ACR Appropriateness Criteria® Screening for Abdominal Aortic Aneurysm.

Abdominal aortic aneurysm (AAA) is a significant vascular disease found in 4% to 8% of the screening population. If ruptured, its mortality rate is between 75% and 90%, and it accounts for up to 5% of sudden deaths in the United States. Therefore, screening of AAA while asymptomatic has been a crucial portion of preventive health care worldwide. Ultrasound of the abdominal aorta is the primary imaging modality for screening of AAA recommended for asymptomatic adults regardless of their family history or smoking history. Alternatively, duplex ultrasound and CT abdomen and pelvis without contrast may be appropriate for screening. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision process support the systematic analysis of the medical literature from peer reviewed journals. Established methodology principles such as Grading of Recommendations Assessment, Development, and Evaluation or GRADE are adapted to evaluate the evidence. The RAND/UCLA Appropriateness Method User Manual provides the methodology to determine the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where peer reviewed literature is lacking or equivocal, experts may be the primary evidentiary source available to formulate a recommendation.

ACR Appropriateness Criteria® Dizziness and Ataxia: 2023 Update.

Diagnostic evaluation of a patient with dizziness or vertigo is complicated by a lack of standardized nomenclature, significant overlap in symptom descriptions, and the subjective nature of the patient's symptoms. Although dizziness is an imprecise term often used by patients to describe a feeling of being off-balance, in many cases dizziness can be subcategorized based on symptomatology as vertigo (false sense of motion or spinning), disequilibrium (imbalance with gait instability), presyncope (nearly fainting or blacking out), or lightheadedness (nonspecific). As such, current diagnostic paradigms focus on timing, triggers, and associated symptoms rather than subjective descriptions of dizziness type. Regardless, these factors complicate the selection of appropriate diagnostic imaging in patients presenting with dizziness or vertigo. This document serves to aid providers in this selection by using a framework of definable clinical variants. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision process support the systematic analysis of the medical literature from peer reviewed journals. Established methodology principles such as Grading of Recommendations Assessment, Development, and Evaluation or GRADE are adapted to evaluate the evidence. The RAND/UCLA Appropriateness Method User Manual provides the methodology to determine the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where peer reviewed literature is lacking or equivocal, experts may be the primary evidentiary source available to formulate a recommendation.

Use of unattended automated office blood pressure in Utah primary care clinics.

AIM: Unattended automated office blood pressure (BP) measurement (u-AOBP) improves office BP measurement accuracy and reduces white-coat BP elevation. u-AOBP is recommended as the preferred office BP measurement technique by multiple hypertension guidelines. This study examines utilization, performance, and potential barriers to implementation of u-AOBP in Utah primary care clinics following 5 years of promotional efforts by the Utah Million Hearts Coalition (UMHC). METHODS: An online questionnaire was administered to 285 Utah primary care clinics to evaluate self-reported use of u-AOBP and u-AOBP technique, interpretation of results, and perceived barriers to implementation. RESULTS: Seventy-nine of 285 clinics (27.7%) completed the full questionnaire. Fifty-nine clinics (74.7%) use u-AOBP. Nearly 65% first learned about u-AOBP through UMHC promotional efforts rather than from the medical literature. One-half of these clinics noted no significant barriers to u-AOBP implementation, and over 80% noted no reduction in medical staff productivity. However, important knowledge deficits concerning correct u-AOBP performance and interpretation of results were apparent from answers to the questionnaire. CONCLUSION: After 5 years of UMHC promotional efforts, at least 20% of the 285 Utah primary care clinics invited to take the questionnaire and 75% of the 79 clinics completing the survey have incorporated u-AOBP and found it feasible in a primary care setting. Ongoing promotion of u-AOBP implementation at the local and regional level is required to extend its utilization. Effective, accessible educational materials and local technical assistance from public health and community partners are needed to correct knowledge and performance deficits to optimize u-AOBP utilization in primary care.

Diagnosing Hypertension in Primary Care Clinics According to Current Guidelines.

