A computationally designed ACE2 decoy has broad efficacy against SARS-CoV-2 omicron variants and related viruses in vitro and in vivo.

SARS-CoV-2, especially B.1.1.529/omicron and its sublineages, continues to mutate to evade monoclonal antibodies and antibodies elicited by vaccination. Affinity-enhanced soluble ACE2 (sACE2) is an alternative strategy that works by binding the SARS-CoV-2 S protein, acting as a 'decoy' to block the interaction between the S and human ACE2. Using a computational design strategy, we designed an affinity-enhanced ACE2 decoy, FLIF, that exhibited tight binding to SARS-CoV-2 delta and omicron variants. Our computationally calculated absolute binding free energies (ABFE) between sACE2:SARS-CoV-2 S proteins and their variants showed excellent agreement to binding experiments. FLIF displayed robust therapeutic utility against a broad range of SARS-CoV-2 variants and sarbecoviruses, and neutralized omicron BA.5 in vitro and in vivo. Furthermore, we directly compared the in vivo therapeutic efficacy of wild-type ACE2 (non-affinity enhanced ACE2) against FLIF. A few wild-type sACE2 decoys have shown to be effective against early circulating variants such as Wuhan in vivo. Our data suggest that moving forward, affinity-enhanced ACE2 decoys like FLIF may be required to combat evolving SARS-CoV-2 variants. The approach described herein emphasizes how computational methods have become sufficiently accurate for the design of therapeutics against viral protein targets. Affinity-enhanced ACE2 decoys remain highly effective at neutralizing omicron subvariants.

Low dose vs high dose tocilizumab in COVID-19 patients with hypoxemic respiratory failure.

PURPOSE: Tocilizumab has been shown to decrease mortality when used concomitantly with steroids in COVID-19 with 8 mg/kg (max 800 mg) being the standard dose. Our study sought to assess whether a low dose (400 mg) shows similar benefit compared to a high dose for COVID patients concurrently on the same median dose of steroids. MATERIALS/METHODS: A retrospective, multihospital observational study of COVID-19 patients who received tocilizumab in conjunction with steroids between March 2020 and August 2021 was conducted. RESULTS: A total of 407 patients were analyzed with low dose group being significantly more ill at baseline as a higher percentage of patients received vasopressors, were admitted to the ICU and on mechanical ventilation. In the propensity-matched analysis, both groups receiving a median dexamethasone equivalent dose of 10 mg showed no difference in 28-day mortality (p = 0.613). The high dose group had a higher rate of fungal and viral infections. CONCLUSION: Compared to low dose tocilizumab, the high dose did not provide additional efficacy and mortality benefit but resulted in higher fungal and viral infections. This study illustrates that low dose tocilizumab can be an alternative to high dose during a drug shortage of tocilizumab without compensating for efficacy and safety, conserving resources for more patients.

Kindergarten teachers' experiences during the COVID-19 pandemic in Bangladesh

Across the world COVID-19 has impacted teachers' lives both professionally and personally. In many parts of the world kindergarten teachers have been able to adapt practices to ensure that children's education and care is provided. However some countries have not responded adequately to support kindergarten teachers' ongoing employment. Bangladesh is one such country. The aim of this study was to understand the experiences of 16 Bangaldeshi kindergarten teachers during the COVID-19 pandemic. The study used an interpretive social constructionist approach, with semi-structured interviews of the 16 kindergarten teachers. Findings revealed the 16 participants experienced significant disruption to their professional and personal lives during COVID-19. With the long-term closures of schools and early childhood services, the teachers were found to be significantly impacted resulting in hardship to their personal, physical, human and social lives. Governments are called on to demonstrate value and support kindergarten teachers at all times, not only during the pandemic. Such support will sustain the early childhood profession, and ensure the rights of young children to access consistent education and care are met. [ABSTRACT FROM AUTHOR] Copyright of International Journal of Early Years Education is the property of Routledge and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Kindergarten teachers' experiences during the COVID-19 pandemic in Bangladesh

