Consistent with symptoms experienced in MS, we demonstrate that EAE mice widely exhibit features of GI dysmotility that persisted in the absence of extrinsic innervation, suggesting direct involvement of ENS neurocircuitry. The absence of GI dysmotility in B cell-deficient mice with EAE together with EAE and MS serum immunoreactivity against ENS targets suggests that MS could be classified among other diseases known to induce autoimmune GI dysmotility.

Multiple Sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) that impacts approximately 2 million people worldwide. The etiology of the disease is multifactorial, consisting of multiple environmental and genetic risk factors. A major risk factor is chronic infection with the gammaherpesvirus, Epstein Barr Virus (EBV). The mechanisms by which EBV increases MS risk, including the role of host genetics, are still unclear. To examine the role of host genetics on gammaherpesvirus infection outcomes, we infected male and female C57BL/6 (B6) and wild-derived PWD/PhJ (PWD) mice with MHV-68, a gammaherpesvirus homologous to EBV. Given the central role of CD4 T cells in MS, we first determined the effect of latent gammaherpesvirus infection on the CD4 T cell transcriptome. CD4 T helper cells were isolated from chronically infected mice followed by transcriptional profiling. Chronic MHV-68 infection resulted in a dramatic upregulation of genes characteristic of so-called cytotoxic T helper cell (ThCTL) phenotypes, including Gzmb, Cx3cr1, Klrg1, Prdm1, and Tbx21, which was most pronounced in B6 females, and highly muted in PWD mice of either sex. Flow cytometric analyses confirmed the genotype-specific expansion of ThCTL-like cells, beginning within 9 days of infection and continued into latency. Analysis of MHV-68 replication kinetics demonstrated that PWD mice had remarkably superior control of viral load early and late in infection. Because poor control of EBV viral load and enhanced anti-EBV responses are associated with greater MS risk, taken together, our findings suggest that the increased risk of MS due to EBV infection might be due to genetically determined poor control of viral load and augmented ThCTL responses. Supported by a grant from the NIH (R21 NS095007)

Multiple Sclerosis (MS) is a complex disease with remarkable heterogeneity in disease course and progression, the genetic basis of which remains obscure. Here we leveraged the Collaborative Cross (CC) - a highly genetically diverse mouse strain panel - and myelin oligodendrocyte glycoprotein peptide 35–55 (MOG35–55) induced experimental autoimmune encephalomyelitis (EAE), to model genetics of MS disease course. 33 CC strains were selected based on compatible MHC haplotypes (H2b and H2g7), which captured a wide spectrum of distinct EAE phenotypes, compared with typical chronic EAE in C57BL/6 mice. CC028 mice exhibited severe and rapidly progressing disease. In contrast, several strains, including CC011 and CC040, were highly resistant to EAE. Sex differences in EAE course were observed in 4 strains, including CC042. Remitting-relapsing EAE was observed in 4 strains, including CC002. In addition to classical EAE clinical signs (ascending paralysis), we identified two strains, CC004 and CC083 that exhibited high incidence of axial rotary (AR)-EAE, including profound ataxia, head tilt, and axial rotation. Preliminary quantitative trait locus (QTL) analysis revealed a distinct linkage pattern in each sex for classical EAE severity, with several emerging peaks on chromosome (Chr) 2, 8, 12, 18, and X in females, Chr10 in males, and Chr4 in both sexes. QTL analysis of AR-EAE severity revealed a narrow interval on Chr18 (39.2–41.0Mb) passing suggestive linkage significance at the 90% confidence threshold. Experiments are ongoing to determine the immunopathologic basis of distinct genetically controlled EAE phenotypes in CC strains of interest. Supported by grants from NIH (R21 AI145306-01) and the National MS Society (RG-1901-33309)

