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Introduction Proactive outreach offering tobacco treatment is a promising strategy outside of clinical settings, but little is known about factors for engagement. The study objective is to examine the impact of caller area code in a proactive, phone-based outreach strategy on consenting low-income smokers to a quitline e-referral. Aims and Methods This pragmatic randomized trial included unassisted adult smokers (n = 685), whose preferred language was English or Spanish, in a Los Angeles safety-net health system. Patients were randomized to receive a call from a local or generic toll-free area code. Log-binomial regression was used to examine the association between area code and consent to a quitline e-referral, adjusted for age, gender, language, and year. Results Overall, 52.1% of the patients were contacted and, among those contacted, 30% consented to a referral. The contact rate was higher for the local versus generic area code, although not statistically significant (55.6% vs. 48.7%, p = .07). The consent rate was higher in the local versus generic area code group (adjusted prevalence ratio 1.29, 95% CI 1.01–1.65) and also higher for patients under 61 years old than over (adjusted prevalence ratio 1.47, 95% CI 1.07–2.01), and Spanish-speaking than English-speaking patients (adjusted prevalence ratio 1.40, 95% CI 1.05–1.86). Conclusions Proactive phone-based outreach to unassisted smokers in a safety net health system increased consent to a quitline referral when local (vs. generic) area codes were used to contact patients. While contact rate did not differ by area code, proactive phone-based outreach was effective for engaging younger and Spanish-speaking smokers. Implications Population-based proactive phone-based outreach from a caller with a local area code to unassisted smokers in a safety net health system increases consent to an e-referral for quitline services. Findings suggest that a proactive phone-based outreach, a population-based strategy, is an effective strategy to build on the visit-based model and offer services to tobacco users, regardless of the motivational levels to quit.

While much is known about governance models for research informatics programs in academic medical centers and similarly situated cancer centers, community and public health systems have been less well-characterized. As part of implementing an enterprise research governance framework, leaders in the Los Angeles County Department of Health Services established a research informatics program, including research data warehousing. The strategy is focused on high-priority, patient-centered research that leverages the investment in health IT and an efficient, sustained contribution from 2 affiliated Clinical Translational Sciences Institutes. This case study describes the foundational governance framework and policies that were developed. We share the results of several years of planning, implementation, and operations of an academically funded research informatics service core embedded in a large, multicenter county health system. We include herein a Supplementary Appendix of governance documents that may serve as pragmatic models for similar initiatives.

Background Since the advent of COVID-19, accelerated adoption of systems that reduce face-to-face encounters has outpaced training and best practices. Electronic consultations (eConsults), structured communications between PCPs and specialists regarding a case, have been effective in reducing face-to-face specialist encounters. As the health system rapidly adapts to multiple new practices and communication tools, new mechanisms to measure and improve performance in this context are needed. Objective To test whether feedback comparing physicians to top performing peers using co-specialists’ ratings improves performance. Design Cluster-randomized controlled trial Participants Eighty facility-specialty clusters and 214 clinicians Intervention Providers in the feedback arms were sent messages that announced their membership in an elite group of “Top Performers” or provided actionable recommendations with feedback for providers that were “Not Top Performers.” Main Measures The primary outcomes were changes in peer ratings in the following performance dimensions after feedback was received: (1) elicitation of information from primary care practitioners; (2) adherence to institutional clinical guidelines; (3) agreement with peer’s medical decision-making; (4) educational value; (5) relationship building. Key Results Specialists showed significant improvements on 3 of the 5 consultation performance dimensions: medical decision-making (odds ratio 1.52, 95% confidence interval 1.08–2.14, p

We describe the implementation of a novel electronic platform for specialty referral and consultation, eConsult Mental Health. This innovation aims to address mental health care access and coordination challenges in the nation's second largest public health system in Los Angeles. eConsult Mental Health is one of the largest documented electronic platforms to facilitate the integration of behavioral health services in primary care. Although implementation has been met with barriers unique to mental health care, eConsult Mental Health appears to be a promising tool to expand the spectrum of care for Los Angeles County safety net primary care providers in patient-centered medical homes.

This study characterizes the prevalence of reverse-transcriptase polymerase chain reaction results positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) among patients presenting with influenzalike illness who underwent nasopharyngeal swab testing for influenza and respiratory syncytial virus over 4 days in March 2020.

IMPORTANCE: For critically ill patients with advanced medical illnesses and poor prognoses, overuse of invasive intensive care unit (ICU) treatments may prolong suffering without benefit. OBJECTIVE: To examine whether use of time-limited trials (TLTs) as the default care-planning approach for critically ill patients with advanced medical illnesses was associated with decreased duration and intensity of nonbeneficial ICU care. DESIGN, SETTING, AND PARTICIPANTS: This prospective quality improvement study was conducted from June 1, 2017, to December 31, 2019, at the medical ICUs of 3 academic public hospitals in California. Patients at risk for nonbeneficial ICU treatments due to advanced medical illnesses were identified using categories from the Society of Critical Care Medicine guidelines for admission and triage. INTERVENTIONS: Clinicians were trained to use TLTs as the default communication and care-planning approach in meetings with family and surrogate decision makers. MAIN OUTCOMES AND MEASURES: Quality of family meetings (process measure) and ICU length of stay (clinical outcome measure). RESULTS: A total of 209 patients were included (mean [SD] age, 63.6 [16.3] years; 127 men [60.8%]; 101 Hispanic patients [48.3%]), with 113 patients (54.1%) in the preintervention period and 96 patients (45.9%) in the postintervention period. Formal family meetings increased from 68 of 113 (60.2%) to 92 of 96 (95.8%) patients between the preintervention and postintervention periods (P

Lack of timely access to specialty care is a significant problem among disadvantaged populations, such as those served by the Los Angeles County Department of Health Services. In 2012 the department implemented an electronic system for the provision of specialty care called the eConsult system, in which all requests from primary care providers for specialty assistance were reviewed by specialists. In many cases, the specialist can address the primary care provider's question via an electronic dialogue, thereby eliminating the need for the patient to see a specialist in person. We observed rapid growth in the use of eConsult: By 2015 the system was in use by over 3,000 primary care providers, and 12,082 consultations were taking place per month, compared to 86 in the third quarter of 2012. The median time to an electronic response from a specialist was one day, and 25 percent of eConsults were resolved without a specialist visit. Three to four years after implementation, the median time to a specialist appointment decreased significantly, while the volume of visits remained stable. eConsult systems are a promising and sustainable intervention that could improve access to specialist care for underserved patients.

