Cell-type profiling in salamanders identifies innovations in vertebrate forebrain evolution.

The evolution of advanced cognition in vertebrates is associated with two independent innovations in the forebrain: the six-layered neocortex in mammals and the dorsal ventricular ridge (DVR) in sauropsids (reptiles and birds). How these innovations arose in vertebrate ancestors remains unclear. To reconstruct forebrain evolution in tetrapods, we built a cell-type atlas of the telencephalon of the salamander Pleurodeles waltl. Our molecular, developmental, and connectivity data indicate that parts of the sauropsid DVR trace back to tetrapod ancestors. By contrast, the salamander dorsal pallium is devoid of cellular and molecular characteristics of the mammalian neocortex yet shares similarities with the entorhinal cortex and subiculum. Our findings chart the series of innovations that resulted in the emergence of the mammalian six-layered neocortex and the sauropsid DVR.

Quantifying Patient Investment in Novel Neurological Drug Development.

While the drug development literature provides numerous estimates of the financial costs to bring a new drug to market, the investment of patient-participants in the research process has not been described. Trial participants and their caregivers, like companies, invest time and undertake risk when they participate in prelicense trials. We determined the average number of patient-participants needed to develop a novel neurological drug. We created a cohort of 108 unapproved drugs first tested for efficacy between 2006 and 2011 and used ClinicalTrials.gov to capture enrollment in all subsequent prelicense trials of these drugs over a 9-year period. Our primary outcome was the average number of patients enrolled in prelicense neurological drug trials per drug that ultimately attained FDA approval, including patients who participated in both successful and unsuccessful development efforts. Five drugs (4.6%) were FDA approved, and 66,751 patient-participants were enrolled across successful and unsuccessful drug development efforts, resulting in an average of 13,350 patients for each drug attaining approval (95% CI 7155 to 54,954). Our estimates reveal the substantial amount patients and their caregivers contribute to private drug development.