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Background: Convenient administration of coronavirus disease 2019 (COVID-19) treatment in community settings is desirable. Sotrovimab is a pan-sarbecovirus dual-action monoclonal antibody formulated for intravenous (IV) or intramuscular (IM) administration for early treatment of mild/moderate COVID-19. Method: This multicenter phase 3 study based on a randomized open-label design tested the noninferiority of IM to IV administration according to an absolute noninferiority margin of 3.5%. From June to August 2021, patients aged ≥12 years with COVID-19, who were neither hospitalized nor receiving supplemental oxygen but were at high risk for progression, were randomized 1:1:1 to receive sotrovimab as a single 500-mg IV infusion or a 500- or 250-mg IM injection. The primary composite endpoint was progression to (1) all-cause hospitalization for >24 hours for acute management of illness or (2) all-cause death through day 29. Results: Sotrovimab 500â mg IM was noninferior to 500â mg IV: 10 (2.7%) of 376 participants vs 5 (1.3%) of 378 met the primary endpoint, respectively (absolute adjusted risk difference, 1.06%; 95% CI, -1.15% to 3.26%). The 95% CI upper limit was lower than the prespecified noninferiority margin of 3.5%. The 250-mg IM group was discontinued early because of the greater proportion of hospitalizations vs the 500-mg groups. Serious adverse events occurred in <1% to 2% of participants across groups. Four participants experienced serious disease-related events and died (500â mg IM, 2/393, <1%; 250â mg IM, 2/195, 1%). Conclusions: Sotrovimab 500-mg IM injection was well tolerated and noninferior to IV administration. IM administration could expand outpatient treatment access for COVID-19. Clinical Trials Registration: ClinicalTrials.gov: NCT04913675.
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A bracing device for stabilizing cardiac catheters inside the heart was developed to provide surgical-level dexterity to minimally invasive catheter-based procedures for cardiac valve disease. The brace was designed to have a folding structure, which lies flat along a catheter during navigation through vasculature and then unfolds into a rigid bracing configuration after deployment across the interatrial septum. The brace was designed to be easily deployable, provide bracing support for a transseptal catheter, and also be compliant enough to be delivered to the heart via tortuous vasculature. This aims to improve dexterity in catheter-based mitral valve repair and enable other complex surgical procedures to be done with minimally invasive instruments.
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UNLABELLED: Nonalcoholic fatty liver disease (NAFLD), the accumulation of lipid within hepatocytes, is increasing in prevalence. Increasing fructose consumption correlates with this increased prevalence, and rodent studies directly support fructose leading to NAFLD. The mechanisms of NAFLD and in particular fructose-induced lipid accumulation remain unclear, although there is evidence for a role for endoplasmic reticulum (ER) stress and oxidative stress. We have evidence that NAFLD models demonstrate activation of the target of rapamycin complex 1 (Torc1) pathway. We set out to assess the contribution of ER stress, oxidative stress, and Torc1 up-regulation in the development of steatohepatitis in fructose-treated larval zebrafish. Zebrafish were treated with fructose or glucose as a calorie-matched control. We also treated larvae with rapamycin, tunicamycin (ER stress), or valinomycin (oxidative stress). Fish were stained with oil red O to assess hepatic lipid accumulation, and we also performed quantitative polymerase chain reaction (qPCR)and western blot analysis. We performed immunostaining on samples from patients with NAFLD and nonalcoholic steatohepatitis (NASH). Treatment with fructose induced hepatic lipid accumulation, mitochondrial abnormalities, and ER defects. In addition, fructose-treated fish showed activation of inflammatory and lipogenic genes. Treatment with tunicamycin or valinomycin also induced hepatic lipid accumulation. Expression microarray studies of zebrafish NAFLD models showed an elevation of genes downstream of Torc1 signaling. Rapamycin treatment of fructose-treated fish prevented development of hepatic steatosis, as did treatment of tunicamycin- or valinomycin-treated fish. Examination of liver samples from patients with hepatic steatosis demonstrated activation of Torc1 signaling. CONCLUSION: Fructose treatment of larval zebrafish induces hepatic lipid accumulation, inflammation, and oxidative stress. Our results indicate that Torc1 activation is required for hepatic lipid accumulation across models of NAFLD, and in patients.
