Potential Candidates for Emergency Department Initiated Extracorporeal Cardiopulmonary Resuscitation (ECPR) in a Canadian Institution.

Introduction Out-of-hospital cardiac arrest (OHCA) patients experience poor survival. The use of extracorporeal membrane oxygenation (ECMO), a form of heart-lung bypass, in the setting of cardiac arrest, termed extracorporeal cardiopulmonary resuscitation (ECPR), has promise in improving survival with good neurologic outcomes. The study objective was to determine the number of potential annual ECPR candidates among the OHCA population in a health region within the Atlantic Canadian province of Nova Scotia. Methods A retrospective chart review was conducted over a five-year period: January 1st, 2012 to December 31st, 2016. Consecutive non-traumatic OHCA and emergency department (ED) cardiac arrests occurring in a pre-determined catchment area (20-minute transport to ECMO center) defined by a geographic bounding box were identified. Criteria for ECPR were developed to identify candidates for activation of a "Code ECPR": (1) age 16-70, (2) witnessed arrest, (3) no flow duration (time to CPR, including bystander) <10 minutes, (4) resuscitation >10 minutes without return of spontaneous circulation (ROSC), (5) emergency medical service (EMS) transport to hospital <20 minutes, (6) no patient factors precluding ongoing resuscitation (do not resuscitate status (DNR), palliative care involvement, or metastatic cancer), and (7) initial rhythm not asystole. Candidates were stratified by initial rhythm. Candidates were considered ultimately ED ECPR eligible if they failed conventional treatment, defined by death or resuscitation >30 minutes. Clinical data related to candidacy was extracted by an electronic query from prehospital and ED electronic records and manual chart review by three researchers. Results Our search yielded 561 cases of EMS-treated OHCA or in-ED arrests. Of those 204/561 (36%; 95% CI 33-40%) met the criteria for activation of a "Code ECPR". Ultimately 79/204 (34%; 95% CI 28-41%) of those who met activation criteria were considered ED ECPR eligible; which is 14% (95% CI 11-17%) of the total number of arrests-of the total number of arrests, the initial rhythms were pulseless electrical activity (PEA) 33/79 (42%; 95% CI 32-53%) and shockable 46/79 (58%; 95% CI 47-69%). Conclusion Of all cardiac arrests in the area surrounding our ECMO center, approximately 41 per year met the criteria for a Code ECPR activation, with 16 per year ultimately being eligible for ED ECPR. This annual estimate varies based on the inclusion of initial rhythm. This provides insight into both prehospital and hospital implications of an ED ECPR program and will help guide the establishment of a program within our Nova Scotian health region. This study also provides a framework for similar investigation at other institutions contemplating ED ECPR program implementation.

CEPP: Canadian Extracorporeal Life Support (ECLS) Protocol Project.

Background: Extracorporeal life support (ECLS) is associated with high morbidity and mortality. Complications and mortality are higher at lower-volume centres. Most Canadian ECLS institutions are low-volume centres. Protocols offer one way to share best practices among institutions to improve outcomes. Whether Canadian centres have ECLS protocols, and whether these protocols are comprehensive and homogenous across centres, is unknown. Methods: Purposeful sampling with mixed methods was used. A Delphi panel defined key elements relevant to the ECLS process. Documentation used in the delivery of ECLS services was requested from programs. Institutional protocols were assessed using deductive coding to determine the presence of key elements. Results: A total of 37 key elements spanning 5 domains (referral, initiation, maintenance, termination, and administration) were identified. Documentation from 13 institutions across 10 provinces was obtained. Institutions with heart or lung transplantation programs had more-complete documentation than did non-transplantation programs. Only 5 key elements were present in at least 50% of protocols (anticoagulation strategy, ventilation strategy, defined referral process, selection criteria, weaning process), and variation was seen in how institutions approached each of these elements. Conclusions: The completeness of ECLS protocols varies across Canada. Programs describe variable approaches to key elements. This variability might represent a lack of evidence or consensus in these areas and creates the opportunity for collaboration among institutions to share protocols and best practice. The key-element framework provides a common language that programs can use to develop ECLS programs, initiate quality-improvement projects, and identify research agendas.