Across the world COVID-19 has impacted teachers’ lives both professionally and personally. In many parts of the world kindergarten teachers have been able to adapt practices to ensure that children’s education and care is provided. However some countries have not responded adequately to support kindergarten teachers’ ongoing employment. Bangladesh is one such country. The aim of this study was to understand the experiences of 16 Bangaldeshi kindergarten teachers during the COVID-19 pandemic. The study used an interpretive social constructionist approach, with semi-structured interviews of the 16 kindergarten teachers. Findings revealed the 16 participants experienced significant disruption to their professional and personal lives during COVID-19. With the long-term closures of schools and early childhood services, the teachers were found to be significantly impacted resulting in hardship to their personal, physical, human and social lives. Governments are called on to demonstrate value and support kindergarten teachers at all times, not only during the pandemic. Such support will sustain the early childhood profession, and ensure the rights of young children to access consistent education and care are met. [ FROM AUTHOR] Copyright of International Journal of Early Years Education is the property of Routledge and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full . (Copyright applies to all s.)

Coronavirus Disease 2019 and the Injured Patient: A Multicenter Review.

INTRODUCTION: Coronavirus disease 2019 (COVID-19) has been shown to affect outcomes among surgical patients. We hypothesized that COVID-19 would be linked to higher mortality and longer length of stay of trauma patients regardless of the injury severity score (ISS). METHODS: We performed a retrospective analysis of trauma registries from two level 1 trauma centers (suburban and urban) from March 1, 2019, to June 30, 2019, and March 1, 2020, to June 30, 2020, comparing baseline characteristics and cumulative adverse events. Data collected included ISS, demographics, and comorbidities. The primary outcome was time from hospitalization to in-hospital death. Outcomes during the height of the first New York COVID-19 wave were also compared with the same time frame in the prior year. Kaplan-Meier method with log-rank test and Cox proportional hazard models were used to compare outcomes. RESULTS: There were 1180 trauma patients admitted during the study period from March 2020 to June 2020. Of these, 596 were never tested for COVID-19 and were excluded from the analysis. A total of 148 COVID+ patients and 436 COVID- patients composed the 2020 cohort for analysis. Compared with the 2019 cohort, the 2020 cohort was older with more associated comorbidities, more adverse events, but lower ISS. Higher rates of historical hypertension, diabetes, neurologic events, and coagulopathy were found among COVID+ patients compared with COVID- patients. D-dimer and ferritin were unreliable indicators of COVID-19 severity; however, C-reactive protein levels were higher in COVID+ relative to COVID- patients. Patients who were COVID+ had a lower median ISS compared with COVID- patients, and COVID+ patients had higher rates of mortality and longer length of stay. CONCLUSIONS: COVID+ trauma patients admitted to our two level 1 trauma centers had increased morbidity and mortality compared with admitted COVID- trauma patients despite age and lower ISS. C-reactive protein may play a role in monitoring COVID-19 activity in trauma patients. A better understanding of the physiological impact of COVID-19 on injured patients warrants further investigation.

The incidence of propofol infusion syndrome in critically-ill patients.

PURPOSE: PRIS is a potentially fatal syndrome characterized by various clinical symptoms and abnormalities. Experts suggest that propofol treatment duration ≥48 h or dose ≥83 µg/kg/min is associated with developing PRIS. We hypothesized PRIS might be underdiagnosed due to the overlap of PRIS clinical manifestations with critical illnesses. MATERIALS AND METHODS: Multihospital, retrospective study of adult patients who received continuous propofol infusion ≥48 h or dose ≥60µg/kg/min for >24 h since admission were assessed for the development of PRIS. RESULTS: The incidence of PRIS was 2.9% with a PRIS-associated mortality rate of 36.8%. In PRIS patients, propofol was administered at a median dose of 36.4 µg/kg/min and over a median duration of 147.0 h. The development of PRIS was observed at a median of 125.0 h post-propofol initiation and a cumulative dose of 276.5 mg/kg. The development of metabolic acidosis (78.9%), cardiac dysfunction (52.6%), hypertriglyceridemia (100%), and rhabdomyolysis (26.3%) were observed in our PRIS patients. CONCLUSION: PRIS can often be overlooked and underdiagnosed. It is important to monitor for early signs of PRIS in patients who are on prolonged propofol infusion. Prompt recognition and interventions can minimize the dangers resulting from PRIS.

