Background: Bacillus Calmette-Guérin (BCG) vaccination policies of countries are postulated to have effect on the course of coronavirus disease 2019 (COVID-19) pandemic. Methods: Retrospective cross-sectional study was conducted between March 11-June 10, 2020 in a chest clinic in a state hospital in Istanbul,Turkey. Adults with diagnosis of COVID-19 pneumonia confirmed with severe acute respiratory syndrome coronavirus 2 polymerase chain reaction positivity in a nasopharyngeal sample and pulmonary infiltrates in computed chest tomography were included consecutively. Sociodemographic characteristics, body-mass index, smoking status, comorbid diseases, income rates, and BCG-vaccination status were compared between severe and mild patients with COVID-19 pneumonia. Results: Study population consisted of 123 adults (mean age, 49.7 years [standard deviation, 13.3 years]; 82 (66.7%) male). The proportion of BCG-vaccinated cases was significantly lower among severe patients than mild patients with COVID-19 pneumonia (68.5% vs 88.2%; p=.026). Mean age (54.0 ± 11.5 years vs 38.3 ±10.7 years; p <.001), diabetes rate (32.6% vs 5.9%; p=.002) and low-income (84.3% vs 52.9% p<.001) are higher in patients with severe COVID-19 pneumonia than in patients with mild COVID-19 pneumonia. Multivariate logistic regression analysis showed that increasing age (odds ratio [OR], 1.112; 95% confidence interval [CI], 1.058 – 1.169; p<.001) and low income (OR, 3.369; 95% CI, 1.074 – 10.570; p =.037) are associated with severe COVID-19 pneumonia. Conclusion: Clinical data does not support that being vaccinated with BCG is associated with disease severity in COVID-19 pneumonia. Age and low-income are the major predictors for disease severity.

Olfactory and gustatory dysfunctions are common presentations in COVID-19 patients. We present three patients who received smell and taste tests after recovery. The smell test suspected persistent impairment of olfactory function in these patients. The report proposes continued evaluation of olfactory function by a smell test in COVID-19 patients.

Background: The novel coronavirus disease (Covid-19) can progress with mild to moderate or self-limiting clinical findings in children. The aim of this study was to investigate the disease features of Covid-19 in Turkish children. Methods: Children diagnosed by the method of RT-PCR for Covid-19 at the Dicle University Department of Pediatric, between April and June 2020, were evaluated. Hospital records were investigated retrospectively. Results: One hundred and five patients children with the mean age of 108.64±65.61 were enrolled in this study. The most common cause of transmission in pediatric patients was contacting with a family member diagnosed with COVID-19 (n=91, 86.7%).The most common admission complaints were dry cough (n=17, 16.2%), fever (n=16, 15.2%), lassitude and fatigue (n=14, 13.3%) respectively. More than 95 % of all children with Covid-19 had asymptomatic, mild, or moderate cases. CRP was identified only independent factor associated with long duration of hospitalization. Conclusion: The results of this study show preliminary results of a study investigating the effect of Covid-19 on Turkish children. A clear understanding of the local epidemiology of corona virus infections and identification of risk factors is critical for the successful implementation of the prevention and control program.

Nitric oxide (NO) is a comprehensive regulator of vascular and airway tone. Endogenous NO produced by nitric oxide synthases regulates multiple signaling cascades, including activation of soluble guanylate cyclase to generate cGMP, relaxing smooth muscle cells. Inhaled NO is an established therapy for pulmonary hypertension, especially in neonates, and has been recently proposed for treatment of hypoxic respiratory failure and acute respiratory distress syndrome due to COVID-19. In this review, we summarize the effects of endogenous and exogenous NO on protein S-nitrosylation, which is the selective and reversible covalent attachment of a nitrogen monoxide group to the thiol side chain of cysteine. This post-translational modification targets specific cysteines based on the acid/base sequence of surrounding residues, with significant impacts on protein interactions and function. S-nitrosothiol (SNO) formation is tightly compartmentalized and enzymatically controlled, but also propagated by non-enzymatic transnitrosylation of downstream protein targets. Redox-based nitrosylation and denitrosylation pathways dynamically regulate the equilibrium of SNO-proteins. We review the physiological roles of SNO proteins, including nitrosohemoglobin and autoregulation of blood flow through hypoxic vasodilation, and pathological effects of nitrosylation including inhibition of critical vasodilator enzymes; and discuss the intersection of NO source and dose with redox environment, in determining the effects of protein nitrosylation.

A document by Jacqueline Montoya. Click on the document to view its contents.

