MOLNUPIRAVIR COMPARED TO NIRMATRELVIR/RITONAVIR FOR COVID-19 IN HIGH-RISK PATIENTS WITH HAEMATOLOGICAL MALIGNANCY IN EUROPE. A MATCHED-PAIRED ANALYSIS FROM THE EPICOVIDEHA REGISTRY

Introduction: Molnupiravir and nirmatrelvir/ritonavir are antivirals used to prevent progression to severe SARS-CoV-2 infections, which reduce both hospitalization and mortality rates. Nirmatrelvir/ritonavir was authorised in Europe in December 2021, while molnupiravir is not yet licensed in Europe as of February 2022. Molnupiravir may be an alternative to nirmatrelvir/ritonavir, because it displays less frequent drug-drug interactions and contraindications. A caveat connected to molnupiravir derives from the mode of action inducing viral mutations. In clinical trials on patients without haematological malignancy, mortality rate reduction of molnupiravir appeared less pronounced than that of nirmatrelvir/ritonavir. Little is known about the comparative efficacy of the two drugs in patients with haematological malignancy at high-risk of severe COVID-19. Thus, we here assess the effectiveness of molnupiravir compared to nirmatrelvir/ritonavir in our cohort of patients with haematological malignancies. Methods: Clinical data of patients treated either with molnupiravir or nirmatrelvir/ritonavir monotherapy for COVID-19 were retrieved from the EPICOVIDEHA registry. Patients treated with molnupiravir were matched by sex, age (±10 years), and baseline haematological malignancy severity to controls treated with nirmatrelvir/ritonavir. Results: A total of 116 patients receiving molnupiravir for the clinical management of COVID-19 were matched to an equal number of controls receiving nirmatrelvir/ritonavir. In each of the groups, 68 (59%) patients were male; with a median age of 64 years (IQR 53-74) for molnupiravir recipients and 64 years (IQR 54-73) for nirmatrelvir/ritonavir recipients; 57% (n=66) of the patients had controlled baseline haematological malignancy, 13% (n=15) stable, and 30% (n=35) had active disease at COVID-19 onset in each of the groups. During COVID-19 infection, one third of patients from each group were admitted to hospital. Although a similar proportion of vaccinated patients was observed in both groups (molnupiravir n=77, 66% vs nirmatrelvir/ritonavir n=87, 75%), those treated with nirmatrelvir/ritonavir had more often received four doses (n=27, 23%) as compared to patients treated with molnupiravir (n=5, 4%, p<0.001). No differences were detected in COVID-19 severity (p=0.39) or hospitalization (p=1.0). No statistically significant differences were identified in overall mortality rate (p=0.78) or in survival probability (d30 p=0.19, d60 p=0.67, d90 p=0.68, last day of follow up p=0.68). In all patients, deaths were either attributed to COVID-19 or the infection contributed to death as per treating physician's judgement. Conclusions: In high-risk patients with haematological malignancies and COVID-19, molnupiravir showed rates of hospitalization and mortality comparable to those of nirmatrelvir/ritonavir in this matched-pair analysis. Molnupiravir appears to be a plausible alternative to nirmatrelvir/ritonavir for COVID-19 treatment in patients with haematological malignancy

Nirmatrelvir/ritonavir in COVID-19 patients with haematological malignancies: a report from the EPICOVIDEHA registry

