2007-2008 Core Research

[ Improving Medication Adherence in Comorbid Conditions] [ Cognitive Impairment Related to Anastrozole Use in Women ] [ Preference and Vegetarian Diet in Weight Loss Treatment ]
[ Reproductive Health Intervention for Teen Girls with Diabetes ]
[ Psychiatric Morbidity Late Post Heart Transplant ] [ A Randomized Controlled Trial of the NIA Intervention ] [ Improving Adherence to Antiretroviral Therapy ]
[ Understanding the Process of Medication Taking in Persons with Alzheimer’s Disease ]
[ Improving Communication with NonSpeaking ICU Patients ] [ Enhancing Exercise Participation in Overweight Women ] [ Biobehavioral Factors in Atherosclerotic Progression ]
[ Treating Family Caregivers to Late-Life Depression Patients ] [ Medication Adherence in Young Adults with Schizophrenia Using Relational Agent Technology ] [ Disparate MBC Symptom Severity and Management Barriers ] [ Diabetic Children Grow Up: Cognitive Complications ]
[ Improving Physical Activity in Comorbidity ]
[ Beliefs and Preferences About Participation in Clinical ] [ Caregiver Intervention for Caregivers of SCI Patients ] [ Personality and Medication Adherence in Transplantation ] [ Adherence and Health Outcomes after Liver Transplantation ] [ Sleep and Health: Influence of Hemodialysis ]
[ Cardiovascular Disease in Rheumatoid Arthritis ]

• Improving Medication Adherence in Comorbid Conditions Jacqueline Dunbar-Jacob, PhD, RN, (PI) School of Nursing
  • During this study year we have completed recruitment and are focusing on follow-up of the remaining participants. In addition we have been maintaining data entry, editing and checking data, and quality assurance of procedures and data. In spite of our delayed start and recruitment challenges early on, we have been successful at achieving, and slightly surpassing our goal of 198 poor adherers in the study. We have screened 358 participants in the study. Of these, 320 completed screening and were assigned to study groups. Specifically, we have 118 participants in the Good Adherers arm of the study, and 202 in the Poor Adherers arm of the study. Two hundred and forty four of our participants have completed the post-treatment visit at 7 months and 192 of these participants have completed the final visit and have exited the study.
• Cognitive Impairment Related to Anastrozole Use in Women Catherine Bender, PhD, RN, (PI) School of Nursing
  • The aims of this proposed study are: 1) to examine and compare the effect of anastrozole on cognitive function in four cohorts of women (n = 360; 90 per group): a) women with breast cancer who receive chemotherapy plus anastrozole; b) women with breast cancer who receive chemotherapy alone; c) women with breast cancer who receive anastrozole alone; and d) a healthy control group of women matched on age, race and level of education and 2) to develop a characteristic profile of women at risk for cognitive impairment. Secondary aims are to explore: 1) the quality of life of women who receive anastrozole and whether cognitive impairment affects quality of life in this sample; 2) whether anastrozole adherence and changes in hormone levels are mediators of cognitive function; and 3) whether mood, fatigue, treatment related symptoms, and concomitant medications are moderators of cognitive impairment and quality of life. Using a prospective, four-group, repeated measures design, we plan to evaluate cognitive function, quality of life and potential mediators and moderators of cognitive function at three time points; at baseline, prior to the initiation of therapy and six and 12 months post-baseline. Repeated measures analysis, using a mixed modeling approach, logistic regression and latent variable growth curve modeling, will be used to analyze data to address the study aims.