PURPOSE: This descriptive study examines hypertension diagnostic practices in Utah primary care clinics relative to the 2015 US Preventive Services Task Force (USPSTF) recommendations for the accurate diagnosis of hypertension. We assessed clinic procedures in place to facilitate accurate in-office and out-of-office blood pressure (BP) measurement. METHODS: An online questionnaire was administered to 321 primary care clinics. We compared current clinic BP measurement practices with the USPTF recommendations and assessed the level of adherence to the recommendations by level of clinic integration with a hospital. RESULTS: Of the 321 primary care clinics that received the assessment, 123 (38.3%) completed the questionnaire. Clinics varied significantly in their ability to provide accurate in-office measurement, ranging from 57.5% to 93.5% of clinics complying with USPSTF recommendations. Only 25.2% of clinics reported having access to ambulatory monitoring and 36.6% had instructional materials for accurate home BP monitoring. Clinics integrated with a hospital were more likely to report adherence to recommendations than solo or independent clinics (36.4% vs 10.5%; P < .01). CONCLUSION: This assessment shows that many primary care clinics are not well prepared to implement the USPSTF guidelines for accurate diagnosis of hypertension. Most office practices will benefit from support to develop their capacities.

A Fibroblast Growth Factor 21-Pregnane X Receptor Pathway Downregulates Hepatic CYP3A4 in Nonalcoholic Fatty Liver Disease.

Nonalcoholic fatty liver disease (NAFLD) alters drug response. We previously reported that NAFLD is associated with reduced in vivo CYP3A drug-metabolism activity and hepatic CYP3A4 expression in humans as well as mouse and human hepatoma models of the disease. Here, we investigated the role of the lipid- and glucose-modulating hormone fibroblast growth factor 21 (FGF21) in the molecular mechanism regulating CYP3A4 expression in NAFLD. In human subjects, mouse and cellular NAFLD models with lower CYP3A4 expression, circulating FGF21, or hepatic FGF21 mRNA levels were elevated. Administration of recombinant FGF21 or transient hepatic overexpression of FGF21 resulted in reduced liver CYP3A4 luciferase reporter activity in mice and decreased CYP3A4 mRNA expression and activity in cultured Huh7 hepatoma cells. Blocking canonical FGF21 signaling by pharmacological inhibition of MEK1 kinase in Huh7 cells caused de-repression of CYP3A4 mRNA expression with FGF21 treatment. Mice with high-fat diet-induced simple hepatic steatosis and lipid-loaded Huh7 cells had reduced nuclear localization of the pregnane X receptor (PXR), a key transcriptional regulator of CYP3A4 Furthermore, decreased nuclear PXR was observed in mouse liver and Huh7 cells after FGF21 treatment or FGF21 overexpression. Decreased PXR binding to the CYP3A4 proximal promoter was found in FGF21-treated Huh7 cells. An FGF21-PXR signaling pathway may be involved in decreased hepatic CYP3A4 metabolic activity in NAFLD.

Relationships between Endogenous Plasma Biomarkers of Constitutive Cytochrome P450 3A Activity and Single-Time-Point Oral Midazolam Microdose Phenotype in Healthy Subjects.

Due to high basal interindividual variation in cytochrome P450 3A (CYP3A) activity and susceptibility to drug interactions, there has been interest in the application of efficient probe drug phenotyping strategies, as well as endogenous biomarkers for assessment of in vivo CYP3A activity. The biomarkers 4ß-hydroxycholesterol (4ßHC) and 6ß-hydroxycortisol (6ßHCL) are sensitive to CYP3A induction and inhibition. However, their utility for the assessment of constitutive CYP3A activity remains uncertain. We investigated whether endogenous plasma biomarkers (4ßHC and 6ßHCL) are associated with basal CYP3A metabolic activity in healthy subjects assessed by a convenient single-time-point oral midazolam (MDZ) phenotyping strategy. Plasma 4ßHC and 6ßHCL metabolic ratios (MRs) were analysed in 51 healthy adult participants. CYP3A activity was determined after administration of an oral MDZ microdose (100 µg). Simple linear and multiple linear regression analyses were performed to assess relationships between MDZ oral clearance, biomarkers and subject covariates. Among study subjects, basal MDZ oral clearance, 4ßHC and 6ßHCL MRs ranged 6.5-, 10- and 13-fold, respectively. Participant age and alcohol consumption were negatively associated with MDZ oral clearance (p = 0.03 and p = 0.045, respectively), while weight and female sex were associated with lower plasma 4ßHC MR (p = 0.0003 and p = 0.032, respectively). Neither 4ßHC nor 6ßHCL MRs were associated with MDZ oral clearance. Plasma 4ßHC and 6ßHCL MRs do not relate to MDZ single-time-point metabolic phenotype in the assessment of constitutive CYP3A activity among healthy individuals.

