Ethical implications of COVID-19 management-is freedom a desired aim, or a desired means to an end?

Most developed societies managed, due to their prosperity and resource abundance, to structure relationships among free individuals in such a way to leave them fundamentally unstructured, according to the free market principle. As the pandemic illustrated well, this lack of structure when facing collective threats makes it impossible to collectively and proportionately assess and manage its implications and consequences. This may be particularly precarious when introducing comprehensive, monitoring and tracking, surveillance systems dependent on the vaccination status of the individual. If our previously shared aims were successfully and collectively enacted with the greatest of costs, is it permissible that the degree of personal freedom is a commodity, and everyone is a compulsory participant? The need to control one's COVID-19 status allows the individual to become legally free from excessive enactment of sovereignty of the state. Should these rights be regulated by the free market?

Wearing masks to prevent one epidemic may mask another.

Background: With attempts at lifting most COVID-19 pandemic-related restrictions, other common respiratory viruses have caused more health concern than in earlier seasons in pediatric populations. Objective: To explore the role of non-pharmaceutical interventions (NPIs) in a rebound in other respiratory viral pathogens, especially in light of general vaccination fatigue, COVID-19 boosters, and operational challenges in the healthcare system. Methods: A research-based commentary supported with recent literature review. Findings: Pandemic-related lockdowns in Europe, Australia, and New Zealand have created a significant population of susceptible young children without preexisting immunity due to lack of exposure during the colder months. Relying on NPIs for a prolonged period due to low vaccination rates may lead to increased respiratory infection susceptibility, especially among young children less than 5 years old. The key public health question is whether NPIs should be implemented in the long run and what are the long-term implications on the dynamics of endemic infections and population immunity. Discussion: Prevention cannot be the only cure for any infectious disease, and long-term impact of NPIs depends on the dynamics of population susceptibility. The SARS-CoV-2 pandemic has reinforced the importance of vaccination and the knowledge on vaccine use combined with NPIs will be of great value in controlling other known and unknown respiratory pathogens. Combining NPIs and vaccination is paramount in disease control, and the discussion on how to prevent collateral damage to sensitive populations while relaxing NPI-related measures should also merit attention.

The Association between Glycosylated Hemoglobin Level and Platelets Reactivity in Patients with Diabetes Mellitus Undergoing Elective Coronary Artery Bypass Grafting.

BACKGROUND: Diabetic patients tend to have increased platelet reactivity after coronary artery bypass grafting (CABG). The aim of this study was to determine the association between hemoglobin A1c (HbA1c) values and platelet reactivity and to evaluate the consequent impact on clinical outcomes in patients undergoing CABG. METHODS: This prospective observational trial consecutively enrolled 225 diabetic patients undergoing CABG, between February 2014 and October 2018. HbA1c levels and platelet function (multiple electrode aggregometry [MEA]) were analyzed the day before surgery and on postoperative day 4 (POD 4). Patients were divided into two groups according to the HbA1c value: HBA1c < 7% and HbA1c ≥ 7%. RESULTS: Significantly higher postoperative ASPI (platelet function test based on arachidonic acid) and ADP (platelet function test based on adenosine diphosphate) test values were observed at POD 4 compared with preoperative values (ASPI test: p < 0.001; ADP test: p < 0.001). The prevalence of preoperative aspirin resistance (AR) was 46.4% relative to 57.2% after surgery showing consistent increase in postoperative AR by approximately 10%. In addition, the prevalence of AR in the HbA1c < 7% group was higher by 10% compared with the HbA1c ≥ 7% group, both before and after surgery. We did not demonstrate differences in clinical outcomes between the HbA1c groups. CONCLUSION: Perioperative assessment of platelet reactivity in diabetic patients detects those with AR who may be at increased risk of adverse ischemic events. A personalized approach guided by MEA and administration of early and more potent antiaggregation therapy after CABG can be beneficial in this group of patients.

