Proof-of-Concept Study of Liposomes with a Set of SARS-CoV-2 Viral Peptidic T-Cell Epitopes as a Vaccine

Abstract: Potential nonameric epitopes of CD8+ T lymphocytes were selected from the composition of structural, accessory, and nonstructural proteins of the SARS-CoV-2 virus (13 peptides) and a 15-mer epitope of CD4+ T lymphocytes, from the S-protein, based on the analysis of publications on genome-wide immunoinformatic analysis of T-cell epitopes of the virus (Wuhan strain), as well as a number of clinical studies of immunodominant epitopes among patients recovering from COVID-19 disease. The peptides were synthesized and five compositions of 6–7 peptides were included in liposomes from egg phosphatidylcholine and cholesterol (~200 nm size) obtained by extrusion. After double subcutaneous immunization of conventional mice, activation of cellular immunity was assessed by the level of cytokine synthesis by splenocytes in vitro in response to stimulation with relevant peptide compositions. Liposomal formulation exhibiting the best result in terms of the formation of specific cellular immunity in response to vaccination was selected for further experiments. Evaluation of the protective efficacy of this formulation in an infectious mouse model showed a positive trend in the frequency of occurrence of hyaline-like membranes in the lumen of the alveoli, as well as a somewhat lower severity of microcirculatory disorders. The latter circumstance can potentially help reduce the severity of the disease and prevent its adverse outcomes. A method to produce liposome preparations with peptide compositions for long-term storage is under development. © 2022, Pleiades Publishing, Ltd.

α-Conotoxin RgIA and oligoarginine R8 in the mice model alleviate long-term oxaliplatin induced neuropathy.

Оligoarginines were recently discovered (Lebedev et al., 2019 Nov) as a novel class of nicotinic acetylcholine receptors (nAChRs) inhibitors, octaoligoarginine R8 showing a relatively high affinity (44 nM) for the α9/α10 nAChR. Since the inhibition of α9/α10 nAChR by α-conotoxin RgIA and its analogs is a possible way to drugs against neuropathic pain, here in a mice model we compared R8 with α-conotoxin RgIA in the effects on the chemotherapy-induced peripheral neuropathy (CIPN), namely on the long-term oxaliplatin induced neuropathy. Tests of cold allodynia, hot plate, Von Frey and grip strength analysis revealed for R8 and α-conotoxin RgIA similar positive effects, expressed most prominently after two weeks of administration. Histological analysis of the dorsal root ganglia sections showed for R8 and RgIA a similar partial correction of changes in the nuclear morphology of neurons. Since α9/α10 nAChR might be not the only drug target for R8, we analyzed the R8 action on rat TRPV1 and TRPA1, well-known nociceptive receptors. Against rTRPV1 at 25 µM there was no inhibition, while for rTRPA1 IC50 was about 20 µM. Thus, involvement of rTRPA1 cannot be excluded, but in view of the R8 much higher affinity for α9/α10 nAChR the latter seems to be the main target and the easily synthesized R8 can be considered as a potential candidate for a drug design.

Prophylactic versus therapeutic anticoagulation for survival of patients with covid-19 on steroid and remdesivir

Introduction: Previous observational and randomized studies suggested potential benefit of therapeutic anticoagulation during hospitalization, but this treatment remains controversial Objective: We aimed to investigate the association of prophylactic and therapeutic anticoagulation with mortality for patients with COVID-19 who were treated with steroids and Remdesivir, which is the current standard treatments. Methods: This retrospective study was conducted by review of the electronic medical records for 9,565 patients with laboratory confirmed COVID-19 hospitalized in the Mount Sinai Health system between March 1 2020 and March 30 2021. The primary outcome of interest was the in-hospital mortality. Acute kidney injury was defined as any increase of creatinine by more than 0.3mg/dL or to more than 1.5 times baseline. A propensity score analysis (matching and weighting by inverse probability treatment weights) and multiple imputation was performed. Results: Of the 1,443 patients, 420 (29.1%) had therapeutic anticoagulation therapy. The 1,023 (70.9%) patients with prophylactic anticoagulation were older and had more comorbidities. After matching by propensity score (N=334 in each group), in-hospital mortality was not significantly different between patients with therapeutic anticoagulation and those with prophylactic anticoagulation (26.9% vs. 22.8%, P=0.24). Furthermore, IPTW and multiple imputation for missing data did not change the result (therapeutic versus prophylactic;odds ratio [95% confidential interval]: 1.14 [0.83-1.59], P=0.40];1.20 [0.84-1.73], P=0.31, respectively). Interestingly, patients with therapeutic anticoagulation had higher rate of acute kidney injury as compared to patients with prophylactic anticoagulation (26.6% vs. 16.8%, P=0.003). Conclusions: In conclusion, prophylactic versus therapeutic anticoagulation showed similar inhospital mortality of COVID-19 patients treated with steroids and remdesivir, but therapeutic anticoagulation increased the risk of acute kidney injury compared to prophylactic anticoagulation.