Pharmacist-provided diabetes management and education via a telemonitoring program.

OBJECTIVE: To assess clinical outcomes (glycosylated hemoglobin [A1C], blood pressure, and lipids) and other measurements (disease state knowledge, adherence, and self-efficacy) associated with the use of approved telemonitoring devices to expand and improve chronic disease management of patients with diabetes, with or without hypertension. SETTING: Four community health centers (CHCs) in Utah. PRACTICE DESCRIPTION: Federally qualified safety net clinics that provide medical care to underserved patients. PRACTICE INNOVATION: Pharmacist-led diabetes management using telemonitoring was compared with a group of patients receiving usual care (without telemonitoring). INTERVENTIONS: Daily blood glucose (BG) and blood pressure (BP) values were reviewed and the pharmacist provided phone follow-up to assess and manage out-of-range BG and BP values. EVALUATION: Changes in A1C, BP, and low-density lipoprotein (LDL) at approximately 6 months were compared between the telemonitoring group and the usual care group. Patient activation, diabetes/hypertension knowledge, and medication adherence were measured in the telemonitoring group. RESULTS: Of 150 patients, 75 received pharmacist-provided diabetes management and education via telemonitoring, and 75 received usual medical care. Change in A1C was significantly greater in the telemonitoring group compared with the usual care group (2.07% decrease vs. 0.66% decrease; P <0.001). Although BP and LDL levels also declined, differences between the two groups were not statistically significant. Patient activation measure, diabetes/hypertension knowledge, and medication adherence with antihypertensives (but not diabetes medications) improved in the telemonitoring group. CONCLUSION: Pharmacist-provided diabetes management via telemonitoring resulted in a significant improvement in A1C in federally qualified CHCs in Utah compared with usual medical care. Telemonitoring may be considered a model for providing clinical pharmacy services to patients with diabetes.

CYP3A Activity and Expression in Nonalcoholic Fatty Liver Disease.

Nonalcoholic fatty liver disease (NAFLD) is the leading cause of liver disease in the Western world, given its association with obesity, type 2 diabetes, and dyslipidemia. Medications are widely used in NAFLD to manage comorbid conditions, and there is significant interest in developing new drug therapies to treat the disease. Despite this, little is known about the effects of NAFLD on drug metabolism. We examined the activity and expression of the major drug-metabolizing enzyme subfamily, CYP3A, in subjects with NAFLD as well as in mouse and cellular models. CYP3A activity was determined in healthy volunteers and subjects with biopsy-proven NAFLD by oral midazolam phenotyping and measurement of plasma 4ß-hydroxycholesterol, an endogenous metabolic biomarker. CYP3A4 transcriptional activity, metabolic activity, and expression were also assessed in a mouse and cellular model of NAFLD. Subjects with nonalcoholic steatohepatitis (NASH) had 2.4-fold higher plasma midazolam levels compared with controls. Plasma 4ß-hydroxycholesterol was 51% and 37% lower than controls in subjects with simple steatosis and NASH, respectively. Fibrosis was associated with 57% lower plasma 4ß-hydroxycholesterol levels than controls. Furthermore, hepatic CYP3A4 mRNA expression in NASH was 69% lower than control livers. CYP3A4 gene luciferase activity in the livers of NAFLD mice was 38% lower than that of controls. Lipid-loaded Huh7 human hepatoma cells had a 38% reduction in CYP3A4 activity and 80% lower CYP3A4 mRNA expression compared with the control. CYP3A activity is reduced in human NAFLD in addition to mouse and in vitro cell models of the disease.

Trimethylamine-N-oxide: A Novel Biomarker for the Identification of Inflammatory Bowel Disease.

