Mayo Clinic Rochester Research Articles

NON-SUSTAINED VENTRICULAR TACHYCARDIA IN EXERCISE TESTING: NOT SO BENIGN

Relevance of non-sustained ventricular tachycardia (NSVT) recorded during treadmill exercise testing (TMET) is unknown. Residents of Olmsted and neighboring counties undergoing clinically indicated TMET with the Bruce or modified McNaughton protocol at the Mayo Clinic Rochester, Minnesota between

Safety and Efficacy of Cryoablation in Patients With Ventricular Arrhythmias Originating From the Para-Hisian Region

This study aimed to assess the outcome of cryoablation in patients with ventricular arrhythmias (VAs) originating from the para-Hisian region. There are few data regarding the outcome of cryoablation in patients with VAs originating from the para-Hisian region, where there is the risk of injury to the conduction system. The study analyzed all patients undergoing cryoablation at the Mayo Clinic (Rochester, Minnesota) as part of an ablation for VAs originating from the para-Hisian region. The study population consisted of 10 patients (64 ± 15 years of age, 7 men). Cryoenergy was applied after an unsuccessful radiofrequency (RF) ablation in 8 (80%) patients. The VAs were successfully ablated with cryoablation in 7(70%) patients; RF ablation after an unsuccessful cryoablation eliminated the VAs at almost the same location with careful monitoring in 1 patient. The authors could not ablate the actual focus because a transient atrioventricular block developed during cryo- and RF energy applications, which led to an unsuccessful ablation in the remaining 2 patients. Acomplete atrioventricular block occurred during the cryoenergy application in 1 patient, who needed a permanent pacemaker implantation. There were no VA recurrences in 4 of 8 (50%) patients with procedural success during a median follow-up period of 122 days (interquartile range: 43 to 574 days). Cryoablation is clinically effective in some patients with VAs originating from the para-Hisian region, where there is the risk of injury to the conduction system, and therefore should be considered as an alternative to or inaddition to RF ablation in these cases. Cryoablation requires care because it can also lead to major complications.

Utility of cardiac computed tomography scanning in the diagnosis and pre-operative evaluation of patients with infective endocarditis.

Transesophageal echocardiography (TEE) is the gold standard imaging study used in the diagnosis of infective endocarditis (IE). Computed tomography angiography (CTA) has undergone rapid advancement as a cardiac imaging technique and has previously shown promise in small non-randomized studies for evaluation of IE. We hypothesized that cardiac CTA would perform similarly to TEE in the detection of endocarditic lesions and that there would be no difference in clinical outcomes whether the coronary arteries were evaluated by CTA or invasive coronary angiography (ICA). 255 adults who underwent surgery for IE at the Mayo Clinic Rochester between January 1, 2006 and June 1, 2014 were identified retrospectively. 251 patients underwent TEE and 34 patients underwent cardiac CTA. TEE had statistically higher detection of vegetations (95.6 vs. 70.0%, p < 0.0001) and leaflet perforations (81.3 vs. 42.9%, p = 0.02) as compared to cardiac CTA. For detection of abscess/pseudoaneurysm TEE had a similar sensitivity to cardiac CTA (90.5 vs. 78.4%, p = 0.21). There was no significant difference in peri-operative outcomes whether coronary arteries were evaluated by CTA or ICA. The greatest advantage of cardiac CT in the setting of IE is its ability to couple the detection of complex cardiac anatomic abnormalities with coronary artery delineation, serving two important components of the diagnostic evaluation, particularly among patients who will require surgical intervention due to IE complications. Cardiac CTA may be considered as an alternate coronary artery imaging modality in IE patients with low to intermediate risk of disease but meet guideline recommendations for coronary artery imaging.

Neuroimaging utilization and findings in headache outpatients: Significance of red and yellow flags.

