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Background: To prepare engineers who can address complex sociotechnical problems, a deep understanding of engineers' complex problem-solving approaches is needed. Purpose/Hypothesis: This study operationalizes comprehensive systems thinking as an analysis framework that attends to aspects of engineering work and relationships among those aspects. Leveraging this framework to analyze engineers' complex problem-solving approaches enables attention to social and technical dimensions. Design/Method: We interviewed 46 engineers about their specific complex problem-solving experiences. To explore a range of perspectives, we purposely sampled participants with varying academic, professional, and personal backgrounds and experiences. Data analysis focused on operationalizing comprehensive systems thinking; we first developed a set of aspects that captured the variety of considerations that participants discussed in their descriptions of solving a complex problem. We then inductively developed a scoring guide to differentiate response quality. Results: The scoring approach differentiated the quality of consideration based on a combination of the number of details provided, the degree of specificity, and analytical depth. While most participants discussed the consideration of a wide range of aspects of engineering work, they discussed far fewer possible relationships between these aspects. Contextual aspects of engineering work were consistently the least commonly identified and least likely to be considered in relation to other aspects of a given problem. Conclusions: Our differentiation of various complex problem-solving approaches can guide the development of educational interventions and tools, ultimately facilitating more comprehensive consideration of aspects--and in particular relationships among aspects--and setting up engineers to be more successful at developing appropriate solutions.

Background Despite improvement in devices, in‐stent restenosis remains a frequent and challenging complication of percutaneous coronary interventions. Methods and Results The RESTO (Morphological Parameters of In‐Stent Restenosis Assessed and Identified by OCT [Optical Coherence Tomography]; study NCT04268875) was a prospective multicenter registry including patients presenting with coronary syndromes related to in‐stent restenosis. All patients underwent preintervention OCT analysis, which led to analysis of in‐stent restenosis phenotype, number of strut layers, and presence of stent underexpansion. The primary end point was the in‐stent restenosis type according to the OCT morphological classification. The 1‐year incidence of target vessel failure (a composite of death from cardiac causes, target‐vessel myocardial infarction, or ischemia‐driven target‐vessel revascularization) was assessed. The study included 297 patients. The culprit stent was a drug‐eluting stent in 74.2% of cases. OCT analysis revealed the presence of neoatherosclerosis in 57% (52% calcified), neointimal hyperplasia in 43% (58% homogeneous), stent underexpansion (minimal stent area

El movimiento de las personas depende de la acción del sistema nervioso sobre grupos musculares específicos que se apoyan sobre la estructura ósea. Algunos procesos patológicos pueden causar alteraciones de la fuerza y coordinación que debe existir entre las respuestas musculares, causando alteraciones en el movimiento esperado. En su fase inicial, la mayoría de estas alteraciones pasan desapercibidas hasta que los daños físicos afectan notoriamente la actividad humana, y en muchos casos de manera irreparable. Actualmente, el método más utilizado para el análisis de la marcha humana se basa en el estudio fotométrico secuencial en espacio limitado, aunque en menor medida también se utilizan sistemas de posicionamiento digital. Este proyecto aborda el desarrollo de tecnología para la captura biométrica del movimiento humano mediante sensores de medición inercial. La idea es detallar el desplazamiento espacial de secciones específicas del cuerpo a partir de la medición de aceleración y la velocidad angular, con el propósito de valorar la respuesta de las articulaciones involucradas. El objetivo es desarrollar un sistema que permita a los médicos especialistas identificar anomalías en el movimiento del paciente en estudio. Los resultados preliminares demuestran la eficiencia del sensor inercial implementado. Utilizando 7 sensores ubicados estratégicamente en el cuerpo del paciente y con una velocidad de adquisición de 100 muestras por segundo en cada sensor, es posible detallar movimientos de marcha menores a 7,5 milímetros y precisión en velocidad angular de hasta 0,1°/0,01 segundo. Con el desarrollo de este instrumento se consigue la capacidad de visualizar y analizar movimientos que normalmente son imperceptibles para el ojo humano.