Key Points Question What are the mortality and readmission rates in patients with COVID-19 pneumonia discharged according to an expected practice approach with supplemental home oxygen? Findings In this cohort study of 621 patients with COVID-19 discharged with supplemental home oxygen from emergency department and inpatient encounters at 2 large urban medical centers, the all-cause mortality rate was 1.3% and the all-cause 30-day return hospital admission rate was 8.5%. No patients died in the ambulatory setting or in transit when returning to acute care setting. Meaning In this study, a careful and systematic expected practice approach to treatment of patients with COVID-19 using home oxygen was associated with low all-cause mortality and low 30-day return admission rates., Importance To optimize patient outcomes and preserve critical acute care access during the COVID-19 pandemic, the Los Angeles County Department of Health Services developed the SAFE @ HOME O2 Expected Practice (expected practice), enabling ambulatory oxygen management for COVID-19. Objective To assess outcomes of patients with COVID-19 pneumonia discharged via the expected practice approach to home or quarantine housing with supplemental home oxygen. Design, Setting, and Participants This retrospective cohort study included 621 adult patients with COVID-19 pneumonia who were discharged from 2 large urban public hospitals caring primarily for patients receiving Medicaid from March 20 to August 19, 2020. Patients were included in the analysis cohort if they received emergency or inpatient care for COVID-19 and were discharged with home oxygen. Interventions Patients receiving at least 3 L per minute of oxygen, stable without other indication for inpatient care, were discharged from either emergency or inpatient encounters with home oxygen equipment, educational resources, and nursing telephone follow-up within 12 to 18 hours of discharge. Nurses provided continued telephone follow up as indicated, always with physician back-up. Main Outcomes and Measures All-cause mortality and all-cause 30-day return admission. Results A total of 621 patients with COVID-19 pneumonia (404 male [65.1%] and 217 female [34.9%]) were discharged with home oxygen. Median age of these patients was 51 years (interquartile range, 45-61 years), with 149 (24.0%) discharged from the emergency department and 472 (76%) discharged from inpatient encounters. The all-cause mortality rate was 1.3% (95% CI, 0.6%-2.5%) and the 30-day return hospital admission rate was 8.5% (95% CI, 6.2%-10.7%) with a median follow-up time of 26 days (interquartile range, 15-55 days). No deaths occurred in the ambulatory setting. Conclusions and Relevance In this cohort study, patients with COVID-19 pneumonia discharged on home oxygen had low rates of mortality and return admission within 30 days of discharge. Ambulatory management of COVID-19 with home oxygen has an acceptable safety profile, and the expected practice approach may help optimize outcomes, by ensuring right care in the right place at the right time and preserving access to acute care during the COVID-19 pandemic., This cohort study assesses mortality and readmission rates of adult patients with COVID-19 pneumonia discharged from 2 centers in Los Angeles County, California, via an expected practice approach to home or quarantine housing with supplemental home oxygen.

A primary barrier to translation of clinical research discoveries into care delivery and population health is the lack of sustainable infrastructure bringing researchers, policymakers, practitioners, and communities together to reduce silos in knowledge and action. As National Institutes of Health's (NIH) mechanism to advance translational research, Clinical and Translational Science Award (CTSA) awardees are uniquely positioned to bridge this gap. Delivering on this promise requires sustained collaboration and alignment between research institutions and public health and healthcare programs and services. We describe the collaboration of seven CTSA hubs with city, county, and state healthcare and public health organizations striving to realize this vision together. Partnership representatives convened monthly to identify key components, common and unique themes, and barriers in academic-public collaborations. All partnerships aligned the activities of the CTSA programs with the needs of the city/county/state partners, by sharing resources, responding to real-time policy questions and training needs, promoting best practices, and advancing community-engaged research, and dissemination and implementation science to narrow the knowledge-to-practice gap. Barriers included competing priorities, differing timelines, bureaucratic hurdles, and unstable funding. Academic-public health/health system partnerships represent a unique and underutilized model with potential to enhance community and population health.

In facing the challenge of taking better care of more patients at lower cost, health care organizations can learn from safety-net systems: one innovation prompted by clinical exigencies, eReferral, offers a new model for integrating primary and specialty care.

Background Preconsultation exchange is an emerging model of specialty care proposed by the American College of Physicians that seeks to answer a clinical question without a formal patient visit to the specialty clinic. This form of specialty care has been little studied. We sought to determine the appropriateness of preconsultation exchange for ambulatory hepatology consultations within our urban health care system. Methods Retrospective study of referrals for ambulatory hepatology consultation in the safety net health care system of San Francisco, Calif from January 2007 through April 2010. Results Of the 500 referrals reviewed, 87 were excluded as repeat requests. The most common reasons for referral were hepatitis B (34.9%) and hepatitis C (32.0%). Fifty-six referrals (13.6%) were appropriate for preconsultation exchange, and 190 (46.0%) were inappropriate for preconsultation exchange. One hundred sixty-seven (40.4%) referrals did not include enough information to determine appropriateness for preconsultation exchange. Most of these (83.8%) were made for hepatitis B or hepatitis C, despite the presence of explicit referral guidelines. Midlevel providers were more likely than physicians to provide enough information to determine appropriateness for preconsultation exchange. Conclusion In our urban health care system, preconsultation exchange appears to be an appropriate form of specialty care for some ambulatory hepatology consultations. Communication between primary care provider and specialist appears to be an important barrier to broader implementation of preconsultation exchange. Optimizing the preconsultation exchange is critical to improve the primary-specialty care interface, and to build a true Patient-Centered Medical Home Neighborhood.