Background Neuroimaging for headache commonly exceeds published guideline recommendations and may be overutilized. Methods We conducted a retrospective cross-sectional study of all outpatient community patients at Mayo Clinic Rochester who underwent a neuroimaging study for a headache indication in 2015. We assessed the neuroimaging utilization pattern, clinical application of red flags, and concordance with neuroimaging guidelines. Results We identified 190 outpatients who underwent 304 neuroimaging studies for headache. The median age was 46.5 years (range 18-91 years), 65% were female, and most reported no prior history of headache (n = 97, 51%). A minority of patients had prior brain imaging studies (n = 44, 23%) and neurological consultations for headache (n = 29, 15%). Few studies were ordered after consultation with a neurologist (n = 14, 7%). Seventy-seven percent of patients were documented to have a "red flag" justifying the imaging study. Abnormal neuroimaging findings were found in 3.1% of patients with warning flags (5/161); carotid dissection (n = 3) and reversible cerebral vasoconstrictive syndrome (n = 2). An estimated 35% of patients were imaged against guidelines. Conclusions The prevalence of serious causes of headache in a community practice was low despite the presence of a documented red flag symptom. Inadequate understanding or application of red flags may be contributing to recommendations to image patients against current guidelines. Interventions to reduce unnecessary neuroimaging of patients with headache need to be designed and implemented.

The End–of-Life Experience for International Patients: Review from a Destination Medical Center (S763)

•Recognize the unique nature of the population of seriously ill international patients.•Review the end-of-life experience of seriously ill international patients at a major US referral center. Patients from all over the world travel to the United States to receive medical care. Seriously ill international patients and their families may face barriers to goal concordant end-of-life (EOL) care, especially those whose illness severity prevents a return to their home country. Little is known about the EOL experiences of this diverse group. This review was designed to characterize the EOL experiences of all international patients that died at Mayo Clinic Rochester, a tertiary care academic medical center with a large international referral base, from 2005-2015. After institutional review board approval, charts in the electronic medical record were reviewed for patients that died from 01/01/2005-12/31/2015 with a primary address outside of the United States. Data were abstracted and analyzed with standard statistical methods. Eighty-two (n = 82) international patients meeting the inclusion criteria died at Mayo Clinic between 2005-2015 with a median age at death of 59.5 years (range 21-88). Forty-eight patients (59%) were male, and the top three countries of origin were Saudi Arabia (n = 20), Kuwait (n = 16), and Canada (n = 9). The median length of the terminal hospital stay was 13 days (range 1-231 days). Nine patients (11%) had completed an advanced directive and 74% of patients had a DNR status at time of death. Thirty-four patients (42%) received palliative medicine consultation during terminal admission at a median of 8.5 days before death. Most changes to resuscitation preferences occurred during terminal hospitalization; three patients (4%) had do not resuscitate (DNR) status on admission and 61 patients (74%) were DNR at time of death. Compared to other published datasets of American patients, our cohort demonstrated a much lower completion of advance directives (11%).

A pilot study of ponatinib in cholangiocarcinoma patients with FGFR2 fusions.

TPS532 Background: Recent studies have shown that FGFR2 fusions may represent recurrent (prevalence ~10-15% in larger cohorts) driver events amenable to therapeutic targeting in patients with advanced, intrahepatic cholangiocarcinoma. Methods: This single arm pilot study (NCT02265341) is being conducted at 3 centers (Mayo Clinic Arizona, Mayo Clinic Florida and Mayo Clinic Rochester; enrollment initiated December 2014). Next-generation sequencing based assays and a FISH-break apart assay are used to identify tumors with FGFR2 fusions. Patients must additionally have histologically/cytologically confirmed cholangiocarcinoma, ECOG performance score 0-2, measurable disease, preserved hematologic/renal and hepatic function and absence of cardiac events/stroke in the preceding 6 months. Ponatinib is administered at 45 mg once daily. Patients will be treated until disease progression, intolerable toxicity or patient decision to not pursue further therapy. The primary objective of the study is to estimate the clinical benefit rate (defined as composite of partial response rate, complete response rate and stable disease rate ≥ 4 months; as defined by RECIST criteria v1.1). Secondary endpoints include estimation of progression-free survival, overall survival, CA19-9 response rate (defined as &gt; 50% reduction from baseline) and evaluation of the overall adverse event profile of ponatinib in this patient population. Translational objectives include serial circulating DNA (ct-DNA) monitoring, target knockdown assessments in tumor tissue (p-FGFR2, p-FRS2, p-Akt and p-ERK) and evaluation of mechanisms of resistance through comparison of baseline and progression biopsy samples using multi-platform sequencing (exome, RNA-Seq and methyl-Seq). Additionally, quality of life assessments will be evaluated using EORTC-QLQ-C30 and BIL21 tools. A total of 30 patients will be enrolled into the study (12 of 30 patients have been enrolled). The trial is designed using an underlying assumption of clinical benefit rate (CBR) of 5% with significance level of 0.15 and 80% power to detect a 20% CBR. Clinical trial information: NCT02265341.

