Mesenchymal Stem/Stromal Cells: BIOLOGICAL THREAT AGENT RICIN INTOXICATION OF THE LUNGS IS EFFECTIVELY TREATED BY MESENCURE, A PROFESSIONALIZED ALLOGENEIC MESENCHYMAL CELL THERAPY, PREFERABLY VIA THE SUBCUTANEOUS ROUTE

Background & Aim: Ricin is one of the most lethal toxins, particularly if inhaled, and is considered a biological threat agent due to its wide availability and ease of production. Pulmonary ricin intoxication manifests in ARDS, cytokine storm, immune infiltration, and severe edema. Passive immunization is the preferred measure against pulmonary ricinosis, but only if administered shortly after exposure. Despite their potential to remedy pulmonary injury and inflammation, mesenchymal cell (MSC) therapies were never investigated in ricinosis. Here, we report the potential for treating pulmonary ricinosis with MesenCure, a professionalized allogeneic MSC therapy shown to reduce the mortality of patients suffering from severe pulmonary manifestations of COVID by 68%. Methods, Results & Conclusion(s): Preliminary studies demonstrated positive MesenCure effects in a sub-lethal pulmonary ricinosis model in CD1 mice. This model is regarded as highly translational due to the broad heterogeneity of these outbred mice. Positive effects included a reduction in excess protein content of the bronchoalveolar lavage fluid (BALF) by 45% when MesenCure was injected intravenously (IV) at 125k cells/animal, 48h post-exposure (PE) and evaluated one day later (p<0.05, Fig. 1A). Moreover, we found up to 52% reduction in the excess BALF leukocytes, when MesenCure was injected IV, 24h PE using the same dose (p<0.05, Fig. 1B) or 6h PE using a double dose (p<0.01, Fig. 1C), and evaluated two days PE. Optimizing the dose and administration route further improved the therapeutic outcome of MesenCure applied 6h PE as assessed by weight loss. As shown in Fig. 1D-E, IV injection of 250k-500k MesenCure cells/animal slightly protected the intoxicated animals against weight loss (p for treatment x time interaction <0.01 or <0.05 for 250k and 500k cells/animal, respectively). Interestingly, one million cells IV resulted in a lesser effect (not shown), however when injected subcutaneously (SC), 1M cells were very effective (p<0.001, Fig. 1F), seemingly even more effective than 2M cells/animal SC (Fig. 1G). Surprisingly, 2M thawed cells/animal injected SC protected the animals against weight loss almost completely (p<0.0001, Fig. H). In conclusion, we provide evidence for the potential of SC MSCs, specifically MesenCure, for treating pulmonary ricinosis and possibly other forms of ARDS. In agreement with Giri and Galipeau (2020), we provide further evidence for the dependency of MSC outcomes on their specific state and administration route. [Figure presented]Copyright © 2023 International Society for Cell & Gene Therapy

The impact of Covid-19 on the digital transformation of the airports

The smart airport concept has become the future of airport operations and it can completely change the industry towards adapting to modern technologies. The paper is focused on the digital transformation of the airports and the impact of Covid-19 on the digital transformation of the airports. The paper contains qualitative primary research in the form of structured interviews with competent persons working in executive functions in the field of operation, safety and maintenance at the airports that were the subject of the research. Qualitative primary research is focused on airports in Slovak republic and Czech Republic. The data that are obtained via structured interviews create a comprehensive picture of the issue of digital maturity of Czech and Slovak international airports as well as the impact of Covid-19 on digital transformation of the observed airports. © 2022 The Authors. Published by ELSEVIER B.V.

Digital Maturity of Selected Regional Airports in the Slovak and Czech Republic

The use of digital technologies has become popular in recent years. Digital technologies can be found almost in every sector, with the transport sector being no exception. The Covid-19 pandemic has brought a number of restrictions, which have resulted in various measures being taken to reduce the spread of the virus. Therefore, in some cases, it was necessary to introduce digital technologies, in particular the elimination of personal contact, in order to reduce the spread of the virus. Airports had to adapt to this situation if they wanted to survive, so they began to apply various smart solutions to protect passengers' health as much as possible, which of course encouraged digitization at small and regional airports as well. At present, not all regional airports are digitized, whereas efforts to implement digital technologies are very strong. The main goal of this paper is to find out which digital technologies are currently used by regional airports in the Slovak Republic and Czech Republic, and what digital technologies have been introduced as a result of the pandemic. Research has shown that regional airports want to adapt and implement digital technologies, but this is not possible due to their poor financial situation and minimal traffic. © 2022 Czech Technical University in Prague.