ObjectivesWe examined colorectal cancer (CRC) stage at presentation and mortality in a vulnerable population compared with nationally representative data.MethodsCRC cases were identified from San Francisco General Hospital (SFGH) and the Surveillance Epidemiology and End Results (SEER) database.ResultsFifty-five percent of the SFGH cohort presented with advanced disease, compared with 44% of the SEER cohort. Increased risk of advanced stage at presentation at SFGH compared with SEER was most evident among blacks and Asians. There was weak evidence for worse survival at SFGH compared with SEER overall. This varied by race with poorer survival at SFGH among whites and possibly blacks but some evidence for better survival among Asians. Among CRC patients at SFGH, Asians and Hispanics had better survival than whites and blacks. At SFGH, 44% had a diagnosis of CRC within 1 year of establishing care there. Of those who had established care at SFGH for at least 1 year, only 22% had exposure to CRC screening tests.ConclusionsThese findings allow examination of CRC presentation by ethnicity in vulnerable populations and identify areas where access and utilization of CRC screening can be improved.

Hepatic stellate cells (HSCs) are well-characterized non-parenchymal cells of the liver with established roles in fibrosis, repair and immunity (1). During liver injury, quiescent HSCs undergo activation, secreting a repertoire of molecules involved in cell proliferation, chemotaxis, inflammation and fibrosis, among others. Although their role in fibrogenesis is well established, the contributions of HSCs to acute hepatocellular damage and tissue homeostasis are not well understood. Models to manipulate HSC function or number offer an appealing strategy to clarify this issue. However, only two models have been established to deplete HSCs in vivo thus far, by using gliotoxin (2) or gliotoxin-coupled antibodies against synaptophysin (3, 4). Gliotoxin reportedly induces selective apoptosis of HSCs by subverting NF-κB-mediated survival (2), and can reduce fibrosis and enhance resolution in experimental models, especially when targeted using HSC-specific antibodies (3–5). However, gliotoxin also has broad actions in vivo and in culture, targeting not only HSCs but also immune and endothelial cells and hepatocytes (5, 6). An alternative strategy is to ectopically express the herpes simplex virus-thymidine kinase (HSV-Tk) gene in target cells, which renders them susceptible to killing by the antiviral agent ganciclovir (GCV), but only when the cells are proliferating. This possibility was first reported as an anti-cancer approach (7) and further refined (8) in murine sarcoma and lymphoma cells, provoking both apoptotic and non-apoptotic cell death (9, 10). The approach has also been reported in liver injury models and in cultured HSCs (11), but has not been used to deplete HSCs in vivo (12). We have exploited this strategy by using mice expressing the HSV-Tk gene driven by the GFAP promoter, which is a marker of HSCs in rodent liver (1). The approach has uncovered a novel and unexpected role for HSCs in amplifying acute liver injury.

There is scarce information about the link between specific single-nucleotide polymorphisms (SNPs) and risk of liver disease among Latinos, despite the disproportionate burden of disease among this population. Our aim was to investigate nine SNPs in or near the following genes: PNPLA3, LYPLAL1, PPP1R3B, GCKR, NCAN, IRS1, PPARG, and ADIPOR2 and examine their association with persistently elevated alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels in Mexican adults. Data and samples were collected from 741 participants in the Mexican Health Worker Cohort Study, in Cuernavaca, Mexico. We identified 207 cases who had persistently elevated levels of ALT or AST (≥40 U/L) and 534 controls with at least two consecutive normal ALT or AST results in a 6 month period, during 2004-2006 and 2011-2013. TaqMan assays were used to genotype the SNPs. The risk allele of PNPLA3 rs738409 was found to be associated with persistently elevated levels of ALT or AST, adjusting for age, sex, BMI, type 2 diabetes, and ancestry: (OR 2.28, 95% CI 1.13, 4.58). A significant association was found between the LYPLAL1, PPP1R3B, and GCKR risk alleles and elevated ALT or AST levels among overweight/obese adults. These results suggest that among Mexicans, the PNPLA3 (rs738409), LYPLAL1 (rs12137855), PPP1R3B (rs4240624), and GCKR (rs780094) polymorphisms may be associated with a greater risk of chronic liver disease among overweight adults. This study is the first to examine these nine SNPs in a sample of adults in Mexico.

This Viewpoint describes approaches taken by the Los Angeles Department of Health Services to reduce clinical practice variaton across the system.

Inflammatory bowel disease (IBD) patients display elevated levels of intraluminal nitric oxide (NO). NO can react with other molecules to form toxic compounds, which has led to the idea that NO may be an important mediator of IBD. However, the cellular source of NO and how its production is regulated in the intestine are unclear. In this study we aimed to determine if intestinal myofibroblasts produce NO in response to the IBD-associated cytokines IL-1β, TNFα, and IFNγ. Intestinal myofibroblasts were isolated from mice and found to express inducible nitric oxide synthase (iNOS) mRNA, but not endothelial NOS or neuronal NOS. Individual treatment of myofibroblasts with IL-1β, TNFα, or IFNγ had no effect on NO production, but stimulation with combinations of these cytokines synergistically increased iNOS mRNA and protein expression. Treatment with TNFα or IFNγ increased cell surface expression of IFNγRI or TNFRII, respectively, suggesting that these cytokines act in concert to prime NO production by myofibroblasts. Impairment of NF-κB activity with a small molecule inhibitor was sufficient to prevent increased expression of IFNγRI or TNFRII, and inhibition of Akt, JAK/STAT, or NF-κB blocked nearly all NO production induced by combinatorial cytokine treatment. These data indicate that intestinal myofibroblasts require stimulation by multiple cytokines to produce NO and that these cytokines act through a novel pathway involving reciprocal cytokine receptor regulation and signaling by Akt, JAK/STAT, and NF-κB.