Neuroradiologic manifestations of Erdheim-Chester disease.

We describe the neuroradiologic features of a cohort of patients with Erdheim-Chester disease. We assessed patients at Mayo Clinic Rochester between January 1, 1990, and July 31, 2016, with pathologically confirmed Erdheim-Chester disease (n = 53). Neuroimaging, including head CT (n = 17), brain MRI (n = 39), orbital MRI (n = 15), and spine MRI (n = 16), was available for 42 participants. Median age at diagnosis was 55 years (interquartile range 46-66) with higher male prevalence (33:20). Neurologic symptoms were identified in 47% (25/53); BRAFV600E mutation in 58% (15/26). Median follow-up was 2 years (range 0-20) with 18 patients deceased. Radiologic disease evidence was seen in dura (6/41), brainstem (9/39), cerebellum (8/39), spinal cord (2/16), spinal epidura (2/16), hypothalamic-pituitary axis (17/39), and orbits (13/42). T2 white matter abnormalities (Fazekas score ≥1) were present in 21/34 patients. Diabetes insipidus was present in 30% (16/53); 8 had abnormal hypothalamic-pituitary axis imaging. Radiographic evidence of CNS involvement (i.e., dural, brain, including Fazekas score >1, or spinal cord) occurred in 55% (22/40) and was unassociated with significantly increased mortality. Erdheim-Chester disease commonly and variably involves the neuraxis. Patients with suspected Erdheim-Chester disease should undergo MRI brain and spine and screening investigations (serum sodium, serum and urine osmolality) for diabetes insipidus to clarify extent of neurologic disease.

Ki67 Proliferative Index in Carcinoid Tumors Involving Ovary

Primary ovarian carcinoid tumors are rare neoplasms that constitute less than 0.1% of all ovarian carcinomas. However, carcinoid tumors metastatic to ovaries are more common. Cell proliferative rate is an important factor in the determination of neuroendocrine tumor prognosis. Limited data are available as regards Ki67 proliferation index in predicting the physiological features of carcinoid tumors involving the ovary. Pathology files of Mayo Clinic Rochester (1995–2014) were searched, and clinical information was collected from medical records. All cases were stained with an antibody against Ki67, and digital analysis was performed with digital imaging analysis. A total of 36 cases (median age 64 years, range 33–83 years), including 9 primary (median age 68 years, range 33–73 years) and 27 metastatic carcinoid cases (median age 64 years, range 36–83 years), were investigated in the current study. Seven out of nine (77.8%) primary ovarian carcinoids are associated with mature teratoma. Twenty two metastatic carcinoids (81.5%) were from the GI tract, four (14.8%) from the pancreas, and one (3.7%) from the posterior thorax location. There was significant difference of Ki67 index between primary (median 2.3%, range, 0.6–8.4%) and metastatic carcinoid tumors (median 9.7%, range, 1.3–46.7%) (p = 0.002). The survival time is much shorter among patients with metastatic carcinoid tumor (median survival 5.8 years) comparing to primary ovarian carcinoid tumor (median 14.2 years) (p = 0.0005). A strong association between Ki67 index and patient survival time was identified (Hazard ratio for 1-percentage point increase 1.11, p = 0.001). Comparing to primary ovarian carcinoid tumor, metastatic carcinoid usually exhibits a higher Ki67 index and a worse outcome.

A Collaborative for Implementation of an Evidence-Based Clinical Pathway for Enhanced Recovery in Colon and Rectal Surgery in an Affiliated Network of Healthcare Organizations

