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Asthma is a heterogeneous disease, with multiple underlying inflammatory pathways and structural airway abnormalities that impact disease persistence and severity. Recent progress has been made in developing targeted asthma therapeutics, especially for subjects with eosinophilic asthma. However, there is an unmet need for new approaches to treat patients with severe and exacerbation-prone asthma, who contribute disproportionately to disease burden. Extensive deep phenotyping has revealed the heterogeneous nature of severe asthma and identified distinct disease subtypes. A current challenge in the field is to translate new and emerging knowledge about different pathobiologic mechanisms in asthma into patient-specific therapies, with the ultimate goal of modifying the natural history of disease. Here, we describe the Precision Interventions for Severe and/or Exacerbation-Prone Asthma (PrecISE) Network, a groundbreaking collaborative effort of asthma researchers and biostatisticians from around the United States. The PrecISE Network was designed to conduct phase II/proof-of-concept clinical trials of precision interventions in the population with severe asthma, and is supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health. Using an innovative adaptive platform trial design, the PrecISE Network will evaluate up to 6 interventions simultaneously in biomarker-defined subgroups of subjects. We review the development and organizational structure of the PrecISE Network, and choice of interventions being studied. We hope that the PrecISE Network will enhance our understanding of asthma subtypes and accelerate the development of therapeutics for severe asthma.

Mepolizumab is a therapy for severe asthma. We have little knowledge of the characteristics of people in the US that discontinue mepolizumab in clinical care. To investigate the real-world efficacy and time to clinical discontinuation of mepolizumab, we evaluated individuals with asthma started on mepolizumab at the Cleveland Clinic. We hypothesized that individuals that discontinue mepolizumab have more severe and uncontrolled asthma at baseline. Between 2016 and 2022, patients who started on mepolizumab consented to be assessed over 18 months. At baseline, a questionnaire including demographic and medical history was collected. Laboratory findings such as ACT score, FENO (Fractional Excretion of Nitric Oxide), and spirometry were recorded. At the conclusion of the observation period, the participants were divided into two categories: Group A and Group B. Group B [N = 28] discontinued mepolizumab (p < 0.05) at an average of 5.8 months (SD 4.2 months). Group A [N = 129] stayed on the therapy for at least 1 year. A participant with an ACT score less than 13 has an odds ratio of 6.64 (95% CI, 2.1 − 26.0) of discontinuing mepolizumab therapy. For a male, the odds of discontinuing mepolizumab therapy is 3.39 (95% CI, 1.1–11.2). In this real-world study, we find that high eosinophil count may not be adequate in screening which individuals will benefit from mepolizumab. Up to 17% of patients fail therapy within 6 months, with male sex and low ACT score increasing risk of mepolizumab discontinuation at Cleveland Clinic. [ABSTRACT FROM AUTHOR]

This invited Article both reviews the Tenth Circuit's stance on the circuit split addressing repleading counterclaims in amended answers and observes broader interpretive-approach trends in Federal Rules of Civil Procedure cases. In Sinclair Wyoming Refining Co. v. A & B Builders, Ltd., the Tenth Circuit holds that, absent prejudice to the opposing party, the failure to replead a counterclaim in an amended answer does not constitute abandonment; thus, taking the so-called permissive side of a circuit split on this question. In so doing, the Tenth Circuit adopts a purposivist approach to interpretation of the Federal Rules of Civil Procedure. In reviewing all of the Tenth and other circuits' significant, published, 2021, Federal Rules of Civil Procedure cases, we conclude that the circuits deploy textualist reasoning less often for Rules issues than they do for other questions. In particular, we find that both the Tenth Circuit, at 1.9%, and the other circuits, at 1.8%, deployed textualist reasoning seldomly for Rules issues. Yet, in this same dataset of cases, the courts used textualist reasoning for non-Rules issues often: the Tenth Circuit, at 23.1%, and the other circuits, at 21.3%. We also found the Tenth Circuit, at 1.9%, trailed the other circuits, at 5.3%, in the use of purposivist reasoning in Rules analyses. [ABSTRACT FROM AUTHOR]