Background: Nirmatrelvir/ritonavir treatment decreases the hospitalisation rate in immunocompetent patients with COVID-19, but data on efficacy in patients with haematological malignancy are scarce. Here, we describe the outcome of nirmatrelvir/ritonavir treatment in a large cohort of the latter patients. Methods: This is a retrospective cohort study from the multicentre EPICOVIDEHA registry (NCT04733729) on patients with haematological malignancy, who were diagnosed with COVID-19 between January and September 2022. Patients receiving nirmatrelvir/ritonavir were compared to those who did not. A logistic regression was run to determine factors associated with nirmatrelvir/ritonavir administration in our sample. Mortality between treatment groups was assessed with Kaplan-Meier survival plots after matching all the patients with a propensity score. Additionally, a Cox regression was modelled to detect factors associated with mortality in patients receiving nirmatrelvir/ritonavir. Findings: A total of 1859 patients were analysed, 117 (6%) were treated with nirmatrelvir/ritonavir, 1742 (94%) were treated otherwise. Of 117 patients receiving nirmatrelvir/ritonavir, 80% had received ≥1 anti-SARS-CoV-2 vaccine dose before COVID-19 onset, 13% of which received a 2nd vaccine booster. 5% were admitted to ICU. Nirmatrelvir/ritonavir treatment was associated with the presence of extrapulmonary symptoms at COVID-19 onset, for example anosmia, fever, rhinitis, or sinusitis (aOR 2.509, 95%CI 1.448-4.347) and 2nd vaccine booster (aOR 3.624, 95%CI 1.619-8.109). Chronic pulmonary disease (aOR 0.261, 95%CI 0.093-0.732) and obesity (aOR 0.105, 95%CI 0.014-0.776) were not associated with nirmatrelvir/ritonavir use. After propensity score matching, day-30 mortality rate in patients treated with nirmatrelvir/ritonavir was 2%, significantly lower than in patients with SARS-CoV-2 directed treatment other than nirmatrelvir/ritonavir (11%, p = 0.036). No factor was observed explaining the mortality difference in patients after nirmatrelvir/ritonavir administration. Interpretation: Haematological malignancy patients were more likely to receive nirmatrelvir/ritonavir when reporting extrapulmonary symptoms or 2nd vaccine booster at COVID-19 onset, as opposed to chronic pulmonary disease and obesity. The mortality rate in patients treated with nirmatrelvir/ritonavir was lower than in patients with targeted drugs other than nirmatrelvir/ritonavir. Funding: EPICOVIDEHA has received funds from Optics COMMIT (COVID-19 Unmet Medical Needs and Associated Research Extension) COVID-19 RFP program by GILEAD Science, United States (Project 2020-8223)

Age, Successive Waves, Immunization, and Mortality in Elderly COVID-19 Haematological Patients: EPICOVIDEHA Findings

Introduction: elderly patients with haematologic malignancies face the highest risk of severe COVID-19 outcomes. The infection impact in different age groups remains unstudied in detail. Methods: We analysed elderly patients (age groups: 65-70, 71-75, 76-80 and >80 years old) with hematologic malignancies included in the EPICOVIDEHA registry between January 2020 and July 2022. Univariable and multivariable Cox regression models were conducted to identify factors influencing death in COVID-19 patients with haematological malignancy. results: the study included data from 3,603 elderly patients (aged 65 or older) with haematological malignancy, with a majority being male (58.1%) and a significant proportion having comorbidities. The patients were divided into four age groups, and the analysis assessed COVID-19 outcomes, vaccination status, and other variables in relation to age and pandemic waves.tThe 90-day survival rate for patients with COVID-19 was 71.2%, with significant differences between groups. The pandemic waves had varying impacts, with the first wave affecting patients over 80 years old, the second being more severe in 65-70, and the third being the least severe in all age groups. factors contributing to 90-day mortality included age, comorbidities, lymphopenia, active malignancy, acute leukaemia, less than three vaccine doses, severe COVID-19, and using only corticosteroids as treatment. Conclusions: These data underscore the heterogeneity of elderly haematological patients, highlight the different impact of COVID waves and the pivotal importance of vaccination, and may help in planning future healthcare efforts

Risk factors associated with adverse fetal outcomes in pregnancies affected by Coronavirus disease 2019 (COVID-19): a secondary analysis of the WAPM study on COVID-19.

