Manufactured ACE2 receptor treatments triumphs over mutational avoid associated with SARSCoV2

Machupo virus, known to cause hemorrhagic fevers, enters human cells via binding with its envelope glycoprotein to transferrin receptor 1 (TfR). Similarly, the receptor interactions have been explored in biotechnological applications as a molecular system to ferry therapeutics across the cellular membranes and through the impenetrable blood-brain barrier that effectively blocks any such delivery into the brain. Study of the experimental structure of Machupo virus glycoprotein 1 (MGP1) in complex with TfR and glycoprotein sequence homology has identified some residues at the interface that influence binding. There are, however, no studies that have attempted to optimize the binding potential between MGP1 and TfR. In pursuits for finding therapeutic solutions for the New World arenaviruses, and to gain a greater understanding of MGP1 interactions with TfR, it is crucial to understand the structure-sequence relationship driving the interface formation. By displaying MGP1 on yeast surface we have examined the contributions of individual residues to the binding of solubilized ectodomain of TfR. We identified MGP1 binding hot spot residues, assessed the importance of posttranslational N-glycan modifications, and used a selection with random mutagenesis for affinity maturation. We show that the optimized MGP1 variants can bind more strongly to TfR than the native MGP1, and there is an MGP1 sequence that retains binding in the absence of glycosylation, but with the addition of further amino acid substitutions. The engineered variants can be used to probe cellular internalization or the blood-brain barrier crossing to achieve greater understanding of TfR mediated internalization.Family studies routinely employ biased sampling schemes in which individuals are randomly chosen from a disease registry and genetic and phenotypic data are obtained from their consenting relatives. We view this as a two-phase study and propose the use of an efficient selection model for the recruitment of families to form a phase II sample subject to budgetary constraints. Simple random sampling, balanced sampling and use of an approximately optimal selection model are considered where the latter is chosen to minimize the variance of parameters of interest. We consider the setting where family members provide current status data with respect to the disease and use copula models to address within-family dependence. The efficiency gains from the use of an optimal selection model over simple random sampling and balanced sampling schemes are investigated as is the robustness of optimal sampling to model misspecification. An application to a family study on psoriatic arthritis is given for illustration.
Friedreich ataxia (FA) is a progressive genetic neurodegenerative disorder with no approved treatment. Omaveloxolone, an Nrf2 activator, improves mitochondrial function, restores redox balance, and reduces inflammation in models of FA. We investigated the safety and efficacy of omaveloxolone in patients with FA.
We conducted an international, double-blind, randomized, placebo-controlled, parallel-group, registrational phase 2 trial at 11 institutions in the United States, Europe, and Australia (NCT02255435, EudraCT2015-002762-23). Eligible patients, 16 to 40 years of age with genetically confirmed FA and baseline modified Friedreich's Ataxia Rating Scale (mFARS) scores between 20 and 80, were randomized 11 to placebo or 150mg per day of omaveloxolone. The primary outcome was change from baseline in the mFARS score in those treated with omaveloxolone compared with those on placebo at 48 weeks.
One hundred fifty-five patients were screened, and 103 were randomly assigned to receive omaveloxolone (n = 51) or placebo (n = 52), with 40 omaveloxolone patients and 42 placebo patients analyzed in the full analysis set. Changes from baseline in mFARS scores in omaveloxolone (-1.55 ± 0.69) and placebo (0.85 ± 0.64) patients showed a difference between treatment groups of -2.40 ± 0.96 (p = 0.014). Transient reversible increases in aminotransferase levels were observed with omaveloxolone without increases in total bilirubin or other signs of liver injury. Headache, nausea, and fatigue were also more common among patients receiving omaveloxolone.
In the MOXIe trial, omaveloxolone significantly improved neurological function compared to placebo and was generally safe and well tolerated. It represents a potential therapeutic agent in FA. ANN NEUROL 2021;89212-225.
In the MOXIe trial, omaveloxolone significantly improved neurological function compared to placebo and was generally safe and well tolerated. It represents a potential therapeutic agent in FA. read more ANN NEUROL 2021;89212-225.
To compare the effectiveness and safety of 2 high-intensity atorvastatin doses (40 mg vs 80 mg) among acute coronary syndrome (ACS) patients.
This retrospective observational cohort study using real-world data included patients admitted with ACS to the Heart Hospital in Qatar between 1 January 2017 and 31 December 2018. The primary endpoint was a composite of cardiovascular disease-associated death, nonfatal ACS and nonfatal stroke. Cox proportional hazard regression analysis was used to determine the association between the 2 high-intensity atorvastatin dosing regimens and the primary outcome at 1 month and 12 months postdischarge.
Of the 626 patients included in the analyses, 475 (75.9%) received atorvastatin 40 mg, while 151 (24.1%) received atorvastatin 80 mg following ACS. Most of the patients were Asian (73%), male (97%) with a mean age of 50 years and presented with ST-elevation myocardial infarction (60%). The incidence of the primary effectiveness outcome did not differ between the atorvastatin 40-and 80-mg groups at 1 month (0.8 vs 1.3%; adjusted hazard ratio = 0.59, 95% confidence interval 0.04-8.13, P = .690) and at 12 months (3.2 vs 4%; adjusted hazard ratio = 0.57, 95% confidence interval 0.18-1.80, P = .340). Similarly, the use of the 2 doses of atorvastatin resulted in comparable safety outcomes, including liver toxicity, myopathy and rhabdomyolysis with an event rate of <1% in both groups.
The use of atorvastatin 40 mg in comparison to atorvastatin 80 mg in patients with ACS resulted in similar cardiovascular effectiveness and safety outcomes.
The use of atorvastatin 40 mg in comparison to atorvastatin 80 mg in patients with ACS resulted in similar cardiovascular effectiveness and safety outcomes.