COVID-19 Antibodies and Outcomes among Outpatient Maintenance Hemodialysis Patients.

Background: Patients on maintenance hemodialysis are particularly vulnerable to infection and hospitalization from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Due to immunocompromised patients and the clustering that occurs in outpatient dialysis units, the seroprevalence of COVID-19 antibodies in this population is unknown and has significant implications for public health. Also, little is known about their risk factors for hospitalization. Methods: Three outpatient maintenance hemodialysis units affiliated with a major teaching hospital in the New York area were studied. We determined rates of SARS-CoV-2 positivity via nasopharyngeal, real-time, reverse-transcriptase PCR (RT-PCR); SARS-CoV-2 IgG seropositivity; hospitalization; and mortality. Results: Of 367 patients, 28% had either SARS-CoV-2 seropositivity or PCR positivity. Prevalence across the three respective units was 7%, 32%, and 70%. Those who were either antibody or PCR positive were significantly younger (65 versus 69 years, P=0.05), and had a higher prevalence of Black race (43% versus 30%, P=0.001) and Hispanic ethnicity (32% versus 12%, P<0.001) compared with those who tested negative. Higher positivity rates were also observed among those who took taxis and ambulettes to and from dialysis, compared with those who used personal transportation. Antibodies were detected in all of the patients with a positive PCR result who underwent serologic testing. Of those that were seropositive, 32% were asymptomatic. The hospitalization rate on the basis of either antibody or PCR positivity was 35%, with a hospital mortality rate of 33%. Aside from COPD, no other variables were more prevalent in patients who were hospitalized. Conclusions: We observed significant differences in rates of COVID-19 infection within three outpatient dialysis units, with universal seroconversion. Among patients with ESKD, rates of asymptomatic infection appear to be high, as do hospitalization and mortality rates.

Assessment of Safety of Remdesivir in Covid - 19 Patients with Estimated Glomerular Filtration Rate (eGFR) < 30 ml/min per 1.73†m2.

PURPOSE: Safety of remdesivir in patients with renal impairment is unknown. Incidence of liver injury secondary to remdesivir is also unknown. The objective of this study is to assess the incidence of acute kidney injury (AKI) and to trend the liver enzymes during remdesivir treatment and change in eGFR from baseline to end of treatment as well as 48 h post completion of remdesivir therapy. METHODS: This is a retrospective chart review study including adult patients admitted with COVID-19 receiving remdesivir with a baseline eGFR < 30 ml/min per 1.73 m^2 from December 2020 to May 2021. The primary outcome was to assess the incidence of AKI and hepatic injury. The secondary outcome was to assess the efficacy of remdesivir defined by change in oxygen requirement. RESULTS: Seventy-one patients were included in the study. Patients experienced an improvement in eGFR from baseline (T0) to end of remdesivir treatment (T1), as well as 48 h after the end of the treatment (T2) ( + 30.3% and + 30.6% respectively, P < .0001). Creatinine reduced from baseline (T0) to T1 and T2 (-20.9% and -20.5% respectively, P < .0001). Creatinine clearance improved from baseline to T1 and T2 ( + 26.6% and + 26.2% respectively, p < .0001). Elevation of aminotransferase (AST) was observed at T1 ( + 2.5%, P = .727), however, AST reduction was seen at T2 (-15.8%, P = .021). Elevation in alanine transaminase (ALT) was observed at T1 and T2 ( + 25% and + 12%, P = .004 and P = .137 respectively). Both direct and total bilirubin remained stable and were not significantly changed from baseline. CONCLUSION: Our study showed that remdesivir use in renally-impaired patients with eGFR < 30 ml/min is safe. Remdesivir may be considered as a therapeutic option in this population with COVID-19 infection.

