Veterinary oncologists and pet owners differ in their perceptions of chemotherapy-related adverse events in cancer-bearing dogs.

OBJECTIVE: Chemotherapy is widely used in veterinary oncology but carries real and perceived risks of adverse events (AEs). Human cancer patients perceive AEs from chemotherapy as more severe than do their attending physicians. It is currently unknown whether this discrepancy exists in veterinary oncology. This survey study's aim was to assess differences in the ways that pet owners and veterinary oncologists perceive chemotherapy-related AEs. We hypothesized that veterinary oncologists would accept higher grade AEs and tolerate a greater risk of AEs of any grade than pet owners. SAMPLE: 152 pet owners and 111 veterinary oncologists. METHODS: Separate surveys were derived for pet owners and veterinary oncologists. Respondents were asked to define maximally acceptable AE scores and risks of AEs given 3 hypothetical outcomes of treatment: (1) cure, (2) extension of life, and (3) improved quality of life. Statistical tests were used to compare responses between groups. RESULTS: Veterinary oncologists accepted higher grade AEs if the hypothetical goal of chemotherapy was cancer cure (P = .003) or extension of life (P = .026), but owners accepted higher grade AEs if the goal of chemotherapy was to improve quality of life (P = .002). Owners accepted greater risk of moderate (P < .0001) or serious (P < .0001) AEs across the 3 treatment outcomes. CLINICAL RELEVANCE: This was the first study to assess how pet owners and veterinary oncologists differ in their perception of chemotherapy-related AEs. These initial results may help to frame discussions with pet owners on the expectations of chemotherapy.

Development and Feasibility Testing of a Multilevel Intervention to Increase Hepatitis C Virus Screening Among Baby Boomers in Primary Care.

Chronic infection with hepatitis C virus (HCV) results in an increased risk of cirrhosis and hepatocellular carcinoma (HCC). Only 15% of baby boomers (born 1945-1965) have ever been screened. We aimed to develop a multilevel intervention to increase HCV screening for baby boomers in a primary care setting. This study included two phases: intervention development (phase 1) and feasibility testing (phase 2). In phase 1, we partnered with a Community Advisory Board and a Provider Advisory Board to develop a multilevel intervention to increase HCV screening to be delivered to both providers and patients in primary care. Phase 2 assessed intervention feasibility, acceptability, and usability by conducting Concurrent Think Aloud (CTA) interviews and surveys using previously validated scales with patients (n = 8) and providers (n = 7). Phase 1 results: The patient-level intervention included a mailed reminder letter and CDC pamphlet and a 7-min in-clinic educational video. The provider-level intervention included a 30-min educational session and monthly performance feedback e-mails. Phase 2 results: Qualitatively, both the patient and provider-level intervention were feasible, acceptable, and usable by the target audiences. Quantitatively, on a 1-4 scale, the range of patient-level scores was 3.00-4.00 and provider level was 3.50-4.00 for feasibility, acceptability, and usability. This intervention could improve HCV screening among a high-risk population and therefore reduce HCV-related morbidity and mortality. This project developed a feasible, acceptable, and usable multilevel intervention aimed at increasing HCV screening in primary care.

Examining how physician factors influence patient satisfaction during clinical consultations about cancer prognosis and pain.

Objective: Patient-physician communication affects cancer patients' satisfaction, health outcomes, and reimbursement for physician services. Our objective is to use machine learning to comprehensively examine the association between patient satisfaction and physician factors in clinical consultations about cancer prognosis and pain. Methods: We used data from audio-recorded, transcribed communications between physicians and standardized patients (SPs). We analyzed the data using logistic regression (LR) and random forests (RF). Results: The LR models suggested that lower patient satisfaction was associated with more in-depth prognosis discussion; and higher patient satisfaction was associated with a greater extent of shared decision making, patient being black, and doctor being young. Conversely, the RF models suggested the opposite association with the same set of variables. Conclusion: Somewhat contradicting results from distinct machine learning models suggested possible confounding factors (hidden variables) in prognosis discussion, shared decision-making, and doctor age, on the modeling of patient satisfaction. Practitioners should not make inferences with one single data-modeling method and enlarge the study cohort to help deal with population heterogeneity. Innovation: Comparing diverse machine learning models (both parametric and non-parametric types) and carefully applying variable selection methods prior to regression modeling, can enrich the examination of physician factors in characterizing patient-physician communication outcomes.

