Samuel B Ho

VA San Diego Healthcare System, San Diego, California, United States

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Publications (125)893.68 Total impact

  • Gastroenterology 04/2015; 148(4):S-1071-S-1072. DOI:10.1016/S0016-5085(15)33662-3 · 13.93 Impact Factor
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    ABSTRACT: Inflammation promotes regeneration of injured tissues through poorly understood mechanisms, some of which involve interleukin (IL)-6 family members, the expression of which is elevated in many diseases including inflammatory bowel diseases and colorectal cancer. Here we show in mice and human cells that gp130, a co-receptor for IL-6 cytokines, triggers activation of YAP and Notch, transcriptional regulators that control tissue growth and regeneration, independently of the gp130 effector STAT3. Through YAP and Notch, intestinal gp130 signalling stimulates epithelial cell proliferation, causes aberrant differentiation and confers resistance to mucosal erosion. gp130 associates with the related tyrosine kinases Src and Yes, which are activated on receptor engagement to phosphorylate YAP and induce its stabilization and nuclear translocation. This signalling module is strongly activated upon mucosal injury to promote healing and maintain barrier function.
    Nature 03/2015; 519(7541):57-62. · 42.35 Impact Factor
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    ABSTRACT: Inflammation promotes regeneration of injured tissues through poorly understood mechanisms, some of which involve interleukin (IL)-6 family members, the expression of which is elevated in many diseases including inflammatory bowel diseases and colorectal cancer. Here we show in mice and human cells that gp130, a co-receptor for IL-6 cytokines, triggers activation of YAP and Notch, transcriptional regulators that control tissue growth and regeneration, independently of the gp130 effector STAT3. Through YAP and Notch, intestinal gp130 signalling stimulates epithelial cell proliferation, causes aberrant differentiation and confers resistance to mucosal erosion. gp130 associates with the related tyrosine kinases Src and Yes, which are activated on receptor engagement to phosphorylate YAP and induce its stabilization and nuclear translocation. This signalling module is strongly activated upon mucosal injury to promote healing and maintain barrier function.
    Nature 03/2015; 519(7541):57-62. DOI:10.1038/nature14228 · 42.35 Impact Factor
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    ABSTRACT: Patients with hepatitis C virus (HCV) infection with psychiatric disorders and/or substance abuse face significant barriers to antiviral treatment. New strategies might be needed to improve treatment rates and outcomes. We investigated whether an integrated care (IC) protocol, which includes multi-disciplinary care coordination and patient case management, could increase the proportion of patients with chronic HCV infection who receive antiviral treatment (a combination of interferon-based and direct acting antiviral agents) and achieve a sustained virologic response (SVR).
    Clinical Gastroenterology and Hepatology 02/2015; DOI:10.1016/j.cgh.2015.02.022 · 6.53 Impact Factor
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    ABSTRACT: Alcoholic liver disease is a leading cause of mortality. Chronic alcohol consumption is accompanied by intestinal dysbiosis, and development of alcoholic liver disease requires gut-derived bacterial products. However, little is known about how alterations to the microbiome contribute to pathogenesis of alcoholic liver disease.
