A Description of a Health System's Emergency Department Patients Who Were Part of a Large Hepatitis A Outbreak.

BACKGROUND: A recent hepatitis A virus (HAV) outbreak in San Diego, California represents one of the largest HAV outbreaks in the United States. The County of San Diego Health and Human Services Agency identified homelessness and illicit or injection drug use as risk factors for contracting HAV during this outbreak. OBJECTIVE: We describe those patients who presented to our Emergency Department (ED) and were identified as HAV positive. METHODS: This was a retrospective descriptive study conducted at a tertiary care university health system's EDs from November 2016 to February 2018. Included were those of all ages who tested positive for HAV immunoglobulin M antibody. Outcome measures included: 1) demographic data; 2) number of patients testing positive for HAV by week and month of the outbreak; 3) homeless status, illicit and injection drug use, and alcohol use; 4) ED chief complaint; 5) initial liver function and coagulopathy test results, hepatitis B and C test results, and initial vital signs; 6) admission status; 7) death; and 8) the 7-day ED revisit rate for nonadmitted patients and the 30-day all-cause readmission rate for admitted patients. RESULTS: We identified 57,721 patients with at least one ED visit, and 1,453 of these were tested for HAV; 133 patients (9.2%) tested positive. Average age was 45.1 years, and 91 (68.4%) were male. Eighty-six patients (64.7%) were homeless and 53 patients (39.8%) reported illicit or injection drug use; 64 patients (48.1%) had chief complaints consistent with typical HAV symptoms. Most patients (112 or 84.2%) were admitted. Nine patients (6.8%) were admitted to a critical care setting; 8 patients (6%) died. CONCLUSIONS: During this large HAV outbreak, 9% of those screened for HAV tested positive. The majority were homeless, and 40% reported illicit or injection drug use. Most required hospitalization, and 6% of patients died.

Chemical genetics of rapamycin-insensitive TORC2 in S. cerevisiae.

Current approaches for identifying synergistic targets use cell culture models to see if the combined effect of clinically available drugs is better than predicted by their individual efficacy. New techniques are needed to systematically and rationally identify targets and pathways that may be synergistic targets. Here, we created a tool to screen and identify molecular targets that may synergize with new inhibitors of target of rapamycin (TOR), a conserved protein that is a major integrator of cell proliferation signals in the nutrient-signaling pathway. Although clinical results from TOR complex 1 (TORC1)-specific inhibition using rapamycin analogs have been disappointing, trials using inhibitors that also target TORC2 have been promising. To understand this increased therapeutic efficacy and to discover secondary targets for combination therapy, we engineered Tor2 in S. cerevisiae to accept an orthogonal inhibitor. We used this tool to create a chemical epistasis miniarray profile (ChE-MAP) by measuring interactions between the chemically inhibited Tor2 kinase and a diverse library of deletion mutants. The ChE-MAP identified known TOR components and distinguished between TORC1- and TORC2-dependent functions. The results showed a TORC2-specific interaction with the pentose phosphate pathway, a previously unappreciated TORC2 function that suggests a role for the complex in balancing the high energy demand required for ribosome biogenesis.

Unbiased discovery of glypican as a receptor for LRRTM4 in regulating excitatory synapse development.

Leucine-rich repeat (LRR) proteins have recently been identified as important regulators of synapse development and function, but for many LRR proteins the ligand-receptor interactions are not known. Here we identify the heparan sulfate (HS) proteoglycan glypican as a receptor for LRRTM4 using an unbiased proteomics-based approach. Glypican binds LRRTM4, but not LRRTM2, in an HS-dependent manner. Glypican 4 (GPC4) and LRRTM4 localize to the pre- and postsynaptic membranes of excitatory synapses, respectively. Consistent with a trans-synaptic interaction, LRRTM4 triggers GPC4 clustering in contacting axons and GPC4 induces clustering of LRRTM4 in contacting dendrites in an HS-dependent manner. LRRTM4 positively regulates excitatory synapse development in cultured neurons and in vivo, and the synaptogenic activity of LRRTM4 requires the presence of HS on the neuronal surface. Our results identify glypican as an LRRTM4 receptor and indicate that a trans-synaptic glypican-LRRTM4 interaction regulates excitatory synapse development.