Repeat subcutaneous administration of casirivimab and imdevimab in adults is well-tolerated and prevents the occurrence of COVID-19.

OBJECTIVES: A phase 1, double-blind, placebo-controlled trial was conducted to evaluate the safety, tolerability, and exploratory efficacy of repeat monthly doses of subcutaneous (SC) casirivimab and imdevimab (CAS+IMD) in uninfected adult volunteers. METHODS: Participants were randomized (3:1) to SC CAS+IMD 1200 mg or placebo every 4 weeks for up to six doses. Primary and secondary end points evaluated safety, pharmacokinetics, and immunogenicity. Exploratory efficacy was evaluated by the incidence of COVID-19 or SARS-CoV-2 seroconversion. RESULTS: In total, 969 participants received CAS+IMD. Repeat monthly dosing of SC CAS+IMD led to a 92.4% relative risk reduction in clinically defined COVID-19 compared with placebo (3/729 [0.4%] vs 13/240 [5.4%]; odds ratio 0.07 [95% CI 0.01-0.27]), and a 100% reduction in laboratory-confirmed COVID-19 (0/729 vs 10/240 [4.2%]; odds ratio 0.00). Development of anti-drug antibodies occurred in a small proportion of participants (<5%). No grade ≥3 injection-site reactions (ISRs) or hypersensitivity reactions were reported. Slightly more participants reported treatment-emergent adverse events with CAS+IMD (54.9%) than with placebo (48.3%), a finding that was due to grade 1-2 ISRs. Serious adverse events were rare. No deaths were reported in the 6-month treatment period. CONCLUSION: Repeat monthly administration of 1200 mg SC CAS+IMD was well-tolerated, demonstrated low immunogenicity, and showed a substantial risk reduction in COVID-19 occurrence.

Emergency biliary sonography: utility of common bile duct measurement in the diagnosis of cholecystitis and choledocholithiasis.

BACKGROUND: Measurement of the common bile duct (CBD) has traditionally been considered an integral part of gallbladder sonography, but accurate identification of the CBD can be difficult for novice sonographers. OBJECTIVE: To determine the prevalence of isolated sonographic CBD dilation in emergency department (ED) patients with cholecystitis or choledocholithiasis without laboratory abnormalities or other pathologic findings on biliary ultrasound. METHODS: We conducted a retrospective chart review on two separate ED patient cohorts between June 2000 and June 2010. The first cohort comprised all ED patients undergoing a biliary ultrasound and subsequent cholecystectomy for presumed cholecystitis. The second cohort consisted of all ED patients receiving a biliary ultrasound who were ultimately diagnosed with choledocholithiasis. Ultrasound data and contemporaneous laboratory values were collected. Postoperative gallbladder pathology reports and endoscopic retrograde cholangiopancreatography (ERCP) reports were used as the criterion standard for final diagnosis. RESULTS: Of 666 cases of cholecystitis, there were 251 (37.7%) with a dilated CBD > 6 mm and only 2 cases (0.3%; 95% confidence interval [CI] 0.0-0.7%) of isolated CBD dilation with an otherwise negative ultrasound and normal laboratory values. Of 111 cases of choledocholithiasis, there were 80 (72.0%) with a dilated CBD and only 1 case (0.9%; 95% CI 0.0-2.7%) with an otherwise negative ultrasound and normal laboratory values. CONCLUSION: The prevalence of isolated sonographic CBD dilation in cholecystitis and choledocholithiasis is <1%. Omission of CBD measurement is unlikely to result in missed cholecystitis or choledocholithiasis in the setting of a routine ED evaluation with an otherwise normal ultrasound and normal laboratory values.

Regulation of translation by the redox state of elongation factor G in the cyanobacterium Synechocystis sp. PCC 6803.

Elongation factor G (EF-G), a key protein in translational elongation, was identified as a primary target of inactivation by reactive oxygen species within the translational machinery of the cyanobacterium Synechocystis sp. PCC 6803 (Kojima, K., Oshita, M., Nanjo, Y., Kasai, K., Tozawa, Y., Hayashi, H., and Nishiyama, Y. (2007) Mol. Microbiol. 65, 936-947). In the present study, we found that inactivation of EF-G (Slr1463) by H(2)O(2) was attributable to the oxidation of two specific cysteine residues and formation of a disulfide bond. Substitution of these cysteine residues by serine residues protected EF-G from inactivation by H(2)O(2) and allowed the EF-G to mediate translation in a translation system in vitro that had been prepared from Synechocystis. The disulfide bond in oxidized EF-G was reduced by thioredoxin, and the resultant reduced form of EF-G regained the activity to mediate translation in vitro. Western blotting analysis showed that levels of the oxidized form of EF-G increased under strong light in a mutant that lacked NADPH-thioredoxin reductase, indicating that EF-G is reduced by thioredoxin in vivo. These observations suggest that the translational machinery is regulated by the redox state of EF-G, which is oxidized by reactive oxygen species and reduced by thioredoxin, a transmitter of reducing signals generated by the photosynthetic transport of electrons.

Oxidation of elongation factor G inhibits the synthesis of the D1 protein of photosystem II.

Oxidative stress inhibits the repair of photodamaged photosystem II (PSII). This inhibition is due initially to the suppression, by reactive oxygen species (ROS), of the synthesis de novo of proteins that are required for the repair of PSII, such as the D1 protein, at the level of translational elongation. To investigate in vitro the mechanisms whereby ROS inhibit translational elongation, we developed a translation system in vitro from the cyanobacterium Synechocystis sp. PCC 6803. The synthesis of the D1 protein in vitro was inhibited by exogenous H2O2. However, the addition of reduced forms of elongation factor G (EF-G), which is known to be particularly sensitive to oxidation, was able to reverse the inhibition of translation. By contrast, the oxidized forms of EF-G failed to restore translational activity. Furthermore, the overexpression of EF-G of Synechocystis in another cyanobacterium Synechococcus sp. PCC 7942 increased the tolerance of cells to H2O2 in terms of protein synthesis. These observations suggest that EF-G might be the primary target, within the translational machinery, of inhibition by ROS.

Retrospective analysis of emergency department ultrasound for acute appendicitis.

OBJECTIVES: To determine whether emergency physicians (EPs) who have skills in the other applications of ultrasound can apply these in appendicitis diagnosis. METHODS: EPs did not have focused training in bedside ultrasound for appendicitis. We identified patients receiving an ED bedside ultrasound evaluation for appendicitis from our ultrasound log. Criterion reference was radiology ultrasound (RUS), CT scan, or pathology report. RESULTS: We performed 155 ED ultrasounds for appendicitis. There were 27/155 cases where the ED ultrasound was true positive and agreed with pathology (sensitivity = 39%, 95% CI 28 - 52%). In 42/155 (27%) the ED ultrasound was non-diagnostic (false negative) with pathology positive. In 77 cases the ED ultrasound was true negative with non-visualization of the appendix in concert with non-visualization by RUS or CT scan (specificity = 90%, 95% CI 81-95%). In nine cases (6%), ED ultrasound was falsely positive, compared to CT scan with surgical consult. CONCLUSION: ED ultrasound by EPs prior to focused appendicitis ultrasound training is insufficiently accurate.