Abstract Conflicting results remain on the impacts of climate change on marine organisms, hindering our capacity to predict the future state of marine ecosystems. To account for species-specific responses and for the ambiguous relation of most metrics to fitness, we develop a meta-analytical approach based on the deviation of responses from reference values (absolute change) to complement meta-analyses of directional (relative) changes in responses. Using this approach, we evaluate responses of fish and invertebrates to warming and acidification. We find that climate drivers induce directional changes in calcification, survival, and metabolism, and significant deviations in twice as many biological responses, including physiology, reproduction, behavior, and development. Widespread deviations of responses are detected even under moderate intensity levels of warming and acidification, while directional changes are mostly limited to more severe intensity levels. Because such deviations may result in ecological shifts impacting ecosystem structures and processes, our results suggest that climate change will likely have stronger impacts than those previously predicted based on directional changes alone.

Lithodes santolla (SKC) and Paralomis granulosa (FSKC) are economically important resources exploited in southern South America. The effect of refrigerated storage (4 °C on flake ice) on physico-chemical (pH, thiobarbituric reactive substances (TBARs), total volatile basic nitrogen (TVB-N), water holding capacity (WHC), and water content (WC)), microbiological (total viable mesophilic bacteria (TVMC), psychrotrophic bacteria (TVPC), Staphylococcus spp, coliforms, enterobacteria, molds and yeasts) and sensory (odor, appearance, texture, juiciness, and taste) parameters was analyzed in the cooked SKC and FSKC merus. For each species, cooked merus from 36 animals were randomly distributed into 6 groups, corresponding to 0, 2, 5, 8, 11, and 14 days of storage. On each day, samples were taken for physico-chemical (n = 6), microbiological (n = 3), and sensory (n = 15) analyses. The pH values increased over time (P 0.05) in all cases. The presence of TVCM, TVCP, and Staphylococcus spp. in both species was observed from day 0. Furthermore, pathogenic microorganisms (S. aureus, coliforms, and enterobacteria) were not detected, and only the TVCP in SFKC reached the suggested microbial limit after 11 days. All sensory scores significantly decreased (P

Background: Personal characteristics (e.g., race/ethnicity, gender, and precollege experiences) are known to shape students' pathways to engineering, as well as persistence decisions in college. However, the role of psychological cost in postgraduation intentions has received less scholarly attention. Purpose: The purpose of this study is to examine sociocognitive factors that shape students' postgraduation intentions in the early college years. Guided by Social Cognitive Career Theory and the concept of psychological cost, we examine the role of self-efficacy beliefs, outcome expectations, and psychological cost, as well as key background characteristics, in students' postgraduation intentions. Method: We analyzed survey responses from four cohorts of undergraduate engineering students at a large public university. Participants responded to items measuring self-efficacy beliefs, outcome expectations, and psychological cost after their first and second years of college. We used structural equation modeling to examine the relationships between the sociocognitive variables and students' graduate school and career intentions. Results: The sociocognitive variables predicting postgraduation intentions after Year 1 differed from those predicting intentions after Year 2. After Year 1, we found no statistically significant sociocognitive variables predicting graduate school intentions or engineering career plans. After Year 2, both self-efficacy and outcome expectations were significant predictors of postgraduation intentions. The psychological cost was significantly related to both self-efficacy and outcome expectations. Finally, we found significant differences in racial/ethnic identity, sex, and first-generation status. Conclusion: Examining psychological cost provides additional insights into the factors informing students' postgraduation intentions over the course of their collegiate careers and suggests new directions for research on students' thinking about engineering careers.

Abstract Aims Impact of skin mottling has been poorly studied in patients admitted for cardiogenic shock. This study aimed to address this issue and identify determinants of 30-day and 1-year mortality in a large cardiogenic shock cohort of all etiologies. Methods and results FRENSHOCK is a prospective multicenter observational registry conducted in French critical care units between April and October, 2016. Among the 772 enrolled patients (mean age 65.7 ± 14.9 years; 71.5% male), 660 had skin mottling assessed at admission (85.5%) with almost 39% of patients in cardiogenic shock presenting mottling. The need for invasive respiratory support was significantly higher in patients with mottling (50.2% vs. 30.1%, p

