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1.
SSRN;
Preprint in English | SSRN | ID: ppcovidwho-326406

ABSTRACT

Background: Since there is no available data on the trends of caesarean section (CS) rates in pregnant women with COVID-19 through the pandemic, we aimed to analyse the trends in caesarean section rate in a large cohort of pregnant women with COVID-19 according to the Robson Ten Group Classification System of deliveries. Methods: We prospectively enrolled pregnant women with diagnosis of COVID-19 who delivered in our Center between March 2020 and November 2021. Deliveries were classified according to Robson group classification and according to three time periods: 1) deliveries from March 2020 to December 2020;2) deliveries from January 2021 to April 2021;3) deliveries from May 2021 to November 2021.We compared pregnancy characteristics and incidence of caesarean section according to the Robson category in the total population and according to the three time periods. Findings: We included in our analysis 457 patients matching the inclusion criteria . We found that overall CS rate significantly decreased over time from period 1 to period 3 (152/222, 68.5% vs 81/134, 60.4% vs 58/101, 57.4%, χ 2 =4.261, p=0.039). CS rate significantly decreased over time in Robson category 1 (48/80, 60% vs 27/47,57.4% vs 8/24, 33.3%, χ2 =4.097, p=0.043) and Robson category 3 (13/42, 31% vs 6/33, 18.2% vs 2/22, 9.1%, χ2 =4.335, p=0.037). We also found that incidence of induction of labor significantly increased over time (8/222, 3.6% vs 12/134, 9% vs 11/101, 10.9%, χ2 =7.245, p=0.027). Interpretation Our data provide an overview of the temporal changes in the management and obstetric outcome of COVID-19 pregnant women through the pandemic, confirming that working in a high-volume referral center for COVID-19 in pregnancy improved standards of obstetrical assistance over time. Funding: None to declare.

2.
Am J Obstet Gynecol MFM ; 4(3): 100592, 2022 05.
Article in English | MEDLINE | ID: covidwho-1670131

ABSTRACT

BACKGROUND: Different factors may influence the closure of the uterine wall, including suture material. Suture materials may indeed influence tissue healing and therefore the development of scar defects. OBJECTIVE: To test whether uterine closure using synthetic absorbable monofilament sutures at the time of cesarean delivery would reduce the rate of cesarean scar defects compared with uterine closure using synthetic absorbable multifilament sutures. STUDY DESIGN: Parallel-group, nonblinded, randomized clinical trial of women with singleton pregnancies undergoing cesarean delivery at term in a single center in Italy. The inclusion criteria were singleton pregnancy, first or second cesarean delivery, scheduled and emergent or urgent cesarean deliveries, and gestational age between 37 0/7 and 42 0/7 weeks. Eligible participants were randomly allocated in a 1:1 ratio to either the monofilament group (polyglytone 6211 [Caprosyn]; Covidien, Dublin, Ireland) or the multifilament suture group (coated polyglactin 910 suture with Triclosan [Vicryl Plus]; Ethicon, Inc, Raritan, NJ). The primary outcome was the incidence of cesarean scar defect at ultrasound at the 6-month follow-up visit. The secondary outcomes were residual myometrial thickness and symptoms. RESULTS: Overall, 300 women were included in the trial. Of the randomized women, 151 were randomized to the monofilament group and 149 to the multifilament group. However, 27 women were lost to follow-up: 15 in the monofilament group and 12 in the multifilament group. Of note, 6 months after delivery, the incidence rates of cesarean scar defect were 18.4% (25 of 136 patients) in the monofilament group and 23.4% (32 of 137 patients) in the multifilament group (relative risk, 0.79; 95% confidence interval, 0.41-1.25; P=.31). The mean residual myometrial thicknesses were 7.6 mm in the monofilament group and 7.2 mm in the multifilament group (mean difference, +0.40 mm; 95% confidence interval, -0.23 to 1.03). There was no between-group substantial difference found in the incidence of symptoms, including pelvic pain, painful periods, and dyspareunia. CONCLUSION: In singleton pregnancies undergoing primary or second cesarean delivery, the use of synthetic absorbable monofilament sutures at the time of uterine wall closure was not associated with a reduction in the rate of cesarean scar defect 6 months after delivery compared with the use of synthetic absorbable multifilament sutures.