    Gastroenterology 09/2014; 148(1). DOI:10.1053/j.gastro.2014.09.014 · 13.93 Impact Factor
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    ABSTRACT: Intestinal barrier dysfunction is an important contributor to alcoholic liver disease (ALD). Translocated microbial products trigger an inflammatory response in the liver and contribute to steatohepatitis. Our aim was to investigate mechanisms of barrier disruption after chronic alcohol feeding. A Lieber‐DeCarli model was used to induce intestinal dysbiosis, increased intestinal permeability, and liver disease in mice. Alcohol feeding for 8 weeks induced intestinal inflammation in the jejunum, which is characterized by an increased number of tumor necrosis factor alpha (TNF‐α)‐producing monocytes and macrophages. These findings were confirmed in duodenal biopsies from patients with chronic alcohol abuse. Intestinal decontamination with nonabsorbable antibiotics restored eubiosis, decreased intestinal inflammation and permeability, and reduced ALD in mice. TNF‐receptor I (TNFRI) mutant mice were protected from intestinal barrier dysfunction and ALD. To investigate whether TNFRI on intestinal epithelial cells mediates intestinal barrier dysfunction and ALD, we used TNFRI mutant mice carrying a conditional gain‐of‐function allele for this receptor. Reactivation of TNFRI on intestinal epithelial cells resulted in increased intestinal permeability and liver disease that is similar to wild‐type mice after alcohol feeding, suggesting that enteric TNFRI promotes intestinal barrier dysfunction. Myosin light‐chain kinase (MLCK) is a downstream target of TNF‐α and was phosphorylated in intestinal epithelial cells after alcohol administration. Using MLCK‐deficient mice, we further demonstrate a partial contribution of MLCK to intestinal barrier dysfunction and liver disease after chronic alcohol feeding. Conclusion: Dysbiosis‐induced intestinal inflammation and TNFRI signaling in intestinal epithelial cells mediate a disruption of the intestinal barrier. Therefore, intestinal TNFRI is a crucial mediator of ALD. (Hepatology 2015;61:883–894)
    Hepatology 09/2014; 61(3). DOI:10.1002/hep.27489 · 11.19 Impact Factor
  • Gastroenterology 05/2014; 146(5):S-737. DOI:10.1016/S0016-5085(14)62672-X · 13.93 Impact Factor
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    ABSTRACT: Antiviral therapy for the hepatitis C virus (HCV) reduces all-cause and liver-related morbidity and mortality. Few studies are available from populations with multiple medical and psychiatric comorbidities where the impact of successful antiviral therapy might be limited. The purpose of this study was to determine the effect of sustained virologic response (SVR) on all-cause and liver-related mortality in a cohort of HCV patients treated in an integrated hepatitis/mental health clinic. This was a retrospective review of all patients who initiated antiviral treatment for chronic HCV between January 1, 1997 and December 31, 2009. Cox regression analysis was used to determine factors involved in all-cause mortality, liver-related events and hepatocellular carcinoma. A total of 536 patients were included in the analysis. Median follow-up was 7.5 years. Liver and non-liver-related mortality occurred in 2.7 and 5.0 % of patients with SVR and in 17.8 and 6.4 % of patients without SVR. In a multivariate analysis, SVR was the only factor associated with reduced all-cause mortality (HR 0.47; 95 % CI 0.26-0.85; p = 0.012) and reduced liver-related events (HR 0.23; 95 % CI 0.08-0.66, p = 0.007). Having stage 4 liver fibrosis increased all-cause mortality (HR 2.50; 95 % CI 1.23-5.08; p = 0.011). Thrombocytopenia at baseline (HR 2.66; 95 % CI 1.22-5.79; p = 0.014) and stage 4 liver fibrosis (HR 4.87; 95 % CI 1.62-14.53; p = 0.005) increased liver-related events. Despite significant medical and psychiatric comorbidities, SVR markedly reduced liver-related outcomes without a significant change in non-liver-related mortality after a median follow-up of 7.5 years.
    Digestive Diseases and Sciences 02/2014; 59(4). DOI:10.1007/s10620-014-3050-5 · 2.55 Impact Factor
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    ABSTRACT: Methamphetamine (MA) use has increased in the United States in the last 20 years and is a risk factor for hepatitis C virus(HCV) infection. The purpose of this study was to determine the characteristics and HCV infection outcomes of patients with a history of MA use. Subjects consisted of newly entered patients in the Veterans Affairs (VA) HCV registry at a single VA medical center from January 1, 2004, to June 30, 2004, and from January 1, 2007, to June 30, 2007. Univariate and multivariate analyses related to HCV infection antiviral treatment outcomes through 2010 was performed. A total of 198 consecutive eligible HCV registry patients were analyzed, and 40% had a history of MA use. Of patients with MA use history, 46% (36/79) had active use (within 6 months) at initial contact. Active MA users were significantly younger (mean age, 45.5 years), with more concomitant drug use (86%), compared with patients without MA use (mean age, 53.5 years; 42% minority; 29% other drug use). Overall, 71% of the 198 patients reported a history of problematic alcohol use, and 47% of those reported active abuse. Logistic regression analyses indicated that MA use did not significantly adversely affect antiviral treatment initiation, completion, or sustained virological response rates compared with that in patients without MA use. Active alcohol users had lower treatment initiation than patients without alcohol use. MA use is common in recent US veterans with HCV infection and occurs in younger patients with polysubstance use. Prior history or active MA use does not seem to adversely affect HCV infection clinic treatment compared with that in HCV-infected patients without MA use.
