Effectiveness of an Interdisciplinary, Nurse Driven In-Hospital Code Stroke Protocol on In-Patient Ischemic Stroke Recognition and Management.

BACKGROUND: In-hospital strokes account for up to nearly 1 in 5 strokes. Clinical outcomes, such as length of stay, disability, and mortality are worse for in-hospital strokes than for those that occur in the community. For a variety of reasons, stroke can be more difficult to recognize and treat in hospitalized patients. Earlier recognition of stroke results in better clinical outcomes, presumably due to faster diagnosis and subsequently, prompt treatment. METHODS: This investigation was a retrospective, interrupted time series, observational study of all in-hospital stroke patients between 2008 and 2017. This investigation was a quality improvement project, and a waiver was granted from the institutional review board. We used Lean methodologies to standardize our stroke protocol and optimize skill-task alignment to improve the time from onset of symptoms to brain imaging (primary outcome). RESULTS: Overall, we observed significant improvement in the time from onset of symptoms to brain imaging from a median of 69 minutes to 37 minutes (P = .002). CONCLUSIONS: If successfully implemented, this approach may be useful in other care settings with potential to improve stroke outcomes, and decrease associated complications of stroke.

BG1 has a major role in MHC-linked resistance to malignant lymphoma in the chicken.

Pathogen selection is postulated to drive MHC allelic diversity at loci for antigen presentation. However, readily apparent MHC infectious disease associations are rare in most species. The strong link between MHC-B haplotype and the occurrence of virally induced tumors in the chicken provides a means for defining the relationship between pathogen selection and MHC polymorphism. Here, we verified a significant difference in resistance to gallid herpesvirus-2 (GaHV-2)-induced lymphomas (Marek's disease) conferred by two closely-related recombinant MHC-B haplotypes. We mapped the crossover breakpoints that distinguish these haplotypes to the highly polymorphic BG1 locus. BG1 encodes an Ig-superfamily type I transmembrane receptor-like protein that contains an immunoreceptor tyrosine-based inhibition motif (ITIM), which undergoes phosphorylation and is recognized by Src homology 2 domain-containing protein tyrosine phosphatase (SHP-2). The recombinant haplotypes are identical, except for differences within the BG1 3'-untranslated region (3'-UTR). The 3'-UTR of the BG1 allele associated with increased lymphoma contains a 225-bp insert of retroviral origin and showed greater inhibition of luciferase reporter gene translation compared to the other allele. These findings suggest that BG1 could affect the outcome of GaHV-2 infection through modulation of the lymphoid cell responsiveness to infection, a condition that is critical for GaHV-2 replication and in which the MHC-B haplotype has been previously implicated. This work provides a mechanism by which MHC-B region genetics contributes to the incidence of GaHV-2-induced malignant lymphoma in the chicken and invites consideration of the possibility that similar mechanisms might affect the incidence of lymphomas associated with other oncogenic viral infections.

Improving access to pre-exposure prophylaxis for HIV prescribing in a primary care setting.

Although emtricitabine-tenofovir was approved for HIV pre-exposure prophylaxis (PrEP) in 2012, use by persons at risk of acquiring HIV has been limited. Because many primary care providers lacked familiarity and comfort prescribing PrEP, at our institution PrEP prescribing was concentrated among the infectious disease specialists, effectively limiting access. This project sought to increase the number of patients receiving new prescriptions for PrEP. The interventions targeted primary care providers (including internal medicine and family medicine), and were designed to increase the number of unique providers offering PrEP to their patients. The overall strategy was to expand the clinical scope of practice for primary care providers through education and provision of detailed care templates in the electronic health record. These initiatives were implemented through a series of informal Plan-Do-Study-Act cycles, then generalised throughout the medical system. To evaluate the success of the project, we queried the electronic medical record for all new prescriptions for PrEP, with provider name and specialty, for all outpatients 18 years of age and older from 2012 through 2020. In 2015, prior to the intervention, only 78 patients received new prescriptions for PrEP at our institution, and only 38% (30 of 78) of these were from primary care clinicians. After the intervention, the number of patients receiving PrEP increased to 190 in 2019, with 85% (162 of 190) prescribed by primary care providers. In addition, the number of primary care providers making a new prescription for PrEP increased from 20 in 2015 to 73 in 2019. We conclude that targeted clinical education, combined with electronic health record templates, was associated with a significant increase in PrEP prescribing.