• Preference and Vegetarian Diet in Weight Loss Treatment
  Lora E. Burke, PhD, MPH, RN, (PI) School of Nursing
  • The PREFER Trial recruited and enrolled participants into the study in three cohorts. The first cohort had 58 participants, the second 67, and the third 57, N = 182. Participants were first randomized to either: standard behavioral treatment with a standard weight-reducing diet or standard behavioral treatment with a lacto-ovo-vegetarian, weight-reducing diet. The participants who were randomized to Treatment Preference-Yes were assigned to the group they preferred. All participants participated in treatment sessions over 12 months and then completed a 6-month maintenance phase prior to their final assessment at 18 months. Cohort 1 participants completed their 18-month assessment in the study in June 2004 with an 82% retention rate; cohort 2 completed their 18-month assessment in January 2005 with a 73% retention rate, and cohort 3 completed the study in August 2005 with a 72% retention rate. We developed an ancillary study that is focused on studying patterns of self-monitoring among participants in the third cohort. To conduct this study, we used instrumented paper diaries, which were developed by Arthur Stone and colleagues in their original work on self-monitoring and diary compliance. The diary that a participant uses is the traditional paper diary, which is housed in a zipped black binder with the pages on rings that have photosensors embedded in them. The photosensors detect the change in light when the binder is opened and closed and date and time stamp each event. We are studying participants in the third cohort in this ancillary study. A subset of 16 participants who used the instrumented paper diaries has been interviewed for a qualitative analysis of self-monitoring for weight loss. This sub-sample of 16 includes 4 males and 6 minority group members. The CRCD provided seed funding for the initial period of the study; since then we obtained a competitive administrative supplement from NIDDK to support the use of these diaries throughout the full study for the third cohort. In September 2005, we obtained additional internal funding through the Ruth P. Kuehn Award to continue to follow all the PREFER participants for one additional assessment in anticipation of a continuation study that will extend follow-up for 3 more years and add genetic tests and indicators of inflammation, as well as sub-clinical measures of atherosclerosis. A grant application was submitted to the Competitive Medical Research Funding on January 18, 2006 for additional funding for the follow-up of this cohort and a competing continuation application is being submitted to NIH March 1, 2006. Two published papers reporting on this study are attached; two manuscripts are under review, and several are in preparation.
• Reproductive Health Intervention for Teen Girls with Diabetes
  Denise Charron-Prochownik, PhD, RN, CPNP, (PI) School of Nursing
  • Diabetes (DM) can cause reproductive complications. In women with DM, planning a pregnancy and maintaining metabolic control through Preconception Counseling (PC) and care reduces the incidence of congenital abnormalities from 9% to 2%. The American Diabetes Association recommends that, beginning at puberty, PC be given to all women of childbearing age. However, two-thirds of diabetic women continue to have unplanned pregnancies. We previously reported that many teens with type 1 DM were sexually active, unaware of PC and these problems, and are at high risk for an unplanned pregnancy. Our team developed a theory-based "Reproductive-health Education and Awareness of Diabetes in Youth for Girls" (READY-Girls) program tailored specifically for teen women with type 1 DM as a CD and book. The program evaluation showed that either CD or book alone were effective (r)2=. 062-.291) in enhancing the short-range outcomes of reproductive health awareness, knowledge, attitudes, and positively influencing intentions of 16-19 yr. olds with type 1 DM to prevent an unplanned pregnancy and seek PC. Although some effects were sustained over 3-mnths, several attitudes and intentions towards behaviors were not. These results, along with the recent epidemic in type 2 DM, especially among minority female adolescents, emphasize the compelling need for an earlier cost-effective, more individualized, maintenance intervention program that will also include information for teens with type 2 DM. Using a mental models approach, we plan to restructure the program to maximize its efficacy. We will then conduct a multi-site randomized-controlled multi-session study to evaluate the effects of a combined DVD and book intervention with a health professional resource component on long-range cognitive, psychosocial, behavioral and biological outcomes and its cost-effectiveness in 13- <20 yr. old teens with type 1 or 2 DM. IRB approvals have been obtained from the Coordinating Center (University of Pittsburgh), Wayne State University, and Carnegie Mellon University. Project staff have been hired and oriented according to protocol at Wayne State University and Carnegie Mellon University. Phase 1 of this study is underway. Subject recruitment and metal model interviewing are being conducted.