The association of hemoglobin drop with inhospital outcomes in covid-19 patients

Background: Bleeding events can be critical in hospitalized patients with COVID-19, especially those with aggressive anticoagulation therapy. Objective: We aimed to investigate whether hemoglobin drop associated with increased risk of acute kidney injury (AKI) and in-hospital mortality among patients with COVID-19. Methods: This retrospective study was conducted by review of the medical records of 6,683 patients with laboratory confirmed COVID-19 hospitalized in the Mount Sinai Health system between March 1 , 2020 and March 30 2021. We compared patients with and without hemoglobin drop >3g/dL during hospitalization within a week after admissions, using inverse probability treatment weighted analysis (IPTW). Outcomes of interest were in-hospital mortality and AKI which was defined as increased of creatine 1.5 times or 0.3mg/dL. Results: Of the 6,683 patients admitted due to COVID-19, 750 (11.2%) presented with a marked hemoglobin drop. Patients with hemoglobin drop were more likely to receive therapeutic anticoagulation within two days after admissions. Patients with hemoglobin drop had higher crude in-hospital mortality (40.8% versus 20.0%, P<0.001) as well as AKI (51.4% versus 23.9%, P<0.001) compared to those without. IPTW analysis showed that hemoglobin drop was associated with higher in-hospital mortality compared to those without (odds ratio (OR) [95% confidential interval (CI)]: 2.21 [1.54-2.88], P<0.001) as well as AKI (OR [95% CI]: 2.79 [2.08-3.73], P<0.001). Finally, the smooth spline curve showed the association of hemoglobin drop and adjusted odds ratio for in-hospital mortality, which reflected the association of hemoglobin drop and in-hospital mortality (Figure). Conclusions: Hemoglobin drop during COVID-19 related hospitalizations was associated with a higher risk of AKI and in-hospital mortality. Figure Legends: Smooth spline curve of the association of hemoglobin drop and adjusted odds ratio of in-hospital mortality.

The association of statins use with survival of covid-19 patients

Introduction: Statins are frequently prescribed for patients with hypertension, dyslipidemia and diabetes mellitus. These comorbidities are highly prevalent in COVID-19 patients. Statin's beneficial effect on mortalities in COVID-19 infection has been reported in several studies, but still inconclusive. Hypothesis: The inconclusive study results in association of satin use and COVID-19 can be resulted from variable timing of statins used among the studies. Our aim was to investigate whether consistent use of statins before and during hospitalization was effective to decrease the mortality due to COVID-19. Methods: We conducted a retrospective study among 6,095 patients with COVID-19 hospitalized in New York City between March 1st 2020 and May 7th 2021. Patients were stratified into two groups: statins use prior or during hospitalization (N=2,423) versus no statins (N=3,672). We evaluated inhospital mortality as a primary outcome using propensity score matching and inverse probability treatment weighted (IPTW) analysis. In addition, we compared continuous use of statins (N=1,108) versus no statins. Results: Statins use prior or during hospitalization group were older (70.8±12.7 versus 59.2±18.2, P<0.001) and had more comorbidities compared to no statins group. After matching by propensity score (1,790 pairs), there were no significant differences in in-hospital mortality between patients with statins versus those without (28.9% versus 31.0%, P=0.19, odds ratio (OR) [95% confidence interval (CI)]: 0.91 [0.79-1.05]). This result was confirmed using IPTW analysis (OR [95% CI]: 0.96 [0.81-1.12], P=0.53). As the additional analysis comparing continuous use of statins versus no statins group, in-hospital mortality was significantly lower in continuous use of statins compared to no statins group (26.3% versus 34.5%, P<0.001, OR [95% CI]: 0.68 [0.55-0.82]) after matching by propensity score (944 pairs). IPTW analysis showed the similar result (OR [95% CI]: 0.77 [0.64-0.94], P=0.009). Conclusions: Use of statins prior or during hospitalization was not associated with a decreased risk of in-hospital mortality, however, continuous use of statins might have potential benefit of a decreased risk of in-hospital mortality due to COVID-19.