Subject(s)
Cicatrix , Suture Techniques , Cesarean Section/adverse effects , Cicatrix/epidemiology , Cicatrix/etiology , Cicatrix/prevention & control , Female , Humans , Male , Polyglactin 910 , Pregnancy , Suture Techniques/adverse effects , Sutures
3.
J Gynecol Oncol ; 33(1): e10, 2022 01.
Article in English | MEDLINE | ID: covidwho-1573883

ABSTRACT

OBJECTIVE: Coronavirus disease 2019 (COVID-19) outbreak has correlated with the disruption of screening activities and diagnostic assessments. Endometrial cancer (EC) is one of the most common gynecological malignancies and it is often detected at an early stage, because it frequently produces symptoms. Here, we aim to investigate the impact of COVID-19 outbreak on patterns of presentation and treatment of EC patients. METHODS: This is a retrospective study involving 54 centers in Italy. We evaluated patterns of presentation and treatment of EC patients before (period 1: March 1, 2019 to February 29, 2020) and during (period 2: April 1, 2020 to March 31, 2021) the COVID-19 outbreak. RESULTS: Medical records of 5,164 EC patients have been retrieved: 2,718 and 2,446 women treated in period 1 and period 2, respectively. Surgery was the mainstay of treatment in both periods (p=0.356). Nodal assessment was omitted in 689 (27.3%) and 484 (21.2%) patients treated in period 1 and 2, respectively (p<0.001). While, the prevalence of patients undergoing sentinel node mapping (with or without backup lymphadenectomy) has increased during the COVID-19 pandemic (46.7% in period 1 vs. 52.8% in period 2; p<0.001). Overall, 1,280 (50.4%) and 1,021 (44.7%) patients had no adjuvant therapy in period 1 and 2, respectively (p<0.001). Adjuvant therapy use has increased during COVID-19 pandemic (p<0.001). CONCLUSION: Our data suggest that the COVID-19 pandemic had a significant impact on the characteristics and patterns of care of EC patients. These findings highlight the need to implement healthcare services during the pandemic.


Subject(s)
COVID-19 , Endometrial Neoplasms , Endometrial Neoplasms/epidemiology , Endometrial Neoplasms/therapy , Female , Humans , Pandemics , Retrospective Studies , SARS-CoV-2
4.
Eur J Med Chem ; 226: 113863, 2021 Dec 15.
Article in English | MEDLINE | ID: covidwho-1433179

ABSTRACT

COVID-19 pandemic, starting from the latest 2019, and caused by SARS-CoV-2 pathogen, led to the hardest health-socio-economic disaster in the last century. Despite the tremendous scientific efforts, mainly focused on the development of vaccines, identification of potent and efficient anti-SARS-CoV-2 therapeutics still represents an unmet need. Remdesivir, an anti-Ebola drug selected from a repurposing campaign, is the only drug approved, so far, for the treatment of the infection. Nevertheless, WHO in later 2020 has recommended against its use in COVID-19. In the present paper, we describe a step-by-step in silico design of a small library of compounds as main protease (Mpro) inhibitors. All the molecules were screened by an enzymatic assay on Mpro and, then, cellular activity was evaluated using Vero cells viral infection model. The cellular screening disclosed compounds 29 and 34 as in-vitro SARS-CoV-2 replication inhibitors at non-toxic concentrations (0.32 < EC50 < 5.98 µM). To rationalize these results, additional in-vitro assays were performed, focusing on papain like protease (PLpro) and spike protein (SP) as potential targets for the synthesized molecules. This pharmacological workflow allowed the identification of compound 29, as a dual acting SARS-CoV-2 proteases inhibitor featuring micromolar inhibitory potency versus Mpro (IC50 = 1.72 µM) and submicromolar potency versus PLpro (IC50 = 0.67 µM), and of compound 34 as a selective SP inhibitor (IC50 = 3.26 µM).


Subject(s)
Antiviral Agents/pharmacology , Drug Design , Protease Inhibitors/pharmacology , SARS-CoV-2/drug effects , Animals , Chlorocebus aethiops , Computer Simulation , SARS-CoV-2/enzymology , Vero Cells
5.
Int J Mol Sci ; 22(17)2021 Aug 30.
Article in English | MEDLINE | ID: covidwho-1379977

ABSTRACT

A novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been identified as the pathogen responsible for the outbreak of a severe, rapidly developing pneumonia (Coronavirus disease 2019, COVID-19). The virus enzyme, called 3CLpro or main protease (Mpro), is essential for viral replication, making it a most promising target for antiviral drug development. Recently, we adopted the drug repurposing as appropriate strategy to give fast response to global COVID-19 epidemic, by demonstrating that the zonulin octapeptide inhibitor AT1001 (Larazotide acetate) binds Mpro catalytic domain. Thus, in the present study we tried to investigate the antiviral activity of AT1001, along with five derivatives, by cell-based assays. Our results provide with the identification of AT1001 peptide molecular framework for lead optimization step to develop new generations of antiviral agents of SARS-CoV-2 with an improved biological activity, expanding the chance for success in clinical trials.


