Global Safety Assessment of Adverse Events of Special Interest Following 2 Years of Use and 772 Million Administered Doses of mRNA-1273.

Background: Large-scale use of mRNA COVID-19 vaccines during the pandemic was associated with enhanced safety monitoring to ensure accurate and timely review of safety. We reviewed the mRNA-1273 (original strain) safety profile following 2 years of use (>772 million administered doses), primarily focusing on predefined safety topics (ie, adverse events of special interest [AESIs]) proposed in advance of COVID-19 vaccine use. Methods: Cumulative mRNA-1273 safety data were included from spontaneous adverse event (AE) cases reported to Moderna's global safety database between 18 December 2020 and 17 December 2022. Reporting rates of AESIs were calculated per 1 million doses of mRNA-1273 administered. Observed-to-expected (OE) ratios were computed by comparing observed rates of AESIs with the background/expected rate for these events to evaluate potential associations with mRNA-1273. Results: There were 658 759 identified case reports associated with 2 517 669 AEs. Most AEs were nonserious (83.4%; 2 098 954/2 517 669). Overall 0.7% (17 751/2 517 669) were fatal. AESIs represented 13.7% of all AEs (344 921/2 517 669), with reporting rates for most AESIs below the expected background incidence. Exceptions included anaphylaxis (OE ratio 3 days after vaccination, 2.09; 95% CI, 1.93-2.25) and, among individuals aged 12 to 40 years, myocarditis (OE ratio 7 days after any dose, 3.89 [3.50-4.32]; among men after dose 2, 8.57 [6.88-10.68]) and pericarditis (OE ratio 7 days after vaccination, 3.47; 2.89-4.16). Conclusions: This safety analysis of mRNA-1273 identified evidence of increased risk for anaphylaxis, myocarditis, and pericarditis but not for other AESIs identified for enhanced monitoring ahead of COVID-19 vaccine use.

Role of Augmented Basis Sets and Quest for ab Initio Performance/Cost Alternative to Kohn-Sham Density Functional Theory.

Following a previous work, we have assessed the feasibility of MP2/CBS(d, t) as an alternative to state-of-the-art density functionals. The effect of using augmented basis sets is here tested on the 76 barrier heights and 10 isomerization reactions previously utilized. Moreover, calculations for 20 sets of the GMTKN24 database for thermochemistry, kinetics, and noncovalent interactions have been performed. For the density functional theory calculations, M06-2X and B3LYP-D3 functionals are utilized as two representative functionals, while MP2 and CCSD(T) methods are employed as the ab initio counterparts. The results show that MP2 calculations perform similarly to the ones obtained with M06-2X insofar as accuracy and computational cost are concerned. For all methods, the use of augmented basis sets yields enhanced results for anionic systems when compared with the ones from non-augmented bases. Otherwise, the basis-set change effect is found to be minimal. It is therefore concluded that the use of large basis sets is unjustified when facing the increase in computational cost.

Radiobiological parameters for breast cancer: a Monte Carlo analysis of START trial published results.

OBJECTIVE:: Trial results are usually given in terms of end point confidence intervals, the data concerning the participating patients being not available. Sometimes, it would be useful or necessary to obtain derived quantities, such as dose-response relationships, from the known information. In this work, we describe a methodology that allows to do that and illustrate it by analyzing the UK standardization of breast radiotherapy (START) trials. METHODS:: Using Monte Carlo techniques, virtual data sets were generated by sampling trial outcome distributions in terms of the tumor control probability (described by means of a logistic dose response and the equations of isoeffect in the linear-quadratic model). After fitting the available experimental data, the radiobiological parameters of interest and their confidence intervals were obtained from the TCP vs 'EQD2 curve in which the surgery effect is also taken into account. RESULTS:: The value of [Formula: see text] obtained for breast cancer was 3.6 Gy, with a 95% confidence interval of (1.5,15.5) Gy, in agreement with the one estimated by the START group. The time factor, referred to a scheme of 2 Gy per fraction, was 0.74 (0.41,2.67) Gy day-1, of the same order than that estimated for head and neck cancers. CONCLUSION:: A methodology permitting an analysis of trial results was developed and tested with the results of the START trials. The procedure does not require detailed knowledge of the distributions actually found in the trials. The values obtained for the parameters are similar to those of the START estimations and this can be considered an independent confirmation of their validity, thus showing the model usefulness. The methodology presented here relies on basic statistical methods that are general enough to permit it to be applied to any kind of trial. This may be particularly interesting when the original data are no longer available. ADVANCES IN KNOWLEDGE:: The main novelty of this paper is to provide with a Monte Carlo based tool that permits an independent analysis of published trial results in order to obtain radiobiological parameters without a detailed knowledge of the data corresponding to the participating patients.

Safety and efficacy of a protocol using bougienage or endoscopy for the management of coins acutely lodged in the esophagus: a large case series.

STUDY OBJECTIVE: We report our experience using the bougienage procedure in the management of esophageal coins. METHODS: Observational case series of all patients presenting to our emergency departments with coins acutely lodged in the esophagus between 1994 and 2006. All patients were treated according to our protocol with either endoscopy or bougienage. Patients are eligible for bougienage if they have had a witnessed coin ingestion less than 24 hours before presentation and if esophageal coin position is confirmed by chest radiograph and there is no history of esophageal disease, surgery, or foreign body. Primary outcomes measured were complications, efficacy of procedure, hospital charges, length of stay, and return to the hospital. Length of stay and hospital charges data were gathered for patients presenting in the final 24 months of the study. RESULTS: Six hundred twenty patients were identified as having esophageal coins. Three hundred fifty-five patients had a successful bougienage, and 17 patients had unsuccessful bougienage. By comparison, 248 patients underwent endoscopy, and the coin was successfully removed in all but 1 of these patients. Of patients undergoing endoscopy, 89 were eligible for bougienage, but patient, parent, or physician preference was for endoscopic management. Eleven patients required reevaluation or readmission for complaints related to esophageal coin. The only complication was subglottic edema, causing respiratory distress in a single patient who had undergone endoscopy. Patients undergoing endoscopy had an average length of stay of 6.1 hours and average hospital charges were $6,087. Patients undergoing bougienage had an average length of stay of 2.2 hours and average hospital charges of $1,884. CONCLUSION: In properly screened patients with coins acutely lodged in the esophagus, bougienage offers a safe and effective alternative to other methods of coin management.

The conduct of in vitro and in vivo drug-drug interaction studies: a Pharmaceutical Research and Manufacturers of America (PhRMA) perspective.

Current regulatory guidances do not address specific study designs for in vitro and in vivo drug-drug interaction studies. There is a common desire by regulatory authorities and by industry sponsors to harmonize approaches, to allow for a better assessment of the significance of findings across different studies and drugs. There is also a growing consensus for the standardization of cytochrome P450 (P450) probe substrates, inhibitors and inducers and for the development of classification systems to improve the communication of risk to health care providers and to patients. While existing guidances cover mainly P450-mediated drug interactions, the importance of other mechanisms, such as transporters, has been recognized more recently, and should also be addressed. This article was prepared by the Pharmaceutical Research and Manufacturers of America (PhRMA) Drug Metabolism and Clinical Pharmacology Technical Working Groups and represents the current industry position. The intent is to define a minimal best practice for in vitro and in vivo pharmacokinetic drug-drug interaction studies targeted to development (not discovery support) and to define a data package that can be expected by regulatory agencies in compound registration dossiers.