Clinical spotlight intervention to accelerate translation of evidence-based practices in primary care.

Evidence-based medical practice is often slow to diffuse into widespread clinical practice. To accelerate translation of updated best practices into clinical care, we developed a quality improvement intervention called the 'Clinical Spotlight'. This programme was based on a knowledge translation model of four steps: education on evidence-based practices, using Lean for incorporation into patient care flow, support of implementation and sustainability, and measurement of outcomes. Using the Clinical Spotlight intervention for addressing the care of patients with type 2 diabetes was associated with appropriate increases in the use of newer classes of glycaemic control medications. We demonstrate statistically significant increases in the use of promoted glycaemic control agents (sodium-glucose cotransporter-2 inhibitor and glucagon-like peptide-1 receptor agonist classes of drugs) at the time of intervention. We conclude that translation of evidence-based practices into clinical care can be enhanced through an educational intervention linked to Lean process improvement and with supported implementation. We are currently expanding our programme to additional clinical areas in primary care.

Focusing hospitalist roles on either admitting or rounding facilitates unit-based assignment and is associated with improved discharge efficiency.

BACKGROUND: Unit-based teams may improve care delivery for hospitalized patients but can be challenging to implement broadly across all acute care units in a hospital. OBJECTIVE: To determine the effect of a Lean-guided transition to hospital-wide unit-based assignment on care delivery outcomes. DESIGN, SETTING, AND PARTICIPANTS: The study was a retrospective time-series with primary outcomes of discharge efficiency, 30-day readmissions, and length of stay, performed at a 336-bed tertiary academic referral hospital in the Pacific Northwest with approximately 17,000 admissions annually. INTERVENTION: Implementation of a Lean-guided quality improvement intervention included division of hospitalist duties into 'admitters' and 'rounders,' with simulated patient flow exercises to determine the optimal staffing model. MAIN OUTCOMES AND MEASURES: Discharge efficiency (number of patients discharged by hospitalists divided by the number of hospitalist patient encounter days per month) and 30-day readmissions were compared using the t-test or chi-square, and length of stay was analyzed in a multivariate time-series regression model. RESULTS: The intervention was associated with a significant improvement in discharge efficiency, by 0.014 (from 0.168 to 0.181) discharges/encounter (95% CI = 0.024, 0.004), p = 0.009. Mean length of stay decreased by 0.98 days (95% CI 0.50, 1.47) after adjustment for patient age, patient type (medical versus surgical), critical care admissions, and discharge disposition, without a corresponding change in 30-day readmission rate (12.2% (1948/15,902) pre-intervention to 11.7% (397/3379) post-intervention (p = 0.42)). CONCLUSIONS: Dividing hospitalist roles into admitters and rounders enabled implementation of unit-based teams across the hospital, with corresponding improvements in discharge efficiency and length of stay.

Implementing screening for social determinants of health using the Core 5 screening tool.

Social determinants of health (SDOH) have been documented to underpin 80% of overall health and are being increasingly recognised as key factors in addressing tertiary health outcomes. Yet, despite the widespread acceptance of the association of SDOH with health outcomes, more than two-thirds of hospitals do not screen for social risk factors that indicate individual-level adverse SDOH. Such screening for social risk factors represents the first step in connecting patients with resources and documents the prevalence of social needs. The aim of this project was to implement the Core 5 social risk screening tool and evaluate its efficacy and usability in identifying social risk factors in a presurgical spine population. Prior to this implementation, screening for social risk had not been performed. The Model for Improvement provided a framework for implementing and evaluating the Core 5 social risk screening tool. Methods included implementation of a patient self-report social risk screening tool, referral workflow to connect patients with needed resources and evaluation of staff feasibility in using the Core 5 tool. The results indicated that the screening tool identified patients with social risk factors and staff reported perceptions of efficacy and usability in clinical workflow. Overall, 52 of 88 (59%) of subjects in the presurgical spine population were effectively screened. Of these, five patients (10%) had identified social needs that needed to be addressed prior to surgery. The staff usability survey for the Core 5 tool demonstrated high acceptance and usability, with an average score of 4.4 (out of 5). Future work should evaluate the efficacy of the screening tool in other ambulatory and tertiary settings.