A case study of complex disasters within the resilience framework in Zagreb, Croatia: Two earthquakes in one pandemic.

This paper is an analysis of complex crisis management and the importance of resilience on the example of co-occurring disasters. A resilience framework model was analyzed based on epidemiologic data and the interplay of several disasters; the COVID-19 pandemic and two 2020 Zagreb, Croatia earthquakes. A dose-response principle may be applied to a complex crisis scenario, within a resilience-vulnerability framework. The available data present the concept of balance between vulnerability and resilience of the population affected by complex crises as well as possible adaptation mechanisms. Multiple disasters that last for a prolonged period reduce the populations' resilience and increase the risk of the next crisis becoming a disaster as well. Such complex disasters should not be approached by multiple risk management protocols, but rather by a single, multilayered protocol. Health policies that predict the possible effects of complex disasters on health risk management need to provide measures to maintain and promote resilience instead of collapse. These is a clear need to adopt green environmental policies, reduce socioeconomic inequality, train volunteer managers during crises, introduce timely evidence-informed policies and transfer new research and innovations in society rapidly.

The cherry effect or the issue behind well-being.

Humans define well-being on predefined assumptions, based on inner and outer criteria as references. As illustrated, these criteria are subject to constant change, even in a situation when one is acting freely and is in control of all possible external influences. Even in scenarios that seemingly allow autonomy with one variable to analyse, underlying "irrationality" affects our ability to define and operationalize any desirable trait or state, such as well-being, euthymia or health. Before eating a bowl full of cherries, one creates an idea of how much cherries he/she will eat. However, as one starts eating, perception and following assumptions change. As cherries labeled as most desirable disappear, other cherries start to appear more alluring. The cherry effect could be of relevance in defining the terms such as well-being, euthymia and basically any other term encompassing a complex category of the human condition dependent on our perceived reality.

Preponderance of microbial isolates among heart transplantation recipients requiring renal replacement therapy: a propensity score-adjusted analysis.

AIM: To assess the association between renal replacement therapy (RRT) and post-transplant infection incidence. METHODS: This single-center retrospective cohort study included 158 patients who underwent heart transplantation (HTx) in our center from 2008 to 2016, survived beyond the first post-procedural day, and had available microbial data. The patients were dichotomized according to the need for periprocedural RRT. Twenty-seven patients in RRT group had lower preoperative creatinine clearance, greater body mass index, and higher likelihood of having diabetes. Propensity score adjustment was used to account for multiple covariates. The primary outcome measure was the presence of bacteremia in patients with and without the need for RRT. The secondary outcome measures were the presence of microbial isolates from any culture and clinical outcome data. RESULTS: Unadjusted analysis showed that the RRT group had higher incidence of any positive microbial isolate (93% vs 73%; odds ratio [OR] 4.77, 95% confidence interval [CI] 1.01-30.53; P=0.026) and an increased susceptibility to bacteremia (50% vs 22%; OR 3.50, 95% CI 1.28-9.67; P=0.012). Propensity score-adjusted analysis corroborated the between-group difference in positive blood cultures (OR 3.97, 95% CI 1.28-12.32; P=0.017). There was no difference in the incidence of total microbial isolates between the groups (OR 4.55, 95% CI 0.90-23.05; P=0.067). CONCLUSIONS: Patients requiring RRT after HTx had an increased susceptibility to infections via various portals of entry, predominantly due to an increase in blood-borne infections. Understanding the underlying conditions leading to infection-related morbidity is important for infection control and prevention.

De Novo Aortic Regurgitation After Continuous-Flow Left Ventricular Assist Device Implantation.

Continuous-flow left ventricular assist devices (cf-LVAD) play an important role in the management of patients with advanced heart failure. De novo aortic regurgitation after cf-LVAD implantation may adversely impact device performance. We performed a systematic search of PubMed, SCOPUS, and Cochrane Library for articles reporting on the incidence and predictors of de novo aortic regurgitation among cf-LVAD recipients. Eight studies totaling 548 patients were identified in the meta-analysis. The pooled incidence of de novo AR across the analyzed studies was 37%. Factors influencing its development and progression are older age, persistent aortic valve closure, being female, and duration of cf-LVAD support.