Objectives To evaluate the strength of association between maternal and pregnancy characteristics and the risk of adverse perinatal outcomes in pregnancies with laboratory confirmed COVID-19. Methods Secondary analysis of a multinational, cohort study on all consecutive pregnant women with laboratory-confirmed COVID-19 from February 1, 2020 to April 30, 2020 from 73 centers from 22 different countries. A confirmed case of COVID-19 was defined as a positive result on real-time reverse-transcriptase-polymerase-chain-reaction (RT-PCR) assay of nasal and pharyngeal swab specimens. The primary outcome was a composite adverse fetal outcome, defined as the presence of either abortion (pregnancy loss before 22 weeks of gestations), stillbirth (intrauterine fetal death after 22 weeks of gestation), neonatal death (death of a live-born infant within the first 28 days of life), and perinatal death (either stillbirth or neonatal death). Logistic regression analysis was performed to evaluate parameters independently associated with the primary outcome. Logistic regression was reported as odds ratio (OR) with 95% confidence interval (CI). Results Mean gestational age at diagnosis was 30.6+/-9.5 weeks, with 8.0% of women being diagnosed in the first, 22.2% in the second and 69.8% in the third trimester of pregnancy. There were six miscarriage (2.3%), six intrauterine device (IUD) (2.3) and 5 (2.0%) neonatal deaths, with an overall rate of perinatal death of 4.2% (11/265), thus resulting into 17 cases experiencing and 226 not experiencing composite adverse fetal outcome. Neither stillbirths nor neonatal deaths had congenital anomalies found at antenatal or postnatal evaluation. Furthermore, none of the cases experiencing IUD had signs of impending demise at arterial or venous Doppler. Neonatal deaths were all considered as prematurity-related adverse events. Of the 250 live-born neonates, one (0.4%) was found positive at RT-PCR pharyngeal swabs performed after delivery. The mother was tested positive during the third trimester of pregnancy. The newborn was asymptomatic and had negative RT-PCR test after 14 days of life. At logistic regression analysis, gestational age at diagnosis (OR: 0.85, 95% CI 0.8-0.9 per week increase; pPeer reviewe

Predictors for prolonged hospital stay solely to complete intravenous antifungal treatment in patients with candidemia: Results from the ECMM candida III multinational European observational cohort study

Background To date, azoles represent the only viable option for oral treatment of invasive Candida infections, while rates of azole resistance among non-albicans Candida spp. continue to increase. The objective of this sub-analysis of the European multicenter observational cohort study Candida III was to describe demographical and clinical characteristics of the cohort requiring prolonged hospitalization solely to complete intravenous (iv) antifungal treatment (AF Tx). Methods Each participating hospital (number of eligible hospitals per country determined by population size) included the first ~ 10 blood culture proven adult candidemia cases occurring consecutively after July 1st, 2018, and treating physicians answered the question on whether hospital stay was prolonged only for completion of intravenous antifungal therapy. Descriptive analyses as well as binary logistic regression was used to assess for predictors of prolonged hospitalization solely to complete iv AF Tx. Findings Hospital stay was prolonged solely for the completion of iv AF Tx in 16% (100/621) of candidemia cases by a median of 16 days (IQR 8 – 28). In the multivariable model, initial echinocandin treatment was a positive predictor for prolonged hospitalization to complete iv AF Tx (aOR 2.87, 95% CI 1.55 – 5.32, p < 0.001), while (i) neutropenia, (ii) intensive care unit admission, (iii) catheter related candidemia, (iv) total parenteral nutrition, and (v) C. parapsilosis as causative pathogen were found to be negative predictors (aOR 0.22 – 0.45; p < 0.03). Interpretation Hospital stays were prolonged due to need of iv AF Tx in 16% of patients with candidemia. Those patients were more likely to receive echinocandins as initial treatment and were less severely ill and less likely infected with C. parapsilosis

Aortic valve repair or replacement in patients with aortic regurgitation: A systematic review and meta-analysis

Objective: To systematically compare clinical outcomes between aortic valve repair and replacement in patients with aortic regurgitation. Methods: A comprehensive literature search was undertaken among the four major databases (PubMed, Embase, Scopus, and Ovid) to identify all published data comparing clinical outcomes of aortic valve repair vs replacement. Database searched from inception to November 2018. Results: A total of 1071 patients were analyzed in eight articles. Mean age was similar in both groups of patients (47.2 ± 12.8 vs 48.3 ± 12.7 years, P = 0.83, aortic valve repair and replacement, respectively). The preoperative left ventricular ejection fraction was better in the repair group (56.7% ± 4.8 vs 53.3% ± 4.2, P = 0.005). The rate of moderate-to-severe regurgitation and bicuspid aortic valve were similar in both cohorts (81% vs 78%, P = 0.90% and 58% vs 55%, P = 0.46). In-hospital and 1-year mortality was lower in repair cohort, although not reaching statistical significance (1.3% vs 3.6%, P = 0.12; 5.9% vs 9.3%, P = 0.77). Reoperation rate was higher in repair patients at 1 year (8.8% vs 3.7%, P = 0.03). Conclusion: Aortic valve repair offers comparable perioperative outcomes to aortic valve replacement in aortic regurgitation patients at the expense of higher late reintervention rate. Larger trials with long-term follow-up are required to confirm the long-term benefits of aortic valve repair. © 2019 Wiley Periodicals, Inc

