Outpatient Use of Monoclonal Antibodies Casirivimab and Imdevimab in Pregnancy for Mild-to-Moderate Coronavirus Disease 2019.

OBJECTIVE: The aim of this study was to report the use casirivimab/imdevimab therapy in pregnant women with moderate coronavirus disease 2019 (COVID-19). STUDY DESIGN: We report 12 cases of unvaccinated pregnant patients with mild-to-moderate COVID-19 treated with casirivimab/imdevimab. RESULTS: Twelve unvaccinated pregnant patients with mild-to-moderate COVID-19 received casirivimab/imdevimab at the dose of 1200/1200 mg by intravenous infusion over 60 minutes. All women were managed outpatient. None experienced severe adverse drug reaction and none progressed to severe disease. CONCLUSION: Casirivimab/imdevimab should be considered for outpatient treatment of unvaccinated pregnant women with mild-to-moderate COVID-19 to decrease the risk of severe disease. KEY POINTS: · Casirivimab/imdevimab is not well studied in pregnant women.. · Casirivimab/imdevimab in pregnant women with mild-to-moderate COVID-19 decreases the risk of severe disease.. · Casirivimab/imdevimab in pregnant women with mild-to-moderate COVID-19 is well tolerated..

How SARS-CoV-2 Infection Impacts the Management of Patients with Vulvar Cancer: Experience in a Third-Level Hospital of Southern Italy.

Background: Since February 2020, the spread of Coronavirus Disease 2019 (COVID-19) in Italy has induced the government to call for lockdown of any activity apart from primary needs, and changing the lives of each of us. All that has dramatically impacted the management of patients affected by cancer. Patients with vulvar cancer (VC) represent a particularly frail population because they are elderly and affected by multiple comorbidities. The aim of this study is to evaluate the clinical impact of the SARS-CoV-2 infection on VC patients in terms of delay or impossibility of carrying out the scheduled treatment. Methods: The medical records of patients affected by vulvar tumors, referred to "DAI Materno-Infantile" of AOU Federico II of Naples between February 2020 and January 2022 were retrospectively analyzed. The presence of a positive reverse transcription-polymerase chain reaction (RT-PCR) in nasopharyngeal swab defined the positivity to SARS-CoV-2. Results: Twenty-four patients with VC were analyzed and scheduled for treatment. The median age was 70.7 years (range: 59-80). Seven (29.2%) patients were diagnosed with SARS-CoV-2 infection: In three (42.8%) patients, the treatment was delayed with no apparent consequences, in four (57.2%), the treatment was delayed or changed due to cancer progression and, of these four, one died due to respiratory complications of COVID-19, and one died due to oncologic disease progression. Conclusion: COVID-19 caused, in most cases, significant delays in oncologic treatments and high mortality in our series of patients affected by VC.

Stopping or Continuing to Follow Best Practices in Terms of ESG during the COVID-19 Pandemic? An Exploratory Study of European Listed Companies

This study aims to examine the effect of the COVID-19 pandemic on environmental, social, and governance (ESG) performance for European listed companies. The purpose of this study is to understand if and how the COVID-19 pandemic outbreak influenced the behavior of European companies in terms of best practices in ESG. In this paper, we consider the ESG score as a proxy of management practices. The ESG score was collected for all companies included in the STOXX 600 index (from the Refinitiv Eikon database) and analyzed using fixed and random effects. The sample is composed of 600 European listed companies and covers the period from 2018 to 2021. The results show that even in a health crisis with economic repercussions for the whole world, companies have continued to increase their commitment to ESG targets. The results are robust, also considering the different components of the ESG score (environment, social, governance) individually. This paper validates the significance for companies to improve their ESG performance even during unstable times. Our analysis has implications from several perspectives, adding supplementary information and considerations to the uncompleted debate examining the effects of external shocks on ESG performance.

Casirivimab and Imdevimab for Pregnant Women Hospitalized for Severe Coronavirus Disease 2019 (COVID-19).

OBJECTIVE: To evaluate safety and efficacy of casirivimab/imdevimab therapy in pregnant women with severe COVID-19 requiring oxygen therapy. METHODS: This was a prospective case series study aimed to evaluate safety and efficacy of casirivimab/imdevimab therapy in unvaccinated pregnant women with severe COVID-19. Inclusion criteria were: SARS CoV-2 infection documented with PCR, pregnancy, severe COVID-19 requiring oxygen therapy, duration of symptoms of 10 days or less, able to provide informed consent. Vaccinated women, and those with mild-to-moderate disease were excluded from the study. Included patients received casirivimab and imdevimab as single intravenous dose of 4000/4000 mg. Women were also treated with low molecular weight heparin, steroids and antibiotics, if necessary. The primary outcome was maternal death. Secondary outcomes were: rate of adverse events during infusion or within 72 hours, and rate of abortion. RESULTS: Thirteen hospitalized unvaccinated pregnant women with severe COVID-19 requiring oxygen and treated with casirivimab/imdevimab were included in the study. We observed no maternal death, and no patients required intubation or admission to intensive care unit. No abortion or fetal loss were recorded. Nine pregnancies were still ongoing, and there were three cesarean deliveries and one vaginal delivery. Two were preterm deliveries (at 31 and 34 weeks), and two were term deliveries. CONCLUSION: Casirivimab/imdevimab therapy may be considered as therapy in unvaccinated pregnant women with severe COVID-19.