Role of Marek's disease herpesvirus in the induction of tumours in Japanese quail (Coturnix coturnix japonica) by methylcholanthrene.

The QT35 cell line, established from 20-methylcholanthrene (MCA)-induced tumours in Japanese quail, is positive for Marek's disease virus (MDV), and therefore we examined whether MDV is important for the development of MCA-induced tumours. Japanese quail were inoculated with the JM16 strain of MDV at 1 or 3 days of age or left uninoculated. At 3 weeks of age, quail were injected in the breast muscle with 4 mg MCA in corn oil or corn oil alone. Quail were observed for tumours three times/week and at post mortem at 11 to 12 weeks of age. MDV DNA was detected by polymerase chain reaction (PCR) in spleens of 14/20 birds inoculated with JM16+corn oil and of 53/71 birds inoculated with JM16+MCA. Interestingly, 1/74 quail was positive in the MCA group alone for MDV DNA. Tumours were collected for histopathology, cell line development, and PCR and reverse transcriptase-PCR for the presence of MDV. Tumours developed in 38/83 MCA-treated and 32/85 JM16+MCA-treated quail. Fibrosarcomas without metastasis were the only tumours observed in the MCA-treated quail, while quail treated with JM16 and MCA developed undifferentiated tumours, fibrosarcomas, lymphosarcomas or combinations with or without metastasis. One out of 20 quail receiving JM16 alone developed a lymphosarcoma. Cell line development was not influenced by JM16. Tumours from MCA-treated quail were negative for MDV, while 19/29 were positive in the JM16+MCA group. MDV transcripts were present in 13/18 tumours examined in the JM16+MCA group. In conclusion, MDV did not affect tumour development but did influence tumour aggression and histological type.

Reduction of early inpatient transfers and rapid response team calls after implementation of an emergency department intake huddle process.

Patients admitted to the hospital and requiring a subsequent transfer to a higher level of care have increased morbidity, mortality and length of stay compared with patients who do not require a transfer during their hospital stay. We identified that a high number of patients admitted to our intermediate care (IMC) unit required a rapid response team (RRT) call and an early (<24 hours) transfer to the intensive care unit (ICU). A quality improvement project was initiated with the goal to reduce subsequent early transfers to the ICU and RRT calls. We started by focusing on IMC patients, implementing acuity-based nursing assignments and standardised daily nursing rounds in the IMC aiming to reduce early patient transfers to the ICU. Then, we expanded to all patients admitted to a hospital medical unit from the emergency department (ED), targeting patients with gastrointestinal (GI) bleed and sepsis who were at a higher risk for early transfer to the ICU. We then created an ED intake huddle process that over time was refined to target patients with SIRS criteria with an elevated serum lactic acid level greater than 2.0 mmol/L or a GI bleed with a haematocrit value less than 24%. These interventions resulted in an 10.8 percentage points (31.7% (225/710) to 20.9% (369/1764)) decrease in the early transfers to the ICU for all hospital medicine patients admitted to the hospital from the ED. Mean RRT calls/day decreased by 17%, from 3.0 mean calls/day preintervention to 2.5 mean calls/day postintervention. These quality improvement initiatives have sustained successful outcomes for over 6 years due to integrating enhanced team communication as organisational cultural norm that has become the standard.

Use of a real-time, algorithm-driven, publicly displayed, automated signal to improve insulin prescribing practices.