Mesenchymal Stem/Stromal Cells: MESENCURE: A PROFESSIONALIZED CELL THERAPY FOR ARDS REDUCED THE MORTALITY OF SEVERE COVID-19 PATIENTS BY 68% ACCORDING TO A RECENTLY CONCLUDED MULTI-CENTER, CONTROLLED PHASE II STUDY

Background & Aim: The wide gap in severe Covid-19 management is increasingly addressed by mesenchymal cell (MSC) therapies, despite studies that failed to show significant efficacy in ARDS. To improve the therapeutic utility of MSCs in ARDS, Bonus BioGroup developed MesenCure: An allogeneic adipose-derived MSC product professionalized by a combination of culture conditions enhancing the cells’ potency and stability, producing unique transcriptomic, proteomic, and morphological signatures. Up to 100k fresh MesenCure doses with a shelf life sufficient for global supply can be produced from a single donor under 20 PDLs, further preventing potency loss due to cryopreservation and culture aging. Based on preclinical data presented during ISCT2021, demonstrating MesenCure’s advantages over non-professionalized MSCs, and its safety in a Phase I study, Bonus BioGroup initiated a multi-center Phase II trial in severe Covid-19 patients that was recently concluded. Methods, Results & Conclusion: The Phase II trial included 50 severe Covid-19 patients suffering from diffuse pneumonia and oxygen desaturation treated with up to 3 MesenCure doses (1.5x106 cells/kg on days 1, 3, and 5), on top of the Standard of Care (SoC), and 150 similar severe control patients treated by the SoC only and stratified according to gender, age, and comorbidities. A substantial 68% reduction in the mortality rate of the test patients was measured (Fig. 1A, p<0.05), along with a 57% drop in their risk of intubation relative to the control (Fig. 2A, p<0.05). Over 50% of the patients treated with MesenCure were released from the hospital within two days after treatment, and a 38% reduction was measured in the hospital length of stay (LoS) of patients having LoS>7 days (Fig. 1C, p<0.01). Starting from a similar baseline as the control, the median CRP and CK levels of the test patients, after MesenCure treatment, ended 52% (p<0.0001) and 33% (p<0.01) lower than their respective control levels. As shown in Fig. 2 [Figure Presented] Fig. 1 ( 25). (A) Mortality rates among test and control patients at Visit 8 (one month after the first MesenCure dose or the equivalent time points for the control). (B) Test and control patients’ risk of deteriorating to mechanical ventilation. (C) Average hospital length of stay (LoS) of patients having LoS > 7 days. Two-sided p values were calculated using the Fisher Exact test (A and B) or t-test (C). [Figure Presented Fig. 2 ( 25). (A) CRP and (B) CK levels measured at Visit 6, the earliest of two weeks after the first MesenCure dose (Visit 2) or upon hospital release, or the equivalent time points for the control. The test and control groups started from similar median CRP and CK levels. (C) Changes in control and test patients’ LDH levels from Visit 1 (screening) to Visit 6. (D) Area of test patients’ diffuse pneumonia during Visits 1, 6, and 8 (one month after Visit 2). (E) Blood oxygen saturation measured during test patients visits 1, 2-4 (upon or before receiving the first to third MesenCure dose), Visit 5 (the earliest of one week after Visit 2 or upon hospital release), and Visit 6. (F) Test patients’ blood lymphocytes levels (absolute) across Visits 1 and 6. Charts are presented as box-and-whiskers (according to the Tukey method). p values were calculated using the Mann-Whitney test (A, B, and C), Dunn’s multiple comparisons (D and E), or the Wilcoxon test (F). the more profound improvements in inflammatory and tissue damage markers observed in test patients were accompanied by a rapid recovery in pneumonia, respiratory functions, and lymphopenia, emphasizing MesenCure’s powerful effect. In conclusion, we show that MesenCure saves patients’ lives and accelerates their healing, possibly reducing the risk of long-term damages while freeing ICU beds allowing better care for other patients, and reducing the burden associated with hospitalization and additional long-term healthcare costs.