• Psychiatric Morbidity Late Post Heart Transplant
  Mary Amanda Dew, PhD, (PI) School of Medicine Dept. of Psychiatry
  • In this application, we provide the economic, conceptual, and public health rationales for the need to consider these consequences at this time and in this population. There are no data on the nature or course of psychiatric morbidity that may accompany physical health declines, despite the potential impact of such psychiatric morbidity on txp recipients' quality of life and survival time. There are no data on whether the mental health of the patient's primary family caregiver is affected by late-term txp-related health changes. These data, plus identification of factors that create vulnerability or increase psychological resilience in the face of growing physical challenges for the patient will provide the critical knowledge base for the design of mental health interventions for both patients and caregivers during these years. We previously enrolled and followed the only cohort of heart recipients (n=250) ever to have received repeated, extensive psychiatric, behavioral, and psychosocial assessments across the early to middle (0-4) years posttxp. Their family caregiver's mental health and psycho-social status was also assessed. We plan to reassess all cohort survivors (n=132) and their caregivers. At study inception, the bulk of patients will be 9-13 years post-txp. We will collect 3 new waves of data separated by 1 year each in order to address a series of clinical epidemiologic questions pertaining to: (a) the prevalence of depressive and anxiety-related disorders during the late years post-txp, (b) the degree to which patients' and caregivers' risk for psychiatric morbidity in the face of late post-txp physical health stressors is moderated by key psychosocial characteristics, and (c) whether both parties' mental health, in turn, influences patients' continued medical compliance and subsequent physical morbidity. Data collection will involve semi-structured interviews, Txp Program staff evaluations, and medical record reviews.
• A Randomized Controlled Trial of the NIA Intervention
  Willa Doswell, PhD, RN, FAAN, (PI) School of Nursing
  • African American girls face earlier pubertal onset and challenges to be sexually active which places them at high risk of unplanned pregnancy and contraction of STD. The above study evaluates the effectiveness of an intervention to modify risky behaviors among urban, middle-school AA girls.
• Improving Adherence to Antiretroviral Therapy
  Judith A. Erlen, PhD, RN, FAAN, (PI) School of Nursing
  • The primary aim of the above longitudinal study is to compare the effect of two interventions (a structured telephone intervention and an individualized telephone intervention) relative to usual care on adherence of persons infected with HIV to their antiretroviral therapy over time. This research builds on prior NINR funded research with this population, adding depth to the CRCD aims. To date, subjects have been randomized to one of three arms. A small number of subjects have completed the intervention, maintenance, and booster sessions and the corresponding data collection sessions. Recruitment is continuing. Quality control measures have been put into place to monitor the delivery of the intervention, informed consent process, recruitment, and data collection sessions. Given that the study is in progress, data have been entered but not analyzed.
• Understanding the Process of Medication Taking in Persons with Alzheimer’s Disease
  Judith A. Erlen, PhD, RN, FAAN, (PI) School of Nursing
  • The above qualitative study is examining the process of medication taking in persons with Alzheimer’s disease who co-reside in the community with their adult caregivers. This research extends depth and breadth to adherence research by including caregiver influences in self management and adherence. We recruited 18 dyads; however only 16 of them completed the study. Observations and interviews were made during home visits. Data have been transcribed and entered into Atlas Ti ; preliminary codes have been identified. Analysis is continuing. The initial analysis is revealing that level of patient trust and level of caregiver control during medication taking are inversely related.
• Improving Communication with NonSpeaking ICU Patients
  Mary E. Happ, PhD, RN (PI) School of Nursing
  • The above study tests the impact of two experimental interventions, basic communication skills training (BCST) for ICU nurses to evaluate the ease, quality, frequency, and success of communications between nurses and nonspeaking ICU patients. This research extends adherence research to health care providers. Videotaped observations (n=120) of nurse-patient communication have been completed on 30 nurse-patient dyads (4 observations/dyad) in the nonintervention (control group) phase of the study. Subsequent phases of the study will involve measurement of nurse adherence to communication skill guidelines (Phases II & III) and treatment plan (Phase III). Twenty nurses (Phase I & II) have completed enrollment surveys about nurse perceptions of communication with nonspeaking ICU patients as well as demographic information. The BCST module has been developed and refined with delivery to study nurses to begin in late February.