Abstract. The Controlled Human Infection Model and specifically the Human Viral Challenge Model are not dissimilar to standard clinical trials while adding another layer of complexity and safety considerations. The models deliberately infect volunteers, with an infectious challenge agent (CA) to determine the effect of the infection and the potential benefits of the experimental interventions. The Human Viral Challenge Model studies can shorten the time to assess the efficacy of a new vaccine or treatment by combining this with the assessment of safety. The newly emerging SARS-COV-2 virus is highly contagious and the cause pandemic disease COVID-19. An urgent race in is on to develop a new vaccine against this virus in a timeframe never attempted before. The use of the Human Viral Challenge Model has been proposed to accelerate the development of the vaccine. In the early 2000’s the authors successfully developed a pathogenic Human Viral Challenge Model for another virus for which there was no effective treatment and established it to evaluate potential therapies and vaccines against Respiratory Syncytial Virus. The authors feel that the experience gained in the development of that model can help with the development of a COVID-19 HVCM and describe it here. Word count: 197

This letter is meant to inform the community of pediatricians/pediatric intensivists that we suspect SARS-CoV-2 to cause life-threatening bronchiolitis in infants and we therefore suggest maintaining a high level of suspicion of COVID-19, irrespective of an initially negative SARS-CoV-2 RT-PCR testing, when other causes of bronchiolitis are unidentifiable in young children.

Introduction. Locking the humanity in their homes, COVID-19 forced people to use the technology at hand to keep informed about the outbreak and to keep close to their loved ones. During this time, even if physical health is theoretically unaffected, keeping calm and sane can be challenging. The aim of this research was to evaluate whether exposure to COVID-19 information available in the digital space has a different impact on the mental condition of Romanian medical staff, compared to general population, particularly searching for depression and anxiety symptoms. Materials and methods. An online survey was conducted from April 6 to 16, 2020 within the Romanian users of Social Media platforms. The questionnaire assessed depression with the WHO-Five Well-Being Index, anxiety with the Generalized Anxiety Disorder Scale and Social Media exposure by asking how often the respondents saw COVID-19 related information on the most popular Social Media channels in Romania. Information about: gender, age, educational level, occupation, area of living and risk category was also collected. The risk categories were defined as no risk, medium risk, and medical staff. Results. Almost 90% of the 402 participants received daily through at least one Social Media channel information related to the COVID-19 outbreak. The Social Media Exposure significantly associated with the risk group only for Facebook and LinkedIn. However, exposure to information regarding COVID-19 was neither associated with anxiety nor depression. No significant association was identified neither between age class and self-assessed anxiety nor self-assessed depression. The self-assessment of depression was significantly more frequent as compared to self-assessment of anxiety. Conclusion. The results of this research are opposite to most of the already published literature. Depression and anxiety could not be correlated with the context of lockdown and excessive COVID-19-related information.

Background: The COVID19 pandemic gripped every nation’s healthcare system and provisions on all levels. In cardiac and aortic surgery, as it is with most specialities, elective surgeries were halted. Aims of the study: We captured reflections, contingencies, and current practices across of high-volume centres in cardiac and aortic surgery globally. We also aimed this study to assess decision on prioritization of the surgical patients, the need for personal protection equipment and choice of preoperative investigations in current dynamic and fluid climate. Methods: A validated web-based questionnaire was constructed and was circulated to the international surgeons amongst high volume cardiac and aortic surgery centres. Their intrinsic feedback on decision making, impact of the lockdown and perspectives for the future ahead us all were noted. Mixed method approach was constructed. Qualitative data analysis was introduced to signify the impact globally. Results: Overall, 23 centers from 18 countries participated in this international study. 91.7% of the respondents stopped operating on elective patients during the pandemic. Majority of the surgeons agreed that acute aortic dissection (87.1%) should be operated as emergency procedure and stable triple vessel disease (87.1%) to be considered as elective procedure. Three-fifth (60%) of the respondents relied on CT chest as a preoperative screening modality. Conclusion: In the present climate where there is paucity of evidence, this will give an interim consensus for the cardiac surgeons. With the increase in cumulative number of COVID19 patients, careful utilization of the resources regarding hospital beds and manpower is of paramount importance.

The current COVID-19 global pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) of probable bat origin, has highlighted the ongoing need for a One Health response to emerging zoonotic disease events, which are significantly increasing over time. Understanding the human-animal interface and its relevance to disease transmission remains a critical control point for many emerging zoonoses. Determination of the susceptibility of various animal species to infection with SARS-CoV-2 and the role of animals in the epidemiology of the disease will be critical to informing appropriate human and veterinary public health responses to this pandemic. A scoping literature review was conducted to collect, evaluate and present the available research evidence regarding SARS-CoV-2 infections in animals. Experimental studies have successfully demonstrated SARS-CoV-2 infection and transmission in cats, ferrets, hamsters, bats and non-human primates under experimental settings. Dogs appear to have limited susceptibility to SARS-CoV-2, while other domestic species including pigs and poultry do not appear susceptible. Naturally occurring SARS-CoV-2 infections in animals appear uncommon, with 14 pets, 8 captive big cats and an unreported number of farmed mink testing positive to date. Infections typically appear asymptomatic in dogs, while clinical signs of respiratory and/or gastrointestinal disease tend to be mild to moderate in felines, and severe to fatal in mink. Most animal cases have been infected by close contact with COVID-19 patients. In domestic settings, viral transmission is self-limiting, however in high density animal environments there can be sustained between-animal transmission. To date, two potential cases of animal-to-human transmission are being investigated, on infected mink farms. Given the millions of COVID-19 cases worldwide and ongoing potential for further zoonotic and anthroponotic viral transmission, further research and surveillance activities are needed to definitively determine the role of animals in community transmission of SARS-CoV-2.

