Οι βιολογικές θεραπείες στην αντιμετώπιση της νόσου Covid-19

Η ανθρωπότητα από τον Δεκέμβριο του 2019 βιώνει μία νέα πανδημία από τον ιό SARS-CoV-2 επιφέροντας σεισμικές αλλαγές στις ζωές όλων μας. Εκατομμύρια ανθρώπων έχουν πεθάνει ως αποτέλεσμα της πνευμονίας που επιφέρει ο ιός SARS-CoV-2 σε παγκόσμιο επίπεδο παρά τα πρωτοφανή μέτρα περιορισμού που εφαρμόσθηκαν. Η ανάλυση των κλινικών χαρακτηριστικών αυτών των ασθενών έδειξε ότι η φυσική πορεία της νόσου, γνωστή με το ακρωνύμιο Covid-19, είναι πολλές φορές απρόβλεπτη. Πιθανότατα γενετικοί παράγοντες, νόσοι φθοράς αλλά και περιβαλλοντικοί παράγοντες (exposome) συμμετέχουν στη δυσμενή κλινική πορεία ορισμένων ασθενών. Η κατανόηση των πλειοτροπικών δράσεων του ιού και της αλληλεπίδραση με το ανοσοποιητικό σύστημα του ξενιστή φαίνεται να αποτελούν κλειδί στην αντιμετώπιση της νόσου. Δημοσιευμένα δεδομένα προτείνουν ότι η οξεία προ-φλεγμονώδης αντίδραση του ξενιστή, η οποία είναι αρχικά ευεργετική, για λόγους που δεν έχουν αποσαφηνιστεί μπορεί να εκφύγει του ελέγχου και να είναι η αιτία της παρατεταμένης καταστροφής των οργάνων στόχου. Έχοντας αυτό υπόψιν, είναι λογικό να υποθέσουμε ότι η πρόωρη θεραπεία με ένα φάρμακο που μπορεί να τροποποιήσει αποτελεσματικά την απάντηση του ξενιστή και να περιορίσει την υπερ-φλεγμονώδη αντίδραση πιθανώς να αποτρέψει την εκδήλωση σοβαρής αναπνευστικής ανεπάρκειας. Κύριος διαμεσολαβητής αυτής της υπερφλεγμονώδους αντίδρασης φαίνεται να είναι η ιντερλευκίνη 1. Βασιζόμενοι στο νευραλγικό ρόλο που παίζει η ιντερλευκίνη 1 στη φλεγμονώδη αντίδραση, είναι πιθανό ότι η θεραπεία ασθενών με COVID-19 με ανταγωνιστή της ιντερλευκίνη 1 θα μειώσει τις πιθανότητες σοβαρής επίπτωση από τον ιό SARS-CoV-2. Με σκοπό να μελετήσουμε την αποτελεσματικότητα του ανταγωνιστή του υποδοχέα της ιντερλευκίνης (IL)-1 (ανακίνρα) στη σοβαρή COVID-19 λοίμωξη, πραγματοποιήσαμε μια ανοικτού τύπου, μη τυχαιοποιημένη μελέτη σε 130 ασθενείς με σοβαρή COVID-19 λοίμωξη και suPAR ≥6 ng/ml μεταξύ Απριλίου και Σεπτέμβρη του 2020. Το πρωτογενές καταληκτικό σημείο ορίστηκε το αναπνευστικό πηλίκο κάτω από 150 mmHg το οποίο απαιτεί επιβοηθούμενο αναπνευστικό αερισμό (μηχανικό ή μη). Παράλληλα, αξιολογήθηκε η θνητότητα στις 30 μέρες, οι δείκτες φλεγμονής, καθώς και ο δείκτης WHO-CPS. Το πρωτογενές καταληκτικό σημείο επιτεύχθηκε στο 22.3% των ασθενών που έλαβαν ανακίνρα μαζί με καθιερωμένη φροντίδα σε σχέση με 59.2% αυτών που ελάμβαναν μόνο θεραπεία με καθιερωμένη φροντίδα (hazard ratio, 0.30; 95% CI, 0.20–0.46). Επίσης η θνητότητα στις 30 ημέρες εμφανίστηκε μειωμένη σε αυτούς που έλαβαν ανακίνρα (11.5% των ασθενών) σε σχέση με την ομάδα ελέγχου (22.3%) (hazard ratio 0.49; 95% CI 0.25–0.97). Συμπερασματικά, η χορήγηση ανακίνρα συμβάλλει σημαντικά στην κλινική βελτίωση της σοβαρής COVID-19 λοίμωξης.Since December 2019, humanity has been experiencing a new pandemic from the SARS-CoV-2 virus, bringing about seismic changes in the lives of all of us. Millions of people have died as a result of SARS-CoV-2 pneumonia worldwide despite unprecedented containment measures. The analysis of the clinical characteristics of these patients showed that the natural course of the disease, known by the acronym Covid-19, is often unpredictable. Genetic factors, degenerative diseases and environmental factors (exposome) are probably involved in the adverse clinical course of some patients. Understanding the pleiotropic actions of the virus and the interaction with the host's immune system appear to be key to treating the disease. Published data suggest that the host's acute pro-inflammatory response, which is initially beneficial, for reasons that have not been elucidated may run out of control and be the cause of the prolonged target organ destruction. With this in mind, it is reasonable to hypothesize that early treatment with a drug that can effectively modify the host response and limit the hyper-inflammatory response may prevent the onset of severe respiratory failure. A major mediator of this hyperinflammatory reaction appears to be interleukin 1. Based on the crucial role that interleukin 1 plays in the inflammatory response, it is possible that treating patients with COVID-19 with an interleukin 1 antagonist will reduce the chances of severe morbidity from SARS-CoV-2. In order to study the efficacy of interleukin (IL)-1 receptor antagonist (anakinra) in severe COVID-19 infection, we performed an open-label, non-randomized study in 130 patients with severe COVID-19 infection and suPAR ≥6 ng/ ml between April and September 2020. The primary endpoint was defined as respiratory ratio below 150 mmHg necessitating mechanical or non-invasive ventilation. At the same time, mortality at 30 days, inflammation indices, as well as the 28-day WHO-CPS index were evaluated. At the same time, mortality at 30 days, inflammation indices, as well as the WHO-CPS index were evaluated. The primary endpoint was achieved in 22.3% of patients receiving kineret versus 59.2% of those receiving standard of care (hazard ratio, 0.30; 95% CI, 0.20–0.46). Also, mortality at 30 days appeared reduced in those who received kineret (11.5% of patients) compared to the control group (22.3%) (hazard ratio 0.49; 95% CI 0.25–0.97). In conclusion, anakinra administration significantly contributes to the clinical improvement of severe severity of COVID-19 infection

