Imperial Consultants

This study examines the expression of CD45 isoforms on human yellow fever virus vaccine (YFV-17D) specific CD8 T cells longitudinally after vaccination. As expected, effector CD8 T cells at day 14 express CD45RO but within 4 to 6 wk these virus-specific CD8 T cells become CD45RA positive and remain CD45RA for >10 y. The journey for these YFV-specific CD8 T cells goes from naive (CD45RA+ CCR7+) to effector/effector memory (CD45RO+ CCR7-) to Temra (CD45RA+ CCR7-) to stem-cell memory (CD45RA+ CCR7+). These YFV-specific CD8 T cells rarely acquire the canonical Tcm phenotype (CD45RO+ CCR7+). This CD45RO to RA switch coincides with clearance of YFV, so we hypothesized that antigen may be playing a role in regulating CD45 expression. We addressed this issue by ex vivo analysis and provide evidence that this switch is indeed regulated by antigen. Sorted YFV-specific CD45RO effector CD8 T cells reexpress CD45RA when cultured ex vivo in the absence of antigen and retain CD45RO in the presence of cognate peptide. We also extended these ex vivo analysis to human cytomegalovirus (CMV)-specific CD8 T cells and show that CD45RO cells transition to CD45RA in the absence of antigen and CD45RA cells become CD45RO when stimulated with CMV peptide. We then show that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike-specific CD8 T cells can repeatedly undergo the same CD45RA to RO to RA transition in vivo after the SARS-CoV-2 mRNA vaccination. Again, the canonical Tcm phenotype spike-specific memory CD8 T cells were not readily detectable. These studies warrant a reevaluation of how human memory CD8 T cells are defined.

Lorsque l’État de l’Équateur se sépare de la République de Colombie en 1830, le nouveau gouvernement de Quito se lance dans un effort de centralisation pour asseoir une nouvelle gouvernabilité sur la totalité du territoire. Le projet de construction de l’État et de la nation équatoriennes doit se faire à travers de la négociation et la formation de pactes entre le gouvernement central et les pouvoirs locaux afin d’obtenir une forme pérenne d’étatisation. Cependant, les acteurs qui furent sélectionnés pour prendre le poste de gouverneur de la province de Loja pendant les premières années dudit processus étaient presque exclusivement des étrangers (canadiens, français, irlandais). Nous nous intéressons ici aux raisons qui ont pu mener le gouvernement équatorien à choisir ces individus pour la tâche et la manière dont ils l’ont exercée.

Enrollment of women of childbearing potential in clinical trials from early stages of drug development allows the gathering of relevant safety and pharmacokinetics data in the representative disease population. However, risk mitigation strategies are needed to ensure thesafety of thedeveloping embryo in case of unintended pregnancy in female study participants or in female partners of male study participants. These risk mitigation strategies often include contraception requirements, however we observed that such requirements vary widely across sponsors and trials. Some sponsors and contract research organizations adhere to the strictest precautions by default, assuming a worst-case scenario for each new compound's risk assessment. In this review, we provide an overview of the risks addressed by and introduced by contraception requirements in clinical trials. We critically discuss the 'worst-case' approach, and we present a holistic, risk-based approach that takes into account all relevant data, the pros and cons of using hormonal contraceptives, and subject burden.