• Enhancing Exercise Participation in Overweight Women
  John Jakicic, PhD, (PI) Associate Professor, School of Education Health and Physical Activity
  • Obesity is a major health problem in the United States due to the continued increase in prevalence rates. Physical activity is an important component for interventions because of its impact on enhancing weight loss and improving fitness. However, it is unclear if providing time-based strategies to enhance physical activity that compliment a standard behavioral weight loss program will improve weight loss and changes in cardiorespiratory fitness. Purpose: To evaluate effect of time-based behavioral strategies for physical activity on weight loss, physical activity, and cardiorespiratory fitness overweight individuals participating in a standard behavioral weight loss program. Methods: Two-hundred and nineteen sedentary, overweight individuals (age = 42 + 8.7 yrs; BMI = 33 + 3.4 kg/m 2) were randomized to one of three treatment groups. The standard behavioral weight loss intervention (SBWI) included reducing energy intake to 1200-1500 kcal/d, increasing exercise to 200 min/wk, and attending a weekly group session for 24 weeks and biweekly group sessions for the remainder of the 18-month intervention. The a adoption group (ADOPT) the SBWI intervention and also received biweekly telephone contacts from weeks 1-12, one weekly supervised exercise session and a pedometer campaign during months. The maintenance group (MAINT) received the SBWI intervention plus biweekly telephone contact from weeks 13-24, one supervised exercise sessions during months 7-12, and a pedometer campaign during months 12-18. Results: 146 of the subjects have completed the 18 month intervention with the remaining subjects still in the process of completing the intervention. Intention-to-treat analysis revealed significant percent weight loss at 6 months of 7.3 +7.8%, 8.2 +6.3%, and 7.3 +7.8% for ADOPT, MAINT, and SBWI, respectively (p<0.05), with no significant difference between groups. Results at 18 months revealed weight regain with percent weight loss from 0 to 18 months of 4.7 +8.9%, 5.6 +8.2%, and 2.7 +5.0% for ADOPT, MAINT, and SBWI, respectively, with no significant difference between groups. CONCLUSIONS: Preliminary results indicate that behavioral strategies for physical activity added to a standard behavioral weight loss intervention did not improve weight loss at 6 or 18 months. Thus, the addition of time-based strategies that include telephone contact, supervised exercise, and pedometer campaigns that focus on physical activity do not appear to be justified compared to a standard behavioral weight loss. Therefore additional intervention strategies should be examined to enhance long-term weight loss maintenance.
• Biobehavioral Factors in Atherosclerotic Progression
  Thomas Kamarck, PhD, (PI) Dept. of Psychology
  • The above study examines the prospective association between mental stress reactivity, daily behavioral activation, and carotid atherosclerotic progression. The initial study examined 3-year changes in carotid atherosclerosis in a healthy adult sample. A new competing renewal (start date August, 2004) includes an additional 6-year follow-up exploring effects of psychosocial factors on changes in carotid atherosclerotic progression, ambulatory blood pressure, and nocturnal blood pressure declines. As of Feb. 1, 2006, 227 participants have enrolled in the study; 160 subjects have completed all 6 visits that comprise the follow-up protocol.
• Treating Family Caregivers to Late-Life Depression Patients
  Lynn Martire , PhD (PI), School of Medicine
  • Total of 228 patient-caregiver dyads have been recruited into the research project supported by this career development award, with 180 of these dyads consisting of a patient with major depressive disorder and his/her family caregiver and 48 dyads consisting of a patient with bipolar disorder and his/her family caregiver.
    Data from 12 spouses or adult children of 12 older BD patients receiving pharmacotherapy have been examined for their association with concurrent patient characteristics. We have shown that caregiver depressive symptoms, burden, and relationship satisfaction are associated with treatment adherence and psychiatric symptoms. These findings were published in the American Journal of Geriatric Psychiatry (Martire, Schulz, Mulsant, & Reynolds, 2004).
• Medication Adherence in Young Adults with Schizophrenia Using Relational Agent Technology
  Kathryn Puskar , DrPH, RN, (PI) School of Nursing
  • The major goal of this study is to develop and pilot test a software program using relational agent technology to improve medication adherence in young adults with schizophrenia.
• Disparate MBC Symptom Severity and Management Barriers
  Margaret Rosenzweig, PhD, RN, (PI) School of Nursing
  • The immediate goals are [1] to enhance understanding of the difference in symptom occurrence and symptom severity in low income and racially disparate groups of patients with MBC and [2] to better understand the barriers to the use of symptom-management strategies by patients and to determine if these barriers differ based on income or racial factors. Women with MBC were categorized into four groups based on race and income: white low (WL), white high (WH), African American high (AAH) and African American low (AAL). Instruments were 1) Symptom Distress Scale (SDS), (higher scores /worse distress) 2) Functional Assessment of Cancer Therapy (FACT), (higher scores /better QOL) and a 3) semi structured interview assessing MBC experience. Interview analysis utilized grounded theory. Preliminary results are for 51 women.  Mean age was 58.2 years, with mean 24 months since MBC diagnosis. Quantitative data indicated worse quality of life in AA than white women. (P=0.06), with AALI women exhibiting worse symptom distress (P=0.03) as compared to white women.
