The who, the what, and the how: A description of strategies and lessons learned to expand access to medications for opioid use disorder in rural America.

Access to treatment for opioid use disorder (OUD) in rural areas within the United States remains a challenge. Providers must complete 8-24 h of training to obtain the Drug Addiction Treatment Act (DATA) 2000 waiver to have the legal authority to prescribe buprenorphine for OUD. Over the last 4 years, we executed five dissemination and implementation grants funded by the Agency for Healthcare Research and Quality to study and address barriers to providing Medications for Opioid Use Disorder Treatment (MOUD), including psychosocial supports, in rural primary care practices in different states. We found that obtaining the DATA 2000 waiver is just one component of meaningful treatment using MOUD, and that the waiver provides a one-time benchmark that often does not address other significant barriers that providers face daily. In this commentary, we summarize our initiatives and the common lessons learned across our grants and offer recommendations on how primary care providers can be better supported to expand access to MOUD in rural America.

Toward Patient-Centered Innovation: A Conceptual Framework for Patient-Reported Outcome Measures for Transformative Kidney Replacement Devices.

Individuals with dialysis-dependent kidney failure experience considerable disease- and treatment-related decline in functional status and overall well-being. Despite these experiences, there have been few substantive technological advances in KRT in decades. As such, new federal initiatives seek to accelerate innovation. Historically, integration of patient perspectives into KRT product development has been limited. However, the US Food and Drug Administration recognizes the importance of incorporating patient perspectives into the total product life cycle (i.e., from product conception to postmarket surveillance) and encourages the consideration of patient-reported outcomes in regulatory-focused clinical trials when appropriate. Recognizing the significance of identifying patient-reported outcome measures (PROMs) that capture contemporary patient priorities, the Kidney Health Initiative, a public-private partnership between the American Society of Nephrology and US Food and Drug Administration, convened a workgroup to (1) develop a conceptual framework for a health-related quality of life PROM; (2) identify and map existing PROMs to the conceptual framework, prioritizing them on the basis of their supporting evidence for use in the regulatory environment; and (3) describe next steps for identifying PROMs for use in regulatory clinical trials of transformative KRT devices. This paper summarizes the proposed health-related quality-of-life PROM conceptual framework, maps and prioritizes PROMs, and identifies gaps and future needs to advance the development of rigorous, meaningful PROMS for use in clinical trials of transformative KRT devices.

Fostering Innovation in Symptom Management among Hemodialysis Patients: Paths Forward for Insomnia, Muscle Cramps, and Fatigue.

Individuals receiving in-center maintenance hemodialysis bear a high burden of both physical and mood symptoms. More than half of patients on hemodialysis report sleep disturbance, muscle cramps, and fatigue. Patients describe symptoms as having a deleterious effect on their quality of life, suggesting that symptom alleviation may meaningfully improve patient-reported outcomes. Moreover, patients on hemodialysis have identified symptom management as a key area for research and innovation, prioritizing symptom alleviation over other health outcomes such as mortality and biochemical indices. Despite the importance of symptoms to patients, there has been little research explicitly geared toward improving patient symptoms, and therefore minimal innovation in symptom management. In general, the physiologic underpinnings of symptoms are poorly understood, hampering the development of targeted therapies. In fact, there have been few drugs or devices approved by the US Food and Drug Administration for the indication of improving any patient-reported outcomes for patients on hemodialysis. Recognizing this gap in innovation, the Kidney Health Initiative, a public-private partnership between the American Society of Nephrology and US Food and Drug Administration, convened a workgroup to first prioritize symptoms for the development of therapeutic interventions, and then identify near-term actionable research goals for the prioritized physical symptoms of insomnia, muscle cramps, and fatigue. This paper summarizes the pathophysiology of the three prioritized symptoms, identifies key knowledge gaps, acknowledges factors that challenge development of new therapies, and offers the nephrology community actionable research goals for insomnia, muscle cramps, and fatigue.

Symptom Prioritization among Adults Receiving In-Center Hemodialysis: A Mixed Methods Study.