Background The effects of pharmacological therapy on cardiogenic shock (CS) survivors have not been extensively studied. Thus, this study investigated the association between guideline‐directed heart failure (HF) medical therapy (GDMT) and one‐year survival rate in patients who are post‐CS. Methods and Results FRENSHOCK (French Observatory on the Management of Cardiogenic Shock in 2016) registry was a prospective multicenter observational survey, conducted in metropolitan French intensive care units and intensive cardiac care units. Of 772 patients, 535 patients were enrolled in the present analysis following the exclusion of 217 in‐hospital deaths and 20 patients with missing medical records. Patients with triple GDMT (beta‐blockers, renin‐angiotensin system inhibitors, and mineralocorticoid receptor antagonists) at discharge (n=112) were likely to have lower left ventricular ejection fraction on admission and at discharge compared with those without triple GDMT (n=423) (22% versus 28%, P

Conclusion: Despite a higher risk profile of patients in the SC group, SC and PC approaches appear safe and effective in TF TAVR, with a high success rate. SC may be considered when vascular access is anticipated as complex, but this strategy might be confirmed in a randomized study.

Summary: Background: Smoking cigarettes produces carbon monoxide (CO), which can reduce the oxygen-carrying capacity of the blood. We aimed to determine whether elevated expiratory CO levels would be associated with a worse prognosis in smokers presenting with acute cardiac events. Methods: From 7 to 22 April 2021, expiratory CO levels were measured in a prospective registry including all consecutive patients admitted for acute cardiac event in 39 centres throughout France. The primary outcome was 1-year all-cause death. Initial in-hospital major adverse cardiac events (MAE; death, resuscitated cardiac arrest and cardiogenic shock) were also analysed. The study was registered at ClinicalTrials.gov (NCT05063097). Findings: Among 1379 patients (63 ± 15 years, 70% men), 368 (27%) were active smokers. Expiratory CO levels were significantly raised in active smokers compared to non-smokers. A CO level >11 parts per million (ppm) found in 94 (25.5%) smokers was associated with a significant increase in death (14.9% for CO > 11 ppm vs. 2.9% for CO ≤ 11 ppm; p 11 ppm was associated with a significant increase in MAE in smokers during initial hospitalisation after adjustment for comorbidities (odds ratio [OR] 15.75, 95% CI [5.56–44.60]) or parameters of in-hospital severity (OR 10.67, 95% CI [4.06–28.04]). In the overall population, CO > 11 ppm but not smoking was associated with an increased rate of all-cause death (HR 4.03, 95% CI [2.33–6.98] and 1.66 [0.96–2.85] respectively). Interpretation: Elevated CO level is independently associated with a 6-fold increase in 1-year death and 10-fold in-hospital MAE in smokers hospitalized for acute cardiac events. Funding: Grant from Fondation Coeur & Recherche.

A common perception of biomedical engineering (BME) undergraduates is that they struggle to find industry jobs upon graduation. While some statistics support this concern, students continue to pursue and persist through BME degrees. This persistence may relate to graduates' other career interests, though limited research examines where BME students go and why. Scholars are also pushing for research that examines engineering careers in a broader context, beyond traditional industry positions. This study adds to that conversation by asking: How do BME students describe their career interests and perceived job prospects in relation to why they pursue a BME degree? A qualitative study of BME students was performed at a public, R1 institution using semi-structured interviews at three timepoints across an academic year. An open coding data analysis approach explored career-perceptions of students nearing completion of a BME undergraduate degree. Findings indicated that students pursued a BME degree for reasons beyond BME career aspirations, most interestingly as a means to complete an engineering degree that they felt would have interesting enough content to keep them engaged. Participants also discussed the unique career-relevant skills they developed as a BME student, and the career-placement tradeoffs they associated with getting a BME undergraduate degree. Based on these results, we propose research that explores how students move through a BME degree into a career and how career-relevant competencies are communicated in job searches. Additionally, we suggest strategies for BME departments to consider for supporting students through the degree into a career.

