TMPRSS2 gene polymorphism common in East Asians confers decreased COVID-19 susceptibility.

COVID-19 has a wide range of clinical presentations, and the susceptibility to SARS-CoV-2 infection and the mortality rate also vary by region and ethnicity. Here, we found that rs12329760 in the TMPRSS2 gene, a missense variant common in East Asian populations, contributes to protection against SARS-CoV-2 infection. TMPRSS2 is a protease responsible for SARS-CoV-2 entry and syncytium formation. rs12329760 (c.478G>A, p. V160M) was associated with a reduced risk of moderate symptoms. The enzymatic activity of Met160-TMPRSS2 was lower than that of Val160-TMPRSS2, and thus the viral entry and the syncytium formation of SARS-CoV-2 were impaired. Collectively, these results indicate that the genetic variation in TMPRSS2, which is common in East Asians, is one of the molecular determinants of COVID-19 susceptibility.

Consequences of Social Distancing Measures During the COVID-19 Pandemic First Wave on the Epidemiology of Children Admitted to Pediatric Emergency Departments and Pediatric Intensive Care Units: A Systematic Review.

Objectives: To synthesize knowledge describing the impact of social distancing measures (SDM) during the first wave of the COVID-19 pandemic on acute illness in children by focusing on the admission to pediatric emergency departments (PED) and pediatric intensive care units (PICU). Methods: We searched Cochrane Database of Systematic Reviews, Cochrane Controlled Trials Register, EPOC Register, MEDLINE, Evidence-Based Medicine Reviews, EMBASE, WHO database on COVID-19, Cochrane Resources on COVID-19, Oxford COVID-19 Evidence Service, Google Scholar for literature on COVID-19 including pre-print engines such as medRxiv, bioRxiv, Litcovid and SSRN for unpublished studies on COVID-19 in December 2020. We did not apply study design filtering. The primary outcomes of interest were the global incidence of admission to PICU and PED, disease etiologies, and elective/emergency surgeries, compared to the historical cohort in each studied region, country, or hospital. Results: We identified 6,660 records and eighty-seven articles met our inclusion criteria. All the studies were with before and after study design compared with the historical data, with an overall high risk of bias. The median daily PED admissions decreased to 65% in 39 included studies and a 54% reduction in PICU admission in eight studies. A significant decline was reported in acute respiratory illness and LRTI in five studies with a median decrease of 63%. We did not find a consistent trend in the incidence of poisoning, but there was an increasing trend in burns, DKA, and a downward trend in trauma and unplanned surgeries. Conclusions: SDMs in the first wave of the COVID-19 pandemic reduced the global incidence of pediatric acute illnesses. However, some disease groups, such as burns and DKA, showed a tendency to increase and its severity of illness at hospital presentation. Continual effort and research into the subject should be essential for us to better understand the effects of this new phenomenon of SDMs to protect the well-being of children. Systematic Review Registration: Clinicaltrials.gov, identifier: CRD42020221215.

Investigation of predictors of bleeding complications in COVID-19 using rotational thromboelastometry (ROTEMⓇ): A retrospective study.

Background: Hemorrhagic complications in patients with coronavirus 19 disease (COVID-19) are infrequent but associated with a prognosis. This study aimed to elucidate the risk factors for bleeding complications in patients with COVID-19 using rotational thromboelastometry (ROTEM) parameters and blood tests performed at admission. Methods: In total, 31 patients with severe COVID-19 treated intensively at Saga University Hospital were included in this study. Patients were divided into two groups according to the presence or absence of hemorrhagic complications. Results from the blood tests performed at admission and during hospitalization, and ROTEM values acquired upon admission, were compared between the two groups. Results: There were significant differences in ROTEM values upon admission between the bleeding and non-bleeding groups. Receiver operating curve analysis showed that the area under the curve for prothrombin time international normalized ratio (PT-INR) and extrinsically-activated test with tissue factor (EXTEM) amplitude at 10 min (A10) were 0.82 (0.52-0.92) and 0.81 (0.58-0.93), respectively. Logistic regression analysis with PT-INR and EXTEM A10 as factors calculated an odds ratio of 1.94 (1.04-3.62) and EXTEM A10 0.86 (0.71-1.05) for bleeding complications occurrence. Conclusion: ROTEM may be a sensitive predictor for bleeding complications in patients with COVID-19.

