Concentrations of Soluble Angiotensin Converting Enzyme 2 (sACE2) in Children and Adults with and without COVID-19.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), causing the coronavirus disease 2019 (COVID-19) pandemic, leads to illness and death. Various risk factors for a severe course, such as higher age, male gender and pre-existing illnesses are known. However, pathophysiological risk factors are largely unclear. Notably, the mild course of disease in children is conspicuous. Angiotensin converting enzyme 2 (ACE2) serves as a receptor for SARS-CoV-2 and is a key enzyme in infection. Differences in the distribution of ACE2 can provide insights into different courses of COVID-19. Our aim was to elucidate the role of ACE2 as a pathophysiological risk factor by measuring soluble ACE2 (sACE2) via ELISA in blood samples (lithium-heparin-plasma or serum) of 367 individuals including children and adults with and without COVID-19. sACE2-levels were compared between the groups according to age and sex. In adults and children with COVID-19, sACE2-concentrations are significantly higher compared to healthy individuals. sACE2-levels increase with age and are lower in children compared to adults with COVID-19. Sex doesn't significantly influence sACE2-concentration. It remains unclear whether sACE2 concentrations increase because of the infection and what factors could influence this response. In conclusion, the increase of sACE2-concentration with age could indicate that ACE2 concentrations mirror increased COVID-19 severity.

Continuous positive airway pressure as a useful tool in coronavirus disease 2019-related acute hypoxemic respiratory failure: experience from three UK hospitals

Background Many coronavirus disease 2019 (COVID-19) patients suffering acute hypoxemic respiratory failure (AHRF), fail to respond to conventional oxygen therapy (COT). Subsequently, some centers escalate to continuous positive airway pressure (CPAP), while others resort directly to invasive mechanical ventilation (IMV). We conducted a study to compare the use of CPAP versus COT alone in COVID-19-related AHRF. Patients and methods It is a retrospective cohort study of laboratory-confirmed COVID-19 patients suffering AHRF and deemed eligible for IMV escalation at three university hospitals (United Kingdom) during a 3-month period. The primary endpoint was the need for intubation and the secondary endpoint was 60-day mortality. Results In total, 174 patients were included. In total, 84 patients received CPAP (group 1) and 90 received only COT (group 2). Both groups had comparable demographic criteria and disease severity. There was nonsignificant reduction in the need for IMV when using CPAP compared with COT alone (50 vs. 76.6%, P=0.866). Sixty-day mortality was significantly higher in group 2 (25 vs. 37.8%, P=0.02). COT as stand-alone therapy for COVID-19 patients (group 2) was associated with a significant increased relative risk of death (relative risk 2.14, 95% confidence interval 1.39–3.29) corresponding to a number needed to treat of 3.74 (95% confidence interval 2.47–7.73). Among patients who progressed to IMV, there was no difference in the risk of mortality between the two groups. Conclusion Introducing CPAP rather than escalating FiO2 or endotracheal intubation in COVID-19 cases refractory to COT is safe and associated with improved mortality. Clinical trials are needed to guide the optimum timing and selection of patients most likely to benefit.

Autoantibodies against interleukin-1 receptor antagonist in multisystem inflammatory syndrome in children: a multicentre, retrospective, cohort study.

