Lopinavir/Ritonavir and Darunavir/Cobicistat in Hospitalized COVID-19 Patients: Findings From the Multicenter Italian CORIST Study

Background: Protease inhibitors have been considered as possible therapeutic agents for COVID-19 patients. Objectives: To describe the association between lopinavir/ritonavir (LPV/r) or darunavir/cobicistat (DRV/c) use and in-hospital mortality in COVID-19 patients. Study Design: Multicenter observational study of COVID-19 patients admitted in 33 Italian hospitals. Medications, preexisting conditions, clinical measures, and outcomes were extracted from medical records. Patients were retrospectively divided in three groups, according to use of LPV/r, DRV/c or none of them. Primary outcome in a time-to event analysis was death. We used Cox proportional-hazards models with inverse probability of treatment weighting by multinomial propensity scores. Results: Out of 3,451 patients, 33.3% LPV/r and 13.9% received DRV/c. Patients receiving LPV/r or DRV/c were more likely younger, men, had higher C-reactive protein levels while less likely had hypertension, cardiovascular, pulmonary or kidney disease. After adjustment for propensity scores, LPV/r use was not associated with mortality (HR = 0.94, 95% CI 0.78 to 1.13), whereas treatment with DRV/c was associated with a higher death risk (HR = 1.89, 1.53 to 2.34, E-value = 2.43). This increased risk was more marked in women, in elderly, in patients with higher severity of COVID-19 and in patients receiving other COVID-19 drugs. Conclusions: In a large cohort of Italian patients hospitalized for COVID-19 in a real-life setting, the use of LPV/r treatment did not change death rate, while DRV/c was associated with increased mortality. Within the limits of an observational study, these data do not support the use of LPV/r or DRV/c in COVID-19 patients

Safety and efficacy of selective, clopidogrel-based strategies in acute coronary syndrome: a study-level meta-analysis

Objectives: To investigate outcome with selective, clopidogrel-based therapies vs conventional treatment in patients undergoing percutaneous coronary intervention (PCI), especially for acute coronary syndrome. Background: Safety and efficacy of alternative, selective, clopidogrel-based therapies after PCI are not robustly established. Methods: We performed a study-level meta-analysis on six randomized trials investigating selective clopidogrel-based therapies (three on unguided de-escalation, N=3,473; three on guided clopidogrel therapy, N=7,533). Control groups received ticagrelor or prasugrel treatment. Main endpoints were major bleeding, any bleeding, major adverse cardiovascular events (MACE) and net clinical endpoint. Results: The incidence of major bleeding and MACE was similar in the selective, clopidogrel-based therapy vs conventional treatment arm (OR 0·72, 95% CI 0·51-1·01, p=0·06; OR 0·93, 0·72-1·20, p=0·58; respectively). The rates of any bleeding were lower in the selective, clopidogrel-based therapy vs conventional treatment group (OR 0·57, 0·40-0·80, p=0·001); this greater safety was significant for unguided de-escalation (OR 0·43, 0·32-0·58, p=0·00001) and non-significant for guided clopidogrel therapy (OR 0·72, 0·51-1·02, p=0·07; p for interaction 0·03). The incidence of the net clinical endpoint was fewer in the selective, clopidogrel-based therapy vs conventional treatment arm (OR 0·59, 0·41-0·85, p=0·004); this benefit was significant for unguided de-escalation (OR 0·50, 0·39-0·64, p<0·00001) and non-significant for guided clopidogrel therapy (OR 0·85, 0·62-1·16, p=0·30; p for interaction 0·01). Conclusions: As compared with prasugrel/ticagrelor treatment, alternative, selective, clopidogrel-based approaches provide a similar protection from cardiovascular events, reduce the risk of any bleeding and are associated with a greater net benefit. These beneficial effects were prevalent with unguided de-escalation to clopidogrel

Potential role of cardiopulmonary exercise testing in evaluating functional improvement after transcatheter edge-to-edge tricuspid valve repair: a case report

Background Tricuspid regurgitation (TR) is common and severe or greater TR is linked to poor prognosis. Treatment of TR with transcatheter edge-to-edge repair has emerged as a safe and potentially effective therapy in these patients. However, the impact of transcatheter tricuspid repair on functional capacity remains to be elucidated.Case summary We describe the case of a 77-year-old woman complaining of heart failure symptoms, undergoing transcatheter edge-to-edge valve repair for severe TR with the PASCAL Ace (R) device. One month later, cardiopulmonary exercise testing (CPET) showed significant improvement in peak O2 uptake and O2 pulse compared with the test performed before the procedure.Discussion A positive impact of novel transcatheter edge-to-edge valve repair on symptoms and quality of life in patients with severe or greater TR at prohibitive surgical risk has recently emerged. The presence of severe TR has prognostic relevance, and novel percutaneous tricuspid valve repair systems have emerged in the last few years. Cardiopulmonary exercise testing is an established tool to assess functional capacity and prognosis in heart failure patient. Detecting functional capacity improvement after transcatheter edge-to-edge repair for severe TR can be challenging, and CPET may arise as a promising tool to help these purposes

Safety and Efficacy of Different Antithrombotic Strategies After Transcatheter Aortic Valve Implantation: A Network Meta-Analysis

The optimal pharmacological therapy after transcatheter aortic valve implantation (TAVI) remains uncertain. We compared efficacy and safety of various antiplatelet and anticoagulant approaches after TAVI by a network meta-analysis

Biological profile and bioavailability of imidazoline compounds on morphine tolerance modulation

