Background: Long-acting (LA) injectable regimens are a potential therapeutic option in people living with HIV-1. Setting: ATLAS (NCT02951052) and FLAIR (NCT02938520) were 2 randomized, open-label, multicenter, multinational phase 3 studies. Methods: Adult participants with virologic suppression (plasma HIV-1 RNA <50 copies/mL) were randomized (1:1) to continue with their current antiretroviral regimen (CAR) or switch to the long-acting (LA) regimen of cabotegravir (CAB) and rilpivirine (RPV). In the LA arm, participants initially received oral CAB + RPV once-daily for 4 weeks to assess individual safety and tolerability, before starting monthly injectable therapy. The primary endpoint of this combined analysis was antiviral efficacy at week 48 (FDA Snapshot algorithm: noninferiority margin of 4% for HIV-1 RNA ≥50 copies/mL). Safety, tolerability, and confirmed virologic failure (2 consecutive plasma HIV-1 RNA ≥200 copies/mL) were secondary endpoints. Results: The pooled intention-to-treat exposed population included 591 participants in each arm [28% women (sex at birth), 19% aged ≥50 years]. Noninferiority criteria at week 48 were met for the primary (HIV-1 RNA ≥50 copies/mL) and key secondary (HIV-1 RNA <50 copies/mL) efficacy endpoints. Seven individuals in each arm (1.2%) developed confirmed virologic failure; 6/7 (LA) and 3/7 (CAR) had resistance-associated mutations. Most LA recipients (83%) experienced injection site reactions, which decreased in incidence over time. Injection site reactions led to the withdrawal of 6 (1%) participants. The serious adverse event rate was 4% in each arm. Conclusion: This combined analysis demonstrates monthly injections of CAB + RPV LA were noninferior to daily oral CAR for maintaining HIV-1 suppression.
Abstract-Arrhythmogenic cardiac ryanodine receptor (RyR2) mutations are associated with stress-induced malignant tachycardia, frequently leading to sudden cardiac death (SCD). The causative mechanisms of RyR2 Ca 2ϩ release dysregulation are complex and remain controversial. We investigated the functional impact of clinically-severe RyR2 mutations occurring in the central domain, and the C-terminal I domain, a key locus of RyR2 autoregulation, on interdomain interactions and Ca 2ϩ release in living cells. Using high-resolution confocal microscopy and fluorescence resonance energy transfer (FRET) analysis of interaction between fusion proteins corresponding to amino-(N-) and carboxyl-(C-) terminal RyR2 domains, we determined that in resting cells, RyR2 interdomain interaction remained unaltered after introduction of SCD-linked mutations and normal Ca 2ϩ regulation was maintained. In contrast, after channel activation, the abnormal Ca 2ϩ release via mutant RyR2 was intrinsically linked to altered interdomain interaction that was equivalent with all mutations and exhibited threshold characteristics (caffeine Ͼ2.5 mmol/L; Ca 2ϩ Ͼ150 nmol/L). Noise analysis revealed that I domain mutations introduced a distinct pattern of conformational instability in Ca 2ϩ handling and interdomain interaction after channel activation that was absent in signals obtained from the central domain mutation. I domain-linked channel instability also occurred in intact RyR2 expressed in CHO cells and in HL-1 cardiomyocytes. These new insights highlight a critical role for mutation-linked defects in channel autoregulation, and may contribute to a molecular explanation for the augmented Ca 2ϩ release following RyR2 channel activation. Our findings also suggest that the mutational locus may be an important mechanistic determinant of Ca Key Words: ryanodine receptor Ⅲ mutations Ⅲ interdomain interaction Ⅲ arrhythmia T o date, 60 arrhythmogenic mutations in ryanodine receptor (RyR2) have been reported to underlie stress-or exercise-induced malignant tachycardia, frequently leading to sudden cardiac death (SCD). 1-3 The mutations cluster in 3 discrete loci at the amino (N) terminus (15%), a central domain (25%), and at the carboxyl (C) terminus (60%). In a large number of mutations, their segregation into functionally distinct domains within the polypeptide and the complexity of the clinical phenotype may preclude a unifying mechanism of RyR2 Ca 2ϩ channel dysfunction. 1-4 Currently, our understanding of the correlation between mutation location, phenotypic manifestation, and the molecular basis of defective Ca 2ϩ release is incomplete. Several mechanisms underlying RyR2 channel dysfunction in SCD have been proposed, including altered sensitivity to luminal 5 and cytoplasmic Ca 2ϩ , 6 decreased Mg 2ϩ -dependent inhibition, 7 and FKBP12.6-dependent 7,8 and FKBP12.6-independent mechanisms. 9 -11 Despite persistent controversy surrounding the mechanistic basis of RyR2 dysregulation, there is a consensus that mutations functionally characterized to da...
Ryanodine receptors (RyR) function as Ca2؉ channels that regulate Ca 2؉ release from intracellular stores to control a diverse array of cellular processes. The massive cytoplasmic domain of RyR is believed to be responsible for regulating channel function. We investigated interaction between the transmembrane Ca 2؉ -releasing pore and a panel of cytoplasmic domains of the human cardiac RyR in living cells. Expression of eGFP-tagged RyR constructs encoding distinct transmembrane topological models profoundly altered intracellular Ca 2؉ handling and was refractory to modulation by ryanodine, FKBP12.6 and caffeine. The impact of coexpressing dsRed-tagged cytoplasmic domains of RyR2 on intracellular Ca 2؉ phenotype was assessed using confocal microscopy coupled with parallel determination of in situ protein: protein interaction using fluorescence resonance energy transfer (FRET). Dynamic interactions between RyR cytoplasmic and transmembrane domains were mediated by amino acids 3722-4610 (Interacting or "I"-domain) which critically modulated intracellular Ca 2؉ handling and restored RyR sensitivity to caffeine activation. These results provide compelling evidence that specific interaction between cytoplasmic and transmembrane domains is an important mechanism in the intrinsic modulation of RyR Ca 2؉ release channels.
Introduction: Survivors of COVID-19 infection may develop post-covid pulmonary fibrosis (PCF) and suffer from long term multi-system complications. The magnitude and risk factors associated with these are unknown. Objectives: We investigated the prevalence and risk factors associated with PCF and other complications in patients discharged after COVID-19 infection. Methods: Patients had phone assessment 6 weeks post hospital discharge after COVID-19 infection using a set protocol. Those with significant respiratory symptoms were investigated with a CTPA, Pulmonary Function Tests and echocardiogram. Prevalence of myalgia, fatigue, psychological symptoms and PCF was obtained. Risk factors associated with these were investigated. Results: A large number of patients had persistent (45.1%) fatigue, breathlessness (36.5%), myalgia (20.5%) and psychological symptoms (19.5%). PCF was seen in 9.5% of the patients and was associated with persistent breathlessness at 6 weeks and inpatient ventilation [adjusted OR 5.02(1.76-14.27) and 4.45(1.27-15.58)] respectively. It was more common in men and in patients with peak CRP >171.5 mg/L, peak WBC count ≥12 x 10 9/L, severe inpatient COVID-19 CXR changes and CT changes. Ventilation was also a risk factor for persisting fatigue and myalgia, the latter was also more common in those with severe cytokine storm and severe COVID-19 inpatient CXR changes. Conclusions: All the patients discharged after COVID-19 should be assessed using a set protocol by a multidisciplinary team. Patients who had severe COVID-19 infection particularly those who were intubated and who have persistent breathlessness are at risk of developing PCF. They should have a CT Chest and have respiratory follow-up.
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