Mesenchymal Stem/Stromal Cells: Late Breaking Abstract: FIRST EVIDENCE FOR THE TRANSLATIONAL POTENTIAL OF MESENCURE™, A PROFESSIONALIZED ALLOGENEIC MESENCHYMAL CELL THERAPY, FOR TREATING IMMUNOTHERAPY-RELATED CYTOKINE RELEASE SYNDROME

Background & Aim: Cytokine Release Syndrome (CRS) and Immune effector Cell-Associated Neurotoxicity Syndrome (ICANS) are related side effects of immunotherapies seen in up to 76% of patients treated with CAR-T and 48% of those treated with BiTEs. In up to 27% of the patients, these syndromes may lead to severe consequences. Current treatments for severe CRS are ineffective in >30% of the cases and can worsen ICANS prognosis, calling for novel treatments, especially in light of the expanding use of immunotherapies. Despite their obvious potential, mesenchymal cell (MSC) therapies were seldom investigated in this context. In the present study, Bonus BioGroup has set to assess the potential for treating CRS with MesenCure™, our allogeneic MSC platform, professionalized to enhance the cells’ potency and shown safe and effective in severe COVID patients. Methods, Results & Conclusion: A highly translational and validated CRS model was established in humanized NSG mice bearing human PBMCs, B-cell lymphoma, and CAR-T cells. CAR-T introduction significantly increased the serum levels of proinflammatory cytokines in model animals, indicative of CRS (Fig. 1A). Two IV MesenCure injections were well-tolerated in this model (Fig. 1B) and did not obstruct the CAR-Ts’ ability to inhibit tumor growth by 89% (Fig. 1C, p<0.0001). Remarkably, significant reductions in all proinflammatory cytokines tested (excluding IL-6) were measured in model animals treated with MesenCure, substantiating its potential to treat CRS (Fig. 1A). Interestingly, the magnitudes of these reductions resembled those observed in 50 severe COVID patients treated with MesenCure. MesenCure’s robust immunomodulatory capacity was further demonstrated in vitro by its ability to inhibit the proliferation of activated CD4 T cells with an IC50 of 6k MSC/200k PBMCs, twice more effectively than non-professionalized MSCs. Comparable results were also obtained with CD8 T cells. Similarly, MesenCure inhibited neutrophils’ ROS production by up to 80% within an hour following activation (IC50 19k MSC/200k neutrophils). These effects are likely mediated, in part, by IDO, whose RNA levels were found to be 6.8-fold higher in MesenCure cells than in non-professionalized MSCs (p<0.05), two hours after activation with IFNγ. Moreover, IDO inhibition by 1-MT (1 mM) reduced MesenCure’s (Figure Presented) Fig. 1 (A) The levels of serum proinflammatory cytokines measured in tumor-bearing NSG mice after CRS induction by injection of human PBMCs/CAR-Ts (or saline control) and MesenCure treatment (or saline control). Experimental groups’ designation: Control – not injected with PBMCs/CAR-Ts and not treated by MesenCure;CAR-T – CRS model animals, injected with PBMCs/CAR-Ts but not treated with MesenCure;MesenCure – treated with MesenCure but not injected with PBMCs/CARTs;and CAR-T + MesenCure – CRS model animals treated with MesenCure. (B) Relative change in body weight from the day of tumor induction (Day 0) and (C) IVIS analysis of tumor burden (dorsal aspect) in the above four experimental groups. Statistical significance indicators: ns – not significant, * p<0.05, *** p<0.001, **** p<0.0001. Statistical tests: Holm-Šídák’s multiple comparisons test (A) and two- sided t-test (C). ability to inhibit T cells’ proliferation by 73%. In conclusion, we provide the first evidence for the potential of MSCs and MesenCure, in particular, for treating immunotherapy-related CRS.