Background: Multisystem inflammatory syndrome in children (MIS-C) is a rare but serious complication of infection with SARS-CoV-2. A possible involvement of pathogenetically relevant autoantibodies has been discussed. Recently, neutralising autoantibodies against inflammatory receptor antagonists progranulin and interleukin-1 receptor antagonist (IL-1Ra) were found in adult patients with critical COVID-19. The aim of this study was to investigate the role of such autoantibodies in MIS-C. Methods: In this multicentre, retrospective, cohort study, plasma and serum samples were collected from patients (0-18 years) with MIS-C (as per WHO criteria) treated at five clinical centres in Germany and Spain. As controls, we included plasma or serum samples from children with Kawasaki disease, children with inactive systemic juvenile idiopathic arthritis, and children with suspected growth retardation (non-inflammatory control) across four clinical centres in Germany and Spain (all aged ≤18 years). Serum samples from the CoKiBa trial were used as two further control groups, from healthy children (negative for SARS-CoV-2 antibodies) and children with previous mild or asymptomatic COVID-19 (aged ≤17 years). MIS-C and control samples were analysed for autoantibodies against IL-1Ra and progranulin, and for IL-1Ra concentrations, by ELISA. Biochemical analysis of plasma IL-1Ra was performed with native Western blots and isoelectric focusing. Functional activity of the autoantibodies was examined by an in vitro IL-1ß-signalling reporter assay. Findings: Serum and plasma samples were collected between March 6, 2011, and June 2, 2021. Autoantibodies against IL-1Ra could be detected in 13 (62%) of 21 patients with MIS-C (11 girls and ten boys), but not in children with Kawasaki disease (n=24; nine girls and 15 boys), asymptomatic or mild COVID-19 (n=146; 72 girls and 74 boys), inactive systemic juvenile idiopathic arthritis (n=10; five girls and five boys), suspected growth retardation (n=33; 13 girls and 20 boys), or in healthy controls (n=462; 230 girls and 232 boys). Anti-IL-1Ra antibodies in patients with MIS-C belonged exclusively to the IgG1 subclass, except in one patient who had additional IL-1Ra-specific IgM antibodies. Autoantibodies against progranulin were only detected in one (5%) patient with MIS-C. In patients with MIS-C who were positive for anti-IL-1Ra antibodies, free plasma IL-1Ra concentrations were reduced, and immune-complexes of IL-1Ra were detected. Notably, an additional, hyperphosphorylated, transiently occurring atypical isoform of IL-1Ra was observed in all patients with MIS-C who were positive for anti-IL-1Ra antibodies. Anti-IL-1Ra antibodies impaired IL-1Ra function in reporter cell assays, resulting in amplified IL-1ß signalling. Interpretation: Anti-IL-1Ra autoantibodies were observed in a high proportion of patients with MIS-C and were specific to these patients. Generation of these autoantibodies might be triggered by an atypical, hyperphosphorylated isoform of IL-1Ra. These autoantibodies impair IL-1Ra bioactivity and might thus contribute to increased IL-1ß-signalling in MIS-C. Funding: NanoBioMed fund of the University of Saarland, José Carreras Center for Immuno and Gene Therapy, Dr Rolf M Schwiete Stiftung, Staatskanzlei Saarland, German Heart Foundation, Charity of the Blue Sisters, Bavarian Ministry of Health, the Center for Interdisciplinary Clinical Research at University Hospital Münster, EU Horizon 2020.

Autoantibodies against IL-1-receptor-antagonist in multisystem inflammatory syndrome in children (preprint)

Multisystem inflammatory syndrome in children (MIS-C or PIMS) is a rare but serious complication after an infection with SARS-CoV-2. A possible involvement of pathogenetically relevant autoantibodies has been discussed. Recently neutralizing autoantibodies against anti-inflammatory receptor antagonists progranulin (PGRN) and IL-1-receptor antagonist (IL-1-Ra) were discovered in adult patients with critical COVID-19. Plasma of an index case with severe PIMS/MIS-C was analyzed for autoantibodies against IL-1-Ra and PGRN. The study was extended by a case series of 12 additional patients. In addition to ELISA for of antibodies, IL-1-Ra plasma levels were determined and IL-1-Ra was analyzed by Western-blot and isoelectric focusing. Functional activity of the autoantibodies was examined in vitro with IL-1{beta} reporter assays. Antibodies against IL-1-Ra could be detected in 10 of 13 (76.9%) patients with PIMS/MIS-C, but not in controls. In contrast to critical COVID-19 in adults, no IL-1-Ra antibodies of the IgM class were detected in PIMS/MIS-C. IL-1-Ra-antibodies exclusively belonged to IgG1. No antibodies directed against PGRN were detected. Western blots and ELISA showed a concomitant reduction of free IL-1-Ra plasma levels in the presence of IL-1-Ra-antibodies. The antibodies inhibited IL-1-Ra function in IL-1{beta} reporter cell assays. Notably, an additional, hyperphosphorylated, transiently occurring atypical isoform of IL-1-Ra was observed in all IL-1-Ra autoantibody-positive patients. To conclude, IL-1-Ra autoantibodies were observed in high frequency in children with PIMS/MIS-C. They may represent a diagnostic and pathophysiologically relevant marker for PIMS/MIS-C. Their generation is likely to be triggered by an atypical, hyperphosphorylated isoform of IL-1-Ra.