    Journal of Addiction Medicine 12/2013; DOI:10.1097/ADM.0000000000000001 · 1.71 Impact Factor
  • Samuel B Ho
    Digestive Diseases and Sciences 11/2013; 59(2). DOI:10.1007/s10620-013-2935-z · 2.55 Impact Factor
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    ABSTRACT: The intestinal mucus layer protects the epithelium from noxious agents, viruses, and pathogenic bacteria present in the gastrointestinal tract. It is composed of mucins, predominantly mucin-2 (Muc2), secreted by goblet cells of the intestine. Experimental alcoholic liver disease requires translocation of bacterial products across the intestinal barrier into the systemic circulation, which induces an inflammatory response in the liver and contributes to steatohepatitis. We investigated the roles of the intestinal mucus layer, and in particular Muc2, in development of experimental alcohol-associated liver disease in mice. We studied experimental alcohol-induced liver disease, induced by the Tsukamoto-French method (which involves continuous intragastric feeding of an isocaloric diet or alcohol) in wild-type and Muc2(-/-) mice. Muc2(-/-) mice showed less alcohol-induced liver injury and steatosis that developed in wild-type mice. Most notably, Muc2(-/-) mice had significantly lower plasma levels of lipopolysaccharide than wild-type mice after alcohol feeding. In contrast to wild-type mice, Muc2(-/-) mice were protected from alcohol-associated microbiome changes that are dependent on intestinal mucins. The anti-microbial proteins Reg3b and Reg3g were expressed at significantly higher levels in the jejunum of Muc2(-/-) mice fed the isocaloric diet or alcohol, compared with wild-type mice. Consequently, Muc2(-/-) mice showed increased killing of commensal bacteria and prevented intestinal bacterial overgrowth. Conclusion: Muc2(-/-) mice are protected from intestinal bacterial overgrowth and dysbiosis in response to alcohol feeding. Subsequently, lower amounts of bacterial products such as endotoxin translocate into the systemic circulation, decreasing liver disease. (HEPATOLOGY 2013.).
    Hepatology 07/2013; 58(1). DOI:10.1002/hep.26321 · 11.19 Impact Factor
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    Digestive Diseases and Sciences 05/2013; 58(6). DOI:10.1007/s10620-013-2723-9 · 2.55 Impact Factor
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    ABSTRACT: BACKGROUND AND AIM: The Veterans Health Administration (VHA) is the largest single provider of care for hepatitis C virus (HCV) infection in the US. We analyzed the cost-effectiveness of treatment with the HCV protease inhibitors boceprevir and telaprevir in a defined managed care population of 102,851 patients with untreated chronic genotype 1 infection. METHODS: We used a decision-analytic Markov model to examine 4 strategies: standard dual-therapy with pegylated interferon-alfa and ribavirin (PR), the combination of boceprevir and PR triple therapy, the combination of telaprevir and PR, or no antiviral treatment; sensitivity analysis was performed. Sources of data included published rates of disease progression, the census bureau, and VHA pharmacy and hospitalization cost databases. RESULTS: The estimated costs for treating each patient were $8000 for PR, $31,300 for boceprevier and PR, and $41,700 for telaprevir and PR. Assuming VHA treatment rates of 22% and optimal rates of sustained viral response, PR, boceprevir and PR, and telaprevir and PR would reduce relative liver-related deaths by 5.2%, 10.9%, and 11.5%, respectively. Increasing treatment rates to 50% would reduce liver-related deaths by 12%, 24.7%, and 26.1%, respectively. The incremental cost-effectiveness ratios were $29,184/quality of adjusted-life years (QALY) for boceprevir and PR and $44,247/QALY for telaprevir and PR vs only PR. With the current 22% treatment rate, total system-wide costs to adopt boceprevir and PR or telaprevir and PR would range from $708 million to $943 million. CONCLUSIONS: Despite substantial upfront costs of treating HCV-infected patients in the VHA with PR, or telaprevir and PR, each regimen improves quality of life and extends life expectancy, by reducing liver-related morbidity and mortality, and should be cost effective. Further efforts to expand access to direct-acting antiviral therapy are warranted.