• Diabetic Children Grow Up: Cognitive Complications
  Christopher M. Ryan, PhD, (PI) School of Medicine
  • In 1980, we initiated a series of neuropsychological studies of children, 10 to 19 years of age, with and without type 1 diabetes. We found that those who developed diabetes within the first 5 or 6 years of life were more likely to manifest widespread, clinically significant cognitive impairment, as compared to those with a later age at diagnosis, or to nondiabetic comparison subjects. Although the underlying pathophysiological mechanism remains controversial, we now believe that occurrence of diabetes-associated chronic hyperglycemia during a critical period of brain" development adversely affects the central nervous system, and increases its vulnerability to subsequent brain insults, particularly those associated with moderately severe hypoglycemic episodes. Whether these deficits reflect reversible developmental delays, or whether they are evidence of permanent brain damage (which may worsen over time) remains unknown, as does their effect on adult functioning. The goal of our proposed study is to re-contact those individuals first seen by us between 1980 and 1983 (Mean age = 14.5 yrs; initial number: 226) and invite them to complete a detailed neuropsychological assessment, a psychiatric diagnostic interview, and measures of quality of life and vocational adjustment. Diabetic subjects will also have a physical examination with tests to ascertain biomedical complications and review of prior hypoglycemic episodes. Our study has two broad aims: First, to test the early onset vulnerability hypothesis, predicting that adults diagnosed with diabetes before 6 years of age will show greater deterioration in cognitive functioning over time, compared to those with a later onset of diabetes, that all cognitive domains will be affected, that this will eventuate in less vocational attainment and poorer quality of life, and that this will be predicted by number of intercurrent episodes of hypoglycemia, as well as by the incidence of diabetic complications. Second, we aim to provide a comprehensive profile of diabetic patients' neuropsychiatric status in middle-adulthood, with determination of the extent to which hypoglycemic events as well as other biomedical and psychosocial factors predict those outcomes. This will be the first study of diabetic patients to delineate changes in cognitive functioning from late childhood into middle-adulthood, and the first to link functional changes to diabetes-related biomedical variables.
• Improving Physical Activity in Comorbidity
  Elizabeth A. Schlenk, PhD, RN, (PI) School of Nursing
  • This study determines whether a self-efficacy based intervention, designed to promote adherence to quadriceps strengthening and subsequent walking, results in adherence to knee exercise, adoption (6 months) and maintenance (12 months) of regular physical activity (walking), and improvements in cardiorespiratory fitness in persons with impaired fasting glucose and osteoarthritis of the knee.
• Beliefs and Preferences About Participation in Clinical Research Among Older Adults
  Elizabeth A. Schlenk , PhD, RN, (PI) School of Nursing
  • The specific aims of this study are to (1) examine from the perspective of older adults, the expectations, benefits, and barriers of participation in clinical research in general, and (2) examine the preferences and capabilities of older adults for using physical activity assessment strategies in clinical studies in particular.
• Caregiver Intervention for Caregivers of SCI Patients
  Richard Schulz, PhD (PI)
  • The above study tests the efficacy of a multi-component psychosocial/technology intervention to reduce health risks of caregivers of spinal cord survivors and to improve quality of life for the survivors. The research team is multi-site (University of Miami and University of Pittsburgh) and multidisciplinary; it also investigates the associated factor of caregiver health on adherence to management of treatment regimens.
• Personality and Medication Adherence in Transplantation
  Carol Stilley, PhD, RN (PI) School of Nursing
  • This study is ancillary to a larger ongoing longitudinal study of adherence, quality of life, and emotional adjustment in this population. A projected sample of 176 subjects will be recruited from participants in the parent study; 158 subjects have been enrolled since May 1, 2002. Personality traits and the presence of personality disorder were measured once with the NEO-PI-R, a 2-stage version of the SCID-II and the Interpersonal Inventory of Personality at 3-4 mos. post-txp.; all other data is being collected in the parent study. Psychosocial predictors of adherence and adherence was evaluated with interview, self report, laboratory data, and electronic medication caps at 6, 12, and 18 mos post txp. We intend to investigate prospective relationships between personality and subsequent adherence and the moderating effects of personality on the linkage between psychosocial variables and adherence. Personality analyses are complete, recruitment in this study is closed; a descriptive paper is in press. Self reported adherence and psychological variables from the parent study have just become available and are being analyzed. A third no cost extension year will be requested, due to delay in receiving psychosocial and adherence data from the parent study.