Exploring behavioral determinants of handwashing with soap after defecation in an urban setting in Bangladesh: findings from a barrier analysis

Social and behavior change (SBC) has long been recognized as a necessary step in the promotion of handwashing with soap (HHWS), and identifying the barriers and enablers of this behavior are key to increasing its adoption. Based on the health belief model (HBM), the theory of reasoned action (TRA) and other behavioral models, this barrier analysis study was conducted to identify the barriers and enablers of HWWS after defecation in an urban setting in Bangladesh. We conducted interviews with 45 adults who washed their hands with soap after defecation (doers) and compared them to 45 adults who did not (non-doers). The analysis showed that the main barriers of HWWS after defecation were related to perceived self-efficacy, difficulty to remember to buy soap, access to low-cost soap, low perceived severity of diarrhea, and not believing that HWWS would reduce diarrhea. Believing that it is Allah's will when one gets diarrhea was mentioned more frequently by the non-doers, while feeling clean and keeping free from illness were reported as benefits of HWWS significantly by the doers. The results suggest that an SBC strategy that addresses these key barriers and enablers would be more effective in promoting the adoption of HWWS.

Computationally Designed ACE2 Decoy Receptor Binds SARS-CoV-2 Spike (S) Protein with Tight Nanomolar Affinity.

Even with the availability of vaccines, therapeutic options for COVID-19 still remain highly desirable, especially in hospitalized patients with moderate or severe disease. Soluble ACE2 (sACE2) is a promising therapeutic candidate that neutralizes SARS CoV-2 infection by acting as a decoy. Using computational mutagenesis, we designed a number of sACE2 derivatives carrying three to four mutations. The top-predicted sACE2 decoy based on the in silico mutagenesis scan was subjected to molecular dynamics and free-energy calculations for further validation. After illuminating the mechanism of increased binding for our designed sACE2 derivative, the design was verified experimentally by flow cytometry and BLI-binding experiments. The computationally designed sACE2 decoy (ACE2-FFWF) bound the receptor-binding domain of SARS-CoV-2 tightly with low nanomolar affinity and ninefold affinity enhancement over the wild type. Furthermore, cell surface expression was slightly greater than wild-type ACE2, suggesting that the design is well-folded and stable. Having an arsenal of high-affinity sACE2 derivatives will help to buffer against the emergence of SARS CoV-2 variants. Here, we show that computational methods have become sufficiently accurate for the design of therapeutics for current and future viral pandemics.

An in silico approach for identification of novel inhibitors as potential therapeutics targeting COVID-19 main protease.

Respiratory disease caused by a novel coronavirus, COVID-19, has been labeled a pandemic by the World Health Organization. Very little is known about the infection mechanism for this virus. More importantly, there are no drugs or vaccines that can cure or prevent a person from getting COVID-19. In this study, the binding affinity of 2692 protease inhibitor compounds that are known in the protein data bank, are calculated against the main protease of the novel coronavirus with docking and molecular dynamics (MD). Both the docking and MD methods predict the macrocyclic tissue factor-factor VIIa (PubChem ID: 118098670) inhibitor to bind strongly with the main protease with a binding affinity of -10.6 and -10.0 kcal/mol, respectively. The TF-FVIIa inhibitors are known to prevent the coagulation of blood and have antiviral activity as shown in the case of SARS coronavirus. Two more inhibitors, phenyltriazolinones (PubChem ID: 104161460) and allosteric HCV NS5B polymerase thumb pocket 2 (PubChem ID: 163632044) have shown antiviral activity and also have high affinity towards the main protease of COVID-19. Furthermore, these inhibitors interact with the catalytic dyad in the active site of the COVID-19 main protease that is especially important in viral replication. The calculated theoretical dissociation constants of the proposed COVID-19 inhibitors are found to be very similar to the experimental dissociation constant values of similar protease-inhibitor systems.Communicated by Ramaswamy H. Sarma.