Predicting lymphoma in Sjögren's syndrome and the pathogenetic role of parotid microenvironment through precise parotid swelling recording

Objective: Parotid swelling (PSW) is a major predictor of non-Hodgkin lymphoma (NHL) in primary Sjögren's syndrome (pSS). However, since detailed information on the time of onset and duration of PSW is scarce, this was investigated to verify whether it may lead to further improved prediction. NHL localisation was concomitantly studied to evaluate the role of the parotid gland microenvironment in pSS-related lymphomagenesis. Methods: A multicentre study was conducted among patients with pSS who developed B cell NHL during follow-up and matched controls that did not develop NHL. The study focused on the history of salivary gland and lachrymal gland swelling, evaluated in detail at different times and for different durations, and on the localisation of NHL at onset. Results: PSW was significantly more frequent among the cases: at the time of first referred pSS symptoms before diagnosis, at diagnosis, and from pSS diagnosis to NHL. The duration of PSW was evaluated starting from pSS diagnosis, and the NHL risk increased from PSW of 2-12 months to > 12 months. NHL was prevalently localised in the parotid glands of the cases. Conclusion: A more precise clinical recording of PSW can improve lymphoma prediction in pSS. PSW as a very early symptom is a predictor, and a longer duration of PSW is associated with a higher risk of NHL. Since lymphoma usually localises in the parotid glands, and not in the other salivary or lachrymal glands, the parotid microenvironment appears to be involved in the whole history of pSS and related lymphomagenesis