AIM: The clinical andon board (CAB) is a novel electronic surveillance and communication system, which alerts providers to and prompts treatment of dysglycemia. This investigation was designed to determine the CAB's effectiveness in supporting adherence to standardized evidence-based protocols, as well as improving glycemic control. METHODS: This study was a retrospective pre/post analysis of insulin orders and blood glucose values. We used a Student's t-test for continuous variables and Chi2 for all other variables. This study included patients 18 years or older admitted to the hospital medical service as an inpatient with a length of stay greater than 24 h and less than 90 days. We used Pearson's correlation coefficient to evaluate the relationship between CAB and blood glucose. RESULTS: The rate of compliance in prescribing basal insulin for patient with diabetes increased from 56% to 77% (p < 0.001). Similarly, compliance rates for prescribing correctional insulin in patients without diabetes increased from 15% to 37% (p < 0.001). Performance on the CAB was linearly related to blood glucose (p = 0.004), and there was a small statistically (not clinically) significant improvement in mean blood glucose values. CONCLUSION: This approach is effective in alerting and engaging providers to prescribe insulin in a standardized manner with potential to improve glycemic control.

Effectiveness of standardised preoperative assessment and patient instructions on admission blood glucose for patients with diabetes undergoing orthopaedic surgery at a tertiary referral hospital.

Diabetes and hyperglycaemia affect a significant number of people and are associated with a variety of untoward effects, especially under physiological stress such as surgery. Due, in large part to limited evidence, clinical practice in monitoring blood glucose and treating hyperglycaemic conditions in the perioperative period is variable. We used Lean methodologies to implement a standardised approach to preoperative management of patients undergoing elective surgery in an effort to improve glycaemic control. Overall, we saw an appropriate increase in monitoring and a decrease in the rate of hyperglycaemia on presentation to the operating room. This approach may be useful in other care settings or patient populations, potentially contributing to improved glycaemic control and subsequent decrease in associated complications.

A multifaceted intervention to improve the quality of care for patients undergoing total joint arthroplasty.

Knee and hip arthroplasties vary in cost, quality and outcomes. We developed a Lean quality improvement intervention for knee and hip arthroplasty patients encompassing the recognition, readiness, restoration and recovery phases of care. The intervention included standardised, evidence-based pathways, shared decision making, patient and family member engagement, and transdisciplinary rounding, implemented successively through a series of rapid process improvement workshops. We evaluated the intervention through run charts and time series analysis for 2005-2014. Outcomes included length of stay (LOS), 30-day readmission, discharge disposition, postsurgical complications and patient satisfaction. Included were 4253 total joint arthroplasty procedures, 1659 hip and 2594 knee. LOS decreased from 3.2 to 2.4 days postintervention for both hip and knee patients (p<0.001). The 30-day hospital readmission rate for hip patients decreased from 3.1% (18/576) to 1.1% (5/446, p=0.032) with knee patients unchanged. Discharge to home (vs rehabilitation facility or skilled nursing facility) increased from 72% (415/576) to 91% (405/446) (p<0.001) for hip patients, and from 70% (599/860) to 87% (578/663) for knee patients (p<0.001). Our standardised multifaceted Lean quality improvement programme was associated with reduced LOS, decreased readmission rates and improved discharge disposition in total knee and hip arthroplasty patients.

Team-Based Medicine: Incorporating a Clinical Pharmacist into Pain and Opioid Practice Management.