BACKGROUND: The gastrointestinal (GI) microbiome is recognized for potential clinical relevance in inflammatory bowel disease (IBD). Data suggest that there is a disease-dependent loss of microbial diversity in IBD. Trimethylamine-N-oxide (TMAO) is generated by GI anaerobes through the digestion of dietary phosphatidylcholine and carnitine in a microbial-mammalian co-metabolic pathway. IBD-related changes in the gut microbiome may result in disease-specific changes in TMAO plasma concentrations. AIM: To determine whether TMAO plasma levels in IBD are altered compared to controls and whether they correlate with disease presence or activity. METHODS: Liquid chromatography-tandem mass spectrometry was used to measure TMAO, choline, and carnitine plasma levels in 479 subjects (373 non-IBD controls, 106 IBD). Subjects were also genotyped for the flavin monooxygenase (FMO)3 variants, E158K and E308G. RESULTS: Plasma TMAO levels were 2.27 µM lower in the IBD population compared to the control population (p = 0.0001). Lower TMAO levels were similarly seen in active ulcerative colitis (UC) (1.56 µM) versus inactive disease (3.40 µM) (p = 0.002). No difference was seen in active Crohn's disease (CD) versus inactive CD. No intergroup variation existed in plasma TMAO levels based on FMO3 genotype. Choline levels were higher in IBD, while carnitine levels were similar between the two groups, suggesting that lower TMAO levels in IBD were not due to dietary differences. CONCLUSIONS: Decreased TMAO levels are seen in IBD compared to a non-IBD population. These data suggest that TMAO may have potential as a biomarker to support IBD diagnosis as well as to assess disease activity in UC.

Going mobile with diabetes support: a randomized study of a text message-based personalized behavioral intervention for type 2 diabetes self-care.

Objective. Patients with type 2 diabetes often fail to achieve self-management goals. This study tested the impact on glycemic control of a two-way text messaging program that provided behavioral coaching, education, and testing reminders to enrolled individuals with type 2 diabetes in the context of a clinic-based quality improvement initiative. The secondary aim examined patient interaction and satisfaction with the program. Methods. Ninety-three adult patients with poorly controlled type 2 diabetes (A1C >8%) were recruited from 18 primary care clinics in three counties for a 6-month study. Patients were randomized by a computer to one of two arms. Patients in both groups continued with their usual care; patients assigned to the intervention arm also received from one to seven diabetes-related text messages per day depending on the choices they made at enrollment. At 90 and 180 days, A1C data were obtained from the electronic health record and analyzed to determine changes from baseline for both groups. An exit survey was used to assess satisfaction. Enrollment behavior and interaction data were pulled from a Web-based administrative portal maintained by the technology vendor. Results. Patients used the program in a variety of ways. Twenty-nine percent of program users demonstrated frequent engagement (texting responses at least three times per week) for a period of ≥90 days. Survey results indicate very high satisfaction with the program. Both groups' average A1C decreased from baseline, possibly reflecting a broader quality improvement effort underway in participating clinics. At 90 and 180 days, there was no statistically significant difference between the intervention and control groups in terms of change in A1C (P >0.05). Conclusions. This study demonstrated a practical approach to implementing and monitoring a mobile health intervention for self-management support across a wide range of independent clinic practices.

Use of transgenic mouse models to understand the oral disposition and drug-drug interaction potential of cobimetinib, a MEK inhibitor.

