Synthesis of deuterated S-217622 (Ensitrelvir) with antiviral activity against coronaviruses including SARS-CoV-2.

S-217622 (Ensitrelvir) is a reversible severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 3-chymotrypsin-like protease (3CLpro) inhibitor which obtained emergency regulatory approval in Japan for the treatment of SARS-CoV-2 infection on Nov 22, 2022. Herein, analogs of S-271622 with deuterium-for-hydrogen replacement were synthesized for comparison of the antiviral activities and pharmacokinetic (PK) profiles. Compared to the parent compound, C11-d2-S-217622 compound YY-278 retained in vitro activity against 3CLpro and SARS-CoV-2. X-ray crystal structural studies showed similar interactions of SARS-CoV-2 3CLpro with YY-278 and S-271622. The PK profiling revealed the relatively favorable bioavailability and plasma exposure of YY-278. In addition, YY-278, as well as S-217622, displayed broadly anti-coronaviral activities against 6 other coronaviruses that infect humans and animals. These results laid the foundation for further research on the therapeutic potential of YY-278 against COVID-19 and other coronaviral diseases.

US-Net: A lightweight network for simultaneous speckle suppression and texture enhancement in ultrasound images.

BACKGROUND: Numerous traditional filtering approaches and deep learning-based methods have been proposed to improve the quality of ultrasound (US) image data. However, their results tend to suffer from over-smoothing and loss of texture and fine details. Moreover, they perform poorly on images with different degradation levels and mainly focus on speckle reduction, even though texture and fine detail enhancement are of crucial importance in clinical diagnosis. METHODS: We propose an end-to-end framework termed US-Net for simultaneous speckle suppression and texture enhancement in US images. The architecture of US-Net is inspired by U-Net, whereby a feature refinement attention block (FRAB) is introduced to enable an effective learning of multi-level and multi-contextual representative features. Specifically, FRAB aims to emphasize high-frequency image information, which helps boost the restoration and preservation of fine-grained and textural details. Furthermore, our proposed US-Net is trained essentially with real US image data, whereby real US images embedded with simulated multi-level speckle noise are used as an auxiliary training set. RESULTS: Extensive quantitative and qualitative experiments indicate that although trained with only one US image data type, our proposed US-Net is capable of restoring images acquired from different body parts and scanning settings with different degradation levels, while exhibiting favorable performance against state-of-the-art image enhancement approaches. Furthermore, utilizing our proposed US-Net as a pre-processing stage for COVID-19 diagnosis results in a gain of 3.6% in diagnostic accuracy. CONCLUSIONS: The proposed framework can help improve the accuracy of ultrasound diagnosis.

The Prediction Value of D-Dimer on Prognosis in Intensive Care Unit among Old Patients ( ≥65 Years): A 9-Year Single-Center Retrospective Study of 9261 Cases.

Background: D-dimer (DD) has been indicated as a potential indicator due to its connection with the prognosis of the COVID-19 pandemic. Aging is linked to elevated DD levels in coagulation activation. However, few studies have investigated the correlation of DD with prognosis, especially in the old population. Therefore, this study aims at investigating the correlation of DD with prognosis in shock and perioperative populations over 65 years of age. Methods: We analyzed 9261 old patients admitted to intensive care units (ICUs) with either confirmed shock or in perioperative period of high-risk surgery, with 8813 of them had DD levels determined on admission. In-hospital mortality, length of ICU stay and ventilation time (VT) associated variables were assessed using generalized linear models. Results: Although DD levels had no positive correlations with in-hospital mortality (RR, 1.006; 95% CI, 0.998-1.014) and length of ICU stay (RR, 1.012; 95% CI, 0.997-1.028) in Model 3, they were strongly correlated with VT (RR, 1.577; 95% CI, 1.024-2.064). Higher DD levels in females (RR, 1.804; 95% CI, 1.116-2.602), those who used antibiotics (RR, 1.736; 95% CI, 1.092-2.453), those with surgery (RR, 1.640; 95% CI, 1.273-2.114), and those with shock (RR, 1.740; 95% CI, 1.001-2.687) had stronger correlation with longer VT than the counterparts. While patients who were between 65 and 74 years old (RR, 1.023; 95% CI, 1.003-1.043), with no use of antibiotics (RR, 1.007; 95% CI, 1.001-1.013) nor shock (RR, 1.011; 95% CI, 1.002-1.021), but had undergone surgical procedures (RR, 1.030; 95% CI, 1.012-1.048) were correlated with a longer ICU length of stay. Conclusion: DD levels at ICU admission are highly related to increased VT and length of ICU stay in the old population with either confirmed shock or after high-risk surgery, indicating the strong potential of DD as a marker with prognostic utility for all ICU patients in the future.

