, which has reached over 200,000 confirmed Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2) infected subjects and resulted in more than 34000 deaths (data updated to June 19th, 20201).Patients with asthma are potentially more severely affected by by SARS-CoV-2 infection 2 and it is well established that respiratory viral infections are associated with severe adverse outcomes in patients with asthma, including increased risk of asthma exacerbation episodes 3. Nonetheless, according to the epidemiological studies published so far, chronic pulmonary diseases are not amongst the most common clinical conditions in COVID-19 patients4About 5-10% of entire asthma population, are severe asthmatics5 and one would expect increased vulnerability to SARS-CoV-2 infection, but no data is so fare available ti confirm this hypothesis.We investigated the incidence of COVID-19, describing its clinical course, in the population of the Severe Asthma Network in Italy (SANI), one of the largest registry for severe asthma worldwide6, and in an additional Center (Azienda Ospedaliero Univeristaria di Ferrara, Ferrara, Italy). All centers, have been contacted and inquired to report confirmed (i.e. patients with positive test result for the virus SARS-CoV-2 from analysis of nasopharyngeal or oropharyngeal swab specimens) or highly suspect cases of COVID-19 (i.e. patients with symptoms, laboratory findings and lung imaging typical of COVID-19 but without access to nasopharyngeal or oropharyngeal swab specimens because of clinical contingencies/emergency) among their cohorts of severe asthma. Demographic and clinical data of the entire cohort of severe asthmatics enrolled in the study and all reported cases of confirmed or suspect cases of COVID-19, have been obtained from the registry platform and collected from the additional Center. Additional data about COVID-19 symptoms, treatment and clinical course have been collected for all cases reported.Ethical issues and statistical analysis are reported in the online supplementary material.Twenty-six (1.73%) out of 1504 severe asthmatics had confirmed (11 out of 26) or highly suspect COVID-19 (15 out 26); eighteen (69.2%) were females and mean age was 56.2 ± 10 years. The geographical distribution of COVID-19 cases is presented in Figure 1.Nine (34.6%) infected patients experienced worsening of asthma during the COVID-19 symptomatic period; four of them needed a short course of oral corticosteroids for controlling asthma exacerbation symptoms.The most frequent COVID-19 symptoms reported were fever (100% of patients), malaise (84.6%), cough (80.8%), dyspnea (80.8%), headache (42.3%) and loss of smell (42.3%). Four patients (15.3%) have been hospitalized, one of which in intensive care unit; among hospitalized patients, two (7.7%) died for COVID-19 interstitial pneumonia. No deaths have been reported among the non-hospitalized patients.Severe asthmatics affected by COVID-19, had a significantly higher prevalence of non-insulin-dependent diabetes mellitus (NIDDM) compared to non-infected severe asthma patients (15.4% vs 3.8%, p=0.002; odds ratio: 4.7). No difference was found in other comorbidities (including rhinitis, chronic rhinosinusitis with or without nasal polyps, bronchiectasis, obesity, gastroesophageal reflux, arterial hypertension, cardiovascular diseases).Twenty-one patients with COVID-19 were on biological treatments: 15 (71%) were on anti-IL-5 or anti-IL5R agents (Mepolizumab n= 13; Benralizumab n=2 - counting for the 2.9% of all severe asthmatics treated with anti-IL5 in our study population) and 6 (29%) were on anti IgE (Omalizumab - 1.3% of all severe asthmatics treated with omalizumab in our study population).Table I summarizes demographic and clinical characteristics of the 26 COVID-19 patients.In conclusion, in our large cohort of severe asthmatics, COVID-19 was infrequent, not supporting the concept of asthma as a particularly susceptible condition to SARS-COV2 infection 2. This is in line with the first published large epidemiological data on COVID-19 patients, in which asthma is under-reported as comorbidity4. The COVID-19 related mortality rate in our cohort of patients was 7.7%, lower than the COVID-19 mortality rate in the general population (14.5% in Italy 1). These findings suggest that severe asthmatics are not at high risk of the SARS-CoV-2 infection and of severe forms of COVID-19. There are potentially different reasons for this. Self-containment is the first, because of the awareness of virus infections acting as a trigger for exacerbations, and therefore they could have acted with greater caution, scrupulously respecting social distancing, lockdown and hygiene rules of prevention, and being more careful in regularly taking asthma medications.Another possible explanation stands in the intrinsic features of type-2 inflammation, that characterizes a great proportion of severe asthmatics. Respiratory allergies and controlled allergen exposures are associated with significant reduction in angiotensin-converting enzyme 2 (ACE2) expression 7, the cellular receptor for SARS-CoV-2. Interestingly, ACE2 and Transmembrane Serine Protease 2 (TMPRSS2) (another protein mediating SARS-CoV-2 cell entry) have been found highly expressed in asthmatics with concomitant NIDDM8, the only comorbidity that was more frequent reported in our COVID-19 severe asthmatics.The third possible explanation refers to the possibility that inhaled corticosteroids (ICS) might prevent or mitigate the development of Coronaviruses infections. By definition, patients with severe asthma are treated with high doses of ICS 5 and this may have had a protective effect for SARS-CoV-2 infection.Noteworthy, among the patients of our case-series of severe asthmatics with COVID-19, the proportion of those treated anti-IL5 biologics was higher (71%) compared to the number of patients treated with anti-IgE (29%). Although the number of cases is too small to draw any conclusion, it is tempting to speculate that different biological treatments can have specific and different impact on antiviral immune response. In addition we may speculate of the consequence of blood eosinophils reduction: eosinopenia has been reported in 52-90% of COVID-19 patients worldwide and it has been suggested as a risk factor for more severe COVID-19 9.In conclusion, in our large cohort of severe asthmatics only a small minority experienced symptoms consistent with COVID-19, and these patients had peculiar clinical features including high prevalence of NIDDM as comorbidity. Further real-life registry-based studies are needed to confirm our findings and to extend the evidence that severe asthmatics are at low risk of developing COVID-19.

