Human embryonic stem cell (hESC) differentiation promises advances in regenerative medicine 1 – 3 , yet conversion into transplantable tissues remains poorly understood. Using our keratinocyte differentiation system, we employ a multi-dimensional genomics approach to interrogate the contributions of inductive morphogens retinoic acid (RA) and bone morphogenetic protein 4 (BMP4) and the epidermal master regulator p63 4 , 5 during surface ectoderm commitment. In contrast to other master regulators 6 – 9 , p63 effects major transcriptional changes only after morphogens alter chromatin accessibility, establishing an epigenetic landscape for p63 to modify. p63 distally closes chromatin accessibility and promotes accumulation of H3K27me3 modifications. Cohesin HiChIP 10 visualizations of chromosome conformation reveal that p63 and the morphogens contribute to dynamic long-range chromatin interactions, as illustrated with TFAP2C regulation 11 . Our study demonstrates the unexpected dependency of p63 on morphogenetic signaling and provides novel insights into how a master regulator can specify diverse transcriptional programs based on the chromatin landscape induced by specific morphogen exposure.

Drug-induced pulmonary arterial hypertension (D-PAH) is a form of World Health Organization Group 1 pulmonary hypertension (PH) defined by severe small vessel loss and obstructive vasculopathy, which leads to progressive right heart failure and death. To date, 16 different compounds have been associated with D-PAH, including anorexigens, recreational stimulants, and more recently, several Food and Drug Administration-approved medications. Although the clinical manifestation, pathology, and hemodynamic profile of D-PAH are indistinguishable from other forms of pulmonary arterial hypertension, its clinical course can be unpredictable and to some degree dependent on removal of the offending agent. Because only a subset of individuals develop D-PAH, it is probable that genetic susceptibilities play a role in the pathogenesis, but the characterization of the genetic factors responsible for these susceptibilities remains rudimentary. Besides aggressive treatment with PH-specific therapies, the major challenge in the management of D-PAH remains the early identification of compounds capable of injuring the pulmonary circulation in susceptible individuals. The implementation of pharmacovigilance, precision medicine strategies, and global warning systems will help facilitate the identification of high-risk drugs and incentivize regulatory strategies to prevent further outbreaks of D-PAH. The goal for this review is to inform clinicians and scientists of the prevalence of D-PAH and to highlight the growing number of common drugs that have been associated with the disease.

Epidemiologic, level III.

BackgroundIn 2015 there were 36,252 firearm-related deaths and 84,997 nonfatal injuries in the United States. The longitudinal burden of these injuries through readmissions is currently underestimated. We aimed to determine the 6-month readmission risk and hospital costs for patients injured by firearms.MethodsWe used the Nationwide Readmission Database 2010–2015 to assess the frequency of readmissions at 6 months, and hospital costs associated with readmissions for patients with firearm-related injuries. We produced nationally representative estimates of readmission risks and costs.ResultsOf patients discharged following a firearm injury, 15.6% were readmitted within 6 months. The average annual cost of inpatient hospitalizations for firearm injury was over $911 million, 9.5% of which was due to readmissions. Medicare and Medicaid covered 45.2% of total costs for the 5 years, and uninsured patients were responsible for 20.1%.ConclusionsFrom 2010–2015, the average total cost of hospitalization for firearm injuries per patient was $32,700, almost 10% of which was due to readmissions within 6 months. Government insurance programs and the uninsured shouldered most of this.

This national evaluation of the natural history of isolated splenic injuries from index admission through 6 months found that approximately 1 in 5 patients are readmitted within 6 months of discharge after an isolated splenic injury. However, the chance of readmission for splenectomy after initial nonoperative management was 1.2%. This finding suggests that the current management strategies used for isolated splenic injuries in the United States are well matched to patient need.

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Trifluoroacetic acid (TFA) burns are an ill-defined entity due to a lack of reported sizable burns from this chemical. In this case report of the largest reported burn from TFA, we demonstrate that TFA causes extensive, progressive full-thickness tissue injury that may initially appear superficial. Trifluoroacetic acid does not seem to involve the systemic toxicities that result from hydrofluoric acid burns, and there is no role for calcium gluconate in acute management based on this case. Operative intervention should be staged because wound beds may initially seem healthy yet demonstrate continued necrosis.