Subject(s)
Antiviral Agents/pharmacology , Molecular Docking Simulation , Oligopeptides/chemistry , Peptides/metabolism , SARS-CoV-2/drug effects , Antiviral Agents/chemistry , Antiviral Agents/metabolism , Antiviral Agents/therapeutic use , Binding Sites , COVID-19/drug therapy , COVID-19/virology , Catalytic Domain , Cell Line , Cytomegalovirus/drug effects , Drug Repositioning , Herpesvirus 3, Human/drug effects , Humans , Molecular Dynamics Simulation , Peptides/chemical synthesis , Peptides/pharmacology , Peptides/therapeutic use , SARS-CoV-2/isolation & purification , SARS-CoV-2/metabolism , Viral Matrix Proteins/chemistry , Viral Matrix Proteins/metabolism
6.
Front Chem ; 8: 628609, 2020.
Article in English | MEDLINE | ID: covidwho-1058409

ABSTRACT

The most severe outcome of COVID-19 infection is the development of interstitial pneumonia causing acute lung injury (ALI) and/or acute respiratory distress syndrome (ARDS), both responsible for the infected patients' mortality. ALI and ARDS are characterized by a leakage of plasma components into the lungs, compromising their ability to expand and optimally engage in gas exchange with blood, resulting in respiratory failure. We have previously reported that zonulin, a protein dictating epithelial and endothelial permeability in several districts, including the airways, is involved in ALI pathogenesis in mouse models, and that its peptide inhibitor Larazotide acetate (also called AT1001) ameliorated ALI and subsequent mortality by decreasing mucosal permeability to fluid and extravasation of neutrophils into the lungs. With the recent crystallographic resolution of the SARS-CoV-2 main protease (Mpro), an enzyme fundamental in the viral lifecycle, bound to peptidomimetic inhibitors N3 and 13b, we were able to perform molecular modeling investigation showing that AT1001 presents structural motifs similar to co-crystallized ligands. Specifically, molecular docking, MM-GBSA-based predictions and molecular dynamics showed that AT1001 docks extremely well in the Mpro catalytic domain through a global turn conformational arrangement without any unfavorable steric hindrance. Finally, we have observed that AT1001 can be superimposed onto the crystallized structures of N3 and 13b, establishing a higher number of interactions and accordingly a tighter binding. In vitro studies confirmed AT1001 anti-Mpro and preliminary investigation indicted an anti-viral activity. Combined, these studies suggest that AT1001, besides its well-demonstrated effect in ameliorating mucosal permeability in ALI/ARDS, may also exert a direct anti-SARS-CoV-2 effect by blocking the Mpro. AT1001 has been used extensively in a variety of animal models of ALI demonstrating robust safety and efficacy; it is currently in phase 3 trials in celiac subjects showing strong safety and efficacy profiles. We therefore propose its use as a specific anti-SARS-CoV-2 multitargeting treatment for the current pandemic.

7.
RSC Adv ; 10(67): 40867-40875, 2020 Nov 09.
Article in English | MEDLINE | ID: covidwho-943925

ABSTRACT

The recent release of the main protein structures belonging to SARS CoV-2, responsible for the coronavirus disease-19 (COVID-19), strongly pushed for identifying valuable drug treatments. With this aim, we show a repurposing study on FDA-approved drugs applying a new computational protocol and introducing a novel parameter called IVSratio. Starting with a virtual screening against three SARS CoV-2 targets (main protease, papain-like protease, spike protein), the top-ranked molecules were reassessed combining the Inverse Virtual Screening novel approach and MM-GBSA calculations. Applying this protocol, a list of drugs was identified against the three investigated targets. Also, the top-ranked selected compounds on each target (rutin vs. main protease, velpatasvir vs. papain-like protease, lomitapide vs. spike protein) were further tested with molecular dynamics simulations to confirm the promising binding modes, obtaining encouraging results such as high stability of the complex during the simulation and a good protein-ligand interaction network involving some important residues of each target. Moreover, the recent outcomes highlighting the inhibitory activity of quercetin, a natural compound strictly related to rutin, on the SARS-CoV-2 main protease, strengthened the applicability of the proposed workflow.

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