BackgroundCardiogenic shock (CS) is the most severe form of heart failure (HF), resulting in high early and long-term mortality. Characteristics of CS secondary to supraventricular tachycardia (SVT) are poorly reported. Based on a large registry of unselected CS, we aimed to compare 1-year outcomes between SVT-triggered and non-SVT-triggered CS.MethodsFRENSHOCK is a French prospective registry including 772 CS patients from 49 centers. For each patient, the investigator could report 1–3 CS triggers from a pre-established list (ischemic, mechanical complications, ventricular/supraventricular arrhythmia, bradycardia, iatrogenesis, infection, non-compliance, and others). In this study, 1-year outcomes [rehospitalizations, mortality, heart transplantation (HTx), ventricular assist devices (VAD)] were analyzed and adjusted for independent predictive factors.ResultsAmong 769 CS patients included, 100 were SVT-triggered (13%), of which 65 had SVT as an exclusive trigger (8.5%). SVT-triggered CS patients exhibited a higher proportion of male individuals with a more frequent history of cardiomyopathy or chronic kidney disease and more profound CS (biventricular failure and multiorgan failure). At 1 year, there was no difference in all-cause mortality (43% vs. 45.3%, adjusted HR 0.9 (95% CI 0.59–1.39), p = 0.64), need for HTx or VAD [10% vs. 10%, aOR 0.88 (0.41–1.88), p = 0.74], or rehospitalizations [49.4% vs. 44.4%, aOR 1.24 (0.78–1.98), p = 0.36]. Patients with SVT as an exclusive trigger presented more 1-year rehospitalizations [52.8% vs. 43.3%, aOR 3.74 (1.05–10.5), p = 0.01].ConclusionSVT is a frequent trigger of CS alone or in association in more than 10% of miscellaneous CS cases. Although SVT-triggered CS patients were more comorbid with more pre-existing cardiomyopathies and HF incidences, they presented similar rates of mortality, HTx, and VAD at 1 year, arguing for a better overall prognosis.Clinical Trial Registrationhttps://clinicaltrials.gov, identifier: NCT02703038.

Background: Co-curricular student outcomes research has focused on connecting outcomes to activities based on the co-curricular type. Less work has explored what aspects of those co-curricular activities could lead to student outcomes. Purpose: Our research aimed to identify common elements of co-curricular activities that connected to students’ development of professional, career, or personal outcomes and can inform how we study and design co-curricular activities in engineering. Design: We recruited participants from one biomedical engineering (BME) program. We used a one-year series of four semi-structured interviews with fourteen upper-level BME students to explore students’ perceptions of their co-curricular learning. Using a qualitative, causal analysis approach, we identified elements of students’ co-curricular experiences in research or a multi-disciplinary design team, as well as other co-curricular experiences (e.g., internships, professional societies), that linked to professional, career, or personal learning outcomes that have been previously identified as important in engineering education. Findings: We identified patterns of connections between unique “experience elements” and a variety of “outcome categories” through participant activities we called “participant actions.” The most prevalent connections—those experience elements and participant actions that connected to multiple outcome categories—included the experience elements Independent Project Work, Project Work That Engages Multiple Disciplines, STEM Education Opportunities, and Mentorship from a Skilled Other as well as a participant action Reflecting on Experience. We found connections to the outcome categories of Leadership, Design, Business, Interdisciplinary Competence, Disciplinary Competence, Communication, and Career Direction Outcomes. Conclusions: Based on our findings, educators and mentors should consider the value of supporting students’ decision-making autonomy and multidisciplinary interactions in projects to support learning. They could also incorporate opportunities for students to teach each other technical content, receive structured mentorship, and reflect on their experiences as they are happening. Further, this work demonstrates a need to explore co-curricular learning processes in new ways that can lead to better understandings of students’ learning processes.

Background: Percutaneous (PC) access has become the first‐line strategy for transfemoral (TF) transcatheter aortic valve replacement (TAVR), but surgical cutdown (SC) may be required in selected and usually challenging cases. We aimed to compare the efficacy and safety of SC versus echo‐guided PC approach in TF TAVR. Methods: Between November 2019 and December 2020, all patients undergoing TF TAVR were included in a prospective study. The choice of PC or SC strategy was left at operators' discretion, according to predictable access site difficulties. The primary endpoint included all vascular complications (VCs) and all bleeding at 1‐month follow‐up according to Valve Academic Research Consortium‐2 criteria. Results: Among 225 patients, 166 (73.8%) and 59 (26.2%) underwent PC or SC approach, respectively. Median age was 82 years, EuroSCORE 2 was higher (p = 0.02), and peripheral arterial disease (p < 0.001) was more common in the SC group. Femoral access was successful in 100% in the SC group vs 97.6% in the PC group (p = 0.2). The primary endpoint was reached in 32 patients (14.2%), 5 (8.4%) in the SC group and 27 (16.2%) in the PC group (p = 0.1) with low incidence of major VC in both groups (1.7% vs 3% in the SC and PC groups respectively, p = 0.6). Conclusion: Despite a higher risk profile of patients in the SC group, SC and PC approaches appear safe and effective in TF TAVR, with a high success rate. SC may be considered when vascular access is anticipated as complex, but this strategy might be confirmed in a randomized study. Trial Registration: ClinicalTrials.gov identifier: NCT03865043 [ABSTRACT FROM AUTHOR]