Background Hepatitis C (HCV) knowledge is limited in injection drug users (IDU). Vulnerable populations including IDUs are disproportionally affected by HCV. Effective HCV education can potentially reduce disparity in HCV prevalence and its outcome in this population. Aim This study aimed to assess the impact of formal HCV education and factors associated with improved HCV knowledge in the vulnerable population. Methods Over 18 months, 201 HCV-infected patients underwent a 2-h standardized education and completed demographic and pre- and post-education questionnaires. Results Patient characteristics were: 69% male, mean age 49 ± 10, 49% White (26% AA, 10% Latino), 75% unemployed, 83% high school education and above, 64% were IDU, and 7% were HIV co-infected. On multivariate analysis, baseline knowledge scores were higher in patients with at least a high school education (coef 7.1, p = 0.045). Baseline knowledge scores were lower in African Americans (coef −12.3, p = 0.004) and older patients (coef −0.7, p = 0.03). Following HCV education, the overall test scores improved significantly by 14% (p = 0.0001) specifically in the areas of HCV transmission (p = 0.003), general knowledge (p = 0.02), and health care maintenance (p = 0.004). There was a high compliance with liver specialty clinic attendance following education. Conclusions Formal HCV education is effective in improving HCV knowledge. Although White race, younger age, and higher education were predictors of having more HCV knowledge prior to education, all patients independent of racial background had a significant improvement in their knowledge after education. Therefore, promoting effective HCV education among vulnerable populations may be an important factor in reducing the disparities in HCV disease.

Background Inflammatory bowel disease (IBD) is increasingly common among non-Caucasian populations, but interracial differences in disease characteristics and management are not well-characterized. Aims We tested the hypothesis that disease characteristics and management vary by race among IBD patients in an ethnically diverse healthcare system. Methods A retrospective study of the safety net healthcare system of San Francisco, CA, from 1996 to 2009 was undertaken. Patient records with International Classification of Diseases, 9th Revision (ICD9) codes 555.xx, 556.xx, and 558.xx were reviewed. Adult patients with confirmed IBD diagnoses were included. Interracial variations in disease characteristics and management were assessed broadly; focused between-race comparisons identified specific differences. Results The 228 subjects included 77 (33.4%) with Crohn’s disease (CD), 150 (65.8%) with ulcerative colitis, and 1 (0.4%) with IBD, type unclassified. The race distribution included 105 (46.1%) white, 34 (14.9%) black, 35 (15.4%) Hispanic, and 51 (22.4%) Asian subjects. Asians and Hispanics were diagnosed at older ages (41.0 and 37.1 years, respectively) and had shorter disease durations (5.4 and 5.2 years, respectively) than whites (30.5 years at diagnosis and 8.6 years duration, P

Importance Safety-net health systems across the country are implementing electronic consult (eConsult) systems in which primary care practitioners (PCPs) submit all requests for specialty assistance electronically to be reviewed and discussed with specialists. Evidence suggests that eConsult systems can make significant improvements in specialty access, but the outcomes of these systems for frontline PCPs is poorly understood. Objective To understand PCP perceptions of the results of eConsult initiation on PCP workflow, specialist access, and patient care. Design, Setting, and Participants Qualitative interviews were conducted from December 1, 2016, to April 15, 2017, with 40 safety-net PCPs in Los Angeles County who use the Los Angeles County Department of Health Services (DHS) eConsult system. Interviewees were recruited to include diversity in PCP type, practice setting, and employer (DHS employed vs DHS affiliated). Participants were interviewed about their perceptions of clinical workflow, access to specialists, relationships with specialists, and referral decision making. Main Outcomes and Measures Perceptions of the results of eConsult, including positive and negative themes and remaining perceived gaps in specialty care. Results Of the 40 participants, 27 (68%) were women; 24 (60%) PCPs performed 5 or more eConsults per week. Primary care practitioners’ perceptions of eConsult clustered around 4 main themes: access and timeliness of specialty care, shift of work to PCPs, relationships with specialists, and eConsult interface issues. Many PCPs praised the improved timeliness of specialist input with eConsult, as well as the added clinical and educational value of dialogue with specialists, particularly compared with the limitations of the prior referral process. However, PCPs also consistently perceived that eConsult shifted some of the work of specialty care to them. Many PCPs believed that this extra burden was worth the effort given the benefits of eConsult, such as improved timeliness of care and ability to manage specialty conditions. In contrast, others were frustrated by the increased administrative burden, broadened clinical responsibility, and restructuring of specialty care delivery. Conclusions and Relevance While associated with improved specialty care access, eConsult systems simultaneously created new challenges for PCPs, such as an increased burden of work in providing specialty care. Primary care practitioners varied in their enthusiasm for these workflow changes with diverging perceptions of the same processes. Our findings provide insights on challenges future primary care transformation efforts may face.

BACKGROUND Poor communication between referring clinicians and specialists may lead to inefficient use of specialist services. San Francisco General Hospital implemented an electronic referral system (eReferral) that facilitates iterative pre-visit communication between referring and specialty clinicians to improve the referral process. OBJECTIVE The purpose of the study was to determine the impact of eReferral (compared with paper-based referrals) on specialty referrals. DESIGN The study was based on a visit-based questionnaire appended to new patient charts at randomly selected specialist clinic sessions before and after the implementation of eReferral. PARTICIPANTS Specialty clinicians. MAIN MEASURES The questionnaire focused on the self-reported difficulty in identifying referral question, referral appropriateness, need for and avoidability of follow-up visits. KEY RESULTS We collected 505 questionnaires from speciality clinicians. It was difficult to identify the reason for referral in 19.8% of medical and 38.0% of surgical visits using paper-based methods vs. 11.0% and 9.5% of those using eReferral (p-value 0.03 and