PERSPECTIVES OF THE INFORMATION TECHNOLOGY USE IN ACCOUNTING - IMPLICATIONS OF THE COVID-19 PANDEMIC

The continuous development of information technology and its application in accounting has provided new opportunities but also numerous challenges for accounting practice. It is possible to identify a wide variety of information technologies that have had a significant impact on accounting in the 21st century but also certain constraints that have slowed the integration of information technology into accounting. The COVID-19 pandemic dictates new business conditions and models that create numerous changes in business operations where the use of information technology has become extremely important for the survival of businesses. The changed conditions did not bypass the accounting profession either which also had to adapt to the new circumstances. This paper aims to analyze whether the COVID-19 pandemic has accelerated the integration of information technology into accounting and the transition to 'Accounting 4.0'. Also, the paper reviews recent studies and analyzes challenges that accountants faced in a pandemic and the ways they have adapted to the changing environment. In this context, the paper analyzes various types of information technology that enabled accountants to become more efficient and effective with special emphasis on Cloud-based technology, Blockchain, and Artificial Intelligence. The paper also identifies the advantages and risks of information technology integration in accounting and future directions of integration. The fast development of information technologies creates a continuous need for accountants to acquire knowledge and skills related to new technologies. Therefore, skills that are expected of accountants concerning information technology are also highlighted in the paper. The current pandemic has had a severe impact on business operations and demonstrated the benefits of using information technology but not without certain risks. In this context, the implications for accounting and the accounting profession have also been investigated.

Possible Divergent Local and Peripheral Immunological Effects of Low-Dose Mesencure, an Enhanced Mesenchymal Cell Therapy, May Contribute to Its Success in Treating Severe Covid-19 Patients

Mesenchymal stromal cells (MSC) are widely investigated for treating ARDS in Covid-19. Nonetheless, these efforts are overshadowed by studies predating the pandemic that mostly failed to show MSC efficacy in ARDS and recent disappointments with repurposed MSC products. Relying on years of MSC-related experience, Bonus BioGroup developed MesenCure: An enhanced allogeneic MSC therapy for Covid-19, professionalized by a unique combination of culture conditions and optimized in ARDS-relevant models. MesenCure is currently evaluated in a Phase II study in severe Covid-19 patients and administered (IV) in three doses (1.5M cells/kg, d1, d3, d5). A Phase I/II study on ten severe patients demonstrated a significant improvement in ARDS-related parameters following MesenCure treatment. Patients were discharged within one day (median) following treatment, requiring no respiratory support. Speedy recovery from local inflammation was observed in these patients, demonstrated by a rapid reduction in diffuse lung pneumonia, from 55% of the lung area to 15% within 5-6 days from the first dose (p<0.01, Fig. A-C). A corresponding drop in CRP was detected (p<0.01), which returned to normal. A multivariate regression analysis revealed that the reduction in CRP was mainly associated with the number of doses administered and not and the time elapsed since the first dose. MesenCure efficacy may be attributable to the cells' de novo expression of the gene encoding for the IL-6 receptor, making them more responsive to inflammation than non-professionalized naïve MSC (NA-MSC);as well as >8-fold upregulation of the EDIL3 gene, encoding for an endogenous inhibitor of immune infiltration. A corresponding immunosuppressive effect of MesenCure MSCs was demonstrated in vitro, showing their ability to suppress T cells activation twice more effectively than NA-MSC. In this study, MesenCure inhibited the proliferation of primary CD4 T cells in a concentration-depended manner following non-specific activation. Over 98% inhibition was achieved in co-culture of 1:10 MSC-to-PBMC with an IC 50 of 6k MSC/200k PBMCs (r 2=1.00) compared to 12k NA-MSC/200k PBMCs (r 2=0.95). Comparable results were also obtained for CD8 T cells. Similarly, MesenCure inhibited ROS production by primary neutrophils remarkably fast and by up to 80% within less than 40 minutes following their activation (IC 50 = 19k MSC/200k neutrophils, r 2=1.00). In addition to local immunosuppressive outcomes, a significant increase in blood leukocytes was observed in patients treated with MesenCure (p<0.05, Fig. D-F). Further analysis suggested that the increase in total WBCs and neutrophils was associated with the number of MesenCure doses administered (p<0.05, Fig. G-H). In contrast, the increase in lymphocytes was time-dependent (R=0.72, Fig. I). The seemingly exclusively localized anti-inflammatory effects seen in severe patients treated with MesenCure were also observed in animal (murine) studies. An in vivo study in an acute lung injury model demonstrated a dose-dependent localized reduction in leukocyte counts in the lung fluids of animals treated with MesenCure (IV) using two dose levels. Relative to untreated animals, MesenCure reduced lung leukocyte counts by 35%-43% in animals treated with the low dose and by 62%-67% following high-dose MesenCure treatment (p<0.05). The leukocytes' clearance from the lungs was accompanied by a 41%-57% reduction in lung edema (p<0.05) following MesenCure treatment. Notably, NA-MSC did not achieve the same effect. Similar to our clinical findings, a significant increase was measured in neutrophil counts in animals treated with low-dose MesenCure (p<0.05), which decreased dramatically (p< 0.01) in animals treated with a four-times higher dose. MesenCure is administered at a much lower dose compared to other MSC products administered at up to 10M cells/kg. Considering the increase in blood leukocytes measured in patients treated with low-dose MesenCure and comparable preclinical findings, our data suggest that low-dose MesenCure could elicit a potent ocal anti-inflammatory effect without suppressing, and even enhancing, peripheral immunity that is needed to fight the virus. Further research is inevitably required into the mechanism behind this phenomenon. However, our results indicate MesenCure's potential in relieving local inflammation while giving the patient a fighting chance against viremia. [Formula presented] Disclosures: Bronshtein: Bonus BioGroup: Current Employment. Ben David: Bonus BioGroup: Current Employment. Novak: Bonus BioGroup: Current Employment. Kivity: Bonus BioGroup: Current Employment. Meretzki: Bonus BioGroup: Current Employment. Rozen: Bonus BioGroup: Consultancy.