BACKGROUND AND OBJECTIVES: Individuals receiving in-center hemodialysis experience a high symptom burden that detrimentally affects their quality of life. There are few evidence-based interventions for symptom relief in this population. To stimulate innovation in symptom management, data on patient symptom prioritization and treatment preferences are needed. We undertook this study to (1) identify patient-prioritized symptoms for the development of symptom relief therapies and (2) elicit preferences for treatments among individuals receiving hemodialysis. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We conducted a mixed methods study that included focus groups in Carrboro, North Carolina; Tucson, Arizona; and Seattle, Washington and a nationally distributed online survey. Focus group transcripts were analyzed for patterns, and the highest priority symptoms were determined on the basis of frequency and report severity. We used focus group findings to inform survey items. Focus group and survey results were crossvalidated and synthesized for final symptom prioritization. RESULTS: There were 32 participants across three focus groups and 87 survey respondents from 27 states in the United States. The physical symptoms of insomnia, fatigue, muscle cramping, and nausea/vomiting and the mood symptoms of anxiety and depressed mood were reported by participants in all focus groups. Among survey respondents, fatigue (94%), cramping (79%), and body aches (76%) were the most common physical symptoms, and feeling depressed (66%), worried (64%), and frustrated (63%) were the most common mood symptoms. The top-prioritized symptoms were consistent across focus group and survey participants and included the physical symptoms insomnia, fatigue, and cramping and the mood symptoms anxiety, depression, and frustration. Participants indicated that symptom frequency, duration, unpredictability, and social and financial effects factored most heavily into symptom prioritization. CONCLUSIONS: Patients prioritized the physical symptoms of insomnia, fatigue, and cramping and the mood symptoms of anxiety, depression, and frustration as the top symptoms for which to find new therapies.

Organizational Readiness to Implement the Chronic Disease Self-Management Program in Dialysis Facilities.

A gap exists between the development and uptake of evidence-based health promotion programs in health care settings. One reason for this gap is lack of attention to organizational readiness. The objective of this study was to assess organizational readiness to implement the Chronic Disease Self-Management Program in dialysis facilities. Survey data were collected from dialysis staff using a semi-structured Organizational Readiness for Implementing Change questionnaire. Change efficacy and change commitment scale ratings were all above 3.0, indicating a moderate level of readiness among staff. Profession and level of education were significantly associated with mean change efficacy scale ratings. Textual data revealed benefits to patients, implementation barriers and facilitators, and the influence of facility environment and culture. The findings of the current study suggest that additional efforts to advance the implementation of evidence-based health promotion programs in dialysis facilities are needed.

The PCORI Engagement Rubric: Promising Practices for Partnering in Research.

PURPOSE: Engaging patients, caregivers, and other health care stakeholders as partners in planning, conducting, and disseminating research is a promising way to improve clinical decision making and outcomes. Many researchers, patients, and other stakeholders, however, lack clarity about when and how to engage as partners within the clinical research process. To address the need for guidance on creating meaningful stakeholder partnerships in patient-centered clinical comparative effectiveness research, the Patient-Centered Outcomes Research Institute (PCORI) developed the PCORI Engagement Rubric (Rubric). METHODS: PCORI developed the Rubric drawing from a synthesis of the literature, a qualitative study with patients, a targeted review of engagement plans from PCORI-funded project applications, and a moderated discussion and review with PCORI's Advisory Panel on Patient Engagement. RESULTS: The Rubric provides a framework for operationalizing engagement to incorporate patients and other stakeholders in all phases of research. It includes: principles of engagement; definitions of stakeholder types; key considerations for planning, conducting, and disseminating engaged research; potential engagement activities; and examples of promising practices from PCORI-funded projects. CONCLUSIONS: PCORI designed the Rubric to illustrate opportunities for engagement to researchers interested in applying for PCORI funding and to patients and other stakeholders interested in greater involvement in research. By encouraging PCORI applicants, awardees, and others to apply the rubric, PCORI hopes to shift the research paradigm from one of conducting research on patients as subjects to a pursuit carried out in collaboration with patients and other stakeholders to better reflect the values, preferences, and outcomes that matter to the patient community.

Health researcher views on comparative effectiveness research and research engagement.

AIM: To understand researcher capability for and interest in patient-centered comparative effectiveness research (PC-CER), particularly related to engaging with patients/caregivers. MATERIALS & METHODS: Web-based survey of 508 health researchers recruited via professional health research organizations. RESULTS: Most respondents (94%) were familiar with CER and many (69%) reported having previously conducting some form of CER. Most respondents were familiar with (81%) and interested in (87%) partnering with patients and/or caregivers in research. Resources to assist in training, coordination of partners, guidance in apply for funding and improved infrastructure were commonly cited factors that would help researchers conduct PC-CER. CONCLUSION: There is a significant opportunity for researchers to engage patients and caregivers as partners in CER. Researchers recognize the need for additional training and expertise to leverage those opportunities.

Patient, caregiver and clinician use of comparative effectiveness research findings in care decisions: results from a national study.

AIM: To assess awareness, use and attitudes concerning comparative effectiveness research (CER) findings. MATERIALS & METHODS: Online surveys of patients and caregivers managing rare (n = 560 patients, n = 609 caregivers) or chronic conditions (n = 762 patients, n = 776 caregivers), and practicing clinicians (n = 638). RESULTS: Less than half of patients and caregivers reported exposure to any type of CER findings in the past 12 months. Of those, over half identify healthcare professionals as the information source, yet only 10% of clinicians indicated they were 'very familiar' with CER. Clinicians were concerned about the time required to find relevant evidence and the appropriateness of comparisons in available health research. CONCLUSION: Clinicians, patients and caregivers indicate unmet need for incorporating CER research findings into clinical decision-making.