We sought to identify factors associated with gastroenterology clinic attendance in an urban safety net healthcare system.Missed clinic appointments reduce the efficiency and availability of healthcare, but subspecialty clinic attendance among patients with established healthcare access has not been studied.We performed an observational study using secondary data from administrative sources to study patients referred to, and scheduled for an appointment in, the adult gastroenterology clinic serving the safety net healthcare system of San Francisco, CA. Our dependent variable was whether subjects attended or missed a scheduled appointment. Analysis included multivariable logistic regression and classification tree analysis. A total of 1833 patients were referred and scheduled for an appointment between May 2005 and August 2006. Prisoners were excluded. All patients had a primary care provider.Six hundred eighty-three patients (37.3%) missed their appointment; 1150 patients (62.7%) attended. Language was highly associated with attendance in the logistic regression; non-English speakers were less likely than English speakers to miss an appointment [adjusted odds ratio 0.42 (0.28, 0.63) for Spanish, 0.56 (0.38, 0.82) for Asian language, P0.001]. Other factors were also associated with attendance, but classification tree analysis identified language to be the most highly associated variable.In an urban safety net healthcare population, among patients with established healthcare access and a scheduled gastroenterology clinic appointment, not speaking English was most strongly associated with higher attendance rates. Patient-related factors associated with not speaking English likely influence subspecialty clinic attendance rates, and these factors may differ from those affecting general healthcare access.

Health disparities between various groups in the United States have received increasing attention over the past decade, and solving this problem has become a major public health priority. The Federally-sponsored Healthy People 2010, our nation’s health promotion and disease prevention initiative, calls to “eliminate health disparities, including differences that occur by gender, race or ethnicity, education or income, disability, geographic location, or sexual orientation” (1). These health disparity populations constitute a large proportion of patients with liver disease (2, 3), and evidence suggests that these populations are disproportionately affected by several common hepatic disorders that include viral hepatitis (4-7), non-alcoholic fatty liver disease (8, 9), and hepatocellular carcinoma (10-13). Health disparities, therefore, have special relevance to the field of hepatology. This policy statement aims to inform the hepatology community about the importance of health disparities in our field, provide a framework for approaching health disparities in research and clinical practice, and recommend ways the AASLD and its membership can work toward the reduction and elimination of health disparities in patients with liver disease.

The contraction of hepatic stellate cells has been proposed to mediate fibrosis by regulating sinusoidal blood flow and extracellular matrix remodeling. Abundant data from diverse, yet complementary, experimental methods support a robust model for the regulation of contractile force generation by stellate cells. In this model, soluble factors associated with liver injury, including endothelin 1 and nitric oxide, are transduced primarily through Rho signaling pathways that promote the myosin II-powered generation of contractile force by stellate cells. The enhanced knowledge of the role and differential regulation of stellate cell contraction may facilitate the discovery of new and targeted strategies for the prevention and treatment of hepatic fibrosis.

Chemotaxis (i.e., directed migration) of hepatic stellate cells to areas of inflammation is a requisite event in the liver's response to injury. Previous studies of signaling pathways that regulate stellate cell migration suggest a key role for focal adhesions, but the exact function of these protein complexes in motility remains unclear. Focal adhesions attach a cell to its substrate and therefore must be regulated in a highly coordinated manner during migration. To test the hypothesis that focal adhesion turnover is an essential early event for chemotaxis in stellate cells, we employed a live-cell imaging technique in which chemotaxis was induced by locally stimulating the tips of rat stellate cell protrusions with platelet-derived growth factor-BB (PDGF). Focal adhesions were visualized with an antibody directed against vinculin, a structural component of the focal adhesion complex. PDGF triggered rapid disassembly of adhesions within 6.25 min, subsequent reassembly by 12.5 min, and continued adhesion assembly in concert with the spreading protrusion until the completion of chemotaxis. Blockade of adhesion disassembly by growing cells on fibronectin or treatment with nocodazole prevented a chemotactic response to PDGF. Augmentation of adhesion disassembly with ML-7 enhanced the chemotactic response to PDGF. These data suggest that focal adhesion disassembly is an essential early event in stellate cell chemotaxis in response to PDGF.

The Center for Disease Control and Prevention (CDC) recommends screening and surveillance of dialysis patients for hepatitis C virus (HCV), but there are limited data on the real life performance of confirmatory tests. We performed a cost-identification analysis of CDC recommendations using a large database of dialysis subjects. Screening and surveillance were performed according to CDC guidelines: enzyme immunoassay (EIA) testing upon entry then biannual surveillance. All positive EIA tests were confirmed by either polymerase chain reaction (PCR) or radioimmunoblot assay (RIBA). A total of 12,563 patients were tested from 1997 to 2004. By EIA, the prevalence of HCV was 8.4% and annual incidence was 0.96%. The prevalence after confirmation by RIBA and PCR was 5.8% and 4.8%, respectively. The annual incidence of hepatitis C confirmed by RIBA and PCR was 0.13% and 0.084%, respectively. Using Medicare reimbursement, the cost to screen and confirm one case of hepatitis C by RIBA was $372 versus $503 by PCR. However, the cost to identify an incident infection increased to $30,594 by RIBA and $48,622 by PCR. In the sensitivity analysis, the cost of identifying incident HCV infection dropped by 50% when the surveillance interval was extended to 1 year or when seroconversion rates for EIA occurred at 2%. Due to high surveillance cost, further studies are necessary to determine optimal intervals and settings.