Introduction: L'assistance cardiorespiratoire extracorporelle (ACRE) est associée à des taux élevés de morbidité et de mortalité. Les taux de complications et de mortalité sont plus élevés dans les centres à volume plus faible. La plupart des établissements qui offrent l'ACRE au Canada sont des centres à volume faible. Les protocoles constituent un moyen de partager des pratiques exemplaires entre les établissements afin d'améliorer les résultats. On ignore si les centres du Canada ont des protocoles d'ACRE, et si ces protocoles sont exhaustifs et homogènes dans tous les centres. Méthodes: Nous avons utilisé un échantillonnage dirigé par méthodes mixtes. Le panel Delphi a défini les éléments fondamentaux pertinents au processus d'ACRE. La documentation utilisée pour la prestation de services d'ACRE a été demandée aux programmes. Nous avons évalué les protocoles des établissements au moyen du processus inductif de codification pour déterminer la présence d'éléments fondamentaux. Résultats: Nous avons relevé un total de 37 éléments fondamentaux couvrant cinq domaines (aiguillage, amorce, maintien, cessation et administration). La documentation provenait de 13 établissements de 10 provinces. Les établissements qui ont des programmes de transplantation cardiaque ou pulmonaire avaient une documentation plus complète que les programmes sans transplantation. Seuls cinq éléments fondamentaux étaient présents dans au moins 50 % des protocoles (stratégie d'anticoagulation, stratégie de ventilation, processus défini d'aiguillage, critères de sélection, processus de sevrage), et une variation était observée dans la façon dont les établissements considéraient chacun de ces éléments. Conclusions: Au Canada, l'exhaustivité des protocoles d'ACRE varie. Les programmes décrivent la variabilité des approches des éléments fondamentaux. Cette variabilité qui pourrait représenter le manque de données probantes ou de consensus dans ces domaines ouvre la voie à la collaboration des établissements au partage des protocoles et des pratiques exemplaires. Le cadre des éléments fondamentaux contribue à offrir un langage commun que peuvent utiliser les programmes pour élaborer des programmes d'ACRE, amorcer des projets d'amélioration de la qualité et établir des programmes de recherche.

Why Intellectual Disability is Not Mere Difference.

A key question in disability studies, philosophy, and bioethics concerns the relationship between disability and well-being. The mere difference view, endorsed by Elizabeth Barnes, claims that physical and sensory disabilities by themselves do not make a person worse off overall-any negative impacts on welfare are due to social injustice. This article argues that Barnes's Value Neutral Model does not extend to intellectual disability. Intellectual disability is (1) intrinsically bad-by itself it makes a person worse off, apart from a non-accommodating environment; (2) universally bad-it lowers quality of life for every intellectually disabled person; and (3) globally bad-it reduces a person's overall well-being. While people with intellectual disabilities are functionally disadvantaged, this does not imply that they are morally inferior-lower quality of life does not mean lesser moral status. No clinical implications concerning disability-based selective abortion, denial of life-saving treatment, or rationing of scarce resources follow from the claim that intellectual disability is bad difference.

Understanding the Patient PPI Journey: Results of a Survey on PPI Treatment Initiation and Patient Experience.

INTRODUCTION: Proton pump inhibitors (PPIs) used in the management of gastro-esophageal reflux disease (GORD) are among the most frequently prescribed classes of drug worldwide. Currently, however, physicians are prescribing PPIs for extended periods, often without an indication, which is not in line with current guidance and therefore preventing appropriate reflux management. Inappropriate or excessive PPI prescribing is becoming increasingly visible, yet there is currently little research available on the impact such current practice has on the patient experience. This study aims to understand patient attitudes toward their PPI treatment and the impact current PPI prescribing patterns have on the patient experience. METHODS: An online survey of current and previous users of PPI for GORD was conducted in the UK and Germany. Topics covered included prior steps taken before first consultation with a physician, initial recommendations, PPI treatment initiation and duration, use of PPI, management of reflux whilst taking a PPI, stopping PPI treatment, and patient attitudes. RESULTS: Among 566 patient participants (UK, n = 372; Germany, n = 194) 69% to 79% reported being prescribed medication at their first visit to a physician, of which 61% to 68% were prescribed a PPI either alone or combined with another treatment. 41% to 48% of patients answered "don't know" when asked how long they expected to continue taking their PPI. 49% to 50% of patients currently on PPIs also reported having concerns with regards to long-term treatment. 70% of patients recalled being well informed on dosage and treatment regimens. However, other safety and usage information was reported as being less frequently discussed. CONCLUSIONS: Although patients reported concerns regarding ongoing long-term PPI treatment, this was not reflected in the prescribing pattern from physicians. More can be done to ensure patients are fully informed about their PPI treatment at consultation. Findings also suggest a disconnect exists between standard treatment guidelines and prescribing patterns, as experienced by patients.