Patient, caregiver and clinician views on engagement in comparative effectiveness research.

AIM: Describe patient, caregiver and clinician views toward engagement as partners in health research. MATERIALS & METHODS: Online surveys of patients and caregivers managing rare (n = 560 patients, n = 609 caregivers) or chronic conditions (n = 762 patients, n = 776 caregivers) and practicing clinicians (n = 638). RESULTS: Over half of respondents were unfamiliar with the concept of partnering with researchers but most expressed interest in working in a research partnership. Potential facilitators endorsed were ensuring research is meaningful, applying results in an understandable way, and sharing results. Lack of time is a potential barrier. Clinicians were most interested in helping researchers decide on intervention comparisons and identifying implications for clinical practice. CONCLUSION: Patients, caregivers and clinicians are interested in research roles that emphasize usefulness and understandability of research.

Multiple Chronic Conditions, Resilience, and Workforce Transitions in Later Life: A Socio-Ecological Model.

Purpose of the Study: Despite the growing prevalence of multiple chronic conditions (MCC), a problem that disproportionally affects older adults, few studies have examined the impact of MCC status on changes in workforce participation in later life. Recent research suggests that resilience, the ability to recover from adversity, may buffer the negative impact of chronic disease. Guided by an adapted socio-ecological risk and resilience conceptual model, this study examined the buffering effect of resilience on the relationship between individual and contextual risks, including MCC, and workforce transitions (i.e., leaving the workforce, working fewer hours, working the same hours, or working more hours). Design and Methods: Using the Health and Retirement Study, this study pooled a sample of 4,861 older workers aged 51 and older with 2 consecutive biannual waves of data. Nonnested multinomial logistic regression analysis was applied. Results: MCC are related to higher risk of transitioning out of the workforce. Resilience buffered the negative effects of MCC on workforce engagement and remained independently associated with increased probability of working the same or more hours compared with leaving work. Implications: MCC are associated with movement out of the paid workforce in later life. Despite the challenges MCC impose on older workers, having higher levels of resilience may provide the psychological resources needed to sustain work engagement in the face of new deficits. These findings suggest that identifying ways to bolster resilience may enhance the longevity of productive workforce engagement.

Wishes left unspoken: engaging underserved populations in end-of-life advance care planning.

The end of life can be a highly emotional and difficult time for patients and their families. Advance care planning for end-of-life care is one option for helping to mitigate the burden of this experience. Despite its advantages, gaps in end-of-life advance care planning participation persist, particularly among underserved segments of the U.S. population who might benefit from it. This column highlights barriers to end-of-life advance care planning among medically underserved populations and discusses opportunities for greater engagement.

Social justice, health disparities, and culture in the care of the elderly.

Older minority Americans experience worse health outcomes than their white counterparts, exhibiting the need for social justice in all areas of their health care. Justice, fairness, and equity are crucial to minimizing conditions that adversely affect the health of individuals and communities. In this paper, Alzheimer's disease (AD) is used as an example of a health care disparity among elderly Americans that requires social justice interventions. Cultural factors play a crucial role in AD screening, diagnosis, and access to care, and are often a barrier to support and equality for minority communities. The "conundrum of health disparities" refers to the interplay between disparity, social justice, and cultural interpretation, and encourages researchers to understand both (1) disparity caused by economic and structural barriers to access, treatment, and diagnosis, and (2) disparity due to cultural interpretation of disease, in order to effectively address health care issues and concerns among elderly Americans.

CYP2C9 genotype and pharmacodynamic responses to losartan in patients with primary and secondary kidney diseases.

BACKGROUND: Losartan is used for anti-proteinuric as well as blood pressure effects in chronic kidney disease (CKD). It is metabolized by cytochrome P450 (CYP) 2C9 to active E-3174. Single nucleotide polymorphisms in CYP2C9 that reduce catalytic activity could reduce clinical benefits. AIM: The study aims were to determine whether CYP2C9 variant alleles (*2 and *3) altered urinary protein excretion, glomerular filtration rate, and blood pressure in Caucasian patients prescribed losartan. METHODS: Differences between baseline and 6-month follow-up outcomes were compared by CYP2C9 genotypes in 59 patients using unpaired t test or Mann-Whitney U test. RESULTS: Primary renal disease patients had a trend toward less favorable antiproteinuric response (-31.7 +/- 156 vs. -125 +/- 323%; p = 0.123) when carrying variant alleles. Patients with secondary renal diseases had less favorable diastolic blood pressure (9.8 +/- 16.0 vs. -3.2 +/- 10.6 mmHg; p = 0.043) and systolic blood pressure (16.2 +/- 27.1 vs. -5.5 +/- 17.5 mmHg; p = 0.044) with CYP2C9 variants. CONCLUSION: These preliminary results suggest a possible influence of CYP2C9 genotype on proteinuria and blood pressure in Caucasian CKD patients treated with losartan.