In 2015 the Mayo Clinic Care Network (MCCN), in an effort to extend medical knowledge and share these best practices, embarked on an education mission to diffuse the clinical practice redesign involving the practice of colon and rectal surgery at Mayo Clinic (Rochester, Minnesota) to members of the MCCN. They elected to use a collaborative framework in an attempt to transfer knowledge to multiple teams in an efficient and supportive manner. Eight MCCN members assembled a multidisciplinary team, which participated in both a didactic learning session delivered by frontline experts, as well as follow-up remote sessions regarding Mayo Clinic's enhanced recovery pathway for colon and rectal surgery. Teams departed the group session with established immediate next steps, communication plans, and an awareness of potential barriers and strategies for mitigation. Monthly coaching calls followed in an effort to help all teams meet their time line and overall goals. Finally, all participants met again after six months to report their clinical outcomes, as well their unique individual organization's successes and barriers encountered. Participating teams felt overwhelmingly that the collaborative program exceeded their expectations and equipped them with the tools to be successful. They also felt that the extended support provided by the Mayo Clinic team was essential, and the collaboration with other members markedly enhanced their experience. Importantly, all teams were able to successfully reduce length of stay, which was the desired main clinical outcome. The collaborative format was instrumental in the rapid diffusion and successful implementation of a transformative practice redesign involving colorectal surgical care of patients.

Leisure Programming at Mayo Clinic in Rochester (MN): A Quality-of-Life and Cafeteria based Approach

Mayo Clinic, rated as the best clinic/hospital system in the United States, provides a range of leisure opportunities for patients as part of their medical service delivery. Leisure services, provided by different units throughout the medical campus, is based on decreasing stress, thus helping patients having a more optimistic and heathier psychological experience when involved in medical treatment or diagnostic procedures. Cafeteria and quality-of-life programming are the two leisure programming approaches most evident at Mayo Clinic (Rochester) and can be duplicated in other clinic/hospital settings.

Hyperglycemic chorea/ballism ascertained over 15 years at a referral medical center

ObjectiveTo describe chorea/ballism triggered by a hyperglycemic event. MethodsWe used the electronic records system at Mayo Clinic–Rochester to identify patients diagnosed with chorea or ballism from January 1st, 2000 through December 31st, 2014. Each record was reviewed to confirm chorea/ballism. From these cases we selected those that developed chorea/ballism within a month after a hyperglycemic episode (blood glucose >300 mg/dL). Clinical, laboratory, and imaging findings were analyzed. ResultsOf the 596 chorea cases, we identified 7 patients (5 women) whose chorea was preceded by a hyperglycemic episode (range 3–30 days) during 15 years of surveillance, including new-onset diabetes in four cases. Median age was 80 years (range, 53–86). The chorea/ballism was unilateral in 6/7 cases and half of these unilateral cases had contralateral putamen T1-hyperintensity on brain MRI. After glucose correction, the chorea resolved within one week without recurrence in only one case. Among the 6 cases with persistent chorea, it was controlled with dopamine blocking/depleting medications. ConclusionsChorea triggered by hyperglycemia is a rare complication of diabetes, with only seven cases identified at our tertiary medical center during 15 years of surveillance. This comprised about 1% of all chorea cases at our center during this time. Hyperglycemic chorea primarily developed in later life, with new-onset diabetes in the majority (4/7). Although MRI putamen T1-hyperintensity is reportedly typical, it was only seen in 3/6 cases. This MRI appearance may be mistaken for a hemorrhagic stroke, given the usual unilateral presentation. The chorea was controlled with dopamine blocking/depleting medications.

Using Human Phenotype Ontology for Phenotypic Analysis of Clinical Notes.

Phenotypes are defined as observable characteristics of organisms. To facilitate the translation between genotype and phenotype, Human Phenotype Ontology (HPO) was developed as a semantically computable standardized vocabulary to capture phenotypic abnormalities found in human. In this study, we investigated the use of HPO to annotate phenotypic information in clinical domain by leveraging a corpus of 12.8 million clinical notes created from 2010 to 2015 for 729 thousand patients at Mayo Clinic Rochester campus.

Phenotypic Analysis of Clinical Narratives Using Human Phenotype Ontology.

Phenotypes are defined as observable characteristics and clinical traits of diseases and organisms. As connectors between medical experimental findings and clinical practices, phenotypes play vital roles in translational medicine. To facilitate the translation between genotype and phenotype, Human Phenotype Ontology (HPO) was developed as a semantically computable vocabulary to capture phenotypic abnormalities found in human diseases discovered through biomedical research. The use of HPO in annotating phenotypic information in clinical practice remains unexplored. In this study, we investigated the use of HPO to annotate phenotypic information in clinical domain by leveraging a corpus of 12.8 million clinical notes created from 2010 to 2015 for 729 thousand patients at Mayo Clinic Rochester campus and assessed the distribution information of HPO terms in the corpus. We also analyzed the distributional difference of HPO terms among demographic groups. We further demonstrated the potential application of the annotated corpus to support knowledge discovery in precision medicine through Wilson's Disease.

