Local delivery of thrombolytics before thrombectomy in patients with ST-elevation myocardial infarction undergoing primary percutaneous coronary intervention — The DISSOLUTION randomized trial

Background: Ranolazine decreases the frequency of arrhythmias during the acute phases of ischemic heart disease (IHD), but it remains unknown if it has similar effects in the chronic phase of the disease. We performed a prospective, randomized, cross-over pilot trial to test the hypothesis that chronic treatment with ranolazine can reduce the incidence of documented arrhythmias and the related symptoms of palpitation in stable patients with IHD. Methods: We randomized 105 patients with stable IHD and symptoms of angina and palpitations already on therapy with betablockers and/or calcium antagonists to ranolazine (750 mg bid, N = 53) or placebo (N = 52) for 30 days (until T-1). After a washout period to avoid any carryover effect, cross-over was performed,and patients were switched to the other drug which was continued for 30 days (until T-2). All patients underwent symptomlimited exercise stress testing and 48-hour ECG Holter monitoring at T1 and T2. During the study period, patients were told to use a OmronN® portable ECG monitor HCG-801 device in case of symptoms of palpitations. Results: Ranolazine reduced the number of anginal episodes more commonly than placebo (5 ± 8 episodes/30 days vs. 21 ± 24 episodes/30 day, p = 0.001) and increased exercise durations at 1 mm ST-segment depression (514 ± 211 s vs. 402 ± 287 s, p = 0.025) and at onset of angina (614 ± 199 s vs. 519 ± 151 s, p = 0.007) at stress testing. These effects were coupled by significant decreases with ranolazine as compared with placebo treatment periods in the occurrence of frequent (N1000 beats) supraventricular arrhythmias (33% vs 52%, p = 0.01) and complex ventricular arrhythmias (17% vs 30%, p = 0.045). Complete resolution of symptoms of palpitations was significantly more common with ranolazine than placebo (31/53 vs 16/52 patients, p = 0.008). Also, portable ECG recordings showed that arrhythmias were less common during ranolazine vs. placebo, with significant decreases in number (7 ± 10 episodes/30 days vs. 23 ± 29 episodes/30 day, p = 0.001) and duration (10 ± 18 min/ 30 days vs. 19 ± 21 min/30 day, p = 0.021) of symptomatic arrhythmic episodes. No severe side effects were recorded during the trial period. Conclusion: The antianginal and antiischemic properties of ranolazine are paralleled by significant decreases in the occurrence of both arrhythmias and the related symptoms of palpitations in stable patients with IHD. (ClinicalTrials.gov identifier: NCT01495520)

Multidisciplinary Oral Rehabilitation of a Severely Compromised Dentition

The decision-making process of complex clinical cases should involve multiple specialists to obtain a predictable result on a long-term basis. In view of the above, the present report is aimed at describing the multidisciplinary management of a partially edentulous female patient presenting with a severely compromised residual dentition. To improve function and aesthetics, the treatment combined multiple extractions, temporary rehabilitation with a complete removable denture, guided bone regeneration and implant insertion, soft tissue management, tooth alignment, and restorative dentistry. Thus, several dental branches were embraced during the treatment phases, including oral surgery and implantology, periodontology, orthodontics, and prosthodontics. The involvement of different specialists ensured the achievement of a good result from biological, functional, and aesthetic aspects. The patient was satisfied with the final outcome. In conclusion, to meet the patient’s expectations particularly in complex clinical situations, the interdisciplinary approach becomes essential from the early phases in order to identify the ideal treatment plan with the correct time sequence

Evolution of enhanced innate immune evasion by SARS-CoV-2.

The emergence of SARS-CoV-2 variants of concern suggests viral adaptation to enhance human-to-human transmission1,2. Although much effort has focused on the characterization of changes in the spike protein in variants of concern, mutations outside of spike are likely to contribute to adaptation. Here, using unbiased abundance proteomics, phosphoproteomics, RNA sequencing and viral replication assays, we show that isolates of the Alpha (B.1.1.7) variant3 suppress innate immune responses in airway epithelial cells more effectively than first-wave isolates. We found that the Alpha variant has markedly increased subgenomic RNA and protein levels of the nucleocapsid protein (N), Orf9b and Orf6-all known innate immune antagonists. Expression of Orf9b alone suppressed the innate immune response through interaction with TOM70, a mitochondrial protein that is required for activation of the RNA-sensing adaptor MAVS. Moreover, the activity of Orf9b and its association with TOM70 was regulated by phosphorylation. We propose that more effective innate immune suppression, through enhanced expression of specific viral antagonist proteins, increases the likelihood of successful transmission of the Alpha variant, and may increase in vivo replication and duration of infection4. The importance of mutations outside the spike coding region in the adaptation of SARS-CoV-2 to humans is underscored by the observation that similar mutations exist in the N and Orf9b regulatory regions of the Delta and Omicron variants

Evolution of enhanced innate immune evasion by SARS-CoV-2.

The emergence of SARS-CoV-2 variants of concern suggests viral adaptation to enhance human-to-human transmission1,2. Although much effort has focused on the characterization of changes in the spike protein in variants of concern, mutations outside of spike are likely to contribute to adaptation. Here, using unbiased abundance proteomics, phosphoproteomics, RNA sequencing and viral replication assays, we show that isolates of the Alpha (B.1.1.7) variant3 suppress innate immune responses in airway epithelial cells more effectively than first-wave isolates. We found that the Alpha variant has markedly increased subgenomic RNA and protein levels of the nucleocapsid protein (N), Orf9b and Orf6-all known innate immune antagonists. Expression of Orf9b alone suppressed the innate immune response through interaction with TOM70, a mitochondrial protein that is required for activation of the RNA-sensing adaptor MAVS. Moreover, the activity of Orf9b and its association with TOM70 was regulated by phosphorylation. We propose that more effective innate immune suppression, through enhanced expression of specific viral antagonist proteins, increases the likelihood of successful transmission of the Alpha variant, and may increase in vivo replication and duration of infection4. The importance of mutations outside the spike coding region in the adaptation of SARS-CoV-2 to humans is underscored by the observation that similar mutations exist in the N and Orf9b regulatory regions of the Delta and Omicron variants

SARS-CoV-2 variants evolve convergent strategies to remodel the host response

SARS-CoV-2 variants of concern (VOCs) emerged during the COVID-19 pandemic. Here, we used unbiased systems approaches to study the host-selective forces driving VOC evolution. We discovered that VOCs evolved convergent strategies to remodel the host by modulating viral RNA and protein levels, altering viral and host protein phosphorylation, and rewiring virus-host protein-protein interactions. Integrative computational analyses revealed that although Alpha, Beta, Gamma, and Delta ultimately converged to suppress interferon-stimulated genes (ISGs), Omicron BA.1 did not. ISG suppression correlated with the expression of viral innate immune antagonist proteins, including Orf6, N, and Orf9b, which we mapped to specific mutations. Later Omicron subvariants BA.4 and BA.5 more potently suppressed innate immunity than early subvariant BA.1, which correlated with Orf6 levels, although muted in BA.4 by a mutation that disrupts the Orf6-nuclear pore interaction. Our findings suggest that SARS-CoV-2 convergent evolution overcame human adaptive and innate immune barriers, laying the groundwork to tackle future pandemics