The Risk Factors for Weaning Failure of Mechanically Ventilated Patients With COVID-19: A Retrospective Study in National Medical Team Work.

Purpose: This study aimed to describe the clinical and laboratory characteristics and the parameters of the respiratory mechanics of mechanically ventilated patients with confirmed COVID-19 pneumonia and to clarify the risk or protective factors for weaning failure. Methods: Patients diagnosed with COVID-19 pneumonia were selected from the special intensive care unit (ICU) of the Sino-French New City Branch of Tong Ji Hospital, Wuhan, and treated by the National Medical Team Work. They were divided into successful weaning (SW) group (N = 15) and unsuccessful weaning (USW) group (N = 18) according to the prognosis. Information of these patients was analyzed. Results: There were 33 patients included in this study. Patients in the USW group were associated with a poor outcome; the 28-day mortality rate was higher than in the SW group (86.7 vs. 16.7% p < 0.001). By comparison, we found that the initial plateau pressure (Pplat) and driving pressure (DP) of the USW group were higher and that compliance was lower than that of the SW group, but there was no difference between positive end-expiratory pressure (PEEP), partial pressure of carbon dioxide (PCO2), and the ratio of partial pressure arterial oxygen and fraction of inspired oxygen (P/F ratio). Comparing the worst respiratory mechanics parameters of the two groups, the results of the Pplat, DP, compliance, and PEEP were the same as the initial data. The PCO2 of the USW group was higher, while the P/F ratio was lower. A logistic regression analysis suggested that higher Pplat might be an independent risk factor and that higher compliance and lower DP might be protective factors for weaning failure of invasive mechanically ventilated patients with COVID-19 pneumonia. Conclusions: Patients with USW were associated with a poor outcome, higher Pplat might be a risk factor, and a higher compliance and a lower DP might be protective factors for the weaning failure of ventilated COVID-19 patients. Mechanical ventilation settings will affect the patient's prognosis.

ECCO2R in 12 COVID-19 ARDS Patients With Extremely Low Compliance and Refractory Hypercapnia.

Purpose: A phenotype of COVID-19 ARDS patients with extremely low compliance and refractory hypercapnia was found in our ICU. In the context of limited number of ECMO machines, feasibility of a low-flow extracorporeal carbon dioxide removal (ECCO2R) based on the renal replacement therapy (RRT) platform in these patients was assessed. Methods: Single-center, prospective study. Refractory hypercapnia patients with COVID-19-associated ARDS were included and divided into the adjusted group and unadjusted group according to the level of PaCO2 after the application of the ECCO2R system. Ventilation parameters [tidal volume (VT), respiratory rate, and PEEP], platform pressure (Pplat) and driving pressure (DP), respiratory system compliance, arterial blood gases, and ECCO2R system characteristics were collected. Results: Twelve patients with refractory hypercapnia were enrolled, and the PaCO2 was 64.5 [56-88.75] mmHg. In the adjusted group, VT was significantly reduced from 5.90 ± 0.16 to 5.08 ± 0.43 ml/kg PBW; DP and Pplat were also significantly reduced from 23.5 ± 2.72 mmHg and 29.88 ± 3.04 mmHg to 18.5 ± 2.62 mmHg and 24.75 ± 3.41 mmHg, respectively. In the unadjusted group, PaCO2 decreased from 94 [86.25, 100.3] mmHg to 80 [67.50, 85.25] mmHg but with no significant difference, and the DP and Pplat were not decreased after weighing the pros and cons. Conclusions: A low-flow ECCO2R system based on the RRT platform enabled CO2 removal and could also decrease the DP and Pplat significantly, which provided a new way to treat these COVID-19 ARDS patients with refractory hypercapnia and extremely low compliance. Clinical Trial Registration: https://www.clinicaltrials.gov/, identifier NCT04340414.