"Do You Smoke?" Physician-Patient Conversations About Smoking and Lung Cancer.

This study examined how physicians initiated and navigated conversations about smoking with patients with lung cancer. While there are numerous health benefits associated with smoking cessation in patients with advanced lung cancer, conversations about smoking cessation are infrequent and often lack tangible cessation support. We conducted a qualitative inductive content analysis on transcripts of conversations (n = 58) recorded during an initial appointment between a physician and a standardized patient (SP). SPs portrayed a 62-year-old male with lung cancer completing an initial visit with a new physician. Qualitative analysis focused on examining how physicians discussed smoking with a new patient. We found that a majority of physicians initiated conversations about smoking, often during the medical history charting process or during conversations about the lung cancer diagnosis. The content of conversations about smoking generally fits within six categories: assesses smoking status, builds smoking history profile, praises smoking cessation, connects smoking behaviors to diagnosis or treatment, provides empathy or understanding, and presents a negative bias about smoking. We found that while a majority of physicians asked patients about smoking, most physicians aimed for these conversations to be short, routine, and medically driven. Conversations about smoking were not tailored to meet the specific needs of patients with lung cancer, which might include additional provision of support for smoking cessation and recognition of smoking-related stigma.

Is physician implicit bias associated with differences in care by patient race for metastatic cancer-related pain?

RATIONALE: Implicit racial bias affects many human interactions including patient-physician encounters. Its impact, however, varies between studies. We assessed the effects of physician implicit, racial bias on their management of cancer-related pain using a randomized field experiment. METHODS: We conducted an analysis of a randomized field experiment between 2012 and 2016 with 96 primary care physicians and oncologists using unannounced, Black and White standardized patients (SPs)who reported uncontrolled bone pain from metastatic lung cancer. We assessed implicit bias using a pain-adaptation of the race Implicit Association Test. We assessed clinical care by reviewing medical records and prescriptions, and we assessed communication from coded transcripts and covert audiotapes of the unannounced standardized patient office visits. We assessed effects of interactions of physicians' implicit bias and SP race with clinical care and communication outcomes. We conducted a slopes analysis to examine the nature of significant interactions. RESULTS: As hypothesized, physicians with greater implicit bias provided lower quality care to Black SPs, including fewer renewals for an indicated opioid prescription and less patient-centered pain communication, but similar routine pain assessment. In contrast to our other hypotheses, physician implicit bias did not interact with SP race for prognostic communication or verbal dominance. Analysis of the slopes for the cross-over interactions showed that greater physician bias was manifested by more frequent opioid prescribing and greater discussion of pain for White SPs and slightly less frequent prescribing and pain talk for Black SPs with the opposite effect among physicians with lower implicit bias. Findings are limited by use of an unvalidated, pain-adapted IAT. CONCLUSION: Using SP methodology, physicians' implicit bias was associated with clinically meaningful, racial differences in management of uncontrolled pain related to metastatic lung cancer. There is favorable treatment of White or Black SPs, depending on the level of implicit bias.

Financial hardship is associated with lower uptake of colorectal, breast, and cervical cancer screenings.

PURPOSE: Cancer screening uptake differs between groups in ways that cannot be explained by socioeconomic status alone. This study examined associations between material, psychosocial, and behavioral aspects of financial hardship and cancer screening behaviors. METHODS: Surveys were mailed to 7,979 people ages 18-75 who were seen in the statewide health system in Indiana. Participants reported SES, feelings about finances, and whether they had to forgo medical care due to cost. This was compared to uptake of mammogram, colonoscopy/sigmoidoscopy, and Pap testing in best-fit multivariable logistic regression analyses controlling for demographic and healthcare characteristics. RESULTS: A total of 970 surveys were returned; the majority of respondents were female (54%), non-Hispanic White (75%), and over 50 years old (76%). 15% reported forgoing medical care due to cost; this barrier was higher among Black than White participants (24% vs. 13%; p = 0.001). In a best fit regression model for colonoscopy/sigmoidoscopy, those who reported they had to forgo medical care due to cost had lower odds of screening (aOR 0.41; 95% CI 0.22-0.74). Forgoing medical care due to cost was not significantly associated with Pap testing in bivariate analyses. For mammogram, forgoing medical care due to cost was significant in bivariate analyses (OR 0.44; 95% CI 0.22-0.88), but was not significant in the multivariable model. CONCLUSION: Associations between financial hardship and cancer screening suggest the need to reduce barriers to cancer screening even among patients who have access to healthcare. Future research should explore barriers related to both healthcare and personal costs.