Objective: In this study, we aimed to determine the prevalence and clinical importance of vitamin D deficiency in children and adolescent patients who were hospitalized with the diagnosis of COVID-19. Material and Methods: 40 patients who were diagnosed to have COVID-19 and hospitalized with the real-time reverse transcription polymerase chain reaction (RT-PCR) method were included. The control group consisted of 45 healthy patients with normal vitamin D levels. The age of admission, clinical and laboratory data, and 25-hydroxycholecalciferol (25-OHD) and parathormone (PTH) levels were recorded. Those with vitamin D levels which are below 20 ng/ml were determined as Group 1 and those with ≥20 ng/ml as Group 2. Results: The median levels of vitamin D level were 13.14 (4.19-69.28) in the group of patients with COVID-19 and 34.81(3.8-77.42) in the control group. Compared to the control group, there was a statistically significantly lower vitamin D level (p <0.001) in the COVID-19 patient group. At admission, the symptom of fever was significantly higher in Group 1 than in Group 2 (p =0.038). The distribution of disease severity according to vitamin D levels was not found significantly different. In conclusion; our study is the first to evaluate vitamin D levels and its relationship with clinical findings in pediatric patients diagnosed with COVID-19. There are significantly lower levels of vitamin D in children with COVID-19 than those in the control group. This shows that vitamin D, which is effective in the immunological mechanism, also has an effect in the physiopathology of the disease.

Coronavirus disease 2019 (COVID-2019) is a viral disease which is declared as a pandemic by WHO. This disease is posing a global threat, and almost every country in the world is now affected by this disease. Currently, there is no vaccine for this disease and because of this containing COVID-19 is not an easy task. It is noticed that elderly people got severely affected by this disease specially in Europe. In the present paper, we propose and analyze a mathematical model for COVID-19 virus transmission by dividing whole population in old and young groups. We find disease-free equilibrium and the basic reproduction number ($R_0$). We estimate the parameter corresponding to rate of transmission and rate of detection of COVID-19 using real data from Italy and Spain by least square method. We also perform sensitivity analysis to identify the key parameters which influence the basic reproduction number and hence regulate the transmission dynamics of COVID-19. Finally, we extend our proposed model to optimal control problem to explore the best cost-effective and time-dependent control strategies that can reduce the number of infectives in a specified interval of time.

COVID-19, the illness caused by SARS-CoV-2, has a wide-ranging clinical spectrum that, in the worst-case scenario, involves a rapid progression to severe acute respiratory syndrome and even death. Epidemiological data show that “diabesity”, the association of obesity and diabetes, is among the main risk factors associated with high morbidity and mortality. The increased susceptibility to SARS-CoV-2 infection documented in diabesity argues for initial defects in defense mechanisms, most likely due to an elevated systemic metabolic inflammation (“metaflammation”). The NLRP3 inflammasome is a master regulator of metaflammation and has a pivotal role in the pathophysiology of diabesity. Here we discuss the most recent findings suggesting contribution of NLRP3 inflammasome to the increase in complications in COVID-19 patients with diabesity. We also review current pharmacological strategies for COVID-19, focusing on treatments whose efficacy could be due, at least in part, to interference with the activation of the NLRP3 inflammasome.

The goal of this study was to assess the clinical effectiveness and safety profile of the COVID-19 treatment protocol (containing both hydroxychloroquine (HCQ) and azithromycin) in an Iraqi specialized hospital. Methods: This prospective study used a pre- and post-intervention design without a comparison group. The intervention was routine Ministry of Health (MOH) approved management of COVID-19 for all patients. The study was conducted in a public healthcare setting in Baghdad, Iraq from March 1st to May 25, 2020. The study outcome measures included the changes in clinical and biochemical parameters during the hospitalization period. Paired t-test and Chi-square test were used to compare the measures of vital signs, lab tests and symptoms before and after treatment. Results: The study included 161 patients who were admitted with positive RT-PCR and clinical symptoms of COVID-19. In terms of severity, 53 (32.9%) patients had mild condition, 47 (29.2%) had moderate condition, 35 (21.7%) had severe condition, and 26 (16.1%) had critical condition. Most patients (84.5%) recovered and were discharged without symptoms after testing negative with RT-PCR, while 11 (6.8%) patients died during the study period. The signs and symptoms of COVID-19 were reduced significantly in response to therapy regimen containing HCQ and azithromycin. The most common reported side effects were stomach pain, hypoglycemia, dizziness, itching, skin rash, QT prolongation, arrhythmia, and conjunctivitis. Conclusions: This natural trial showed that COVID-19 regimen containing both HCQ and azithromycin can be helpful to promote recovery of most patients and reduced their signs and symptoms significantly. It also shows some manageable side effects mostly those related to heart rhythm. In the absence of FDA-approved medications to treat COVID-19, the repurposing of HCQ and azithromycin to control the disease signs and symptoms can be useful.