Outcomes of hospitalization in adults with Fontan palliation: The Mayo Clinic experience

This was a retrospective study of adult Fontan patients hospitalized at Mayo Clinic Rochester in 1990-2015. We selected age- and gender-matched control group of patients with repaired CHD and biventricular circulation hospitalized within the study period. A total of 367 Fontan patients (age 31±7 years and 259 [71%] with atriopulmonary Fontan) had 853 hospital admissions in 4 years (58 hospitalizations per 100 patient-years). The most common indications were arrhythmia (n=188, 22%), heart failure (n=169, 20%), and cardiac surgery (n=133, 16%). Overall in-hospital mortality was 4% (n=38), and the highest in-hospital mortality occurred in patients hospitalized for cardiac surgery (n=15, 11%) and heart failure (n=13, 8%). In comparison to the repaired CHD and biventricular circulation group, the Fontan group had more frequent hospitalizations (22 vs 58 per 100 patient-years, P<.001) and higher overall in-hospital mortality (1% vs 5%, P<.001), mortality after cardiac surgery (2% vs 11%, P=.01), and mortality for heart failure-related hospitalizations (2% vs 8%, P=.04). Adults with Fontan palliation had more frequent hospitalization and in-hospital mortality compared to the rest of the CHD population. Arrhythmia and heart failure were the most common indications for hospitalization. Perhaps optimal management of heart failure and arrhythmia may improve outcomes in this population.

Machine Learning in Detection of Undiagnosed Celiac Disease

Machine Learning in Detection of Undiagnosed Celiac Disease

Association between atopic dermatitis and squamous cell carcinoma: a case-control study.

Conflicting data have been published on whether an association exists between atopic dermatitis (AD) and nonmelanoma skin cancer. This study aimed to determine whether individuals with AD had an increased risk of squamous cell carcinoma (SCC) development. We conducted a retrospective, case-control study of patients residing in Olmsted County, Minnesota. Cases were selected from patients seen at Mayo Clinic (Rochester, Minnesota) who had an initial SCC diagnosis (either invasive SCC or SCC insitu) from January 1, 1996, through December 23, 2010. Age- and sex-matched controls were selected from patients seen at Mayo Clinic with no history of SCC before the case event date. Three hundred ninety-nine individuals with a documented history of SCC were identified and matched with 780 controls who did not have a history of SCC. After adjusting for race, smoking history, ionizing radiation exposure, corticosteroid and cyclosporine use, and non-SCC skin cancers, the odds ratio for SCC development between patients with history of AD versus patients without history of AD was 1.75 (95% CI, 1.05-2.93). Our findings support an increased risk of SCC development in the setting of AD.

Neoadjuvant systemic therapy for regionally advanced melanoma.

Patients with regionally advanced melanoma are at high risk of distant failure and unlikely to be cured by surgery alone. Neoadjuvant therapy may provide benefit in these patients. To evaluate our experience with neoadjuvant systemic therapy in high-risk stage III patients. Retrospective review of patients with advanced stage III disease who received neoadjuvant therapy between August 2009 and August 2016 at Mayo Clinic Rochester. Twenty-three cases met our inclusion criteria, 16 with resectable disease and 7 with unresectable disease. No patients with resectable disease and one patient with borderline resectable disease progressed regionally, prohibiting surgical resection. Five of seven patients with unresectable disease were down-staged to a resectable state. Six of twenty-three (26%) had a CR and five are alive at last follow-up. Fifteen of twenty three patients (65%) progressed with a median progression free survival of 11 months; however, the 5 year overall survival estimate was 84%. Neoadjuvant systemic therapy is a reasonable approach for patients with advanced but resectable/borderline resectable disease and the risk of losing regional control is low. Our data also suggest some patients with unresectable disease will be converted to resectable and a complete clinical response to treatment can be obtained in approximately one quater of patients.

Spotlight on ponatinib in the treatment of chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia: patient selection and perspectives.