The association of obesity level and inhospital survival of patients with covid-19 who received corticosteroids

Introduction: Obesity is one of the most frequent comorbidities among COVID-19 patients. Although previous studies have shown higher body mass index (BMI) is associated with higher mortality, steroids as the current standard treatment for moderate to severe COVID-19 infection were not applied in most patients in these studies. Hypothesis: We hypothesized that patients with higher BMI still have higher mortality even on steroids. Methods: We conducted a retrospective study of 4,587 hospitalized patients with COVID-19 who received corticosteroids between March 1 , 2020, and March 30 , 2021. We divided patients into 6 groups by BMI[MOU1] (less 18.5, 18.5-25, 25-30, 30-35, 35-40, 40 or greater, kg/m2 ) and investigated in-hospital mortality as the primary outcome, in-hospital mortality among severe COVID-19 patients which was defined as requiring intensive care unit or endotracheal intubation as a subgroup analysis, and acute kidney injury (AKI) incidence rate as the secondary outcome. Results: Patients with higher BMI were younger and more likely to have a history of asthma, obstructive sleep apnea, diabetes, and less likely to have malignancies. The smooth spline curve showed J curve association of BMI with risk adjusted in-hospital mortality with flexion point at BMI between 25 and 30 kg/m2 (Figure 1). Compared to overweight (25≤BMI<30 kg/m2 ) patients, class III obesity (BMI>40 kg/m2 ) was associated with higher risk adjusted in-hospital mortality overall (Table 1) as well as among patients with severe COVID-19 (OR [95% CI]: 3.21 [1.86-5.66], P<0.001). Class III obesity was also associated with a higher risk adjusted incidence of AKI (OR [95% CI]: 1.52 [1.06-2.18], P=0.024) compared to overweight patients. Conclusions: Class III obesity was associated with higher in-hospital mortality and AKI incidence rate in COVID-19 patients with steroids treatment.

The effectiveness of combination of 7% hypertonic saline and 0.1% natrii hyaluronas in patients with chronic obstructive pulmonary disease who have suffered a new coronavirus infection

Introduction. New coronavirus infection (COVID-19) contributes to the aggravation of respiratory symptoms in patients with COPD, including affecting the intensity and nature of cough. Hypertonic solution (HS) has a positive effect on the rheological properties of sputum and mucociliary clearance. However, there are no studies in the available literature on the use of HS in patients who have undergone COVID-19. Goal. To evaluate the effect of the combination of 7% hypertonic saline and 0.1% natrii hyaluronas on the intensity and productive nature of cough in patients with COPD who have undergone a new coronavirus infection and the safety of its use in this cohort of patients. Materials and methods. 50 patients with severe COPD in remission who suffered a new coronavirus infection were examined. The rehabilitation stage of treatment was carried out in the conditions of the pulmonology department. From the moment of receiving the last negative PCR result for SARS-CoV-2 to admission to the hospital for rehabilitation, it took from 2 to 3 weeks. The duration of follow-up of patients was 10 days. The patients were divided into two groups: group 1 (n = 25) - patients who received combination of 7% hypertonic saline and 0.1% natrii hyaluronas 7% by inhalation through a nebulizer;group 2 (n = 25) - patients who did not receive combination of 7% hypertonic saline and 0.1% natrii hyaluronas. The severity of cough was assessed (cough severity scale;shortness of breath, cough and sputum scale), clinical and biochemical blood tests, ECG, spirometry. Results. In patients treated with combination of 7% hypertonic saline and 0.1% natrii hyaluronas, a significant decrease in the severity of cough, the amount of sputum was revealed. The tendency to reduce shortness of breath and improve the quality of life is determined. No serious adverse events were detected when using the drug. Conclusions. The use of the combination of 7% hypertonic saline and 0.1% natrii hyaluronas in patients with COPD who have suffered a new coronavirus infection at the rehabilitation stage leads to a decrease in the intensity of cough and improved sputum discharge, which helps to reduce the severity of shortness of breath and improve the quality of life. The use of the drug is safe and does not lead to clinically significant adverse events. © 2021, Remedium Group Ltd. All rights reserved.

The characteristics and outcomes of critically ill patients with COVID-19 who received systemic thrombolysis forpresumed pulmonary embolism: An observational study