Background: Systematic revascularization of asymptomatic coronary artery stenosis before transcatheter aortic valve replacement (TAVR) is controversial. Purpose: The purpose of this study was to evaluate the feasibility and safety of functional evaluation of coronary artery disease (CAD) followed by selective ischemia-guided percutaneous coronary revascularization following TAVR. Methods: This prospective, bi-centric, single-arm, open-label trial included all patients with severe aortic stenosis (AS) eligible for TAVR and with significant CAD defined as ≥1 coronary stenosis ≥ 70%. Patients with left main stenosis ≥ 50%, proximal left anterior descending artery (LAD) stenosis ≥ 90% or > class 2 Canadian Classification Society (CCS) angina were excluded. Myocardial ischemia was evaluated by stress cardiac imaging one month after TAVR. The primary endpoint was a composite of all-cause death, stroke, major bleeding (Bleeding Academic Research Consotium ≥ 3), major vascular complication (Valve Academic Research Consortium 3 criteria), acute coronary syndrome (ACS) and hospitalization for cardiac causes within 6 months of receiving TAVR. Results: Between June 2020 and June 2022, 64 patients were included in this study. The mean age was 84 ± 5.2 years. CAD mostly involved LAD (n = 27, 42%) with frequent multivessel disease (n = 30, 47%) and calcified lesions (n = 39, 61%). Stress cardiac imaging could be achieved in 70% (n = 46) of the patients, while 30% (n = 18) did not attend the stress test. Significant myocardial ischemia was observed in only three patients (4.5%). At 6-month follow-up, fifteen patients (23%) reached the primary endpoint, including death in six patients (9%), stroke in three patients (5%) and major bleeding in three patients (5%). ACS was observed in only two patients (3%) but both had severe coronary stenosis (≥90%) and did not refer for stress imaging for personal reasons. Hospital readmission (n = 27, 41%) was mostly related to non-cardiac causes (n = 17, 27%). Conclusions: In patients with asymptomatic CAD scheduled to undergo TAVR, a selective ischemia-guided coronary revascularization after TAVR seems to be safe, with a very low rate of ACS and few cases of myocardial ischemia requiring revascularization, despite low adherence to medical follow-up in this elderly population. This strategy could be evaluated in a randomized study. [ABSTRACT FROM AUTHOR]

Abstract Aims Published data on cardiogenic shock (CS) are scarce and are mostly focused on small registries of selected populations. The aim of this study was to examine the current CS picture and define the independent correlates of 30 day mortality in a large non‐selected cohort. Methods and results FRENSHOCK is a prospective multicentre observational survey conducted in metropolitan French intensive care units and intensive cardiac care units between April and October 2016. There were 772 patients enrolled (mean age 65.7 ± 14.9 years; 71.5% male). Of these patients, 280 (36.3%) had ischaemic CS. Organ replacement therapies (respiratory support, circulatory support or renal replacement therapy) were used in 58.3% of patients. Mortality at 30 days was 26.0% in the overall population (16.7% to 48.0% depending on the main cause and first place of admission). Multivariate analysis showed that six independent factors were associated with a higher 30 day mortality: age [per year, odds ratio (OR) 1.06, 95% confidence interval (CI): 1.04–1.08], diuretics (OR 1.74, 95% CI: 1.05–2.88), circulatory support (OR 1.92, 95% CI: 1.12–3.29), left ventricular ejection fraction