    Clinical gastroenterology and hepatology: the official clinical practice journal of the American Gastroenterological Association 05/2013; 11(11). DOI:10.1016/j.cgh.2013.05.014 · 6.53 Impact Factor
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    ABSTRACT: Most individuals infected with the hepatitis C have not received antiviral treatment, with mental health and substance abuse problems being the primary barrier. Interventions have been developed to address these barriers among HCV patients considered "high-risk" for antiviral treatment. We present the design and methods of a prospective, randomized controlled multisite trial being conducted in the Veterans Affairs Healthcare System. The study employed a parallel design and the three study sites randomized a total of 364 VA patients with HCV to either Integrated Care (IC) or Usual Care (UC). The IC intervention consisted of a mental health provider (MHP) performing a) brief interventions to address risk factors; b) collaborative consultation with the HCV treatment clinicians; and c) case management prior to and during antiviral treatment. Clinical outcomes were abstracted from patient medical records and self-report questionnaires were completed at baseline, 4-months, 16-months, and 22-months after enrollment. The primary outcome of the study was sustained viral response (SVR). Secondary clinical outcomes were HCV treatment initiation and completion rates. Other secondary outcomes included substance use, depression, PTSD symptoms, quality of life, healthcare satisfaction, and healthcare utilization. The Integrated Care intervention has the potential to transform HCV antiviral treatment by increasing the number of HCV-infected individuals that can be successfully treated.
    Contemporary clinical trials 05/2013; DOI:10.1016/j.cct.2013.05.002 · 1.99 Impact Factor
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    ABSTRACT: Objective. Chronic hepatitis C infection afflicts millions of people worldwide. Although antiviral treatments are increasingly effective, many hepatitis C virus (HCV) patients avoid treatment, do not complete or respond to treatment, or have contraindications. Self-management interventions are one option for promoting behavioral changes leading to liver wellness and improved quality of life. Our objective was to evaluate whether the effects of the HCV self-management program were sustained at the 12-month follow-up assessment. Methods. Veteran Affairs patients with hepatitis C (N = 134; mean age = 54.6 years, 95% male, 41% ethnic minority, 48% homeless in last 5 years) were randomized to either a 6-week self-management workshop or an information-only intervention. The weekly 2-hour self-management sessions were based on a cognitive-behavioral program with hepatitis C-specific modules. Outcomes including hepatitis C knowledge, depression, energy, and health-related quality of life were measured at baseline, 6 weeks, 6 months, and 12 months later. Data were analyzed using repeated measures ANOVA. Results. Compared with the information-only group, participants attending the self-management workshop improved more on HCV knowledge (p < .005), SF-36 energy/vitality (p = .016), and the Quality of Well-Being Scale (p = .036). Similar trends were found for SF-36 physical functioning and Center for Epidemiologic Studies Short Depression Scale. Conclusion. Better outcomes were sustained among self-management participants at the 12-month assessment despite the intervention only lasting 6 weeks. HCV health care providers should consider adding self-management interventions for patients with chronic HCV.
    Health Education &amp Behavior 02/2013; 40(6). DOI:10.1177/1090198113477112 · 1.54 Impact Factor
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    ABSTRACT: Adequate colon cleansing is an important factor in performing quality colonoscopy. Split dose Polyethylene Glycol (PEG) solutions have been shown to improve colon cleansing, but the effectiveness in a large clinical practice of elderly co-morbid patients has not been demonstrated. The aim of this study was to assess the efficacy of a simplified split PEG bowel prep in Veterans Health Administration (VHA) patients. Prospective pre-post study design of VHA patients undergoing routine colonoscopy. Bowel prep quality was assessed using a standardized semi-quantitative 5-point scale. "Standard" 4L PEG prep was consumed once the evening before the procedure. "Split" prep was consumed half in the early evening and half in the late evening or early morning depending on procedure time. Right colon preps were Excellent/Good in 81.4% of split preps (n=199) vs. 63% of standard preps (n=447, p<0.001). Left colon preps were Excellent/Good in 85.9% of split preps vs. 71.6% of standard preps (p<0.001). Diabetics (n=133) had significantly more right colon preps rated fair or worse compared to non-diabetics irrespective of prep (39.9% vs. 29.0%, p=0.02). Split prep in diabetics resulted in fewer right colon preps rated fair or worse compared to diabetics using standard prep (28.3% vs. 45.9%, p=0.049). Average adenomas detected per colonoscopy were 1.04 for split prep vs. 0.85 for standard prep (p=NS). Patient satisfaction was higher for split preps. System-wide implementation of a split PEG prep resulted in significantly improved bowel cleansing in VHA patients, particularly in the right colon. Improved bowel cleansing with split preps was associated with higher patient satisfaction.