Background Autoimmune hepatitis causes chronic hepatitis and often leads to cirrhosis and death without treatment. We wanted to see if having access to primary care or insurance prior to diagnosis is associated with better outcomes for patients in an urban, public hospital with mostly socioeconomically disadvantaged Hispanic patients. Methods We did a retrospective study at our institution. Kaplan Meier survival analysis was done looking at transplant-free overall survival for patients diagnosed at our institution. The log-rank test was done to compare survival between patients with and without prior access to primary care, and between patients with and without insurance at diagnosis. Results Overall 5- and 10-year transplant-free overall survival was 91 % (95 % CI, 83-100 %) and 75 % (95 % CI, 50-99 %), respectively. Patients with primary care prior to diagnosis had significantly better transplant-free overall survival than those without (log rank test p = 0.019). Patients with primary care also had better clinical markers at diagnosis. Having insurance at diagnosis was not associated with better outcomes. Conclusions Outcomes of autoimmune hepatitis are poor in our setting but access to primary care prior to diagnosis was associated with better outcomes. This is likely due to the important role that primary care plays in detecting disease and initiating treatment earlier. With the expansion of access to healthcare that the Affordable Care Act provides, future patients are likely to do better with even rare diseases like autoimmune hepatitis.

Growth cones are highly polarized and dynamic structures confined to the tips of axons. The polarity of growth cones is in part maintained by suppression of protrusive activity from the distal axon shaft, a process termed axon consolidation. The mechanistic basis of axon consolidation that contributes to the maintenance of growth cone polarity is not clear. We report that inhibition of RhoA-kinase (ROCK) or myosin II resulted in unstable consolidation of the distal axon as evidenced by increased filopodial and lamellipodial extension. Furthermore, when ROCK or myosin II was inhibited lamellipodia formed at the growth cone migrated onto the axon shaft. Analysis of EYFP-actin dynamics in the distal axon revealed that ROCK negatively regulates actin polymerization and initiation of protrusive structures from spontaneously formed axonal F-actin patches, the latter being an effect attributable to ROCK-mediated regulation of myosin II. Inhibition of ROCK or myosin II blocked growth cone turning toward NGF by preventing suppression of protrusive activity away from the source of NGF, resulting in aborted turning responses. These data elucidate the mechanism of growth cone polarity, provide evidence that consolidation of the distal axon is a component of guidance, and identify ROCK as a negative regulator of F-actin polymerization underlying protrusive activity in the distal axon.

The contractile force generated by hepatic stellate cells in response to endothelin-1 contributes to sinusoidal blood flow regulation and hepatic fibrosis. This study's aim was to directly test the widely held view that changes in cytosolic Ca2+ concentration ([Ca2+]i) mediate stellate cell force generation. Contractile force generation by primary cultures of rat hepatic stellate cells grown in three-dimensional collagen gels was directly and quantitatively measured using a force transducer. Stellate cell [Ca2+]i, myosin activation, and migration were quantified using standard techniques. [Ca2+]i was modulated using ionomycin, BAPTA, KCl, and removal of extracellular Ca2+. Removal of extracellular Ca2+ did not alter endothelin-1-stimulated force development or [Ca2+]i. Ionomycin, a Ca2+ ionophore, triggered an increase in [Ca2+]i that was three times greater than that stimulated by endothelin-1, but only induced 16% of the force and 38% of the myosin regulatory light chain (MLC) phosphorylation induced by endothelin-1. Physiological increases in [Ca2+]i induced by hyperkalemia had no effect on contractile force. Loading BAPTA, a Ca2+ chelator, in stellate cells completely blocked endothelin-1-induced increases in [Ca2+]i but had no effect on endothelin-1-stimulated force generation or MLC phosphorylation. In contrast, Y-27632, a selective rho-associated kinase inhibitor, inhibited endothelin-1-stimulated force generation by at least 70% and MLC phosphorylation by at least 80%. Taken together, these observations indicate that changes in [Ca2+]i are neither necessary nor sufficient for contractile force generation by rat stellate cells. Our results challenge the current model of contractile regulation in hepatic stellate cells and have important implications for our understanding of hepatic pathophysiology.

Intestinal response to injury requires coordinated regulation of the tension exerted by subepithelial myofibroblasts (SEM). However, the signals governing relaxation of intestinal SEM have not been investigated. Our aim was to test the hypothesis that signal transduction pathways initiated by C-type natriuretic peptide (CNP) induce intestinal SEM relaxation. We directly quantified the effects of CNP on isometric tension exerted by cultured human colonic SEM. We also measured the effects of CNP on cGMP content, myosin regulatory light chain (MLC) phosphorylation, and cytosolic Ca2+concentration. CNP induced relaxation of SEM within 10 s. By 10 min, relaxation reached a plateau that was sustained for 2 h. CNP-induced relaxation was saturable, with a maximal decrease in tension (51.7 ± 3.8 dyn) observed at 250 nM. SEM relaxation in response to CNP constituted ∼23% of total basal tension. CNP increased intracellular cGMP content and reduced MLC phosphorylation. Effects of CNP on cGMP and MLC exhibited the same dose dependence as CNP-induced relaxation. MLC phosphorylation decreased within 2 min of CNP exposure and was sustained for at least 45 min. CNP also stimulated a large transient increase in cytosolic Ca2+concentration that occurred within 30 s and was nearly complete by 1 min. We also observed that calyculin-A, a potent inhibitor of MLC phosphatase, completely abolished the reduction in MLC phosphorylation induced by CNP. These results suggest that CNP induces intestinal SEM relaxation through cGMP-associated reductions in MLC phosphorylation. Moreover, these findings raise the possibility that CNP plays a role in intestinal wound healing.

Purpose To assess the evidence supporting the efficacy of weight reduction for patients with nonalcoholic fatty liver. Methods Potentially relevant studies were identified by a computerized search of databases and a manual search of abstracts from scientific meetings. Studies were included if they reported histology, serum aminotransferase levels, or radiological imaging of the liver in obese adult patients who had undergone weight reduction. Weight reduction regimens included diet, exercise, antiobesity medications, gastric bypass, gastroplasty, or any combination of these interventions. Studies involving jejunoileal or small bowel bypass surgery were excluded. Results We identified 517 potentially relevant studies, of which 15 met the inclusion criteria: one randomized controlled trial (in abstract form), two nonrandomized controlled trials, nine case series, one retrospective review, and two case reports. Three studies included more than 50 patients, whereas nine studies had 25 or fewer patients. Twelve studies used behavioral, dietary, or pharmacologic therapy for weight reduction, and three studies used surgical interventions. Although all 15 studies demonstrated overall improvement in the measurements of liver outcome after weight reduction, more than half did not report histologic results. Conclusion Despite general acceptance that weight reduction is an effective therapy for nonalcoholic fatty liver, this systematic review found little data to support or refute this recommendation.