Empathy and boundary turbulence in cancer communication.

OBJECTIVES: To describe and deepen our understanding of patient-centeredness, empathy, and boundary management in challenging conversations. Previous studies show frequent physician self-disclosure, while empathy and boundary management are infrequent. METHODS: Three standardized patients (SPs) portrayed cancer patients consulting a new community-based physician, resulting in 39 audio-recorded SP visits to 19 family physicians and 20 medical oncologists. Transcripts underwent qualitative iterative thematic analysis, informed by grounded theory, followed by directed content analysis. We further defined the identified communicative categories with descriptive and correlational calculations. RESULTS: We identified patient-centered physician response categories--empathy, affirmation, and acknowledgement; and physician-centered categories-transparency, self-disclosure, and projection. Acknowledgement and affirmation responses were frequent and empathy rare. Physician transparency and self-disclosure were common. Useful and not useful self-disclosures were highly correlated; empathy, useful and not useful transparency, and projection were moderately correlated. Most physicians used self-disclosure but few of these were judged patient-centered. CONCLUSIONS: Physicians expressing empathy and patient-centered transparency were also more likely to use projection and physician-centered transparency, thus engaging in communication "boundary turbulence." Patients may benefit from physicians' improved use of empathy and boundary management.

The Influence of Patient Race and Activation on Pain Management in Advanced Lung Cancer: a Randomized Field Experiment.

BACKGROUND: Pain management racial disparities exist, yet it is unclear whether disparities exist in pain management in advanced cancer. OBJECTIVE: To examine the effect of race on physicians' pain assessment and treatment in advanced lung cancer and the moderating effect of patient activation. DESIGN: Randomized field experiment. Physicians consented to see two unannounced standardized patients (SPs) over 18 months. SPs portrayed 4 identical roles-a 62-year-old man with advanced lung cancer and uncontrolled pain-differing by race (black or white) and role (activated or typical). Activated SPs asked questions, interrupted when necessary, made requests, and expressed opinions. PARTICIPANTS: Ninety-six primary care physicians (PCPs) and oncologists from small cities, and suburban and rural areas of New York, Indiana, and Michigan. Physicians' mean age was 52 years (SD = 27.17), 59% male, and 64% white. MAIN MEASURES: Opioids prescribed (or not), total daily opioid doses (in oral morphine equivalents), guideline-concordant pain management, and pain assessment. KEY RESULTS: SPs completed 181 covertly audio-recorded visits that had complete data for the model covariates. Physicians detected SPs in 15% of visits. Physicians prescribed opioids in 71% of visits; 38% received guideline-concordant doses. Neither race nor activation was associated with total opioid dose or guideline-concordant pain management, and there were no interaction effects (p > 0.05). Activation, but not race, was associated with improved pain assessment (ẞ, 0.46, 95% CI 0.18, 0.74). In post hoc analyses, oncologists (but not PCPs) were less likely to prescribe opioids to black SPs (OR 0.24, 95% CI 0.07, 0.81). CONCLUSIONS: Neither race nor activation was associated with opioid prescribing; activation was associated with better pain assessment. In post hoc analyses, oncologists were less likely to prescribe opioids to black male SPs than white male SPs; PCPs had no racial disparities. In general, physicians may be under-prescribing opioids for cancer pain. TRIAL REGISTRATION: NCT01501006.

Addressing personal barriers to advance care planning: Qualitative investigation of a mindfulness-based intervention for adults with cancer and their family caregivers.