    10/2012; 2(4):177-182. DOI:10.4161/jig.23748
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    ABSTRACT: To determine the pattern of secreted mucin expression in Helicobacter pylori (H. pylori)-related, nonsteroidal anti-inflammatory drug (NSAID)-related and idiopathic gastric ulcers. We randomly selected 92 patients with H. pylori-associated (n = 30), NSAID-associated (n = 18), combined H. pylori and NSAID-associated gastric ulcers (n = 24), and patients with idiopathic gastric ulcers (n = 20). Immunohistochemistry for T-cell CD4/CD8, and for mucin 5AC (MUC5AC) and mucin 6 (MUC6), was performed on sections of the mucosa from the ulcer margin. Inflammation score was assessed according to the Sydney system. MUC5AC was expressed on the surface epithelium (98.9%) and neck glands (98.9%) with minimal expression in the deep glands (6.5%). MUC6 was strongly expressed in the deep glands (97.8%), variable in the neck glands (19.6%) and absent in the surface epithelium (0%). The pattern of mucin expression in idiopathic ulcer margins was not different from the expression in ulcers associated with H. pylori, NSAIDs, or combined H. pylori and NSAIDs. CD4/CD8 ratio was higher in H. pylori-positive patients (P = 0.009). Idiopathic ulcers are associated with hospitalized patients and have higher bleeding and mortality rates. Idiopathic ulcers have a unique clinical profile. Gastric mucin expression in idiopathic gastric ulcers is unchanged compared with H. pylori and/or NSAID-associated ulcers.
    World Journal of Gastroenterology 09/2012; 18(33):4597-603. DOI:10.3748/wjg.v18.i33.4597 · 2.43 Impact Factor
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    ABSTRACT: BACKGROUND AND AIM: Iron deficiency anemia (IDA) is a common problem among the elderly, and often no cause is identified after routine upper endoscopy and colonoscopy exams. The purpose of this study was to determine the long-term outcomes and predictors of gastrointestinal pathology and death in patients with endoscopy-negative IDA. METHODS: This was a retrospective review of consecutive endoscopy negative-IDA patients during 2002-2004 at the VA San Diego Healthcare System. RESULTS: Mean age was 69.3 years (range 42-93), and included 105 men and nine women. Mean length of follow-up was 65.1 months. IDA resolved in 56 patients. None of these patients developed evidence of any clinically significant gastrointestinal pathology. The remaining 58 patients had persistent anemia (n = 47) or recurrent anemia (n = 11). Only 2/47 patients with persistent anemia were found to have clinically significant but benign gastrointestinal pathology during follow-up. In contrast, 6/11 patients with recurrent anemia were subsequently found to have gastrointestinal pathology. Deaths during follow-up occurred in 7 (12.5 %) patients with resolved anemia, compared with 20 (34.5 %) patients with recurrent or persistent anemia (p = 0.006). Significant independent predictors of death included persistent or recurrent anemia, anti-platelet or anticoagulant use, and congestive heart failure. CONCLUSIONS: Patients with iron deficiency anemia and negative upper endoscopy and colonoscopy often have a favorable outcome, especially if the anemia resolves with treatment. In patients with recurrent anemia a malignancy within reach of standard endoscopy and colonoscopy are possible, and repeating these procedures is warranted before consideration of further investigations.