Although hepatic myofibroblast (HMF) migration contributes to the development of fibrosis, the mechanisms coordinating this movement are uncertain. We determined the effects of lysophosphatidic acid (LPA) and platelet-derived growth factor-BB (PDGF) on actin polymerization, FAK tyrosine phosphorylation, and migration of cultured human HMFs. LPA (0.4-100 microM) stimulated migration, FAK tyrosine phosphorylation, and stress fiber assembly with a sigmoidal dose response. PDGF (1-250 ng/ml) stimulated migration, FAK tyrosine phosphorylation, and actin polymerization with a bell-shape dose-response characterized by a maximum at 10-25 ng/ml. Concentrations of cytochalasin D, which abolished FAK tyrosine phosphorylation, also blocked LPA- and PDGF-induced migration. A dose of 1-10 ng/ml PDGF acted synergistically with LPA (10 microM) to stimulate FAK tyrosine phosphorylation and migration, whereas higher concentrations of PDGF (100-250 ng/ml) inhibited FAK tyrosine phosphorylation and migration in response to LPA (10 microM). These data indicate that PDGF and LPA coordinately govern the migration of HMFs by differentially regulating FAK and suggest a novel model in which PDGF, acting as an amplifier/attenuator of LPA-induced signaling, facilitates HMF accumulation within injured areas of the liver.

A decision-analysis model was developed to compare the strategies to maintain hepatitis B virus (HBV) immunity in hemodialysis patients who responded to the primary HBV vaccine. Our hypothesis is that the routine, annual administration of the vaccine booster to all hemodialysis patients (non-screening strategy) is more cost-effective than the current strategy of vaccination based on anti-HBs titers (screening strategy). Under baseline assumptions, the screening strategy was less costly and was associated with fewer HBV infections than the non-screening strategy. The results of our model did not support our hypothesis, and indicate that regularly screening patients for HBV immunity before revaccination is less costly and more effective than the empiric vaccination of hemodialysis patients.

Although the migration of hepatic myofibroblasts (HMFs) contributes to the development of fibrosis, the signals regulating migration of these cells are poorly understood. In this study, we tested the hypothesis that HMF migration is stimulated by platelet-derived growth factor-BB (PDGF-BB) through p38 mitogen-activated protein (MAP) kinase and extracellular signal-regulated kinase (ERK) signaling pathways. This hypothesis was addressed by directly visualizing the migration of cultured human HMFs into a wound. PDGF-BB stimulated membrane ruffling, migration, and proliferation. PDGF-BB also induced activation of p38 MAP kinase, its downstream effector, heat shock protein (HSP) 27, ERK 1 and ERK 2, and p125 focal adhesion kinase (FAK). Selective antagonism of p38 MAP kinase blocked PDGF-BB-stimulated HSP 27 phosphorylation, membrane ruffling, and migration, but did not alter PDGF-BB-induced proliferation. Selective antagonism of ERK kinase inhibited PDGF-BB-induced ERK phosphorylation and proliferation, but did not affect PDGF-BB-stimulated migration. Concentrations of PDGF-BB that stimulated migration and proliferation did not influence myosin-dependent contractility. Neither selective inhibition of p38 MAP kinase nor ERKs altered PDGF-BB-induced activation of FAK. In conclusion, these results provide novel evidence indicating that (1) HMF migration is stimulated by PDGF-BB through the regulation of membrane ruffling by a p38 MAP kinase signaling pathway, (2) whereas p38 MAP kinase mediates PDGF-BB-stimulated migration, but not proliferation, ERKs mediate PDGF-induced proliferation, but not migration, and (3) increases in myosin-dependent contractility are not required for PDGF-BB-stimulated migration.

The role of G protein-coupled receptors and their ligands in intestinal epithelial cell signaling and proliferation is poorly understood. Here, we demonstrate that arginine vasopressin (AVP) induces multiple intracellular signal transduction pathways in rat intestinal epithelial IEC-18 cells via a V1Areceptor. Addition of AVP to these cells induces a rapid and transient increase in cytosolic Ca2+concentration and promotes protein kinase D (PKD) activation through a protein kinase C (PKC)-dependent pathway, as revealed by in vitro kinase assays and immunoblotting with an antibody that recognizes autophosphorylated PKD at Ser916. AVP also stimulates the tyrosine phosphorylation of the nonreceptor tyrosine kinase proline-rich tyrosine kinase 2 (Pyk2) and promotes Src family kinase phosphorylation at Tyr418, indicative of Src activation. AVP induces extracellular signal-related kinase (ERK)-1 (p44mapk) and ERK-2 (p42mapk) activation, a response prevented by treatment with mitogen-activated protein kinase kinase (MEK) inhibitors (PD-98059 and U-0126), specific PKC inhibitors (GF-I and Ro-31-8220), depletion of Ca2+(EGTA and thapsigargin), selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (tyrphostin AG-1478, compound 56), or the selective Src family kinase inhibitor PP-2. Furthermore, AVP acts as a potent growth factor for IEC-18 cells, inducing DNA synthesis and cell proliferation through ERK-, Ca2+-, PKC-, EGFR tyrosine kinase-, and Src-dependent pathways.