Placental findings in the covid era: Comparison between asymptomatic and symptomatic pregnancy

INTRODUCTION Viral infections are common and have different pattern in pregnancy. This paper aims to talk about placental findings in pregnant patients with a positive nasopharyngeal swab for COVID-19, comparing two groups: the first one made up of patients with severe respiratory symptoms and the second one made up of asymptomatic patients. The question that arose is to check if in patients with symptoms and pulmonary damage, the viral disease has also caused placental alterations or if the placenta has the same characteristics in the two groups of patients. METHODS We compared placentas from SARS-CoV-2 positive symptomatic and asyntomatic pregnant women. The placentas included were 27 (4 belonging to symptomatic patients and 23 to asymptomatic patients). The patients included in the study were really 24 because two of them were bicorial twin pregnancies and one of them was monocorial biamniotic pregnancy. We applied these inclusion criteria: we have considered positive patients who delivered in the department of Obstetrics and Gynecology in Udine from May 2020 to March 2021 and have undergone placental hystological examination. RESULTS The case group consisted of three patients (one of them was a twin bicorial biamniotic pregnancy): two patients developed pneumonia that required ventilator support and treatment with steroid, antibiotics and antithrombotic therapy. The last patient was symptomatic of cough, fever and muscle aches. None of the patients was symptomatic at delivery. Five patients gave birth before 37 weeks. No significant differences were identified between the two study groups. Considering the symptomatic group two patients presented obstetric comorbidities: the first pregnant was affected by fetal growth restriction and gestational hypertension while the second one had a twin bicorial pregnancy with a selective FGR, cholestasis and gestational diabetes. The third patient had an uncomplicated pregnancy. In the other group of the study (asymptomatic patient) 9 women had an uncomplicated pregnancy while the other 13 had a pregnancy complicated by a combination of fetal growth restriction (4 cases), preeclampsia(2 cases), gestational diabetes (7 cases), cholestasis (2 cases) and inherited thrombophilia (1 cases). In both groups the placentas showed the most common findings of maternal malperfusion such as:immature villi(18 cases, 66%), cotiledonary hyperamification(15 cases, 55%), chorangiosis (9 cases, 33%),fibrin deposits (4 cases, 15%),chronic villitis (7 cases, 26%).Two placentas in the group of asymptomatic patients showed traces of meconium. Only one placentas showed signs of fetal malperfusion (carioressi and focal area of vascular occlusion)and only one placenta was normal. Unfortunately it was not possible the viral identification in the analyzed placentas. CONCLUSIONS Data collected do not report specific findings of placental injury in patients with a pregnant symptomatic infections. According to our data, Jaiswal compared hystological findings of placental of asymptomatic and mildly symptomatic pregnant women with hystological exam of placental of negative singleton pregnancy: in COVID-19 positive pregnancies, there were placental findings of maternal vascular malperfusions. Also in our cases, the studied placental has malperfusion findings except for only one of them. Other studies concerning maternal vascular malperfusion were conducted by Smithgall: villous agglutination and subchorionic thrombi were present more frequently in third-trimester placentas from COVID19 positive women than in those from negative ones. Our study has limitations that should be addressed. It did not have power to detect differences in individual adverse outcomes.