Determinants of soluble angiotensin-converting enzyme 2 concentrations in adult patients with complex congenital heart disease.

BACKGROUND: Angiotensin-converting enzyme (ACE) 2 is known to be a functional receptor for SARS-CoV-2 in the current pandemic. Soluble ACE2 (sACE2) concentrations are elevated in patients with various cardiovascular disorders including heart failure. METHODS: In a total of 182 consecutive adult patients with complex congenital heart disease (CHD) and 63 healthy controls, sACE2 concentrations were measured in serum using the Human ACE2® assay by Cloud-Clone Corporation and associated with clinical, laboratory and echocardiographic parameters. RESULTS: Median sACE2 levels were increased in patients with complex CHD as compared to healthy controls (761.9 pg/ml vs 365.2 pg/ml, p < 0.001). Moreover, sACE2 concentrations were significantly elevated in patients with a higher NYHA class ≥ III (1856.2 pg/ml vs 714.5 pg/ml in patients with NYHA class I/II, p < 0.001). Using linear regression analysis, higher sACE2 levels were associated with a higher NYHA class ≥ III, more severe CHD, a morphological left systemic ventricle, higher creatinine and the use of mineralocorticoid receptor antagonists (MRA) in the univariable model. The use of ACE inhibitors or angiotensin receptor blockers (ARB) was associated with lower sACE2 levels. In the multivariable model, higher sACE2 levels were independently associated with a higher NYHA class ≥ III (p = 0.002) and lower sACE2 levels with the use of ACE inhibitors or ARB (p = 0.001). CONCLUSION: Soluble ACE2 concentrations were significantly increased in all types of complex CHD with highest levels found in patients with NYHA class ≥ III. Moreover, a higher NYHA class ≥ III was the most significant determinant that was independently associated with elevated sACE2 concentrations.

Identification and prediction of time-varying parameters of COVID-19 model: a data-driven deep learning approach (preprint)

Data-driven deep learning provides efficient algorithms for parameter identification of epidemiology models. Unlike the constant parameters, the complexity of identifying time-varying parameters is largely increased. In this paper, a variant of physics-informed neural network (PINN) is adopted to identify the time-varying parameters of the Susceptible-Infectious-Recovered-Deceased model for the spread of COVID-19 by fitting daily reported cases. The learned parameters are verified by utilizing an ordinary differential equation solver to compute the corresponding solutions of this compartmental model. The effective reproduction number based on these parameters is calculated. Long Short-Term Memory (LSTM) neural network is employed to predict the future weekly time-varying parameters. The numerical simulations demonstrate that PINN combined with LSTM yields accurate and effective results.

TEACHING MUST GO ON: flexibility and advantages of peer assisted learning during the COVID-19 pandemic for undergraduate medical ultrasound education - perspective from the "sonoBYstudents" ultrasound group.