Background: Although the contractile, migratory, and proliferative responses of subepithelial myofibroblasts to injury have been postulated to be important events in intestinal wound healing, contractile force generation and migration by these cells has not been investigated previously, and the signals that regulate proliferation by these cells are poorly understood. Aims: The primary aim of this study was to test the hypothesis that the inflammatory mediator endothelin-1 modulates contraction, migration, and proliferation of intestinal myofibroblasts. We also sought to examine the signal transduction pathways which might underlie these putative effects. Methods: Contraction, migration, proliferation, cytosolic [Ca 2+ ], and myosin phosphorylation were measured in human colonic subepithelial myofibroblasts in the absence and presence of endothelin receptor agonists and antagonists. Results: Endothelin-1, but not interleukin 1α, interleukin 6, interleukin 8, interleukin 10, or tumour necrosis factor α, induced a rapid and robust generation of contractile force, which was associated with an increase in cytosolic [Ca 2+ ] and myosin phosphorylation. Inhibition of rho associated kinase reduced endothelin-1 stimulated myosin phosphorylation and contractile force development. Endothelin-1 stimulated migration with a dose-response relationship similar to that observed for contraction. Endothelin A and B receptors mediated contraction while migration was mediated predominantly through endothelin B receptors. Platelet derived growth factor and serum, but not endothelin-1, induced proliferation. Conclusions: Endothelin-1 stimulates colonic subepithelial myofibroblast contraction and migration via endothelin receptor mediated myosin phosphorylation. These results support an important role for subepithelial myofibroblasts in the injury response of the gut and consequently intestinal wound repair.

This meta-analysis synthesizes the evidence about the association of thiazolidinedione therapy with advanced liver fibrosis in nonalcoholic steatohepatitis.

Hepatitis C virus (HCV) infection is common in patients undergoing chronic hemodialysis, with an estimated yearly incidence of 0.2% and prevalence between 8% and 10%. Although a screening strategy based on alanine aminotransferase (ALT) values is currently recommended, this strategy has not been evaluated for cost-effectiveness compared with other potential screening strategies. A comparison therefore was made using a decision-analysis model of a simulated cohort of 5,000 hemodialysis patients followed up for 5 years. Using direct medical costs, three strategies were evaluated, including: (1) ALT values with confirmatory testing (biochemical), (2) serial enzyme-linked immunosorbent and strip immunoblot assay testing (serological), and (3) polymerase chain reaction (viral). Under baseline assumptions, the per-patient cost of screening hemodialysis patients for HCV was $378 for biochemical-based testing, $195 for serological-based testing, and $696 for viral-based testing. Our model was robust when varying the costs of testing, as well as the incidence and prevalence of HCV infection. Results of sensitivity analysis by varying costs, HCV incidence, and HCV prevalence indicated that serological-based screening was less costly than biochemical testing. Biochemical testing was in turn less costly than viral-based screening. Serological-based testing was also more effective in the diagnosis of de novo HCV infection, with a likelihood ratio of 85, in contrast to the likelihood ratio of 44 with biochemical-based testing using viral-based screening as the gold standard. A serological-based screening strategy is less costly and more effective than biochemical-based screening in the diagnosis of de novo HCV infection. Serological-based screening should be considered for HCV screening in hemodialysis populations.

Although migration of stellate cells during hepatic injury is essential for wound-healing and fibrosis of the liver, the extracellular and intracellular signals that regulate stellate cell migration are incompletely understood. In this study we tested the hypothesis that wound-induced migration of stellate cells is modulated by endothelin-1 (ET-1) through rho-kinase-mediated alterations in the acto-myosin cytoskeleton. To address this hypothesis, a method was established for direct visualization of wound-induced migration of culture-activated stellate cells with subcellular resolution. Migration in response to wounding was characterized by (1) plasma membrane ruffling and protrusion into the wound, (2) lamellipodia formation at the leading edge, (3) focal adhesion and stress fiber assembly, and (4) myosin reorganization. Exogenous ET-1 accelerated wound-induced migration of stellate cells, but did not alter wound-induced proliferation. Experiments using ET-1 antagonists in the absence of exogenous ET-1 showed that wound-induced migration was also stimulated by endogenous ET-1. Selective inhibition of rho-associated kinase decelerated migration in response to wounding. Moreover, inhibition of rho-associated kinase was distinguished by abrogation of focal adhesion formation, stress fiber assembly, and myosin reorganization. This study shows that rho-kinase-dependent alterations in the acto-myosin cytoskeleton contribute to wound-induced stellate cell migration, which is accelerated by both exogenous and endogenous ET-1. Consequently, these results provide important new evidence suggesting that, migration of stellate cells is modulated by paracrine and autocrine ET-1 stimulation via the action of rho-kinase on the acto-myosin cytoskeleton.

The present study examined the roles of peroxisome proliferator-activated receptors (PPAR) in activation of hepatic stellate cells (HSC), a pivotal event in liver fibrogenesis. RNase protection assay detected mRNA for PPARgamma1 but not that for the adipocyte-specific gamma2 isoform in HSC isolated from sham-operated rats, whereas the transcripts for neither isoforms were detectable in HSC from cholestatic liver fibrosis induced by bile duct ligation (BDL). Semi-quantitative reverse transcriptase-polymerase chain reaction confirmed a 70% reduction in PPARgamma mRNA level in HSC from BDL. Nuclear extracts from BDL cells showed an expected diminution of binding to PPAR-responsive element, whereas NF-kappaB and AP-1 binding were increased. Treatment of cultured-activated HSC with ligands for PPARgamma (10 microm 15-deoxy-Delta(12,14)-PGJ(2) (15dPGJ(2)); 0.1 approximately 10 microm BRL49653) inhibited DNA and collagen synthesis without affecting the cell viability. Suppression of HSC collagen by 15dPGJ(2) was abrogated 70% by the concomitant treatment with a PPARgamma antagonist (GW9662). HSC DNA and collagen synthesis were inhibited by WY14643 at the concentrations known to activate both PPARalpha and gamma (>100 microm) but not at those that only activate PPARalpha (