Global impact of the COVID-19 pandemic on stroke care and intravenous thrombolysis

Objective: The objectives of this study were to measure the global impact of the pandemic on the volumes for intravenous thrombolysis (IVT), IVT transfers, and stroke hospitalizations over 4 months at the height of the pandemic (March 1 to June 30, 2020) compared with two control 4-month periods. Background: The COVID-19 pandemic led to widespread repercussions on the delivery of health care worldwide. Design/Methods: We conducted a cross-sectional, observational, retrospective study across 6 continents, 70 countries, and 457 stroke centers. Diagnoses were identified by ICD-10 codes and/or classifications in stroke center databases. Results: There were 91,373 stroke admissions in the 4 months immediately before compared to 80,894 admissions during the pandemic months, representing an 11.5% (95%CI,-11.7 to-11.3, p<0.0001) decline. There were 13,334 IVT therapies in the 4 months preceding compared to 11,570 procedures during the pandemic, representing a 13.2% (95%CI,-13.8 to-12.7, p<0.0001) drop. Interfacility IVT transfers decreased from 1,337 to 1,178, or an 11.9% decrease (95%CI,-13.7 to-10.3, p=0.001). There were greater declines in primary compared to comprehensive stroke centers (CSC) for stroke hospitalizations (-17.3% vs-10.3%, p<0.0001) and IVT (-15.5% vs-12.6%, p=0.0001). Recovery of stroke hospitalization volume (9.5%, 95%CI 9.2-9.8, p<0.0001) was noted over the two later (May, June) versus the two earlier (March, April) months of the pandemic, with greater recovery in hospitals with lower COVID-19 hospitalization volume, high volume stroke center, and CSC. There was a 1.48% stroke rate across 119,967 COVID-19 hospitalizations. SARS-CoV-2 infection was noted in 3.3% (1,722/52,026) of all stroke admissions. Conclusions: The COVID-19 pandemic was associated with a global decline in the volume of stroke hospitalizations, IVT, and interfacility IVT transfers. Primary stroke centers and centers with higher COVID19 inpatient volumes experienced steeper declines. Recovery of stroke hospitalization was noted in the later pandemic months, with greater recovery in hospitals with lower COVID-19 hospitalizations, high volume stroke centers, and CSCs.

Anti-corruption policy under the conditions of overcoming the consequences of the coronavirus pandemic

Deterioration of the epidemiological situation in the country marked the beginning of rethinking of modern models towards combating corruption risks. Mankind has faced with an extremely serious problem that affects the economic system of the state, intensifies corruption processes and confuses the search for new ways to prevent abuse of officials. The academic paper has considered the basic challenges faced by the world community during the coronavirus pandemic. The destructive consequences of the spread of the coronavirus pandemic have been determined and the directions of improvement and formation of anti-corruption policy under modern conditions have been offered. Particular attention has been paid to the development of current legislation, program and strategic documents, protection of whistleblowers, the need to involve the public in the discussion of key issues in combating corruption, establishment of the principles of integrity, openness and transparency in topical anti-corruption measures in order to overcome the most difficult challenges of nowadays. The need to give priority to the main spheres of public life has been distinguished, where the most significant abuses are possible (health care, public procurement, public administration). Anti-corruption policy under the conditions of counteracting COVID-19 should be formed in accordance with the basic corruption challenges and taking into account current, progressive practices in order to address the issue of eliminating the consequences of illegal activities.