Data from the clinical absolute bioavailability (F) study with cobimetinib suggested that F was lower than predicted based on its low hepatic extraction and good absorption. The CYP3A4 transgenic (Tg) mouse model with differential expression of CYP3A4 in the liver (Cyp3a(-/-)Tg-3A4Hep) or intestine (Cyp3a(-/-)Tg-3A4Int) and both liver and intestine (Cyp3a(-/-)Tg-3A4Hep/Int) were used to study the contribution of intestinal metabolism to the F of cobimetinib. In addition, the effect of CYP3A4 inhibition and induction on cobimetinib exposures was tested in the Cyp3a(-/-)Tg-3A4Hep/Int and PXR-CAR-CYP3A4/CYP3A7 mouse models, respectively. After i.v. administration of 1 mg/kg cobimetinib to wild-type [(WT) FVB], Cyp3a(-/-)Tg-3A4Hep, Cyp3a(-/-)Tg-3A4Int, or Cyp3a(-/-)Tg-3A4Hep/Int mice, clearance (CL) (26-35 ml/min/kg) was similar in the CYP3A4 transgenic and WT mice. After oral administration of 5 mg/kg cobimetinib, the area under the curve (AUC) values of cobimetinib in WT, Cyp3a(-/-)Tg-3A4Hep, Cyp3a(-/-)Tg-3A4Int, or Cyp3a(-/-)Tg-3A4Hep/Int mice were 1.35, 3.39, 1.04, and 0.701 µM⋅h, respectively. The approximately 80% lower AUC of cobimetinib in transgenic mice when intestinal CYP3A4 was present suggested that the intestinal first pass contributed to the oral CL of cobimetinib. Oxidative metabolites observed in human circulation were also observed in the transgenic mice. In drug-drug interaction (DDI) studies using Cyp3a(-/-)Tg-3A4Hep/Int mice, 8- and 4-fold increases in oral and i.v. cobimetinib exposure, respectively, were observed with itraconazole co-administration. In PXR-CAR-CYP3A4/CYP3A7 mice, rifampin induction decreased cobimetinib oral exposure by approximately 80%. Collectively, these data support the conclusion that CYP3A4 intestinal metabolism contributes to the oral disposition of cobimetinib and suggest that under certain circumstances the transgenic model may be useful in predicting clinical DDIs.

The Utah Remote Monitoring Project: improving health care one patient at a time.

BACKGROUND: The expanding role of technology to augment diabetes care and management highlights the need for clinicians to learn about these new tools. As these tools continue to evolve and enhance improved outcomes, it is imperative that clinicians consider the role of telemonitoring, or remote monitoring, in patient care. This article describes a successful telemonitoring project in Utah. SUBJECTS AND METHODS: This was a nonrandomized prospective observational preintervention-postintervention study, using a convenience sample. Patients with uncontrolled diabetes and/or hypertension from four rural and two urban primary care clinics and one urban stroke center participated in a telemonitoring program. The primary clinical outcome measures were changes in hemoglobin A1C (A1C) and blood pressure. Other outcomes included fasting lipids, weight, patient engagement, diabetes knowledge, hypertension knowledge, medication adherence, and patient perceptions of the usefulness of the telemonitoring program. RESULTS: Mean A1C decreased from 9.73% at baseline to 7.81% at the end of the program (P<0.0001). Systolic blood pressure also declined significantly, from 130.7 mm Hg at baseline to 122.9 mm Hg at the end (P=0.0001). Low-density lipoprotein content decreased significantly, from 103.9 mg/dL at baseline to 93.7 mg/dL at the end (P=0.0263). Other clinical parameters improved nonsignificantly. Knowledge of diabetes and hypertension increased significantly (P<0.001 for both). Patient engagement and medication adherence also improved, but not significantly. Per questionnaires at study end, patients felt the telemonitoring program was useful. CONCLUSIONS: Telemonitoring improved clinical outcomes and may be a useful tool to help enhance disease management and care of patients with diabetes and/or hypertension.

The utah beacon experience: integrating quality improvement, health information technology, and practice facilitation to improve diabetes outcomes in small health care facilities.

PURPOSE: The Utah Improving Care through Connectivity and Collaboration (IC3) Beacon community (2010-2013) was spearheaded by HealthInsight, a nonprofit, community-based organization. One of the main objectives of IC(3) was to improve health care provided to patients with diabetes in three Utah counties, collaborating with 21 independent smaller clinics and two large health care enterprises. This paper will focus on the use of health information technology (HIT) and practice facilitation to develop and implement new care processes to improve clinic workflow and ultimately improve patients' diabetes outcomes at 21 participating smaller, independent clinics. INNOVATION: Early in the project, we learned that most of the 21 clinics did not have the resources needed to successfully implement quality improvement (QI) initiatives. IC(3) helped clinics effectively use data generated from their electronic health records (EHRs) to design and implement interventions to improve patients' diabetes outcomes. This close coupling of HIT, expert practice facilitation, and Learning Collaboratives was found to be especially valuable in clinics with limited resources. FINDINGS: Through this process we learned that (1) an extensive readiness assessment improved clinic retention, (2) clinic champions were important for a successful collaboration, and (3) current EHR systems have limited functionality to assist in QI initiatives. In general, smaller, independent clinics lack knowledge and experience with QI and have limited HIT experience to improve patient care using electronic clinical data. Additionally, future projects like IC(3) Beacon will be instrumental in changing clinic culture so that QI is integrated into routine workflow. CONCLUSION AND DISCUSSION: Our efforts led to significant changes in how practice staff optimized their EHRs to manage and improve diabetes care, while establishing the framework for sustainability. Some of the IC(3) Beacon practices are currently smoothly transitioning to new models of care such as Patient-Centered Medical Homes. Thus, IC(3) Beacon has been instrumental in creating a strong community partnership among various organizations to meet the shared vision of better health and lower costs, and the experience over the last few years has helped the community prepare for the changing health care landscape.