BACKGROUND: The Centers for Disease Control and Prevention (CDC) reports that death from opioids has increased by more than five times since 1999. In response, federal and state organizations have released guidelines recommending best practice standards to combat the opioid epidemic. OBJECTIVE: To evaluate the impact of a clinical pharmacist in a team-based care model on the adherence to best practice standards and access to care for management of patients prescribed chronic opioid therapy (COT). DESIGN: Retrospective chart review study. SETTING: An outpatient physical medicine and rehabilitation clinic in a tertiary hospital. PATIENTS: Three hundred eighty-three patients presenting to the clinic between January 2012 and August 2016 with chronic, noncancer pain. METHODS: Comparison of adherence to best practice standards-including changes in morphine equivalent dose (MED), compliance with urine drug screenings, documentation of medication agreements, initiation of nonopioid medications, and the impact of comorbidities-was analyzed before and after a clinical pharmacist was added to the team. Data were gathered from the electronic medical record and the Prescription Monitoring Program. A control group of patients who did not see the pharmacist and were managed only by the physician section head was also compared to the group of patients managed by a clinical pharmacist. OUTCOME MEASUREMENTS: The primary outcome measurement evaluates the change in MED values over time. Secondary outcome measurements are to review compliance with annual urine drug screening, documentation of the medication agreement, initiation of nonopioid medications by the pharmacist, and assessment of the access to care for patients with chronic opioid therapy needs. RESULTS: A clinically significant reduction in MED with an average decrease of 207 mg was seen after five or more visits with the pharmacist. The pharmacist initiated nonopioid medications at 209 unique patient visits (19.5%). The pharmacist completed 1197 visits during the study time frame, increasing physician access by at least two additional visits per patient per year. Completion of urine drug screens and medication agreement reviews improved over time (P < .001). There was an increase in MED for patients who did not complete this monitoring, whereas the MED remained stable in patients who did complete the monitoring. CONCLUSIONS: The addition of a clinical pharmacist to an interdisciplinary team managing COT patients resulted in a MED reduction after five or more visits with the pharmacist, improved adherence to best practice standards, optimization of opioid and nonopioid medication therapy, and increased patient access. Developing a role for advanced practitioners, such as clinical pharmacist providers, working with patients on COT can result in significant improvements in patient access to care, adherence to best practice standards, and patient safety. LEVEL OF EVIDENCE: III.

Process improvement for a complex dual medical procedure.

Pancreatic extracorporeal shock wave lithotripsy followed by endoscopic retrograde cholangiopancreatography is accepted worldwide as a treatment for a large, symptomatic, obstructing pancreatic stones. However, timely completion of the combined process requires coordination of equipment and personnel from two different complex procedures. We used Lean management tools in a week-long event to redesign the process around the patient. Using idea-generated Plan Do Study Act cycles to refine the process, from scheduling to postprocedure recovery, equipment and personnel were aligned to allow these two procedures to occur in immediate succession. The redesigned process resulted in all patients receiving both procedures without delay. This eliminated over 8 hours of wait time. Standard work and a newly created complex scheduler improved flow. We reduced the number of anaesthetics for patients without prolonging the procedure length.

Restructuring hospitalist work schedules to improve care timeliness and efficiency.

Background In 2014, we recognised that the pace of admissions frequently exceeded our ability to assign a hospitalist. Long patient wait times occurred at admission, especially for patients arriving in the late afternoon when hospitalist day shifts were ending. Our purpose was to redesign hospitalist schedules, duties and method of distributing admissions to match demand. Design We used administrative data to tabulate Hospital Medicine admission requests by time of day and identified mismatch between volume and capacity with the current staffing model. We determined that we needed to accommodate 29 admits per day with peak admission volume in the late afternoon and early evening. The current staffing model failed after 22 admits. To realign staffing around patient admissions, we organised a series of Lean quality improvements, starting with a 2-day event in July 2014, and followed by a series of Plan-Do-Study-Act (PDSA) cycles. The improvement team included hospitalists, residents and administrators, and each PDSA cycle involved collection of feedback from all affected providers. Strategy At baseline, our hospitalist group had six daytime and two nighttime services, including teaching services and attending-only services. Four of eight services were available for admissions, while four were rounding-only. Admitting capacity (patients per day) was 22. Through three PDSA cycles, we successively adapted our staffing and admitting model until the final staffing model aligned with patient admissions. The final model included different shift start times, use of all 10 shifts for admissions and addition of an Advanced Registered Nurse Practitioner (ARNP) service. Results Admitting capacity increased to 30. We confirmed success with follow-up data on patient wait times. Emergency department mean patient wait times for admission decreased 36% from 66 to 43 min (p<0.001). Conclusion Quantifying admission demand by time of day, then designing work schedules and duties around meeting this demand was an effective approach to reduce patient wait times.