OBJECTIVE: Advance care planning (ACP) increases quality of life and satisfaction with care for those with cancer and their families, yet these important conversations often do not occur. Barriers include patients' and families' emotional responses to cancer, such as anxiety and sadness, which can lead to avoidance of discussing illness-related topics such as ACP. Interventions that address psychological barriers to ACP are needed. The purpose of this study was to explore the effects of a mindfulness intervention designed to cultivate patient and caregiver emotional and relational capacity to respond to the challenges of cancer with greater ease, potentially decreasing psychological barriers to ACP and enhancing ACP engagement. METHOD: The Mindfully Optimizing Delivery of End-of-Life (MODEL) Care intervention provided 12 hours of experiential training to two cohorts of six to seven adults with advanced-stage cancer and their family caregivers (n = 13 dyads). Training included mindfulness practices, mindful communication skills development, and information about ACP. Patient and caregiver experiences of the MODEL Care program were assessed using semistructured interviews administered immediately postintervention and open-ended survey questions delivered immediately and at 4 weeks postintervention. Responses were analyzed using qualitative methods.ResultFour salient themes were identified. Patients and caregivers reported the intervention (1) enhanced adaptive coping practices, (2) lowered emotional reactivity, (3) strengthened relationships, and (4) improved communication, including communication about their disease.Significance of resultsThe MODEL Care intervention enhanced patient and caregiver capacity to respond to the emotional challenges that often accompany advanced cancer and decreased patient and caregiver psychological barriers to ACP.

Patient and provider characteristics associated with communication about opioids: An observational study.

OBJECTIVE: Our objective is to examine the relationship of patient and provider characteristics and communication with chronic non-cancer pain and opioid management in primary care. METHOD: We conducted an observational study using audio-recorded primary care appointments (up to 3/patient) and self-reported assessments of primary care providers (PCPs) and patients. We coded visit transcripts for 1) opioid and pain management talk and 2) mental health and opioid safety talk. RESULTS: Eight PCPs and 30 patients had complete data for 78 clinic visits. PCPs and patients engaged in more opioid and pain management talk when patients reported greater pain catastrophizing and PCPs reported higher psychosocial orientation. PCPs and patients engaged in talk about mental health and opioid safety when patients reported greater anxiety, higher working alliance with their PCP, and when PCPs reported higher burnout. PCPs' negative attitudes about opioids were associated with fewer discussions about mental health and opioid safety. CONCLUSIONS: Our results should facilitate design of interventions that improve communication and, ultimately, pain outcomes for patients. PRACTICE IMPLICATIONS: Clinicians can use our results to increase patient engagement in discussions about opioid use and pain management or mental health and safety discussions.

Quality of Life in Partners of Young and Old Breast Cancer Survivors.

BACKGROUND: Partners of breast cancer survivors experience the effects of a spouse's cancer years after treatment. Partners of younger survivors (YPs) may experience greater problems than partners of older survivors (OPs), just as younger survivors experience greater problems than their older counterparts. OBJECTIVES: The aims of this study were to (1) compare quality of life (QoL) in YPs and OPs and (2) determine contributing factors to each group's QoL. METHODS: Cross-sectional data were collected from YPs (n = 227) and OPs (n = 281) through self-report. Multivariate analysis of variance was used to determine differences between YPs and OPs on QoL while controlling for covariates. Multiple regression analyses were conducted to determine what contributes to each group's QoL. RESULTS: Partners of younger survivors reported better physical function (effect size [ES], -0.57), lower marital satisfaction (ES, 0.39), and lower overall QoL (ES, 0.43) than OPs. Predictors of QoL also differed between partner groups. For YPs, overall QoL was predicted by greater physical functioning, fewer depressive symptoms, higher marital satisfaction, higher parenting satisfaction, and more personal resources (R = 0.47, F5,195 = 35.05, P < .001). For OPs, overall QoL was predicted by fewer depressive symptoms, higher parenting satisfaction, higher spirituality, and greater social support from the breast cancer survivor spouse (R = 0.33, F4,244 = 29.80, P < .001). CONCLUSION: Partners of older survivors reported greater QoL than YPs. Common factors contributing to QoL between YPs and OPs were fewer depressive symptoms and higher parenting satisfaction. IMPLICATIONS FOR PRACTICE: Partners of breast cancer survivors may need support coping with their spouse/partner's cancer. Partners of younger survivors may require more support than OPs.

The social and behavioral influences (SBI) study: study design and rationale for studying the effects of race and activation on cancer pain management.