Background : Coronavirus disease 2019 (COVID-19) is associated with abnormal hemostasis, autopsy evidence of systemic microthrombosis, and a high prevalence of venous thromboembolic disease (VTE). Tissue plasminogen activator (tPA) has been used in COVID-19 patients with severe hypoxia with high clinical suspicion of pulmonary embolism (PE). Aims : We aimed to describe the clinical outcomes of critically ill COVID-19 patients who received tPA. Methods : A retrospective cohort study was conducted on 6,095 hospitalized COVID-19 patients in the Mount Sinai Health System at 5 hospitals in New York. 57 patients with COVID-19, who were admitted from 3/10 to 4/27, 2020 and received tPA for presumed PE were included in the analysis. Baseline demographic and clinical characteristics, indication for tPA, and overall mortality were reported. Results : Among the 57 patients who received tPA, the mean age was 60.8 ± 10.8 years, and 71.9% (41/57) were male. PE was suspected among 75.4% (43/57) of patients with supporting findings who had rapidly worsening hypoxia or hypotension. Right ventricular (RV) strain was present in 15.8% (9/57), deep venous thrombosis (DVT) in 7.0% (4/57), increased dead space ventilation (V d ) in 31.6% (18/57) of patients. RV strain and RV thrombus were present in 3.5% (2/57), RV strain and DVT in 5.3% (3/57), RV strain and increased V d in 8.8% (5/57), and DVT and increased V d in 3.5% (2/57) of patients. No chest CT angiography was performed for any patients due to clinical instability from critical illness. Following tPA infusion, 49.1% (28/57) of patients demonstrated improvement in either of PaO 2 /FiO 2 ratio, blood pressure or partial arterial carbon dioxide. Bleeding complication was seen in 1 patient. Six patients (10.5%) survived to hospital discharge. Overall mortality was 89.5% (51/57). Conclusions : The overall mortality of critically ill COVID-19 patients who received tPA for presumed PE was 89.5 %. The utility of tPA for this indicaition warrants further studies.

THE ASSOCIATION OF INHALED CORTICOSTEROID BEFORE ADMISSION AND SURVIVAL OF PATIENTS WITH COVID-19

TOPIC: Chest Infections TYPE: Original Investigations PURPOSE: Inhaled corticosteroids (ICS) are widely used in patients with asthma and chronic obstructive pulmonary disease (COPD). The pooled epidemiological studies have shown that patients with asthma or COPD are at lower hospitalization risk, which could be related to the protective effect of ICS. However, some studies showed no protective effects of ICS on the prognosis of COVID-19. The very recent study suggested that the use of ICS, within 2 weeks of admission, improved survival only for patients aged 50 years and older with asthma, but not for those with chronic pulmonary disease. Herein, we are highly concerned about whether the use of ICS affects the prognosis of COVID-19. METHODS: We retrospectively analyzed over 6,095 hospitalized patients with laboratory confirmed COVID-19 at the Mount Sinai Health System in New York between March 1stand May 2nd, 2020. Patients were stratified into those with or without ICS before admission and were assessed for in-hospital mortality as a primary outcome. Patients were matched by propensity score using 1:1 matching scheme without replacement. We performed this analysis with and without multiple imputation for missing data and then performed an inverse probability weighted analysis. All statistical calculations and analyses were performed in R, with p-values <0.05 considered statistically significant. RESULTS: Of the 6,095 patients admitted due to COVID-19 infection, 333 patients (5.5%) used ICS before admission. The patients with ICS were older and had more comorbidities compared to the patients without ICS. However, in-hospital mortality, intensive care unit admission, and endotracheal intubation rate were not significantly different, although the d-dimer levels were significantly lower in patients with ICS compared to those without (1.48 [0.88, 2.76] versus 1.66 [0.88, 3.51] mg/mL, P=0.043). After matching by propensity score (N=204 in each group), in-hospital mortality and intensive care unit admission rate were not different, while endotracheal intubation rate was significantly decreased in the patients with ICS. Multiple imputation for missing data and inverse probability weighted analysis revealed no significant difference in in-hospital mortality between the groups (odds ratio [95% confidential interval]: 0.90 [0.61-1.34], P=0.63;odds ratio [95% confidential interval]: 0.83 [0.54-1.29], P=0.42). To identify the population ICS improves the prognosis of COVID-19, we performed a subgroup analysis among patients with asthma and COPD (N=378). There was no significant difference in in-hospital mortality between patients with ICS and those without even after propensity score matched analysis or inverse probability weighted analysis (odds ratio [95% confidential interval]: 0.86 [0.47-1.60], P=0.64) (Table 1). CONCLUSIONS: In our study, antecedent ICS use showed numerically better outcomes in the propensity score matching analysis and the subgroup analysis of patients with asthma and COPD even though the patients with antecedent ICS use had more comorbidities. Particularly, our propensity score matching analysis revealed that patients with antecedent ICS use showed decreased endotracheal intubation rate. CLINICAL IMPLICATIONS: The potential benefit of antecedent ICS use on COVID-19 patients needs to be examined with larger sample size. DISCLOSURES: No relevant relationships by Natalia Egorova, source=Web Response No relevant relationships by Hiroki Kabata, source=Web Response no disclosure on file for Toshiki Kuno;No relevant relationships by Matsuo So, source=Web Response No relevant relationships by Mai Takahashi, source=Web Response