Effectiveness of a multi-component quality improvement intervention on rates of hyperglycaemia.

PURPOSE: To evaluate the effectiveness of a multifaceted, hospital-wide glycaemic control quality improvement programme. METHODS: The quality improvement intervention comprised three components, derived through root cause analysis: standardising and simplifying care (including evidence-based order sets), increasing visibility (through provider access to clinical data and direct feedback) and educational outreach (directed at the entire institution). Effectiveness was determined at a single urban acute care hospital through time-series analysis with statistical process control charts. Primary outcomes included rate of hyperglycaemia and rate of hypoglycaemia. RESULTS: The study included 70 992 hospital admissions for 50 404 patients, with 3 35 645 patient days. The hyperglycaemia ratio decreased 25.2% from 14.1% to 10.5% (95% CI 3.3 to 3.9 percentage points, p<0.001). The ratio of patient days with highly elevated blood glucose (>299 mg/dL) decreased 31.8% from 4.8% to 3.3% (95% CI 1.4 to 1.7 percentage points, p<0.001). Hypoglycaemia ratio decreased from 5.2% to 4.6% (95% CI 0.27 to 0.89 percentage points, p<0.001) in patients with diabetes, but increased in patients without diabetes from 1.2% to 1.7% (95% CI 0.46 to 0.70 percentage points, p<0.001). CONCLUSIONS: We demonstrate improved hospital-wide glycaemic control after a multifaceted quality improvement intervention in the context of strong institutional commitment, national mentorship and Lean management.

Using lean methodology to improve efficiency of electronic order set maintenance in the hospital.

Order sets, a series of orders focused around a diagnosis, condition, or treatment, can reinforce best practice, help eliminate outdated practice, and provide clinical guidance. However, order sets require regular updates as evidence and care processes change. We undertook a quality improvement intervention applying lean methodology to create a systematic process for order set review and maintenance. Root cause analysis revealed challenges with unclear prioritization of requests, lack of coordination between teams, and lack of communication between producers and requestors of order sets. In March of 2014, we implemented a systematic, cyclical order set review process, with a set schedule, defined responsibilities for various stakeholders, formal meetings and communication between stakeholders, and transparency of the process. We first identified and deactivated 89 order sets which were infrequently used. Between March and August 2014, 142 order sets went through the new review process. Processing time for the build duration of order sets decreased from a mean of 79.6 to 43.2 days (p<.001, CI=22.1, 50.7). Applying Lean production principles to the order set review process resulted in significant improvement in processing time and increased quality of orders. As use of order sets and other forms of clinical decision support increase, regular evidence and process updates become more critical.

Scapholunate Interosseous Ligament Tears: Diagnostic Performance of 1.5 T, 3 T MRI, and MR Arthrography-A Systematic Review and Meta-analysis.

RATIONALE AND OBJECTIVES: The study aimed to perform a systematic review and meta-analysis for evaluating the diagnostic accuracy of 1.5 Tesla and 3.0 Tesla magnetic resonance imaging (MRI), and magnetic resonance arthrography (MRA), in the detection of scapholunate interosseous ligament (SLIL) injury. MATERIALS AND METHODS: A literature search was performed (until July 2015) using the PubMed (MEDLINE), Embase, ISI Web of Science, Scopus, and conference proceedings. Original studies evaluating the diagnostic accuracy of MRI or MRA in the detection of SLIL injuries using arthroscopy or open surgery as the reference standard were included. RESULTS: Of the initial 930 published records and 103 conference proceedings, 24 studies (1902 MRI examinations) were included (median SLIL injury prevalence: 33% [interquartile range: 25-42]). Heterogeneity was detected for 1.5 T MRI (chi-square: 47.93, P < 0.001) but not for 3.0 T MRI (chi-square: 8.00, P value: 0.09) and MRA (chi-square: 14.54, P value: 0.34) studies. The sensitivities of 1.5 T MRI, 3.0 T MRI, and MRA for detection of SLIL injury were 45.7% (95% confidence interval: 40.1-51.4), 75.7% (66.8-83.2), and 82.1% (76.1-87.2), respectively. The specificities of 1.5 T MRI, 3.0 T MRI, and MRA for detection of SLIL injury were 80.5% (77.3-83.4), 97.1% (89.8-99.6), and 92.8% (90.2-94.9), respectively. The diagnostic odds ratios of 1.5 T MRI, 3.0 T MRI, and MRA for detection of SLIL injury were 5.56 (2.71-11.39), 23.23 (3.16-171.00), and 65.04 (32.89-128.62) (P value < 0.001), respectively. The results were consistent after addressing publication bias and sensitivity analyses. CONCLUSIONS: MRA is superior to 3.0 T MRI, and 3.0 T MRI is superior to 1.5 T MRI in terms of diagnostic performance. 3.0 T MRI has the highest specificity for the detection of SLIL injuries.