Background: Facing the global COVID-19 pandemic University teaching has been digitalized and German medical faculties took great effort to offer curricular contents online as they agreed that semesters during pandemic should not be suspended. Skill training is an essential part of medical education and cannot be fully digitalized nor should it be omitted. The pandemic demonstrates that skills like ultrasound are essential when treating critical ill patients. Medical faculties use peer assisted learning (PAL) concepts to teach skills, like ultrasound through specially trained student tutors. Aim: Here, we would like to share our experiences and elaborate how ultrasound teaching can be safely performed during the pandemic with an emphasis on adjustment of an existing PAL teaching concept. Method: At the hospital of Saarland University, we implemented a PAL teaching concept for abdominal, including emergency, ultrasound, and echocardiography, called "sonoBYstudents" to teach sonography to undergraduate medical students. Students are generally taught in small groups of 5 people in 90min sessions over a time of 8 weeks with an objective structured clinical exam (OSCE) at the end of the course program. Each semester nearly 50 students are taught in abdominal and emergency ultrasound and 30 students in echocardiography. Over five years, more than 600 students have been taught with at least 30 students being trained as student tutors. Given the pandemic, course size, course interval and total course time and total course time were adapted to the hygienic precautions. Results: 45 and 30 students were taught in abdominal ultrasound and echocardiography respectively achieving their learning goals measured via OSCE at the end of the courses. OSCE results were the same when compared to previous semesters. Conclusion: PAL as a teaching concept lives out of sustained educational strategies like practical and didactical trainings and an ongoing recruitment of new student tutors. Suspending PAL and its skill teaching would require starting from the beginning which is a time and cost consuming process. With sonoBYstudents we were able to demonstrate that an existing PAL concept can, with some effort, be adjusted to changing teaching circumstances. Apart from this ultrasound is a non-omittable part of medical skill training with easily appliable hygienic precautions during teaching sessions.

CPAP as a useful tool in COVID-19 related Acute Hypoxemic Respiratory Failure: Experience from 3 UK Hospitals (preprint)

Introduction: Severe acute hypoxemic respiratory failure (AHRF) in COVID-19 pneumonia is associated with a high mortality rate, resulting in mounting pressures on intensive care units worldwide. Different oxygenation management protocols are used in different centres. Most centres switch patients who fail to oxygenate adequately using conventional oxygen therapy (COT) methods to non-invasive positive pressure ventilation (NIPPV), usually continuous positive airway pressure (CPAP). Other centres resort to invasive mechanical ventilation (IMV) directly, without a trial of NIPPV. In this trial, we aim to compare the efficacy of different approaches in managing COVID-related AHRF, and ascertain if CPAP therapy reduces the need for IMV. Methods: We carried out a retrospective cohort study on patients with laboratory-confirmed COVID-19 at three university hospitals in Essex, United Kingdom. We included all patients with significant AHRF (defined as needing oxygen therapy FiO2 more than 0.4 to maintain an oxygen saturation of 92%) who were deemed eligible for IMV escalation during a 3-month period (1st March to 31st May 2020).Results: Out of 174 patients who met the criteria, 84 patients received CPAP (Group 1). Half needed intubation (n=42). 90 patients did not have a CPAP trial (Group 2). 76.6% needed intubation (n=69). No difference was found between the two groups in demographic criteria or disease severity. Our results show a significant difference in 60-day mortality between group 1 and 2 (25% versus 37.8%, p=0.02). COT as standalone therapy for COVID-19 patients (group 2) was associated with a trend of more increased risk of intubation and an increased relative risk of death (RR 2.14, 95% CI 1.39 to 3.29). This corresponds to a number needed to treat (NNT) of 3.74 (95% CI 2.47 to 7.73). Patients in group 1 who failed CPAP trial and required intubation did not have an increased risk of mortality when compared to group 2 patients who required intubation.Conclusion: Our results support introducing CPAP rather than escalating FiO2 in cases refractory to COT. Our study suggests CPAP can be safely used to treat patients with AHRF. Clinical trials are needed to guide recommendations for optimum timing and selection of patients most likely to benefit.

A review on Malaysia's solar energy pathway towards carbon-neutral Malaysia beyond Covid'19 pandemic.

COVID'19 pandemic has devastated several industries and solar energy is no exception. In its economic relief package, Malaysia has announced approximately US$ 2.9 billion in expenditure for the installation of new grids, LED street lights and rooftop solar panels. The Government will also open the tender for a 1400 MW solar power project in the year 2020, which is expected to generate 5 billion ringgit (US$1.1 billion) in investments. As these measures are intended to sustain the existing growth of solar energy potential in the country, it is vital to assess its status quo. Hence, this paper aims to review the current status of renewable energy in Malaysia as well as the initiatives taken before the pandemic to promote solar photovoltaic (PV) technology to meet the energy demands through the low-carbon pathway.