Prognostic Value of Tricuspid Annular Plane Systolic Excursion and Right Ventricular Outflow Tract Fractional Shortening in Mechanically Ventilated Septic Patients.

OBJECTIVE: The authors aimed to explore whether tricuspid annular plane systolic excursion (TAPSE) and right ventricular outflow fractional shortening (RVOT-FS) were associated with long-term prognosis in mechanically ventilated septic patients. DESIGN: A prospective observational study. SETTING: A tertiary hospital intensive care unit (ICU). PARTICIPANTS: One hundred eighty-one septic patients who were on mechanical ventilation. INTERVENTIONS: Echocardiography was performed within 24 hours of ICU admission. MEASUREMENTS AND MAIN RESULTS: Several echocardiographic parameters, including TAPSE and RVOT-FS, as well as prognostic information, were collected. A Cox regression survival analysis showed that TAPSE was independently associated with one-year all-cause mortality (hazard ratio [HR] 0.407, 95% confidence interval [CI]: 0.200-0.827, p = 0.013), but ROVT-FS was not (HR 0.997, 95% CI: 0.970-1.025, p = 0.828). ROC analysis showed that the optimal cutoff value for TAPSE and RVOT-FS to determine one-year mortality was TAPSE <18 mm and RVOT-FS <40%. The one-year mortality in patients with low TAPSE (n = 88) and in patients with both low TAPSE and low RVOT-FS (n = 60) was 45.5% and 48.3%, respectively; p = 0.724. In a multivariate analysis, RVOT-FS did not add significant prognostic information to that provided by TAPSE <18 mm (p = 0.197). CONCLUSIONS: TAPSE was an independent predictor of one-year all-cause mortality in mechanically ventilated septic patients. RVOT-FS was not associated with one-year mortality and added no prognostic value to TAPSE in these patients.

Antiphospholipid Antibodies in Critically Ill Patients With COVID-19.

OBJECTIVE: Coagulopathy is one of the characteristics observed in critically ill patients with coronavirus disease 2019 (COVID-19). Antiphospholipid antibodies (aPLs) contribute to coagulopathy, though their role in COVID-19 remains unclear. This study was undertaken to determine the prevalence and characteristics of aPLs in patients with COVID-19. METHODS: Sera collected from 66 COVID-19 patients who were critically ill and 13 COVID-19 patients who were not critically ill were tested by chemiluminescence immunoassay for anticardiolipin antibodies (aCLs), anti-ß2 -glycoprotein I (anti-ß2 GPI) (IgG, IgM, and IgA), and IgG anti-ß2 GPI-domain 1 (anti-ß2 GPI-D1) and IgM and IgG anti-phosphatidylserine/prothrombin (anti-PS/PT) antibodies were detected in the serum by enzyme-linked immunosorbent assay. RESULTS: Of the 66 COVID-19 patients in critical condition, aPLs were detected in 31 (47% ). Antiphospholipid antibodies were not present among COVID-19 patients who were not in critical condition. The IgA anti-ß2 GPI antibody was the most commonly observed aPL in patients with COVID-19 and was present in 28.8% (19 of 66) of the critically ill patients, followed by IgA aCLs (17 of 66, or 25.8%) and IgG anti-ß2 GPI (12 of 66, or 18.2%). For multiple aPLs, IgA anti-ß2 GPI + IgA aCLs was the most common antibody profile observed (15 of 66, or 22.7%), followed by IgA anti-ß2 GPI + IgA aCL + IgG anti-ß2 GPI (10 of 66, or 15.2%). Antiphospholipid antibodies emerge ~35-39 days after disease onset. A dynamic analysis of aPLs revealed 4 patterns based on the persistence or transient appearance of the aPLs. Patients with multiple aPLs had a significantly higher incidence of cerebral infarction compared to patients who were negative for aPLs (P = 0.023). CONCLUSION: Antiphospholipid antibodies were common in critically ill patients with COVID-19. Repeated testing demonstrating medium to high titers of aPLs and the number of aPL types a patient is positive for may help in identifying patients who are at risk of developing cerebral infarction. Antiphospholipid antibodies may be transient and disappear within a few weeks, but in genetically predisposed patients, COVID-19 may trigger the development of an autoimmune condition similar to the antiphospholipid syndrome (APS), referred to as "COVID-19-induced APS-like syndrome." Long-term follow-up of COVID-19 patients who are positive for aPLs would be of great importance in understanding the pathogenesis of this novel coronavirus.