Correlation of Hemoglobin A1C and Outcomes in Patients Hospitalized With COVID-19.

OBJECTIVE: Diabetes is a known risk factor for severe coronavirus disease 2019 (COVID-19). We conducted this study to determine if there is a correlation between hemoglobin A1C (HbA1C) level and poor outcomes in hospitalized patients with diabetes and COVID-19. METHODS: This is a retrospective, single-center, observational study of patients with diabetes (defined by an HbA1C level of ≥6.5% or known medical history of diabetes) who had a confirmed case of COVID-19 and required hospitalization. All patients were admitted to our institution between March 3, 2020, and May 5, 2020. HbA1C results for each patient were divided into quartiles: 5.1% to 6.7% (32-50 mmol/mol), 6.8% to 7.5% (51-58 mmol/mol), 7.6% to 8.9% (60-74 mmol/mol), and >9% (>75 mmol/mol). The primary outcome was in-hospital mortality. Secondary outcomes included admission to an intensive care unit, invasive mechanical ventilation, acute kidney injury, acute thrombosis, and length of hospital stay. RESULTS: A total of 506 patients were included. The number of deaths within quartiles 1 through 4 were 30 (25%), 37 (27%), 34 (27%), and 24 (19%), respectively. There was no statistical difference in the primary or secondary outcomes among the quartiles, except that acute kidney injury was less frequent in quartile 4. CONCLUSION: There was no significant association between HbA1C level and adverse clinical outcomes in patients with diabetes who are hospitalized with COVID-19. HbA1C levels should not be used for risk stratification in these patients.

Low-Dose Tocilizumab With High-Dose Corticosteroids in Patients Hospitalized for COVID-19 Hypoxic Respiratory Failure Improves Mortality Without Increased Infection Risk.

BACKGROUND: Severe hypoxic respiratory failure from COVID-19 pneumonia carries a high mortality risk. There is uncertainty surrounding which patients benefit from corticosteroids in combination with tocilizumab and the dosage and timing of these agents. The balance of controlling inflammation without increasing the risk of secondary infection is difficult. At present, dexamethasone 6 mg is the standard of care in COVID-19 hypoxia; whether this is the ideal choice of steroid or dosage remains to be proven. OBJECTIVES: The primary objective was to assess the impact on mortality of tocilizumab only, corticosteroids only, and combination therapy in patients with COVID-19 respiratory failure. METHODS: A multihospital, retrospective study of adult patients with severe respiratory failure from COVID-19 who received supportive therapy, corticosteroids, tocilizumab, or combination therapy were assessed for 28-day mortality, biomarker improvement, and relative risk of infection. Propensity-matched analysis was performed between corticosteroid alone and combination therapies to further assess mortality benefit. RESULTS: The steroid-only, tocilizumab-only, and combination groups showed hazard reduction in mortality at 28 days when compared with supportive therapy. In a propensity-matched analysis, the combination group (daily equivalent dexamethasone 10 mg and tocilizumab 400 mg) had an improved 28-day mortality compared with the steroid-only group (daily equivalent dexamethasone 10 mg; hazard ratio (95% CI) = 0.56 (0.38-0.84), P = 0.005] without increasing the risk of infection. CONCLUSION AND RELEVANCE: Combination of tocilizumab and corticosteroids was associated with improved 28-day survival when compared with corticosteroids alone. Modification of steroid dosing strategy as well as steroid type may further optimize therapeutic effect of the COVID-19 treatment.