IntroductionThis systematic literature review and pairwise meta-analysis evaluated the comparative effectiveness of mRNA-1273 versus BNT162b2 in patients with at least one underlying medical condition at high risk for severe COVID-19.MethodsMEDLINE, Embase, and Cochrane databases were searched for relevant articles from January 1, 2019 to February 9, 2024. Studies reporting effectiveness data from at least two doses of mRNA-1273 and BNT162b2 vaccination in adults with medical conditions at high risk of developing severe COVID-19 according to the US Centers for Disease Control and Prevention were included. Outcomes of interest were SARS-CoV-2 infection (overall, symptomatic, and severe), hospitalization due to COVID-19, and death due to COVID-19. Risk ratios (RRs) were calculated with random effects models. Subgroup analyses by specific medical conditions, number of vaccinations, age, and SARS-CoV-2 variant were conducted. Heterogeneity between studies was estimated with chi-square testing. The certainty of evidence was assessed using the Grading of Recommendations, Assessments, Development, and Evaluations framework.ResultsSixty-five observational studies capturing the original/ancestral-containing primary series to Omicron-containing bivalent original-BA4-5 vaccinations were included in the meta-analysis. mRNA-1273 was associated with significantly lower risk of SARS-CoV-2 infection (RR, 0.85 [95% CI, 0.79–0.92]; I2 = 92.5%), symptomatic SARS-CoV-2 infection (RR, 0.75 [95% CI, 0.65–0.86]; I2 = 62.3%), severe SARS-CoV-2 infection (RR, 0.83 [95% CI, 0.78–0.89]; I2 = 38.0%), hospitalization due to COVID-19 (RR, 0.88 [95% CI, 0.82–0.94]; I2 = 38.7%), and death due to COVID-19 (RR, 0.84 [95% CI, 0.76–0.93]; I2 = 1.3%) than BNT162b2. Findings were generally consistent across subgroups. Evidence certainty was low or very low because sufficiently powered randomized controlled trials are impractical in this heterogeneous population.ConclusionMeta-analysis of 65 observational studies showed that vaccination with mRNA-1273 was associated with a significantly lower risk of SARS-CoV-2 infection and COVID-19-related hospitalization and death than BNT162b2 in patients with medical conditions at high risk of severe COVID-19.Supplementary InformationThe online version contains supplementary material available at 10.1007/s12325-025-03117-7.

For patients with celiac disease (CeD), the only current management option is adherence to a strict gluten-free diet (GFD); however, many patients on a GFD continue to experience symptoms with asignificant impact on quality of life. Potential new treatments for CeD are under development and a validated patient-reported outcome measure is required to evaluate their utility in clinical trials. The purpose of this article is to provide a history of the development of the Celiac Disease Symptom Diary (CDSD) 2.1© for use in clinical trials. Qualitative and quantitative studies were conducted from 2010 to 2021, including concept elicitation and cognitive debriefing interviews with adult and adolescent participants with CeD (N = 93) diagnosed via biopsy and/or serology and input from eight interviews with CeD clinical experts. During these studies, different iterations of the CDSD were presented to the US Food and Drug Administration and the European Medicines Agency, and modifications were made in line with their feedback. These studies ultimately led to the development of CDSD 2.1©, a daily diary which focuses on key symptoms of CeD (abdominal pain, bloating, diarrhea, nausea and tiredness). This patient-reported outcome measure was readily understood by adult and adolescent participants with CeD and content validity was demonstrated in both populations. CDSD 2.1© is a content-valid patient-reported outcome measure developed in accordance with best practices and regulatory guidance. A thorough exploration of the psychometric properties of CDSD 2.1© for both adult and adolescent participants with CeDis ongoing to support utilization in clinical trials.

Bayesian approaches in drug development: continuing the virtuous cycle R uberg et al. recently published an article with the aim of starting a virtuous cycle in the use of Bayesian approaches in drug development (Nat. Rev. Drug Discov. 22, 235-250; 2023) 1 . Here, we would like to extend important arguments of their article and add recommendations for using Bayesian statistics 2 . The authors emphasize the fundamental distinctions between frequentist and Bayesian approaches 1 . However, we would also like to highlight the similarities between both perspectives. First, Bayesian and (likelihood-based) frequentist approaches will converge towards identical results as more data are collected, because the likelihood based on the observed data will dominate the model. Second, both approaches will give similar if not identical results if a non-informative prior distribution is used. Moreover, a frequentist one-sided p-value can indeed be interpreted as the probability that the null hypothesis is true in this situation because the p-value will be equal to the corresponding posterior predictive probability 3 . Awareness of these similarities may help to bridge both statistical schools of thought and to resolve regulatory concerns around the use of Bayesian approaches that may be less familiar than frequentist approaches to some researchers. The authors propose Bayesian methods for the use of existing external information, such as data from previous clinical trials, while rightly pointing out that the use of external information may not be appropriate in all contexts owing to the potential for bias 1 . Generally speaking, we consider the application of Bayesian methods to be suitable in scenarios in which omitting suitable available evidence and leaving a suffering patient population without treatment options could be counter to common sense and unethical. Such scenarios include, for example, studies on medical devices, early-phase trials, trials involving patients with rare diseases and extrapolation of data from adult to paediatric populations. We would like to illustrate this point by expanding on the excellent example provided by Ruberg et al. 1 . The THAPCA-OH