No abstract

Neuronal programming by forced expression of transcription factors (TFs) holds promise for clinical applications of regenerative medicine. However, the mechanisms by which TFs coordinate their activities on the genome and control distinct neuronal fates remain obscure. Using direct neuronal programming of embryonic stem cells, we dissected the contribution of a series of TFs to specific neuronal regulatory programs. We deconstructed the Ascl1-Lmx1b-Foxa2-Pet1 TF combination that has been shown to generate serotonergic neurons and found that stepwise addition of TFs to Ascl1 canalizes the neuronal fate into a diffuse monoaminergic fate. The addition of pioneer factor Foxa2 represses Phox2b to induce serotonergic fate, similar to in vivo regulatory networks. Foxa2 and Pet1 appear to act synergistically to upregulate serotonergic fate. Foxa2 and Pet1 co-bind to a small fraction of genomic regions but mostly bind to different regulatory sites. In contrast to the combinatorial binding activities of other programming TFs, Pet1 does not strictly follow the Foxa2 pioneer. These findings highlight the challenges in formulating generalizable rules for describing the behavior of TF combinations that program distinct neuronal subtypes.

Background and Aims: Alcohol intoxication may confound the clinical assessment of the trauma patient. Head computed tomography (h-CT) is the standard imaging technique to rule out intracranial injury in most intoxicated trauma patients. The objective of this study was to determine whether certain clinical findings (computed clinical score [CCS]) could predict the h-CT yield, admission, and neurosurgical consultation (NSC) among intoxicated trauma patients. Materials and Methods: This is a 4-year retrospective cohort study (2013–2017) of trauma patients who presented to our level 1 trauma center emergency department with alcohol intoxication. For each patient, a computed clinical score (CCS) was generated based on the following findings: age ≥50 years, Glasgow Coma Scale <13, evidence of trauma above the clavicles, amnesia, loss of consciousness, headache, vomiting, and seizures. The primary endpoints were NSC, admission, and acute h-CT finding. Univariate and multivariate regressions were used to compare predictors of the primary endpoints. Results: We identified 437 intoxicated trauma patients (median age: 35 years [interquartile range: 25–50]; 71.9% men; median blood alcohol content: 207.8 mg/dL). One hundred and twenty-four (30.4%) patients had acute findings on h-CT, 351 (80.3%) were admitted, and 112 (25.6%) received NSC. On multivariate analysis, CCS was the only predictor of acute h-CT (odds ratio [OR] =1.6; 95% confidence interval [CI]: 1.3–2.0; P < 0.0001) and the best predictor of admission (OR = 1.6; 95% CI: 1.3–1.9; P < 0.0001) and NSC (OR = 1.8; 95% CI: 1.5–2.3; P < 0.0001). Conclusions: One-third of intoxicated trauma patients have acute findings on h-CT. While the CCS was the best predictor of acute h-CT findings, hospital admission, and NSC, h-CT scanning should continue to be a standard of care.