Influence of Polarization Processes on the Morphology and Photoluminescence Properties of PP/TiO₂ Polymer Nanocomposites

The paper reports of synthesis and investigation of polymeric nanocomposites based on isotactic polypropylene and titanium dioxide nanoparticles PP+TiO₂ (PPT). The structure of the PPT nanocomposites was studied by scanning electron and atomic force microscopy. There was also studied the influence of the polarization process by corona discharge on the structure and photoluminescence properties of PPT nanocomposites. It was found that intensity of the photoluminescence after the polarization increases, and this depends on the concentration of titan dioxide nanoparticles in the polymer matrix. It was shown that rms roughness for non-polarized sample compositions is 60-100 nm, whereas for polarized samples after the corona discharge polarization, makes 20-40 nm, i.e. there takes place grinding of the structural elements. It is supposed that, in the composite there forms sufficiently high internal local field, due to the boundary charges, so under the influence of this field there were excited additional luminescent centers, and as a result, after the polarization there was observed the increase of luminescence intensity

Treatment of extensive tumors of the jaws by hemimandibuloectomy with simultaniouse reconstruction of the mandible, arthroplasty of temporomandibular joint, orthopedic rehabilitation supported by dental implants

Background. Reconstruction of subtotal and total defects of maxillofacial region after ablative tumor surgery is a challenging task of reconstructive surgery. The “golden rule” is maintaining of radicalism of ablative surgery as well as appropriate surgical reconstruction and prosthodontic rehabilitation, that allows patient return to normal life. Wherein reconstructive procedure is focusing on restoring of mandibular continuity by the means of different flaps and grafts, while prosthodontic rehabilitation is performing after some period of time (usually around year) by the means of removable and non-removable prosthodontic devices. Non-removable device requiring dental implants insertion into grafted material followed by period of osteointegration, that is requiring some time as well. However, within this period of time one could observe significant soft tissue deformity.The objective is to improve the outcomes of surgical reconstruction of extensive defects of the mandible and to carry out rapid prosthodontic rehabilitation supported by dental implants by application of 3D preoperative planning and navigation devices.Clinical case. Forty-nine years-old female patient with recurrent ameloblastoma, that affects vertical and horizontal ramus of the mandible. Within virtual preoperative planning one performed: resection of the mandible associated with exarticulation of condylar head, virtual plate bending according to contours of the mandible (that were determined by application of “mirror” function of virtual planning software), arthroplasty of temporomandibular joint, determination of donor site on fibula bone, osteotomy of fibula free flap, positioning of dental implants, transferring of composite flap and it’s fixation by reconstructive plate. According to acquiring data one performed fabrication of patient specific navigation guides for both fibula flap segmentation and dental implants positioning. Surgical procedure included single-step tumor ablation and exarticulation of condylar head, reconstruction of defect by the means of osseo-myo-cutaneous fibula free flap, that was pre-implanted by dental implants, total joint reconstruction by titanium condylar head and polypropylene fossa, fixation of the flap and condylar head in recipient site by the means of prebended reconstructive plate, as well as insertion of non-removable bridge prosthodontic device. Postoperative result was asses clinically and radiologically. No significant postoperative complications occurred. Restoration of facial contours, mouth opening, I class occlusion, as well as adequate meal and speech were detected. Postoperative radiological investigation revealed adequate positioning of dental implants within neo-mandible, as well as positioning of artificial joint.Conclusion. In cases of extensive tumors of the jaws single-step ablative surgical procedure, reconstruction of missing anatomical structures of the jaws and simultaneous prosthodontic rehabilitation allows to prevent possible deformities of the soft tissues and due to rapid restoration of vital functions has great impact to quality of patient’s life. Adequacy of performing procedures could be reached by implementation of virtual preoperative planning and fabrication of patient-specific surgical guides