    Digestive Diseases and Sciences 09/2012; 58(2). DOI:10.1007/s10620-012-2368-0 · 2.55 Impact Factor
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    ABSTRACT: The ratio of Helicobacter pylori/NSAID-negative gastric ulcers is increasing. Idiopathic gastric ulcers have unique clinical and endoscopic features, and are associated with more bleeding complications and a higher mortality. Alterations in gastric mucin expression and sialylation pattern may be important in ulcer pathogenesis. The purpose of this study was to determine the expression pattern of membrane-bound mucins and side chain sugars in H. pylori associated-, NSAID-, and idiopathic-gastric ulcers. We randomly selected 92 patients with H. pylori (group 1, n = 30), NSAID (group 2, n = 18), combined H. pylori and NSAID associated gastric ulcers (group 3, n = 24), and patients with idiopathic gastric ulcers (group 4, n = 20). Immunohistochemistry for T-cell CD4/CD8, MUC1, MUC4, MUC17, and ECA and SNA lectins staining was performed on sections from the ulcer margins. Inflammation score was assessed according to the Sydney system. Bleeding and mortality rates were significantly higher in group 4. CD4 positive T cell count was higher in H. pylori positive patients (P = 0.009). Staining intensity of MUC17 was higher in group 1 than in group 4, foveola and glands alike, with 11.50 ± 3.47 versus 6.80 ± 4.02, and 9.61 ± 4.26 versus 7.59 ± 3.26, respectively (P < 0.0001). This was a mirror image with MUC1. SNA lectin staining was increased in group 4, in parallel to MUC1 expression, indicating more abundant α2-6 sialylation in that group. Cytoplasmic MUC17 staining was significantly decreased in the cases with idiopathic ulcer. The opposite was demonstrated for MUC1. This observation might be important, since different mucins with altered sialylation patterns likely differ in their protection efficiency against acid and pepsin.
    Digestive Diseases and Sciences 05/2012; 57(10):2535-44. DOI:10.1007/s10620-012-2205-5 · 2.55 Impact Factor
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    ABSTRACT: Liver biopsy remains the standard, recommended method for assessing liver damage associated with chronic hepatitis C (HCV) infection. However, there is considerable debate about how liver biopsy should best be used, especially with the advent of more efficacious antiviral therapies. To identify the factors that influence the use of liver biopsy for HCV patients, we describe variations in liver biopsy use at the delivery system and patient level in a national VA sample. We analyzed VA HCV registry data for 171,893 VA patients with confirmed chronic HCV. Delivery system characteristics included geographic region and specialist time. Patient characteristics included antiviral treatment indicators, contraindications, volume of healthcare visits, and demographic variables. Logistic regression was used to explore correlates of biopsy use. Liver biopsy use in the VA system increased from 1997 to 2003 but began declining in 2004. Rates of liver biopsy from 2004 to 2006 varied by VA region, ranging from 5% to 18%. Treatment contraindications and laboratory tests were significantly associated with more biopsies. Demographic variables (higher age, lower BMI, race/ethnicity, and less% service connected disability) were associated with fewer biopsies. Regional variability remained significant independent of volume of care and specialist time. Liver biopsy rates in the VA system have variability that seems unrelated to clinical need. New antiviral therapies and non-invasive assessment techniques may create additional uncertainty for the role of liver biopsy, perhaps explaining its decline in recent years. The availability of more effective antiviral therapies may also affect biopsy rates in the future.
    Journal of Hepatology 04/2012; 57(2):252-9. DOI:10.1016/j.jhep.2012.03.021 · 10.40 Impact Factor

Publication Stats

3k Citations
893.68 Total Impact Points

Institutions

  • 2008–2015
    • VA San Diego Healthcare System
      San Diego, California, United States
  • 2008–2014
    • University of California, San Diego
      • • Department of Medicine
      • • Department of Psychiatry
      San Diego, California, United States
  • 2012
    • University of California, Irvine
      Irvine, California, United States
  • 2009–2012
    • CSU Mentor
      Long Beach, California, United States
  • 2011
    • National University (California)
      San Diego, California, United States
  • 1996–2007
    • Minneapolis Veterans Affairs Hospital
      Minneapolis, Minnesota, United States
    • Spokane VA Medical Center
      Spokane, Washington, United States
  • 1992–2006
    • University of Minnesota Duluth
      • • Medical School
      • • Laboratory Medicine and Pathology
      Duluth, Minnesota, United States
    • San Francisco VA Medical Center
      San Francisco, California, United States
  • 2005
    • NYU Langone Medical Center
      New York, New York, United States
  • 2004–2005
    • Vanderbilt University
      • Department of Medicine
      Nashville, MI, United States
  • 2003
    • University of Minnesota Medical Center, Fairview
      Minneapolis, Minnesota, United States
  • 2001
    • University of Minnesota Twin Cities
      • Department of Otolaryngology
      Minneapolis, MN, United States
  • 1990
    • University of California, San Francisco
      • Division of Hospital Medicine
      San Francisco, California, United States