Current Use, Capacity, and Perceived Barriers to the Use of Extracorporeal Cardiopulmonary Resuscitation for Out-of-Hospital Cardiac Arrest in Canada.

BACKGROUND: Extracorporeal cardiopulmonary resuscitation (ECPR) is a therapeutic option for refractory cardiac arrest. We sought to perform an environmental scan to describe ECPR utilization in Canada and perceived barriers for application to out-of-hospital cardiac arrest (OHCA). METHODS: This was a national cross-sectional study. We identified all cardiovascular surgery- and extracorporeal membrane oxygenation (ECMO)-capable hospitals in Canada and emergency medical services (EMS) agencies delivering patients to those centres. We requested the medical lead from each hospital's ECMO service and each EMS agency to submit data regarding ECMO and ECPR utilization, as well as perceived barriers to ECPR provision for OHCA. RESULTS: We identified and received survey data from 39 of 39 Canadian hospital institutions and 21 of 22 EMS agencies. Of hospitals, 38 (97%) perform ECMO and 27 (69%) perform ECPR (74% of which perform ≤5 cases per year). Of the 18 (46%) sites offering ECPR for OHCA, 8 apply a formal protocol for eligibility and initiation procedures. EMS agencies demonstrate heterogeneity with intra-arrest transport practices. The primary rationale for nontransport of refractory OHCA is that hospital-based care offers no additional therapies. Perceived barriers to the use of ECPR for OHCA were primarily related to limited evidence supporting its use, rather than resources required. CONCLUSION: Many Canadian cardiovascular surgery- or ECMO-equipped hospitals use ECPR; roughly half employ ECPR for OHCAs. Low case volumes and few formal protocols indicate that this is not a standardized therapy option in most centres. Increased application may be dependent on a stronger evidence base including data from randomized clinical trials currently underway.

CONTEXTE: La réanimation cardiorespiratoire (RCR) extracorporelle est une option thérapeutique en cas d'arrêt cardiaque réfractaire. Nous avons voulu faire une analyse contextuelle de l'utilisation de la RCR extracorporelle au Canada et des obstacles perçus quant à son emploi dans les cas d'arrêt cardiaque en dehors de l'hôpital. MÉTHODOLOGIE: Il s'agissait d'une étude nationale transversale. Nous avons repéré tous les hôpitaux en mesure d'effectuer des chirurgies cardiovasculaires et d'offrir l'oxygénation extracorporelle au Canada et les fournisseurs de services médicaux d'urgence (SMU) transportant les patients vers ces centres. Nous avons demandé au chef médical du service d'oxygénation extracorporelle de chacun des hôpitaux et de chacun des fournisseurs de SMU de présenter leurs données concernant l'utilisation de l'oxygénation extracorporelle et de la RCR extracorporelle, ainsi que les obstacles perçus quant à l'emploi de la RCR extracorporelle dans les cas d'arrêt cardiaque en dehors de l'hôpital. RÉSULTATS: Nous avons obtenu les données de 39 des 39 établissements hospitaliers canadiens ciblés, et de 21 des 22 fournisseurs de SMU. Parmi les hôpitaux, 38 (97%) utilisent l'oxygénation extracorporelle et 27 (69 %), la RCR extracorporelle (74 % ayant eu recours à celle-ci dans ≤ 5 cas par année). Parmi les 18 (46 %) centres offrant la RCR extracorporelle en cas d'arrêt cardiaque en dehors de l'hôpital, 8 appliquaient un protocole officiel pour l'admissibilité et les procédures de mise en place. Les fournisseurs de SMU ont montré des pratiques hétérogènes concernant la réanimation en déplacement. La principale raison justifiant de ne pas transporter les patients présentant un arrêt cardiaque réfractaire en dehors de l'hôpital est que les soins en milieu hospitalier n'offrent pas de traitements additionnels. Les obstacles perçus quant à l'emploi de la RCR extracorporelle dans les cas d'arrêt cardiaque en dehors de l'hôpital étaient principalement liés au peu de données appuyant son utilisation, plutôt qu'aux ressources nécessaires. CONCLUSION: De nombreux hôpitaux canadiens équipés pour la chirurgie cardiovasculaire et l'oxygénation extracorporelle utilisent la RCR extracorporelle; environ la moitié d'entre eux utilisent la RCR extracorporelle en cas d'arrêt cardiaque en dehors de l'hôpital. Le faible nombre de cas et le peu de protocoles officiels indiquent qu'il ne s'agit pas d'une option de traitement standardisée dans la plupart des centres. Une utilisation plus fréquente pourrait nécessiter davantage de données probantes, y compris les résultats des études cliniques à répartition aléatoire qui sont en cours.