Programmed Cell Death Protein 1 Axis Inhibition in Viral Infections: Clinical Data and Therapeutic Opportunities

A vital function of the immune system is the modulation of an evolving immune response. It is responsible for guarding against a wide variety of pathogens as well as the establishment of memory responses to some future hostile encounters. Simultaneously, it maintains self-tolerance and minimizes collateral tissue damage at sites of inflammation. In recent years, the regulation of T-cell responses to foreign or self-protein antigens and maintenance of balance between T-cell subsets have been linked to a distinct class of cell surface and extracellular components, the immune checkpoint molecules. The fact that both cancer and viral infections exploit similar, if not the same, immune checkpoint molecules to escape the host immune response highlights the need to study the impact of immune checkpoint blockade on viral infections. More importantly, the process through which immune checkpoint blockade completely changed the way we approach cancer could be the key to decipher the potential role of immunotherapy in the therapeutic algorithm of viral infections. This review focuses on the effect of programmed cell death protein 1/programmed death-ligand 1 blockade on the outcome of viral infections in cancer patients as well as the potential benefit from the incorporation of immune checkpoint inhibitors (ICIs) in treatment of viral infections

A Deep Learning Approach for Dynamic Balance Sheet Stress Testing

In the aftermath of the financial crisis, supervisory authorities have considerably altered the mode of operation of financial stress testing. Despite these efforts, significant concerns and extensive criticism have been raised by market participants regarding the considered unrealistic methodological assumptions and simplifications. Current stress testing methodologies attempt to simulate the risks underlying a financial institution's balance sheet by using several satellite models. This renders their integration a really challenging task, leading to significant estimation errors. Moreover, advanced statistical techniques that could potentially capture the non-linear nature of adverse shocks are still ignored. This work aims to address these criticisms and shortcomings by proposing a novel approach based on recent advances in Deep Learning towards a principled method for Dynamic Balance Sheet Stress Testing. Experimental results on a newly collected financial/supervisory dataset, provide strong empirical evidence that our paradigm significantly outperforms traditional approaches; thus, it is capable of more accurately and efficiently simulating real world scenarios

One year in review 2021: Sjögren's syndrome

: Sjögren's syndrome (SS) is a multifactorial systemic autoimmune disease of unknown aetiology characterised by a wide spectrum of different clinical manifestations and scattered complications. Recently, great efforts have been made to elucidate mechanisms involved in the pathogenesis of the disease in order to identify exploitable therapeutic targets in SS. Similarly, novel insights have enabled to better define disease phenotypes and different outcomes. Ultimately, the discovery of new potential therapeutic targets and a better stratification of patients are paving new avenues for novel treatment options and treat-to-target therapeutic approach. In this review, we will provide a critical digest of the recent literature published in 2020 on SS pathogenesis, clinical manifestations and novel treatment options

Pulmonary valve replacement in patients with corrected tetralogy of Fallot

Introduction: Development of pulmonary insufficiency in patients with surgically corrected tetralogy of Fallot (TOF) may lead to severe right heart failure with serious consequences. We herein present our experience with pulmonary valve replacement (PVR) in these patients. Methods: From 2005-2013, 99 consecutive patients (71 males/28 females, mean age 38±8 years), underwent PVR after 7 to 40 (mean 29 ± 8) years from the initial correction. Seventy nine of the symptomatic patients presented in NYHA II, 14 in III and 2 in IV. All underwent PVR with a stented bioprosthetic valve, employing a beating heart technique with normothermic extracorporeal circulation support. Concomitant procedures included resection of aneurysmal outflow tract patches (n = 37), tricuspid valve annuloplasty (n = 36), augmentation of stenotic pulmonary arteries (n = 9), maze procedure (n = 2) and pulmonary artery stenting (n = 4). Results: There were 2 perioperative deaths (2%). One patient developed sternal dehiscence requiring rewiring. Median ICU and hospital stay was 1 and 7 days respectively. Postoperative echocardiography at 6 and 12 months showed excellent bioprosthetic valve performance, significant decrease in size of the right cardiac chambers and reduction of tricuspid regurgitation (TR) in the majority of the patients. At mean follow-up of 3.6 ± 2 years, all surviving patients remain in excellent clinical condition. Conclusion: Probability of reoperation for pulmonary insufficiency in patients with surgically corrected TOF increases with time and timely PVR by preventing the development of right heart failure is crucial for long-term survival. Current bioprosthetic valve technology in combination with the beating heart technique provides excellent immediate and short-term results. Further follow-up is necessary to evaluate long-term outcome