Abstract Background Cardiogenic shock (CS) is a life-threatening condition characterized by circulatory insufficiency caused by an acute dysfunction of the heart pump. The pathophysiological approach to CS has recently been enriched by the tissue consequences of low flow, including inflammation, endothelial dysfunction, and alteration of the hypothalamic-pituitary-adrenal axis. The aim of the present trial is to evaluate the impact of early low-dose corticosteroid therapy on shock reversal in adults with CS. Method/design This is a multicentered randomized, double-blind, placebo-controlled trial with two parallel arms in adult patients with CS recruited from medical, cardiac, and polyvalent intensive care units (ICU) in France. Patients will be randomly allocated into the treatment or control group (1:1 ratio), and we will recruit 380 patients (190 per group). For the treatment group, hydrocortisone (50 mg intravenous bolus every 6 h) and fludrocortisone (50 μg once a day enterally) will be administered for 7 days or until discharge from the ICU. The primary endpoint is catecholamine-free days at day 7. Secondary endpoints include morbidity and all-cause mortality at 28 and 90 days post-randomization. Pre-defined subgroups analyses are planned, including: postcardiotomy, myocardial infarction, etomidate use, vasopressor use, and adrenal profiles according the short corticotropin stimulation test. Each patient will be followed for 90 days. All analyses will be conducted on an intention-to-treat basis. Discussion This trial will provide valuable evidence about the effectiveness of low dose of corticosteroid therapy for CS. If effective, this therapy might improve outcome and become a therapeutic adjunct for patients with CS. Trial registration ClinicalTrials.gov , NCT03773822 . Registered on 12 December 2018

Introduction: Patients with cancer have an increased risk of developing venous thromboembolism (VTE), and subsequently a higher risk of bleeding secondary to anticoagulants. Low-molecular weight heparin (LMWH) has been the standard of care for these patients, with emerging data on the use of direct oral anticoagulants (DOACs). The primary objective of the study was to determine the prevalence of major bleeding events in cancer patients taking DOACs or LMWH for VTE. Secondary objectives included the rate of first VTE recurrence and the effect of concomitant antiplatelet agents and/or significant drug interactions on major bleeding or recurrent VTE. Materials and methods: Using the electronic medical record at the University of Rochester Medical Center, we retrospectively identified adult patients with active malignancy who had a diagnosis of VTE requiring therapeutic anticoagulation within the study period of July 1st, 2015 to June 1st, 2019. Patients were excluded if they were receiving prophylactic doses of LMWH per the institution VTE guidelines. Data on anticoagulant medications were collected as well as information on major bleeding and recurrent VTE events. Results and conclusions: There is insufficient evidence of difference in risk of major bleeding among patients who received a DOAC vs LMWH (cause-specific hazard ratio (HR) = 0.77, 95% CI 0.29–2.04, P = 0.60). There was also no evidence of a difference in risk of recurrent VTE between patients who received DOAC vs. LMWH (cause-specific HR = 0.98, 95% CI 0.15–6.26, P = 0.98). These results suggest that DOACs are not significantly less safe than LMWH for patients with cancer.

BackgroundCardiogenic shock (CS) is a life-threatening condition carrying poor prognosis, potentially triggered by ventricular arrhythmia (VA). Whether the occurrence of VA as trigger of CS worsens the prognosis compared to non-VA triggers remains unclear. The aim of this study was to evaluate 1-year outcomes [mortality, heart transplantation, ventricular assist devices (VAD)] between VA-triggered and non-VA-triggered CS.MethodsFRENSHOCK is a prospective multicenter registry including 772 CS patients from 49 centers. One to three triggers can be identified in the registry (ischemic, mechanical complications, ventricular/supraventricular arrhythmia, bradycardia, iatrogenesis, infection, non-compliance). Baseline characteristics, management and 1-year outcomes were analyzed according to the VA-trigger in the CS population.ResultsWithin 769 CS patients included, 94 were VA-triggered (12.2%) and were compared to others. At 1 year, although there was no mortality difference [42.6 vs. 45.3%, HR 0.94 (0.67–1.30), p = 0.7], VA-triggered CS resulted in more heart transplantations and VAD (17 vs. 9%, p = 0.02). Into VA-triggered CS group, though there was no 1-year mortality difference between ischemic and non-ischemic cardiomyopathies [42.5 vs. 42.6%, HR 0.97 (0.52–1.81), p = 0.92], non-ischemic cardiomyopathy led to more heart transplantations and VAD (25.9 vs. 5%, p = 0.02).ConclusionVA-triggered CS did not show higher mortality compared to other triggers but resulted in more heart transplantation and VAD at 1 year, especially in non-ischemic cardiomyopathy, suggesting the need for earlier evaluation by advanced heart failure specialized team for a possible indication of mechanical circulatory support or heart transplantation.Clinical trial registrationhttps://clinicaltrials.gov, identifier NCT02703038.