Culpable Ignorance, Professional Counselling, and Selective Abortion of Intellectual Disability.

In this paper I argue that selective abortion for disability often involves inadequate counselling on the part of reproductive medicine professionals who advise prospective parents. I claim that prenatal disability clinicians often fail in intellectual duty-they are culpably ignorant about intellectual disability (or do not disclose known facts to parents). First, I explain why a standard motivation for selective abortion is flawed. Second, I summarize recent research on parent experience with prenatal professionals. Third, I outline the notions of epistemic excellence and deficiency. Fourth, I defend culpable ignorance as the best explanation of inadequate disability counselling. Fifth, I rebut alternative explanations. My focus is pregnancies diagnosed with mild or moderate intellectual disability.

Introduction of an Extracorporeal Cardiopulmonary Resuscitation Eligibility Protocol for Paramedics in Atlantic Canada: A Pilot Knowledge Translation Project.

Introduction There is currently no protocol for the initiation of extracorporeal cardiopulmonary resuscitation (ECPR) for out of hospital cardiac arrest (OHCA) in Atlantic Canada. Advanced care paramedics (ACPs) perform advanced cardiac life support in the prehospital setting often completing the entire resuscitation on-scene. Implementation of ECPR will present a novel intervention that is only available at the receiving hospital. Our objective is to determine if an educational program can improve identification of ECPR candidates by paramedics. Establishing paramedic competence will ensure rapid transfer of eligible patients for a potentially life-saving intervention. Methods An educational program was delivered to paramedics including a short seminar and pocket card coupled with simulated OHCA cases. A before-and-after study design using a case-based survey was employed. Paramedics were scored on their ability to correctly identify patients suffering OHCA who met the inclusion criteria for our ECPR protocol. A Wilcoxon matched-pairs signed rank test was employed to compare paramedics' scores before and after the education delivery. A six-month follow-up is planned to assess retention. Qualitative data was also collected from paramedics during simulation to help identify practical issues, potential barriers, and to refine inclusion and exclusion criteria prior to the implementation of our protocol in the prehospital setting. Results The median score pre-education was 10 (IQR: 9-10.5) compared to 14 (IQR: 13-15) after education delivery. The median difference between groups was 5. The Wilcoxon matched-pairs test demonstrated a significant improvement in the paramedics' ability to correctly identify ECPR candidates after completing our educational program z = -2.67, p = 0.0039. Conclusion Paramedic training through a didactic session coupled with a pocket card and simulation appeared to be a feasible method of knowledge translation. Six-month follow-up data will help ensure knowledge retention is achieved.

Epistemic Virtue, Prospective Parents and Disability Abortion.

Research shows that a high majority of parents receiving prenatal diagnosis of intellectual disability terminate pregnancy. They have reasons for rejecting a child with intellectual disabilities-these reasons are, most commonly, beliefs about quality of life for it or them. Without a negative evaluation of intellectual disability, their choice makes no sense. Disability-based abortion has been critiqued through virtue ethics for being inconsistent with admirable moral character. Parental selectivity conflicts with the virtue of acceptingness (the commitment to welcome whatever child comes naturally) and exhibits the vice of wilfulness (the project of picking and choosing what children one will take). In this paper I claim that, beyond failures of moral virtue, disability abortion often involves failures of epistemic virtue on the part of parents. I argue two things: parents believe something false, or at least contested, about life with intellectual disability-and they do so because they are not epistemically conscientious. I first explain why a central motivation for disability abortion-that it prevents harm to the child-is mistaken. I next give a brief account of intellectual virtue and culpable ignorance. I then indicate why many parents fail to be intellectually virtuous when choosing to terminate pregnancy. I focus on elimination of intellectual disability and have little to say about physical and sensory impairments.