Tolerance to opioid administration represents a serious medical alert in different chronic conditions. This study compares the effects of the imidazoline compounds 1, 2, and 3 on morphine tolerance in an animal model of inflammatory pain in the rat. 1, 2, and 3 have been selected in that, although bearing a common scaffold, preferentially bind to α2-adrenoceptors, imidazoline I2 receptors, or both systems, respectively. Such compounds have been tested in vivo by measuring the paw withdrawal threshold to mechanical pressure after complete Freund's adjuvant injection. To determine the ligand levels in rat plasma, an HPLC-mass spectrometry method has been developed. All the compounds significantly reduced the induction of morphine tolerance, showing different potency and duration of action. Indeed, the selective imidazoline I2 receptor interaction (2) restored the analgesic response by maintaining the same time-dependent profile observed after a single morphine administration. Differently, the selective α2C-adrenoceptor activation (1) or the combination between α2C-adrenoceptor activation and imidazoline I2 receptor engagement (3) promoted a change in the temporal profile of morphine analgesia by maintaining a mild but long lasting analgesic effect. Interestingly, the kinetics of compounds in rat plasma supported the pharmacodynamic data. Therefore, this study highlights that both peculiar biological profile and bioavailability of such ligands complement each other to modulate the reduction of morphine tolerance. Based on these observations, 1-3 can be considered useful leads in the design of new drugs able to turn off the undesired tolerance induced by opioids

Predictive Value of Echocardiographic Pulmonary to Left Atrial Ratio for In-Hospital Death in Patients with COVID-19

Background: Echocardiographic Pulmonary to Left Atrial Ratio (ePLAR) represents an accurate and sensitive non-invasive tool to estimate the trans-pulmonary gradient. The prognostic value of ePLAR in hospitalized patients with COVID-19 remains unknown. We aimed to investigate the predictive value of ePLAR on in-hospital mortality in patients with COVID-19. Methods: One hundred consecutive patients admitted to two Italian institutions for COVID-19 undergoing early ( 0.28 m/s at baseline showed non-significant but markedly increased in-hospital mortality compared to those having ePLAR ≤ 0.28 m/s (27% vs. 10.8%, p = 0.055). Multivariate Cox regression showed that an ePLAR > 0.28 m/s was independently associated with an increased risk of death (HR 5.07, 95% CI 1.04–24.50, p = 0.043), particularly when associated with increased sPAP (p for interaction = 0.043). Conclusions: A high ePLAR value at baseline predicts in-hospital death in patients with COVID-19, especially in those with elevated pulmonary arterial pressure. These results support an early ePLAR assessment in patients admitted for COVID-19 to identify those at higher risk and potentially guide strategies of diagnosis and care

A human anti-Neuronal Autoantibody Against GABAB Receptor induces Experimental Autoimmune Agrypnia

In the serum and cerebrospinal fluid of a patient with recurrent acute episodes of respiratory crises, autonomic symptoms and total insomnia (agrypnia), we identified a novel anti-neural complement fixing antibody directed against GABA(B) receptor (GABA(B)R). Patient purified IgG recognized a band of approximately 110 kDa on protein extracts of mouse cerebellum, cortex and brainstem and immunolabelled cultured Chinese hamster ovary (CHO) cells, transfected with human GABA(B)R1 and rat GABA(B)R2 receptors. Western blot analysis of transfected CHO homogenates showed the same band using both patient purified IgG and anti-GABA(B)R1 antibody. In order to verify the pathogenic role of these purified antibodies, we injected patient IgG intrathecally into cisterna magna of C57BL/6 mice pre-implanted with EEG electrodes and we observed severe ataxia followed by breathing depression and total suppression of slow wave sleep, as evidenced by EEG recording, in a dose-dependent manner. Immunohistochemistry on brain sections of mice injected with patient IgG showed the simultaneous presence of bound human IgG and C5b-9 deposits on Purkinje cells and cerebellar granular layer. After incubation with anti-GABA(B)R antibody, a marked reduction of receptor immunostaining was found with relative sparing of neuronal architecture. In conclusion we recognized an anti-neuronal autoantibody directed against GABA(B)R that is associated with autoimmune agrypnia and we showed that our patient purified IgG was able to induce in mice experimental autoimmune agrypnia characterized by a complex neurological syndrome affecting several CNS functi

Lopinavir/Ritonavir and Darunavir/Cobicistat in Hospitalized COVID-19 Patients: Findings From the Multicenter Italian CORIST Study

Background: Protease inhibitors have been considered as possible therapeutic agents for COVID-19 patients. Objectives: To describe the association between lopinavir/ritonavir (LPV/r) or darunavir/cobicistat (DRV/c) use and in-hospital mortality in COVID-19 patients. Study Design: Multicenter observational study of COVID-19 patients admitted in 33 Italian hospitals. Medications, preexisting conditions, clinical measures, and outcomes were extracted from medical records. Patients were retrospectively divided in three groups, according to use of LPV/r, DRV/c or none of them. Primary outcome in a time-to event analysis was death. We used Cox proportional-hazards models with inverse probability of treatment weighting by multinomial propensity scores. Results: Out of 3,451 patients, 33.3% LPV/r and 13.9% received DRV/c. Patients receiving LPV/r or DRV/c were more likely younger, men, had higher C-reactive protein levels while less likely had hypertension, cardiovascular, pulmonary or kidney disease. After adjustment for propensity scores, LPV/r use was not associated with mortality (HR = 0.94, 95% CI 0.78 to 1.13), whereas treatment with DRV/c was associated with a higher death risk (HR = 1.89, 1.53 to 2.34, E-value = 2.43). This increased risk was more marked in women, in elderly, in patients with higher severity of COVID-19 and in patients receiving other COVID-19 drugs. Conclusions: In a large cohort of Italian patients hospitalized for COVID-19 in a real-life setting, the use of LPV/r treatment did not change death rate, while DRV/c was associated with increased mortality. Within the limits of an observational study, these data do not support the use of LPV/r or DRV/c in COVID-19 patients