Phenylketonuria (PKU) is a common genetic disorder in humans that arises from deficient activity of phenylalanine hydroxylase (PAH), which catalyzes the conversion of phenylalanine to tyrosine. There is a resultant hyperphenylalanemia with subsequent impairment in cognitive abilities, executive functions and motor coordination. The neuropathogenesis of the disease has not been completely elucidated, however, oxidative stress is considered to be a key feature of the disease process. Hyperphenylalanemia also adversely affects monoaminergic metabolism in the brain. For this reason we chose to evaluate the nigrostriatum of Pah enu2 mice, to determine if alterations of monoamine metabolism resulted in morphologic nigrostriatal pathology. Furthermore, we believe that recent developments in adeno-associated virus (AAV)-based vectors have greatly increased the potential for long-term gene therapy and may be a viable alternative to dietary treatment for this metabolic disorder. In this study we identified neurodegenerative changes with regenerative responses in the nigrostriatum of Pah enu2 mice that are consistent with oxidative injury and occurred as early as 4 weeks of age. These neuropathologic changes were reversed following portal vein delivery of a recombinant adeno-associated virus-mouse phenylalanine hydroxylase-woodchuck hepatitis virus post-transcriptional response element (rAAV-mPAH-WPRE) vector to Pah enu2 mice and corresponded to rapid reduction of serum Phe levels.

Caustic substance ingestion (CSI) is a serious medical problem with potentially devastating short- and long-term consequences. Early upper gastrointestinal endoscopy (EaEn) is recommended to evaluate the extent of injury and guide management but there has been controversy about the timing. There is no nationwide study evaluating adherence to EaEn and outcomes following CSI.Nationwide Inpatient Sample database 2003-2011 was used to identify all-age, nonreferral, urgent/emergent admissions with E-International Classification of Diseases Ninth Revision codes for CSI. We evaluated the association of undergoing late endoscopy (LaEn, >48 hours since admission) with poor clinical (death or systemic complications) and economic (cost for admission and length of stay above the 75th percentile) outcomes after controlling for other demographic and clinical factors using a multivariate analysis.We identified 21,682 patients with a median age of 37 years, 51% males, 43% Caucasians, with suicidal ingestion reported in 40%. Endoscopy was performed in 6011 patients (37%). The majority had EaEn (43% within 24, and 40% within 24-48 hours), whereas 17% had LaEn.Compared to EaEn group, the LaEn group was associated with a three-fold increase (OR = 2.7, P < 0.001) in the risk for poor clinical outcome: a fourfold increase (OR = 4.6, P < 0.001) in high cost admissions, and a fivefold increase (OR = 4.9, P < 0.001) in prolonged hospitalization. There was no significant difference in clinical outcomes based on endoscopy within 24, and 24-48 hours of admission.In this retrospective nationwide database analysis, undergoing LaEn was associated with both negative clinical and economic outcomes. More studies are needed to further examine the reasons for delaying endoscopy and subsequent management pathways based on the endoscopic findings. Early endoscopic evaluation could potentially improve the clinical outcomes and reduce costs of these admissions.

Objective: The objective of this study was to compare posttransplant outcomes in patients undergoing bridging locoregional therapy (LRT) with Y-90 transarterial radioembolization (TARE) based protocol compared with transarterial chemoembolization based protocol for hepatocellular carcinoma (HCC) prior liver transplantation (LT). Materials and Methods: Patients listed for LT with HCC within the Milan criteria at our center who had bridging LRT were treated according to transarterial chemoembolization (TACE) based protocol from May 2012 to April 2014 and a TARE based protocol from October 2014 to December 2017. Early posttransplant survival and tumor recurrence were compared between the groups. Tumor response to LRT, microvascular invasion (mVI), and the rate of delisting was also evaluated. Results: One hundred three patients who were listed for LT with HCC within the Milan criteria received LRT. LT was performed in 65 patients, 28 treated with TARE protocol and 37 on TACE protocol. There were no statistical differences in baseline pretransplant characteristics and tumor recurrence. There was a trend toward improved 3-year survival in the TARE group (92.9% vs. 75.7%; P=0.052). The mVI was seen in 1/28 (3.6%) explants in the TARE group compared with 10/37 (27%) in the TACE group (P=0.013). The TARE group also required fewer LRT treatments (1.46 vs. 2.43; P=0.001) despite no difference in time on the transplant list. Conclusions: Despite requiring fewer LRT treatments, there was significantly less mVI in the explants of patients treated with TARE protocol LRT as a bridge to LT as well as a trend toward improved 3-year survival. Therefore, TARE may be associated with improved tumor control and reduced post-LT recurrence.

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Essential worker absenteeism has been a pressing problem in the COVID-19 pandemic. Nearly 20% of US hospitals experienced staff shortages, exhausting replacement pools and at times requiring COVID-positive healthcare workers to remain at work. To our knowledge there are no data-informed models examining how different staffing strategies affect epidemic dynamics on a network in the context of rising worker absenteeism. Here we develop a susceptible–infected–quarantined-recovered adaptive network model using pair approximations to gauge the effects of worker replacement versus redistribution of work among remaining healthy workers in the early epidemic phase. Parameterized with hospital data, the model exhibits a time-varying trade-off: Worker replacement minimizes peak prevalence in the early phase, while redistribution minimizes final outbreak size. Any “ideal” strategy requires balancing the need to maintain a baseline number of workers against the desire to decrease total number infected. We show that one adaptive strategy—switching from replacement to redistribution at epidemic peak—decreases disease burden by 9.7% and nearly doubles the final fraction of healthy workers compared to pure replacement.