How Feasible is Extracorporeal Cardiopulmonary Resuscitation in a Medium Urban Population Centre?

Background Patients suffering from out-of-hospital cardiac arrest (OHCA) experience poor survival and neurological outcomes, with rates remaining relatively unchanged despite advancements. Extracorporeal membrane oxygenation (ECMO), termed extracorporeal cardiopulmonary resuscitation (ECPR) in arrests, may offer improved outcomes. We developed local screening criteria for ECPR and then estimated the frequency of use by applying those criteria retrospectively to a cardiac arrest database. The purpose was to determine if an ECPR program is feasible in a medium urban population centre in Atlantic Canada. Methods A three-round modified Delphi survey, building upon data from a literature review, was conducted in collaboration with external experts. The resulting selection criteria for potential ECPR candidates were applied to a pre-existing local cardiac arrest database, supplemented by health records review, identifying potential candidates eligible for ECPR. Results Consensus inclusion criteria included witnessed cardiac arrest, age <70, refractory arrest, no-flow time <10min, total downtime <60min, and presumed cardiac or selected non-cardiac etiologies. Consensus exclusion criteria were an unwitnessed arrest, asystole, and select etiologies and comorbidities. Simplified criteria were developed to facilitate emergency medical services transport. Historically, 20.0% (95% CI 16.2-24.3%) of OHCA would be transported to the Emergency Department (ED), with 4.9% (95% CI 3.0% to 7.6%) qualifying for ECPR. Conclusion Despite conservative estimates based upon historically small numbers of select cardiac arrest patients meeting eligibility for transport and initiation of ECPR, a dedicated program may be feasible in our regional hospital setting. Patient care volumes suggest it would not be resource intensive yet would be sufficiently busy to maintain competency.

Animal Navigation: A Novel Map Strategy.

Elegant new experiments show that migrant birds at high European latitudes can use magnetic declination to infer longitude.

Influence of Acute High Glucose on Protein Abundance Changes in Murine Glomerular Mesangial Cells.

The effects of acute exposure to high glucose levels as experienced by glomerular mesangial cells in postprandial conditions and states such as in prediabetes were investigated using proteomic methods. Two-dimensional gel electrophoresis and matrix assisted laser desorption ionization time of flight mass spectrometry methods were used to identify protein expression patterns in immortalized rat mesangial cells altered by 2 h high glucose (HG) growth conditions as compared to isoosmotic/normal glucose control (NG(⁎)) conditions. Unique protein expression changes at 2 h HG treatment were measured for 51 protein spots. These proteins could be broadly grouped into two categories: (1) proteins involved in cell survival/cell signaling and (2) proteins involved in stress response. Immunoblot experiments for a protein belonging to both categories, prohibitin (PHB), supported a trend for increased total expression as well as significant increases in an acidic PHB isoform. Additional studies confirmed the regulation of proteasomal subunit alpha-type 2 and the endoplasmic reticulum chaperone and oxidoreductase PDI (protein disulfide isomerase), suggesting altered ER protein folding capacity and proteasomal function in response to acute HG. We conclude that short term high glucose induces subtle changes in protein abundances suggesting posttranslational modifications and regulation of pathways involved in proteostasis.

Animal Navigation: Birds Have Magnetic Maps.

New 'virtual displacement' experiments demonstrate that migrating reed warblers know the magnetic coordinates of their destination, and can set a novel course to their goal with only magnetic-field parameters as a guide.

Offload zones to mitigate emergency medical services (EMS) offload delay in the emergency department: a process map and hazard analysis.

