Series: Pragmatic trials and real world evidence: Paper 2. Setting, sites, and investigator selection.

This second article in the series on pragmatic trials describes the challenges in selection of sites for pragmatic clinical trials and the impact on validity, precision, and generalizability of the results. The selection of sites is an important factor for the successful execution of a pragmatic trial and impacts the extent to which the results are applicable to future patients in clinical practice. The first step is to define usual care and understand the heterogeneity of sites, patient demographics, disease prevalence and country choice.

Thyroid hormone production rates in rat liver and intestine in vivo: a novel graph theory and experimental solution.

We develop a novel method for finding sufficient experimental conditions for discriminating and quantifying individual biomolecule production sources in distributed, inhomogeneous multisource systems in vivo, and we apply it experimentally to a complex, unsolved problem in endocrinology. The majority of hormonal triiodothyronine (T3) is produced from prohormone thyroxine (T4) in numerous nonthyroidal organs and, with one exception, the T3 production rate has not been fully resolved in any single extrathyroidal organ of any species. Using a readily generalized graphic method called cut-set analysis, we show here that measured steady-state responses in several organs to three independent tracer infusions, two into blood and one directly into the organ(s) of interest, are sufficient to resolve this problem for organs fully accessible to direct infusion in vivo.