BACKGROUND: Racial disparities exist in the care provided to advanced cancer patients. This article describes an investigation designed to advance the science of healthcare disparities by isolating the effects of patient race and patient activation on physician behavior using novel standardized patient (SP) methodology. METHODS/DESIGN: The Social and Behavioral Influences (SBI) Study is a National Cancer Institute sponsored trial conducted in Western New York State, Northern/Central Indiana, and lower Michigan. The trial uses an incomplete randomized block design, randomizing physicians to see patients who are either black or white and who are "typical" or "activated" (e.g., ask questions, express opinions, ask for clarification, etc.). The study will enroll 91 physicians. DISCUSSION: The SBI study addresses important gaps in our knowledge about racial disparities and methods to reduce them in patients with advanced cancer by using standardized patient methodology. This study is innovative in aims, design, and methodology and will point the way to interventions that can reduce racial disparities and discrimination and draw links between implicit attitudes and physician behaviors. TRIAL REGISTRATION: https://clinicaltrials.gov/ , #NCT01501006, November 30, 2011.

Barbershop Prostate Cancer Education: Factors Associated With Client Knowledge.

The purpose of this paper is to identify characteristics of Black barbershop clients and barbers in an urban Midwestern city participating in a health promotion program called Affecting Cancer Together (ACT) that are associated with client knowledge about prostate cancer. Statistical analyses examined client and barber characteristics for their potential association with client prostate cancer knowledge, while controlling for ACT variables. Study findings suggested clients who are married (ß = 0.99; CI [0.38, 1.59]; p < .01) and have higher levels of education (ß = 0.34; CI [0.01, 0.67]; p = .04) may be more likely to know more about prostate cancer. Barbers with at least "some college" education may be more effective in increasing client knowledge (ß = 0.85; CI [0.05, 1.64]; p = .04). Trained peer-helper programs may consider prioritizing limited educational resources for barbers with at least some college education and incorporating the social support of spouses for making informed decisions. Considering the potential of barbershop programs to reach Black men about a serious racially disproportionate health issue, ameliorating adoption, implementation, effectiveness, and sustainment are an important public health priority for underserved populations.

"I'm Not Gonna Pull the Rug out From Under You": Patient-Provider Communication About Opioid Tapering.

In response to increases in harms associated with prescription opioids, opioid prescribing has come under greater scrutiny, leading many health care organizations and providers to consider or mandate opioid dose reductions (tapering) for patients with chronic pain. Communicating about tapering can be difficult, particularly for patients receiving long-term opioids who perceive benefits and are using their medications as prescribed. Because of the importance of effective patient-provider communication for pain management and recent health system-level initiatives and provider practices to taper opioids, this study used qualitative methods to understand communication processes related to opioid tapering, to identify best practices and opportunities for improvement. Up to 3 clinic visits per patient were audio-recorded, and individual interviews were conducted with patients and their providers. Four major themes emerged: 1) explaining-patients needed to understand individualized reasons for tapering, beyond general, population-level concerns such as addiction potential, 2) negotiating-patients needed to have input, even if it was simply the rate of tapering, 3) managing difficult conversations-when patients and providers did not reach a shared understanding, difficulties and misunderstandings arose, and 4) nonabandonment-patients needed to know that their providers would not abandon them throughout the tapering process. PERSPECTIVE: Although opioid tapering can be challenging, helping patients to understand individualized reasons for tapering, encouraging patients to have input into the process, and assuring patients they would not be abandoned all appear to facilitate optimal communication about tapering.

Physicians Talking About Sex, Sexuality, and Protection With Adolescents.

Adolescent-physician communication about sexual behaviors, sexuality, and protective behaviors is vital for the support of sexual minorities and the prevention of sexually transmitted infections and unintended pregnancies. The objective of this review is to identify sexual topics that physicians and adolescents discuss during medical encounters and examine the quantity and quality of that communication. We performed a systematic literature review of major databases through May 2016. We identified 33 papers that focused on adolescent-physician communication about three major sexual health topics: coital or noncoital sexual behaviors, sexual orientation or attractions, and sexually protective or preventative behaviors. Communication between adolescents and physicians about these sexual topics is infrequent and coincides with calls for improvement in clinical sex communication. Communication about sexual attractions, sexual orientation, and noncoital sexual behaviors were the rarest in practice, whereas mentions of contraception were more frequent. The review also highlights substantial limitations with this body of research, and more advanced research designs are warranted. Associations between clinical sexual communication and sexual health outcomes (e.g., contraceptive use and sexually transmitted infection occurrence) would improve knowledge of the effectiveness of communication in practice.