Akt Signaling Pathway Is Activated in the Minor Salivary Glands of Patients with Primary Sjögren’s Syndrome

Primary Sjögren’s syndrome (pSS) is an autoimmune exocrinopathy of mainly the salivary and lacrimal glands associated with high prevalence of lymphoma. Akt is a phosphoinositide-dependent serine/threonine kinase, controlling numerous pathological processes, including oncogenesis and autoimmunity. Herein, we sought to examine its implication in pSS pathogenesis and related lymphomagenesis. The expression of the entire and activated forms of Akt (partially and fully activated: phosphorylated at threonine-308 (T308) and serine-473 (S473), respectively), and two of its substrates, the proline-rich Akt-substrate of 40 kDa (PRAS40) and FoxO1 transcription factor has been immunohistochemically examined in minor salivary glands (MSG) of pSS patients (n = 29; including 9 with pSS-associated lymphoma) and sicca-complaining controls (sicca-controls; n = 10). The entire and phosphorylated Akt, PRAS40, and FoxO1 molecules were strongly, uniformly expressed in the MSG epithelia and infiltrating mononuclear cells of pSS patients, but not sicca-controls. Morphometric analysis revealed that the staining intensity of the fully activated phospho-Akt-S473 in pSS patients (with or without lymphoma) was significantly higher than sicca-controls. Akt pathway activation was independent from the extent or proximity of infiltrates, as well as other disease features, including lymphoma. Our findings support that the Akt pathway is specifically activated in MSGs of pSS patients, revealing novel therapeutic targets

Pulmonary valve replacement in patients with corrected tetralogy of Fallot

Introduction: Development of pulmonary insufficiency in patients with surgically corrected tetralogy of Fallot (TOF) may lead to severe right heart failure with serious consequences. We herein present our experience with pulmonary valve replacement (PVR) in these patients. Methods: From 2005-2013, 99 consecutive patients (71 males/28 females, mean age 38 +/- 8 years), underwent PVR after 7 to 40 (mean 29 +/- 8) years from the initial correction. Seventy nine of the symptomatic patients presented in NYHA II, 14 in III and 2 in IV. All underwent PVR with a stented bioprosthetic valve, employing a beating heart technique with normothermic extracorporeal circulation support. Concomitant procedures included resection of aneurysmal outflow tract patches (n = 37), tricuspid valve annuloplasty (n = 36), augmentation of stenotic pulmonary arteries (n = 9), maze procedure (n = 2) and pulmonary artery stenting (n = 4). Results: There were 2 perioperative deaths (2%). One patient developed sternal dehiscence requiring rewiring. Median ICU and hospital stay was 1 and 7 days respectively. Postoperative echocardiography at 6 and 12 months showed excellent bioprosthetic valve performance, significant decrease in size of the right cardiac chambers and reduction of tricuspid regurgitation (TR) in the majority of the patients. At mean follow-up of 3.6 +/- 2 years, all surviving patients remain in excellent clinical condition. Conclusion: Probability of reoperation for pulmonary insufficiency in patients with surgically corrected TOF increases with time and timely PVR by preventing the development of right heart failure is crucial for long-term survival. Current bioprosthetic valve technology in combination with the beating heart technique provides excellent immediate and short-term results. Further follow-up is necessary to evaluate long-term outcome