Ponatinib, a third-generation tyrosine kinase inhibitor that inhibits BCR/ABL independent of the mutation status, is currently approved for the treatment of patients with chronic myeloid leukemia or acute lymphoblastic leukemia that are either resistant or unable to tolerate another tyrosine kinase inhibitor. Its US Food and Drug Administration approval was based on results from long-term follow-up of the pivotal Phase II PACE trial, which demonstrated deep and durable molecular responses in the treated patients. Despite the remarkable responses, ponatinib has been associated with high frequency of severe vascular events, which led to its withdrawal from the market in 2013. Following analysis of the risk factors of patients who developed vascular side effects, ponatinib was reintroduced in the market 1 year later with specific dose-reduction recommendations and carrying a black box warning. Thus, careful patient selection with identification of patients whose potential benefit from ponatinib exceeds the potential risks associated with its use is crucial. Ongoing and future studies are focusing on earlier detection of mutations, strategies to minimize side effects, and potential expansion of the treatment indications. Clinical trials testing the safety and efficacy of ponatinib as frontline therapy are ongoing.

Clinical, Radiographic, and Microbiologic Features of Infective Endocarditis in Patients With Hypertrophic Cardiomyopathy

Infective endocarditis (IE) is an infection of the inner lining of the heart with high morbidity and mortality despite medical and surgical advancements in recent decades. Hypertrophic cardiomyopathy (HC) is one of several medical conditions that have been linked to an increased risk of IE, but there is a paucity of data on this association. We therefore sought to define the clinical phenotype of IE in patients with HC at a single tertiary care center. A retrospective cohort of 30 adult patients with HC diagnosed with IE between January 1, 2006 and December 31, 2016 at Mayo Clinic Rochester were identified. Similar rates of aortic (n = 14) and mitral (n = 16) valve involvement by IE were noted (47% vs 53%). This finding persisted even in patients with left-ventricular outflow tract obstruction and systolic anterior motion of the mitral valve. Symptomatic embolic complications occurred in 10 cases (33%). Surgical intervention was performed in 11 cases (37%). One-year mortality was remarkably low at 7%. In conclusion, in the largest single-center cohort of IE complicating HC, there were similar rates of both mitral and aortic valve involvement regardless of the presence of left ventricular outflow tract obstruction, which is contrary to a long-standing tenet regarding the association of HC and IE. Moreover, no "high risk" IE subset was identified based on HC-related parameters.

Medical therapy versus radiofrequency endometrial ablation in the initial treatment of heavy menstrual bleeding (iTOM Trial): A clinical and economic analysis.

BackgroundRadiofrequency endometrial ablation (REA) is currently a second line treatment in women with heavy menstrual bleeding (MHB) if medical therapy (MTP) is contraindicated or unsatisfactory. Our objective is to compare the effectiveness and cost burden of MTP and REA in the initial treatment of HMB.MethodsWe performed a randomized trial at Mayo Clinic Rochester, Minnesota. The planned sample size was 60 patients per arm. A total of 67 women with HMB were randomly allocated to receive oral contraceptive pills (Nordette ®) or Naproxen (Naprosyn®) (n = 33) or REA (n = 34). Primary 12-month outcome measures included menstrual blood loss using pictorial blood loss assessment chart (PBLAC), patients’ satisfaction, and Menorrhagia Multi-Attribute Scale (MMAS). Secondary outcomes were total costs including direct medical and indirect costs associated with healthcare use, patient out-of-pocket costs, and lost work days and activity limitations over 12 months.ResultsCompared to MTP arm, women who received REA had a significantly lower PBLAC score (median [Interquartile range, IQR]: 0 [0–4] vs. 15 [0–131], p = 0.003), higher satisfaction rates (96.8%vs.63.2%, p = 0.003) and higher MMAS (median [IQR]: 100 [100–100] vs. 100 [87–100], p = 0.12) at 12 months. Direct medical costs were higher for REA ($5,331vs.$2,901, 95% confidence interval (CI) of mean difference:$727,$4,852), however, when indirect costs are included, the difference did not reach statistical significance ($5,469 vs. $3,869, 95% CI of mean difference:-$339, $4,089).ConclusionFor women with heavy menstrual bleeding, initial radiofrequency endometrial ablation compared to medical therapy offered superior reduction in menstrual blood loss and improvement in quality of life without significant differences in total costs of care.Clinical trial registrationNCT01165307.