Influence of clinical and demographic variables on mycophenolic acid pharmacokinetics in antineutrophil cytoplasmic antibody-associated vasculitis.

BACKGROUND: Mycophenolic acid (MPA) is used off-label to treat many forms of glomerulonephritis. OBJECTIVE: To evaluate the pharmacokinetics of MPA and its glucuronide (MPAG) in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis patients with renal manifestations and to determine the effects of clinical (urinary protein excretion, serum albumin, creatinine clearance) and demographic (age, race, sex) variables on MPA and MPAG pharmacokinetics. METHODS: Twenty-three patients taking MPA at steady-state were evaluated. Plasma and urine samples were collected over 24 hours. Analyses included noncompartmental pharmacokinetics and statistics including Mann-Whitney U test and univariate/multiple regression. RESULTS: MPA clearance (Cl/F 288 +/- 154 mL/min) was approximately 2-fold higher than previously reported from transplant patients and predicted by weight and race (ranked MPA Cl/F = -11.766 + 0.2035 [wt] + 4.9578 [race]; R(2) 41.8%; p = 0.005). Creatinine clearance (CrCl) less than 60 mL/min resulted in higher MPA exposure, total area under the curve (AUC)(0-12), and AUC(6-12), as well as unbound AUC(0-12). The metabolic ratio (MPAG(AUC)/MPA(AUC)) of 8.67 +/- 5.57 was lower than that previously reported in renal transplant recipients. CONCLUSIONS: Diminished kidney function (eg, CrCl <60 mL/min) demonstrated enhanced MPA and MPAG exposure in patients with ANCA vasculitis. However, unlike renal transplant recipients, patients with ANCA vasculitis had enhanced Cl/F and diminished metabolic ratio, suggesting the need to comprehensively evaluate the role of disease-specific factors on MPA pharmacokinetics.

Pharmacokinetics of mycophenolic acid in patients with lupus nephritis.

STUDY OBJECTIVES: To evaluate and describe the pharmacokinetics of mycophenolic acid and its metabolite, mycophenolic acid glucuronide (MPAG), in patients with lupus nephritis, and to determine the effects of clinical parameters (urinary protein excretion as measured by the urinary protein:creatinine ratio, serum albumin level, and creatinine clearance) and demographic variables (age, race, sex) on the pharmacokinetics of total and unbound mycophenolic acid and MPAG. DESIGN: Pharmacokinetic analysis. SETTING: University-affiliated general clinical research center. PATIENTS: Eighteen patients with biopsy-confirmed lupus nephritis who were receiving maintenance therapy with mycophenolic acid for at least 2 weeks. INTERVENTION: Plasma and urine samples were collected for 24 hours and were assayed by high-performance liquid chromatography with ultraviolet detection. MEASUREMENTS AND MAIN RESULTS: Time to maximum concentration was variable (0.5-8 hrs). Mean +/- SD fraction of unbound mycophenolic acid was 2.6 +/- 1.9%, and oral clearance (Cl/F) was about 2-fold higher (343 +/- 200 ml/min) than previously reported. Multiple regression analysis showed that Cl/F of mycophenolic acid was predicted by creatinine clearance and serum albumin level: ln Cl/F = 5.358 + 0.0092 (creatinine clearance) - 0.078 (ranked albumin), R(2)=51.1%, p=0.0195. Patients with urinary protein excretion of 1 g/day or higher had lower minimum (trough) concentrations and area under the concentration-time curve (AUC(0-12)) profiles and higher Cl/F values compared with patients with urinary protein excretion of less than 1 g/day. Patients with serum albumin levels less than 4 g/dl had higher mycophenolic acid unbound clearance and MPAG renal clearance from 0-12 hours versus those with serum albumin levels of 4 g/dl or greater. Recycling AUC (AUC(6-12)), as well as sex and age (both equally), predicted renal clearance of MPAG. CONCLUSION: Both creatinine clearance and serum albumin level were identified as primary contributors to mycophenolic acid exposure and should be considered when evaluating dosages. The results of future studies should clarify the interactions of other variables on drug exposure and treatment responses. Clinicians need to be mindful of clinical changes that occur throughout the course of lupus nephritis in order to maintain efficacy and reduce toxicity from mycophenolic acid therapy.