In the context of the current COVID-19 pandemic, what are the lessons clinical pharmacology could learn to improve our teaching practice and involvement in research and ethics committees to make sure we are better prepared for the next emergency. Is there something in the light of the hydroxychloroquine hype that we as clinical pharmacologists or our professional societies could have done better? We propose updating the way we teach about drug development, rules and ethics of off-label prescribing and critical appraisal of primary sources when guidelines and top-level evidence are not available. Clinical pharmacology should play a leading role in the future re-definition of processes and guidelines for emergencies such as the one we faced in 2020.

There is growing evidence that climatic factors could influence the evolution of the current COVID-19 pandemic. Here, we build on this evidence base, focusing on the southern hemisphere summer and autumn period. The relationship between climatic factors and COVID-19 cases in New South Wales, Australia was investigated during both the exponential and declining phases of the epidemic in 2020, and in different regions. Increased relative humidity was associated with decreased cases in both epidemic phases, and a consistent negative relationship was found between relative humidity and cases. Overall, a decrease in relative humidity of 1% was associated with an increase in cases of 7-8%. Overall, we found no relationship with between cases and temperature, rainfall or wind speed. Information generated in this study confirms humidity as a driver of SARS-CoV-2 transmission.

Background and Purpose. Since the onset of COVID-19 many clinical trials of drugs and/or vaccines are continuing and new ones are introduce daily. Yet the international research process failed to develop a preventative vaccine or potent therapeutic drugs for relieving the severity of the disease. Therefore, at present the best recommendation to people to slow the spread of the disease is; please stay at home and maintain social distancing! Experimental approach. Many aspects of pharmacotherapeutic mechanism of action of some previously approved drugs with anti-inflammatory effects, such as colchicine, in various disorders is not fully understood. Therefore, many potential therapeutic uses for these drugs and its analogues can be imagined. In this hypothesis article, an attempt has been made to evaluate some potential therapeutic effects of colchicine that may be benefit against COVID-19. Key Results. Prophylactic therapy with colchicine regulates the innate inflammatory response by blocking intracellular signaling pathways. This can inhibit respiratory alveolar destruction following COVID-19 pneumonia, which is the main cause of ARDS and death in these patients. Conclusion and Implications Since the macrophage and granulocytes are the main pro-inflammatory mediators in the lung, it seems application of therapeutic doses of colchicine, before the onset of respiratory problems, will protect the lung against severe damages and respiratory failure in COVID-19 patients. Obviously, many clinical trials are required to prove the validity of this claim.

Dear Dr Harky et. al,We appreciate your inquiry regarding our case report. Dr Harky et. al suggested that TEVAR for a Marfan patient could be an unnecessary approach even during the COVID-19 pandemic.We believe in this particular case, the endovascular approach was fully justified as the patient had clear signs of end organ ischemia at presentation. He presented with extreme right leg ischemia with diffuse numbness. There was no detectable distal arterial flow of the right extremity by a Doppler and physical evaluation. Contrast computed tomography scan showed a completely occluded right common iliac artery and diminished flow to the right renal and celiac arteries due to the compression of the true lumen from the false lumen. Preoperative creatinine was elevated to 1.2 mg/dl. She was also suffering ongoing right kidney malperfusion.It was during the time when COVID-19 epidemic started spreading rapidly in New York City. Our hospital beds were filled with COVID-19 patients and there was a shortage of medical supplies with no ventilators immediately available. It was important to reduce exposure of the individual to the hospital environment and minimize length of stay and ventilator needs. As such, we chose to proceed with TEVAR to minimize the risk of lung injury which can occur in open repair. Postoperative respiratory failure is a major issue in open thoracic aortic repair [1]. The patient did not have a risk of respiratory comorbidities but we believed that this pandemic placed all patients at risk for contracting COVID-19 and subsequent acute respiratory distress [2].Due to the high risk of spinal cord ischemia in this particular patient, we performed TEVAR with a distal bare metal component to preserve the blood flow into spinal cord arteries [3]. The initial clinical treatment plan was to perform the TEVAR as a bridge to open repair. We obviously will need to follow-up with her carefully and if any signs of failure of TEVAR is detected, open repair will ultimately be required.Dr Harky et. al suggested axillary femoral artery bypass to rescue the ischemic leg, however, this patient also suffered malperfsuion of the renal and celiac arteries, so further intervention was required.Thank you for your insightful suggestions.References1) Khan FM, Naik A, Hameed I, et al. Open repair of descending thoracic and thoracoabdominal aortic aneurysms: a meta-analysis. Ann Thorac Surg . 2020;S0003-4975(20)30865-1.2) Bai Y, Yao L, Wei T, et al. Presumed Asymptomatic Carrier Transmission of COVID-19. JAMA.  2020;323:1406–7.3) Lombardi JV, Cambria RP, Nienaber CA, et al. Five-year results from the study of Thoracic Aortic Type B Dissection Using Endoluminal Repair (STABLE I) study of endovascular treatment of complicated type B aortic dissection using a composite device design. J Vasc Surg. 2019; 70:1072-81.

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.

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]. 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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. 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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.