Clarifying the importance of CYP2C19 and PON1 in the mechanism of clopidogrel bioactivation and in vivo antiplatelet response.

AIMS: It is thought that clopidogrel bioactivation and antiplatelet response are related to cytochrome P450 2C19 (CYP2C19). However, a recent study challenged this notion by proposing CYP2C19 as wholly irrelevant, while identifying paraoxonase-1 (PON1) and its Q192R polymorphism as the major driver of clopidogrel bioactivation and efficacy. The aim of this study was to systematically elucidate the mechanism and relative contribution of PON1 in comparison to CYP2C19 to clopidogrel bioactivation and antiplatelet response. METHODS AND RESULTS: First, the influence of CYP2C19 and PON1 polymorphisms and plasma paraoxonase activity on clopidogrel active metabolite (H4) levels and antiplatelet response was assessed in a cohort of healthy subjects (n = 21) after administration of a single 75 mg dose of clopidogrel. There was a remarkably good correlation between H4 AUC (0-8 h) and antiplatelet response (r2 = 0.78). Furthermore, CYP2C19 but not PON1 genotype was predictive of H4 levels and antiplatelet response. There was no correlation between plasma paraoxonase activity and H4 levels. Secondly, metabolic profiling of clopidogrel in vitro confirmed the role of CYP2C19 in bioactivating clopidogrel to H4. However, heterologous expression of PON1 in cell-based systems revealed that PON1 cannot generate H4, but mediates the formation of another thiol metabolite, termed Endo. Importantly, Endo plasma levels in humans are nearly 20-fold lower than H4 and was not associated with any antiplatelet response. CONCLUSION: Our results demonstrate that PON1 does not mediate clopidogrel active metabolite formation or antiplatelet action, while CYP2C19 activity and genotype remains a predictor of clopidogrel pharmacokinetics and antiplatelet response.

Removal of sample background buffering ions and myoglobin enrichment via a pH junction created by discontinuous buffers in capillary electrophoresis.

Traditional CE sample stacking is ineffective for samples containing a high concentration of salt and/or buffer. We recently reported the use of a discontinuous buffer system for protein enrichment that was applicable to samples containing millimolar concentrations of salt. In this paper, the technique was investigated for samples containing unwanted buffering ions, including TRIS, MES, and phosphate, which are commonly used in biological sample preparation. Using myoglobin as a model protein, the results demonstrated that background buffering ions can be effectively removed or separated from the enriched protein. The key is to use either the acid or the base of the discontinuous buffers to adjust the pH of the sample, such that the net charge of the unwanted buffering ions is near-zero. The successful isolation and enrichment of myoglobin from up to 100 mM TRIS and 50 mM MES was demonstrated. The enrichment factors remained at approximately 200. Removal of phosphate was more challenging because its net charge was anionic in both the acid and the base of the discontinuous buffers. The enrichment was only achievable up to 30 mM of sodium phosphate, the enrichment factors observed were significantly lower, below 50, and the process was delayed due to the higher ionic strength resulted from phosphate. The migration of phosphate during enrichment was studied using a UV-absorbing analogue, phenyl phosphate. In addition, Simul 5.0 was used to simulate the discontinuous buffers in the absence and presence of TRIS and phosphate. The stimulated TRIS and phosphate concentration profiles were generally in agreement with the experimental results. The simulation also provided a better understanding on the effect of phosphate on the formation of the pH junction.