Investigation of predictors of bleeding complications in COVID‐19 using rotational thromboelastometry (ROTEMⓇ): A retrospective study

BackgroundHemorrhagic complications in patients with coronavirus 19 disease (COVID‐19) are infrequent but associated with a prognosis. This study aimed to elucidate the risk factors for bleeding complications in patients with COVID‐19 using rotational thromboelastometry (ROTEM) parameters and blood tests performed at admission.MethodsIn total, 31 patients with severe COVID‐19 treated intensively at Saga University Hospital were included in this study. Patients were divided into two groups according to the presence or absence of hemorrhagic complications. Results from the blood tests performed at admission and during hospitalization, and ROTEM values acquired upon admission, were compared between the two groups.ResultsThere were significant differences in ROTEM values upon admission between the bleeding and non‐bleeding groups. Receiver operating curve analysis showed that the area under the curve for prothrombin time international normalized ratio (PT‐INR) and extrinsically‐activated test with tissue factor (EXTEM) amplitude at 10 min (A10) were 0.82 (0.52–0.92) and 0.81 (0.58–0.93), respectively. Logistic regression analysis with PT‐INR and EXTEM A10 as factors calculated an odds ratio of 1.94 (1.04–3.62) and EXTEM A10 0.86 (0.71–1.05) for bleeding complications occurrence.ConclusionROTEM may be a sensitive predictor for bleeding complications in patients with COVID‐19.

Analysis of Early Biomarkers Associated with the Development of Critical Respiratory Failure in Coronavirus Disease 2019 (COVID-19).

Certain biomarkers predict death due to acute respiratory distress syndrome in COVID-19 patients. We retrospectively analyzed biomarkers associated with time to mechanical ventilation for respiratory failure due to COVID-19 (time-to-mechanical ventilation) in 135 consecutive patients in our hospital. We analyzed biomarkers that were elevated immediately (at admission) and later (3 days after admission) using Cox proportional hazards regression analysis. Independent biomarkers of time-to-mechanical ventilation were high C-reactive protein (CRP), interleukin (IL)-6, and Krebs von den Lungen-6 (KL-6) concentrations at admission and elevated CRP, high-mobility group box-1 protein (HMGB-1), and d-dimer levels and low platelets 3 days after admission. Receiver operating characteristic analysis for detecting the association between independent biomarkers associated with time-to-event in multivariate analyses and the start of mechanical ventilation revealed that these biomarkers had area under the curve values higher than 0.700. The present study suggests that CRP was the only biomarker associated with time-to-mechanical ventilation both at admission and 3 days after admission. Moreover, IL-6 (an inflammatory cytokine), HMGB-1 (a late inflammatory mediator), and KL-6 (reflecting injury and/or remodeling of type II pneumocytes) were associated with outcomes in COVID-19 as reported previously. In conclusion, increased CRP, IL-6, KL-6, HMGB-1, and d-dimer levels and decreased platelet counts were associated with the start of mechanical ventilation due to COVID-19.

3CL Protease Inhibitors with an Electrophilic Arylketone Moiety as Anti-SARS-CoV-2 Agents.

The novel coronavirus, SARS-CoV-2, has been identified as the causative agent for the current coronavirus disease (COVID-19) pandemic. 3CL protease (3CLpro) plays a pivotal role in the processing of viral polyproteins. We report peptidomimetic compounds with a unique benzothiazolyl ketone as a warhead group, which display potent activity against SARS-CoV-2 3CLpro. The most potent inhibitor YH-53 can strongly block the SARS-CoV-2 replication. X-ray structural analysis revealed that YH-53 establishes multiple hydrogen bond interactions with backbone amino acids and a covalent bond with the active site of 3CLpro. Further results from computational and experimental studies, including an in vitro absorption, distribution, metabolism, and excretion profile, in vivo pharmacokinetics, and metabolic analysis of YH-53 suggest that it has a high potential as a lead candidate to compete with COVID-19.

Potent mouse monoclonal antibodies that block SARS-CoV-2 infection.

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has developed into a global pandemic since its first outbreak in the winter of 2019. An extensive investigation of SARS-CoV-2 is critical for disease control. Various recombinant monoclonal antibodies of human origin that neutralize SARS-CoV-2 infection have been isolated from convalescent patients and will be applied as therapies and prophylaxis. However, the need for dedicated monoclonal antibodies suitable for molecular pathology research is not fully addressed. Here, we produced six mouse anti-SARS-CoV-2 spike monoclonal antibodies that not only exhibit robust performance in immunoassays including western blotting, ELISA, immunofluorescence, and immunoprecipitation, but also demonstrate neutralizing activity against SARS-CoV-2 infection to VeroE6/TMPRSS2 cells. Due to their mouse origin, our monoclonal antibodies are compatible with the experimental immunoassay setups commonly used in basic molecular biology research laboratories, providing a useful tool for future research. Furthermore, in the hope of applying the antibodies of clinical setting, we determined the variable regions of the antibodies and used them to produce recombinant human/mouse chimeric antibodies.

Video Laryngoscope Intubation With an Aerosol Barrier Device: A Randomized Sequential Crossover Pilot Study.