• Adherence and Health Outcomes after Liver Transplantation
  Carol Stilley, PhD, RN (PI) School of Nursing
  • The goal of this R01 application is to determine the extent to which patient factors impact on adherence and health outcomes after liver transplantation (LTX). Transplantation is the only option for survival of end stage liver disease; demand far exceeds supply yet little is known about which patients benefit most from the procedure. There are clear links between treatment adherence and health outcomes both in general medicine and in other transplant patient populations. Determining which LTX patients are at risk of non-adherence and suboptimal health outcomes is an ongoing dilemma for clinicians and a significant public health issue; failure to do so is costly to the healthcare system and society . The proposed research will be the first known prospective study of adherence to the multifaceted LTX regimen. Specific aims of this longitudinal study are to 1) prospectively characterize adherence to medication taking, appointment keeping, and recommended lifestyle changes over the first post-txp year and identify latent classes of adherence trajectories; 2) determine salient individual and environmental factors that underlie variation in adherence and predict health outcomes. Adherence will be tracked with interviews, electronic medication monitors, and medical records review over the first year; individual and environmental patient factors will be assessed with self report measures and interviews at 1-2, 6, and 12 months post-transplant; morbidity and, secondarily, mortality will be tracked with medical records review over the remainder of the study period. This study will be conducted in collaboration with the Thomas E. Starzl Institute, at the University of Pittsburgh Medical Center; all adult recipients who survive the acute post-transplant period will be eligible. Recruitment will occur over a 2.5 year period and sample size is projected to be approximately 300 recipients. The long-term goal of this project is to develop guidelines for transplant clinicians to identify patients prior to or early after transplantation who are at risk of non-adherence and sub-optimal health outcomes for targeted patient-specific interventions to maximize benefit of LTX. The application of this research would serve as the basis to advance significantly the nation’s capacity to protect and preserve health in transplant populations.
• Sleep and Health: Influence of Hemodialysis
  Mark Unruh, MD, MSc (School of Medicine)
  • Poor sleep and fatigue are commonly encountered when caring for adults undergoing hemodialysis. A majority dialysis patient complain of sleep problems, in some cases over twice the rate in the general population. The health burden associated with sleep disturbances is significant; studies have linked sleep problems to greater use of health services, increased use of hypnotics, reduced functional capabilities, higher risk of death and reduced quality of life. Our own preliminary findings support the need for a better understanding of the relationship of sleep apnea to progressive kidney failure and its treatment with hemodialysis. This proposal uses a natural experiment would control for many of the confounding factors that limit the validity of cross-sectional comparisons. The general aim of this study is to characterize sleep and daytime functioning among patients before and after initiating chronic hemodialysis to test the hypothesis that undergoing hemodialysis impacts on sleep apnea and daytime functioning. We will also describe the changes in other sleep disorders and both subjective and objective sleep quality after the initiations of chronic hemodialysis.
• Cardiovascular Disease in Rheumatoid Arthritis
  Mary Chester Wasko, MD, MSc (School of Medicine)
  • Rheumatoid Arthritis (RA) is a chronic, inflammatory autoimmune disorder that affects 1% of the U.S. population, with women of childbearing age preferentially stricken. There is a significant reduction in life expectancy in women with RA, which is due in part to premature cardiovascular disease. Acute myocardial infarction (MI) and congestive heart failure (CHF) are the leading causes of death in RA. This award will provide the opportunity for Mary Chester M. Wasko, to obtain the specific skills necessary to develop into an independent clinical investigator. In this study I propose to: 1) determine the prevalence and predictors of vascular disease in women with RA; 2) compare the prevalence of vascular disease and associated risk factors in RA and systemic lupus erythematosus (SLE), an autoimmune disease also characterized by premature MI and CHF in young women; and 3) compare the prevalence of vascular disease in RA patients with and without a previous cardiovascular event. This study will provide valuable information for designing a future, prospective, multicenter study examining the value of B-mode ultrasound and EBCT in predicting incident cardiovascular events in patients with RA.