Self-collection of specimens for nucleic acid-based diagnosis of pharyngeal, cervicovaginal, urethral, and rectal Neisseria gonorrhoeae and Chlamydia trachomatis infections.

Commercially available nucleic acid amplification tests (NAATs) for Neisseria gonorrhoeae and Chlamydia trachomatis detection allow for self-collection including home-based collection from multiple anatomic sites such as the urethra, cervicovagina, rectum, and pharynx. Verification studies need to be done prior to processing pharyngeal and rectal specimens. We review specimen collection and test characteristics of NAATs at different anatomical sites.

Targeting FGFR4 inhibits hepatocellular carcinoma in preclinical mouse models.

The fibroblast growth factor (FGF)-FGF receptor (FGFR) signaling system plays critical roles in a variety of normal developmental and physiological processes. It is also well documented that dysregulation of FGF-FGFR signaling may have important roles in tumor development and progression. The FGFR4-FGF19 signaling axis has been implicated in the development of hepatocellular carcinomas (HCCs) in mice, and potentially in humans. In this study, we demonstrate that FGFR4 is required for hepatocarcinogenesis; the progeny of FGF19 transgenic mice, which have previously been shown to develop HCCs, bred with FGFR4 knockout mice fail to develop liver tumors. To further test the importance of FGFR4 in HCC, we developed a blocking anti-FGFR4 monoclonal antibody (LD1). LD1 inhibited: 1) FGF1 and FGF19 binding to FGFR4, 2) FGFR4-mediated signaling, colony formation, and proliferation in vitro, and 3) tumor growth in a preclinical model of liver cancer in vivo. Finally, we show that FGFR4 expression is elevated in several types of cancer, including liver cancer, as compared to normal tissues. These findings suggest a modulatory role for FGFR4 in the development and progression of hepatocellular carcinoma and that FGFR4 may be an important and novel therapeutic target in treating this disease.

Liver-specific activities of FGF19 require Klotho beta.

Hepatocyte function is regulated by members of the fibroblast growth factor (FGF) family of proteins, but little is known about the specific molecular mechanisms of this endocrine pathway. FGF19 regulates bile acid homeostasis and gall bladder filling; FGF19 binds only to FGF receptor 4 (FGFR4), but its liver-specific activity cannot be explained solely by the distribution of this receptor. Although it has been suggested that Klotho beta (KLB) may have a role in mediating FGF19 activity, we have provided for the first time definitive evidence that KLB is required for FGF19 binding to FGFR4, intracellular signaling, and downstream modulation of gene expression. We have shown that FGFR4 is widely distributed in mouse, whereas KLB distribution is more restricted. Liver was the only organ in which both genes were abundantly expressed. We show that in mice, FGF19 injection triggers liver-specific induction of c-Fos and repression of CYP7A1. The tissue-specific activity of FGF19 supports the unique intersection of KLB and FGFR4 distribution in liver. These studies define KLB as a novel FGFR4 coreceptor required for FGF19 liver specific functions.