OBJECTIVES: To assess the impact of the use of aerosol barrier device, Splashguard-CG, on the endotracheal intubation with different types of laryngoscope. DESIGN: A pilot randomized sequential crossover simulation study. SETTING: A single academic center in Japan. SUBJECTS: Physicians in a single academic university hospital in Japan. INTERVENTIONS: Use of Splashguard-CG. MEASUREMENTS AND MAIN RESULTS: All participants were asked to perform endotracheal intubation to a manikin simulator using three different devices (Macintosh laryngoscope; Airway Scope [Nihon Kohden, Tokyo, Japan]; and McGRATH MAC [Aircraft Medical, Edinburgh, United Kingdom]) with and without Splashguard-CG in place, which required a total of six attempts and measured the intubation time as the primary outcome. Thirty physicians (15 experienced physicians and 15 less-experienced physicians) were included. Intubation time using Macintosh laryngoscope was significantly longer in the group with Macintosh laryngoscope and Splashguard-CG compared with the group without Splashguard-CG by the median difference of 4.3 seconds (interquartile range, 2.6-7.4 s; p < 0.001). There was no significant increase in the intubation time with or without Splashguard-CG for the Airway Scope (0.6 s; interquartile range, -3.7 to 3.2 s; p = 0.97) and the McGRATH MAC (0.5 s; interquartile range, -1.4 to 4.6 s; p = 0.09). This trend was found in both the experienced and less-experienced groups. We observed significant increases of subjective difficulty of the endotracheal intubation evaluated by using a Visual Analog Scale in the Splashguard-CG groups for all three types of devices. CONCLUSIONS: The use of a video laryngoscope with an aerosol barrier device does not impact the time required endotracheal intubation in a simulation environment. This method can be considered as airway management for coronavirus disease 2019.

Comparison of two methods to clear the airways of critically ill children and adults with COVID-19 infection: a structured summary of a study protocol for a pilot randomized controlled trial.

OBJECTIVES: As there is no treatment for COVID-19 with a proven mortality benefit at this moment in the pandemic, supportive management including mechanical ventilation is the core management in an intensive care unit (ICU). It is a challenge to provide consistent care in this situation, highly demanding and leading to potential staff shortages in ICU. We need to reduce unnecessary exposure of healthcare workers to the virus. This study aims to examine the impact of care using a non-invasive oscillating device (NIOD) for chest physiotherapy in the care of mechanically ventilated patients with COVID-19. In particular, we aim to explore if a NIOD performed by non-specialized personnel is not inferior to the standard chest physiotherapy (CPT) undertaken by physiotherapists caring for patients with COVID-19. TRIAL DESIGN: A pilot multicenter prospective crossover noninferiority randomized controlled trial. PARTICIPANTS: All mechanically ventilated patients with COVID-19 admitted to one of the two ICUs, and CPT ordered by the responsible physician. The participants will be recruited from two intensive care units in Canadian Academic Hospitals (one pediatric and one adult ICU). INTERVENTION AND COMPARATOR: We will implement NIOD and CPT alternatingly for 3 h apart over 3 h. We will apply a pragmatic design, so that other procedures including hypertonic saline nebulization, intermittent positive pressure ventilation, suctioning (e.g., oral or nasal), or changing the ventilator settings or modality (i.e., increasing positive end-expiratory pressure or changing the nasal mask to total face continuous positive airway pressure) can be provided at the direction of bedside intensivists in charge. MAIN OUTCOMES: The primary outcome measurement is the oxygenation level before and after the procedure (SpO2/FiO2 ratio). For cases with invasive ventilation (i.e., the use of an endotracheal tube to deliver positive pressure) and non-invasive ventilation, we will also document expiratory tidal volume, vital signs, and any related complications such as vomiting, hypoxemia, or unexpected extubation. We will collect the data before, 10 min after, and 30 min after the procedure. RANDOMIZATION: The order of the procedures (i.e., NIOD or CPT) will be randomly allocated using manual generated random numbers for each case. Randomization will be carried out by the independent research assistant in the study coordinating center by using opaque sealed envelopes, assigning an equal number of cases to each intervention arm. Stratification will be applied for age (> 18 years or ≤ 18 years of age) and the study sites. BLINDING (MASKING): No blinding will be performed. NUMBERS TO BE RANDOMIZED (SAMPLE SIZE): We estimate the necessary sample size as 25 for each arm (total 50 cases), with a power of 0.90 and an alpha of 0.05, with a non-inferiority design. TRIAL STATUS: The protocol version number 1 was approved on 27 March 2020. Currently, recruitment has not yet started, with the start scheduled by the mid-June 2020 and the end anticipated by December 2020. TRIAL REGISTRATION: ClinicalTrials.gov NCT04361435 . Registered on 28 April 2020 FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional File 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this letter serves as a summary of the key elements of the full protocol.