Neurological Manifestations in Critically Ill Patients With COVID-19: A Retrospective Study.

Background: The complications of coronavirus disease 2019 (COVID-19) involved multiple organs or systems, especially in critically ill patients. We aim to investigate the neurological complications in critically ill patients with COVID-19. Methods: This retrospective single-center case series analyzed critically ill patients with COVID-19 at the intensive care unit of Tongji Hospital, Wuhan, China from February 5 to April 2, 2020. Demographic data, clinical and laboratory findings, comorbidities and treatments were collected and analyzed. Results: Among 86 patients with confirmed COVID-19, 54 patients (62.8%) were male, and the mean (SD) age was 66.6 (11.1) years. Overall, 65% patients presented with at least one neurological symptom. Twenty patients (23.3%) had symptoms involving the central nervous system, including delirium, cerebrovascular diseases and hypoxic-ischemic brain injury, while 6 patients (7%) had neuromuscular involvement. Seven of 86 patients exhibited new stroke and 6 (7%) cases were ischemic. A significantly higher prevalence of antiphospholipid antibodies was observed in patients with ischemic stroke than in those without stroke (83.3 vs. 26.9%, p < 0.05). Patients with ischemic stroke were more likely to have a higher myoglobulin level, and a lower hemoglobin level. Conclusions: The clinical spectrum of neurological complications in critically ill patients with COVID-19 was broad. Stroke, delirium and neuromuscular diseases are common neurological complications of COVID-19. Physicians should pay close attention to neurological complications in critically ill patients with COVID-19.

Correlation between cytokines and coagulation-related parameters in patients with coronavirus disease 2019 admitted to ICU.

BACKGROUND: The novel SARS-CoV-2 caused a large number of infections and deaths worldwide. Thus, new ideas for an appropriated assessment of patients' condition and clinical treatment are of utmost importance. Therefore, in this study, the laboratory parameters of patients with coronavirus disease 2019 (COVID-19) were evaluated to identify the correlation between cytokine expression and other laboratory parameters. METHODS: A retrospective and single-center study was performed in Wuhan, involving 83 severe or critical COVID-19 patients admitted to the intensive care unit (ICU). Laboratory parameters in ICU patients with laboratory-confirmed infection of SARS-CoV2 were collected. The association between parameters was assessed by Spearman's rank correlation. RESULTS: Patients' median age was 66 years (IQR, 57-73), and 55 (66%) were men. Among the 83 patients, 61 (73%) had 1 or more coexisting medical condition. The median concentration of IL-2R, IL-6, IL8, IL10, and TNFα were above the normal range, without IL-1ß. A significant negative correlation between IL-6 and platelet count was discovered (r2 = -0.448, P < 0.001) as well as a significant correlation between IL-6 and other platelet parameters. Finally, a correlation between multiple cytokines and coagulation indicators was found, pro-inflammatory factors were found to be more associated to coagulation parameters, with the highest correlation between IL-6 and the International normalized ratio (INR) (r2 = 0.444, P < 0.001). CONCLUSIONS: Our results suggested that cytokines play an important role in the pathogenesis of COVID-19. In addition, IL-6 seems more relevant in the evaluation of the condition of COVID-19 patients.