Barbershop Prostate Cancer Education: Factors Associated With Client Knowledge.

The purpose of this article is to identify characteristics of Black barbershop clients and barbers in an urban Midwestern city participating in a health promotion program called Affecting Cancer Together (ACT) that are associated with client knowledge about prostate cancer. Statistical analyses examined client and barber characteristics for their potential association with client prostate cancer knowledge, while controlling for ACT variables. Study findings suggested clients who are married (ß = 0.99; confidence interval [CI] = 0.38, 1.59; p < .01) and have higher levels of education (ß = 0.34; CI = 0.01, 0.67; p = .04) may be more likely to know more about prostate cancer. Barbers with at least "some college" education may be more effective in increasing client knowledge (ß = 0.85; CI = 0.05, 1.64; p = .04). Trained peer-helper programs may consider prioritizing limited educational resources for barbers with at least some college education and incorporating the social support of spouses for making informed decisions. Considering the potential of barbershop programs to reach Black men about a serious racially disproportionate health issue, ameliorating adoption, implementation, effectiveness, and sustainment are an important public health priority for underserved populations.

Characterizing Sexual Orientation Disclosure to Health Care Providers: Lesbian, Gay, and Bisexual Perspectives.

This study examines lesbian, gay, and bisexual patients' disclosure patterns of sexual orientation to health care providers. Using a semistructured interview format, researchers conducted interviews with 24 lesbian, gay, bisexual, and queer (LGBQ) adults about sexual orientation disclosure strategies. All interviews were transcribed and independently coded using thematic analysis. Results suggest that patient sexual orientation disclosure may be patient initiated and may occur to clarify or correct provider misinformation. Participants disclosed their orientation early in the medical visit during introductions, during small talk with the provider, and during the history-taking phase of the visit. Participants characterized sexual orientation disclosures as presented with minimal information, casually, and often indirectly. Practical and theoretical implications are discussed.

Effect of a Patient-Centered Communication Intervention on Oncologist-Patient Communication, Quality of Life, and Health Care Utilization in Advanced Cancer: The VOICE Randomized Clinical Trial.

IMPORTANCE: Observational studies demonstrate links between patient-centered communication, quality of life (QOL), and aggressive treatments in advanced cancer, yet few randomized clinical trials (RCTs) of communication interventions have been reported. OBJECTIVE: To determine whether a combined intervention involving oncologists, patients with advanced cancer, and caregivers would promote patient-centered communication, and to estimate intervention effects on shared understanding, patient-physician relationships, QOL, and aggressive treatments in the last 30 days of life. DESIGN, SETTING, AND PARTICIPANTS: Cluster RCT at community- and hospital-based cancer clinics in Western New York and Northern California; 38 medical oncologists (mean age 44.6 years; 11 (29%) female) and 265 community-dwelling adult patients with advanced nonhematologic cancer participated (mean age, 64.4 years, 146 [55.0%] female, 235 [89%] white; enrolled August 2012 to June 2014; followed for 3 years); 194 patients had participating caregivers. INTERVENTIONS: Oncologists received individualized communication training using standardized patient instructors while patients received question prompt lists and individualized communication coaching to identify issues to address during an upcoming oncologist visit. Both interventions focused on engaging patients in consultations, responding to emotions, informing patients about prognosis and treatment choices, and balanced framing of information. Control participants received no training. MAIN OUTCOMES AND MEASURES: The prespecified primary outcome was a composite measure of patient-centered communication coded from audio recordings of the first oncologist visit following patient coaching (intervention group) or enrollment (control). Secondary outcomes included the patient-physician relationship, shared understanding of prognosis, QOL, and aggressive treatments and hospice use in the last 30 days of life. RESULTS: Data from 38 oncologists (19 randomized to intervention) and 265 patients (130 intervention) were analyzed. In fully adjusted models, the intervention resulted in clinically and statistically significant improvements in the primary physician-patient communication end point (adjusted intervention effect, 0.34; 95% CI, 0.06-0.62; P = .02). Differences in secondary outcomes were not statistically significant. CONCLUSIONS AND RELEVANCE: A combined intervention that included oncologist communication training and coaching for patients with advanced cancer was effective in improving patient-centered communication but did not affect secondary outcomes. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01485627.