UNLABELLED: Introduction Offload delay is a prolonged interval between ambulance arrival in the emergency department (ED) and transfer of patient care, typically occurring when EDs are crowded. The offload zone (OZ), which manages ambulance patients waiting for an ED bed, has been implemented to mitigate the impact of ED crowding on ambulance availability. Little is known about the safety or efficiency. The study objectives were to process map the OZ and conduct a hazard analysis to identify steps that could compromise patient safety or process efficiency. METHODS: A Health Care Failure Mode and Effect Analysis was conducted. Failure modes (FM) were identified. For each FM, a probability to occur and severity of impact on patient safety and process efficiency was determined, and a hazard score (probability X severity) was calculated. For any hazard score considered high risk, root causes were identified, and mitigations were sought. RESULTS: The OZ consists of six major processes: 1) patient transported by ambulance, 2) arrival to the ED, 3) transfer of patient care, 4) patient assessment in OZ, 5) patient care in OZ, and 6) patient transfer out of OZ; 78 FM were identified, of which 28 (35.9%) were deemed high risk and classified as impact on patient safety (n=7/28, 25.0%), process efficiency (n=10/28, 35.7%), or both (n=11/28, 39.3%). Seventeen mitigations were suggested. CONCLUSION: This process map and hazard analysis is a first step in understanding the safety and efficiency of the OZ. The results from this study will inform current policy and practice, and future work to reduce offload delay.

Animal navigation: memories of home.

Sea turtles memorize the magnetic coordinates of their natal beach, returning to that combination of parameters to lay eggs decades later. The intervening secular (year-to-year) variation in field intensity and inclination can lead the nesting females to a series of predictably different beaches.

Agents for change: nonphysician medical providers and health care quality.

Quality medical care is a clinical and public health imperative, but defining quality and achieving improved, measureable outcomes are extremely complex challenges. Adherence to best practice invariably improves outcomes. Nonphysician medical providers (NPMPs), such as physician assistants and advanced practice nurses (eg, nurse practitioners, advanced practice registered nurses, certified registered nurse anesthetists, and certified nurse midwives), may be the first caregivers to encounter the patient and can act as agents for change for an organization's quality-improvement mandate. NPMPs are well positioned to both initiate and ensure optimal adherence to best practices and care processes from the moment of initial contact because they have robust clinical training and are integral to trainee/staff education and the timely delivery of care. The health care quality aspects that the practicing NPMP can affect are objective, appreciative, and perceptive. As bedside practitioners and participants in the administrative and team process, NPMPs can fine-tune care delivery, avoiding the problem areas defined by the Institute of Medicine: misuse, overuse, and underuse of care. This commentary explores how NPMPs can affect quality by 1) supporting best practices through the promotion of guidelines and protocols, and 2) playing active, if not leadership, roles in patient engagement and organizational quality-improvement efforts.

In-office, multisinus balloon dilation: 1-Year outcomes from a prospective, multicenter, open label trial.

BACKGROUND: The objective of this prospective, multicenter study was to assess 1-year changes in sinonasal symptoms and health care use after office-based multisinus balloon dilation. METHODS: Adults diagnosed with chronic or recurrent acute rhinosinusitis per the 2007 adult sinusitis guidelines were enrolled in this Institutional Review Board-approved study. Balloon dilation of the maxillary sinuses/ethmoid infundibula with or without frontal or sphenoid ostial dilation was performed in the physician's office under local anesthesia. Intraoperative procedure technical success and subject procedure tolerance were recorded. Efficacy was assessed using the patient-reported 20-item Sino-Nasal Outcome Test (SNOT-20) and Rhinosinusitis Symptom Inventory (RSI). Complications and revision surgeries were also recorded. RESULTS: A total of 313 ostial dilations were attempted and 307 were successfully completed (98.1%) in 81 subjects. Mean procedure tolerance was 2.8 ± 2.2 (0 = no pain; 10 = severe pain). Clinically meaningful and statistically significant (p < 0.0001) mean SNOT-20 symptom improvement was observed at 1 and 6 months and sustained through 1 year. The RSI treatment effect for all major rhinosinusitis symptoms was "large" and improvement in each was significant (p < 0.0001). Compared with the previous 1-year period, patients reported an average of 2.3 fewer acute sinus infections (p < 0.0001), 2.4 fewer antibiotic courses taken (p < 0.0001), and 3.0 fewer sinus-related physician visits (p < 0.0001) after balloon dilation. No serious device or procedure-related adverse events occurred. One subject (1.3%) underwent revision surgery. CONCLUSION: In-office, multisinus balloon dilation is safe, effective, and well tolerated. Patients reported significant reductions in both sinonasal symptoms and health care use after balloon dilation. Efficacy observed at 1 and 6 month follow-up was sustained through 1 year with a very low rate of revision surgery. This study was a part of the clinical trial NCT01612780 registered at www.clinicaltrials.gov.