Rational design of the zonulin inhibitor AT1001 derivatives as potential anti SARS-CoV-2.

Although vaccines are greatly mitigating the worldwide pandemic diffusion of SARS-Cov-2, therapeutics should provide many distinct advantages as complementary approach to control the viral spreading. Here, we report the development of new tripeptide derivatives of AT1001 against SARS-CoV-2 Mpro. By molecular modeling, a small compound library was rationally designed and filtered for enzymatic inhibition through FRET assay, leading to the identification of compound 4. X-ray crystallography studies provide insights into its binding mode and confirm the formation of a covalent bond with Mpro C145. In vitro antiviral tests indicate the improvement of biological activity of 4 respect to AT1001. In silico and X-ray crystallography analysis led to 58, showing a promising activity against three SARS-CoV-2 variants and a valuable safety in Vero cells and human embryonic lung fibroblasts. The drug tolerance was also confirmed by in vivo studies, along with pharmacokinetics evaluation. In summary, 58 could pave the way to develop a clinical candidate for intranasal administration.

Characteristics of Placental Histopathology in Women with Uncomplicated Pregnancies Affected by SARS-CoV-2 Infection at the Time of Delivery: A Single-Center Experience.

The aim of this study was, firstly, to analyze the histopathological characteristics of placentas in women with uneventful pregnancies and affected by COVID-19 at the time of delivery; and secondly, to correlate histological findings to maternal and neonatal characteristics. In our single-center prospective observational study, 46 placentas from term uncomplicated singleton pregnancies of patients with a documented SARS-CoV-2 infection at the time of delivery underwent histological examination. Despite a normal feto-maternal outcome, most of the placentas (82.6%) presented signs of maternal vascular malperfusion, while features of fetal vascular malperfusion were found in 54% of cases. No correlation was detected between maternal and neonatal characteristics and the severity of blood circulation disease, and abnormal findings were also described in asymptomatic patients. Moreover, we did not find any maternal symptoms or clinical details allowing for the prediction of abnormal placental findings in pregnancy complicated by COVID-19 infection. Our results suggest that SARS-CoV-2 infection during pregnancy could lead to acute placental dysfunction.

Trends in Caesarean Section Rate According to Robson Group Classification among Pregnant Women with SARS-CoV-2 Infection: A Single-Center Large Cohort Study in Italy.

BACKGROUND: Since there is no available data on temporal trends of caesarean section (CS) rates in pregnant women with COVID-19 through the pandemic, we aimed to analyze 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 a diagnosis of COVID-19 who delivered in our center between March 2020 and November 2021. Deliveries were classified, according to the 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. RESULTS: We included 457 patients matching the inclusion criteria in our analysis. 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%, χ2 = 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 the 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). CONCLUSION: 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 standards of obstetrical assistance for pregnancies complicated by SARS-CoV-2 infection improved over time.

Rational design of the zonulin inhibitor AT1001 derivatives as potential anti SARS-CoV-2

Although vaccines are greatly mitigating the worldwide pandemic diffusion of SARS-Cov-2, therapeutics should provide many distinct advantages as complementary approach to control the viral spreading. Here, we report the development of new tripeptide derivatives of AT1001 against SARS-CoV-2 Mpro. By molecular modeling, a small compound library was rationally designed and filtered for enzymatic inhibition through FRET assay, leading to the identification of compound 4. X-ray crystallography studies provide insights into its binding mode and confirm the formation of a covalent bond with Mpro C145. In vitro antiviral tests indicate the improvement of biological activity of 4. In silico and X-ray crystallography analysis led to 58, showing a promising activity against three SARS-CoV-2 variants and a valuable safety in Vero cells and human embryonic lung fibroblasts. The drug tolerance was also confirmed by in vivo studies, along with pharmacokinetics evaluation. In summary, 58 could pave the way to develop a clinical candidate for intranasal administration. Graphical Image 1

Monofilament vs multifilament suture for uterine closure at the time of cesarean delivery: a randomized clinical trial.

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.

Characteristics and patterns of care of endometrial cancer before and during COVID-19 pandemic.

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.

Identification of a dual acting SARS-CoV-2 proteases inhibitor through in silico design and step-by-step biological characterization.

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).

Peptide Derivatives of the Zonulin Inhibitor Larazotide (AT1001) as Potential Anti SARS-CoV-2: Molecular Modelling, Synthesis and Bioactivity Evaluation.

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.

In silico Analysis Revealed Potential Anti-SARS-CoV-2 Main Protease Activity by the Zonulin Inhibitor Larazotide Acetate.

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.

Accelerating the repurposing of FDA-approved drugs against coronavirus disease-19 (COVID-19).

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.