Background: Adults with sickle cell disease (SCD) suffer poor quality, disparities, higher utilization and mortality, and unmet medical need. Thus, in 2017 Virginia Commonwealth University Health (VCU) used pilot results and axioms of the Patient-Centered Medical Home (PCMH) and Lean Six Sigma quality improvement to build an Adult SCD Medical Home. Methods and Results: VCU funded the program in October 2017. We implemented it over the next fifteen months. We first used a Six Sigma QI cycle called DMAIC (Define, Measure, Analyze, Improve and Control). Define: we defined three improvement targets in year one: inpatient, emergency department (ED), and ambulatory care. Behavioral health, program evaluation, ambulatory clinical policies, and pediatric to adult transition were added in year two. We identified ourselves or recruited hospital partners as champions/leaders for each care target area. Each formed a multidisciplinary implementation team. The inpatient care team actually preceded Medical Home funding. Where feasible, each team conducted PDSA cycles to test and improve best practices or metrics. Measure: we ranked 567 adult SCD patients based on their CY 2017 30-day readmissions, length of stay, 3-day ED returns, ED discharges, inpatient days and discharges, outpatient visits, ED use, and charges. Each team also developed metrics. Analyze: The top 50 highest utilizers by charges were targeted for intervention. Improve: We aimed for six 12-month intervention patient results: 1) reduce readmissions by 15%; 2) reduce average length of stay by 1.5 days; 3) reduce charges by 15%; 4) improve compliance with SCD inpatient guidelines; 5) improve quality, safety, and financial reporting; 6) improve patient experience. Leaders also used Six Sigma tools weekly to oversee teams, identify resources, plan, and hire staff: for example, we ranked the urgency of steps using "Now, Later, Latest" process charts, and documented progress using "Quick Wins" communication logs. Control: Processes were continuously amended. Stakeholders met and supported us monthly to quarterly. We distributed an annual report. Metric results are presented in a separate abstract. Conclusion: Lean Six Sigma QI principles were effective for developing and implementing an adult SCD medical home. We believe the above processes could be replicated elsewhere. Figure Disclosures Lipato: Novartis: Honoraria. Smith:Novartis: Consultancy, Honoraria.

Background: Hospital readmission rates and acute care utilization among adults with sickle cell disease (SCD) are almost twice the rates of children. Adult patients may have complex medical and psychosocial needs that are not adequately addressed in fragmented healthcare systems. Few systems have implemented evidence-based, comprehensive care for SCD adults, shown to improve both medical and psychosocial outcomes in chronic diseases. Case management (CM) and community health workers (CHWs) are two evidence-based health management strategies that can help reduce health risks, reduce readmission rates, and improve patient-provider relationships. Methods: After years of attempting adult SCD CM with two MDs and one advanced practice provider (APP), Virginia Commonwealth University Medical Center (VCU) built upon a pilot study of CM and CHWs and implemented a multi-disciplinary Adult Sickle Cell Medical Home that assigned one of two CHWs for CM of the 50 highest SCD adult utilizers ranked by calendar year (CY) 2017 VCU charges, then by CY 2017 inpatient days. CHWs followed patients in and out of the hospital, and met with them at home. They were joined by a social worker who provided CM and behavioral therapy, an additional APP, and a project manager. This team met weekly. Medical Home leaders and quality improvement (QI) specialists enlisted other periodic caregivers to form QI teams with Medical Home workers focusing on behavioral health, ambulatory management, inpatient management, and emergency department (ED) management. A prior authorization specialist handled administrative access to opioids. Evaluation compared utilization during CY 2017 (pre-intervention) versus CY 2018 (intervention). For all patients we compared the average 30-day readmission rate, the average length of stay (ALOS), the average 3-Day ED return rate, the number of ED discharges, the numbers of inpatient days, inpatient discharges, and outpatient visits, the number of patients who used the ED, and total VCU charges. For the 50 highest utilizers, we compared the 30-day readmission rate, ALOS, total inpatient days and total VCU charges. VCU had no ambulatory SCD infusion unit, and the VCU ED did not have a special SCD rapid triage protocol. There was no control group. Analysis consisted of chi square and paired and unpaired t-tests. Results: Among 567 SCD adults (Table), including 231 males and 336 females, ages 18 - 80, comparing pre-intervention to intervention, average utilization and VCU charges were either numerically or statistically significantly reduced, with the exception of outpatient visits, which remained flat. For the 50 highest utilizers, mean 30-day readmission rates were flat (45.98% vs 44.35%, p=0.7257), ALOS was significantly reduced (6.1 days vs 4.8 days, p<0.0001), inpatient days were reduced (206 days vs 106 days), and total charges were significantly reduced (25.43%, $5,297,323.73 vs $3,950,267.26, p=0.0037). Conclusions: At VCU, a multi-disciplinary Adult Sickle Cell Medical Home that featured intensive CM and CHWs, but no infusion center or rapid ED triage, reduced annual utilization for adult SCD patients. CM program elements that were most effective should be studied in the future. A randomized controlled trial of CM and CHWs would strengthen evidence of their efficacy in improving utilization. Table. Disclosures Smith: Novartis: Consultancy, Honoraria. Lipato:Novartis: Honoraria. Roberts:Truven Health Analytics: Consultancy; Community Health Network of Connecticut: Consultancy.