Postoperative Atrial Fibrillation Is Associated With High On-Aspirin Platelet Reactivity.

BACKGROUND: Atrial fibrillation (AF) contributes to a prothrombotic state through platelet activation. It is unclear whether increased platelet aggregability in patients with AF is caused by the underlying cardiovascular condition rather than the arrhythmia per se. We investigated the effect of postoperative atrial fibrillation (POAF) on platelet reactivity after coronary artery bypass grafting (CABG). METHODS: This study is a post hoc analysis from a randomized controlled trial (ClinicalTrials.gov: NCT01159639) based on patients undergoing elective primary CABG. Patients were dichotomized according to POAF. Postoperative platelet function testing with arachidonic acid as the platelet agonist (ASPI test) was used to define high on-aspirin platelet reactivity (HAPR). ΔASPI presented the difference between pre- and postoperative ASPI test values. To account for the isolated effect of POAF on platelet reactivity, a propensity score analysis was applied. RESULTS: Overall incidence of POAF was 23% (92 of 398 patients). HAPR was detected in 54% (214 of 398) of patients. HAPR was more prevalent among patients with POAF when compared with patients without POAF (64.1% versus 50.7%; odds ratio [OR], 1.74; 95% confidence interval [CI], 1.08-2.82; p = 0.023). The propensity score model produced a subcohort of patients that was well balanced for comorbidities. When compared with the matched group without POAF, the POAF group maintained its prevalence for HAPR (64.1% versus 45.7%; OR, 2.13; 95% CI, 1.18-3.85; p = 0.012) and had greater ΔASPI values (15.0 [IQR, 0.0-36.0] vs 8.0 [IQR, -5.5-19.5]; p = 0.030). CONCLUSIONS: The main finding of our study indicates there is added platelet activation in patients with POAF after CABG before and after controlling for pathologic conditions through propensity matching. The present study does not prove a causal association between POAF and HAPR.

Impact of aspirin resistance on outcomes among patients following coronary artery bypass grafting: exploratory analysis from randomized controlled trial (NCT01159639).

Individual variability in the response to aspirin, has been established by various platelet function assays, however, the clinical relevance of aspirin resistance (AR) in patients undergoing coronary artery bypass grafting (CABG) has to be evaluated. Our working group conducted a randomized controlled trial (NCT01159639) with the aim to assess impact of dual antiplatelet therapy (APT) on outcomes among patients with AR following CABG. Patients that were aspirin resistant on fourth postoperative day (POD 4) were randomly assigned to receive either dual APT with clopidogrel (75 mg) plus aspirin (300 mg)-intervention arm or monotherapy with aspirin (300 mg)-control arm. This exploratory analysis compares clinical outcomes between aspirin resistant patients allocated to control arm and patients that have had adequate platelet inhibitory response to aspirin at POD 4. Both groups were treated with 300 mg of aspirin per day following surgery. We sought to evaluate the impact of early postoperative AR on outcomes among patients following CABG. Exploratory analysis included a total number of 325 patients. Of those, 215 patients with adequate response to aspirin and 110 patients with AR allocated to aspirin monotherapy following randomization protocol. The primary efficacy end point (MACCEs-major adverse cardiac and cardiovascular events) occurred in 10 and 6 % of patients with AR and with adequate aspirin response, respectively (p = 0.27). Non-significant differences were observed in bleeding events occurrence. Subgroup analysis of the primary end point revealed that aspirin resistant patients with BMI > 30 kg/m(2) tend to have a higher occurrence of MACCEs 18 versus 5 % (relative risk 0.44 [95 % CI 0.16-1.16]; p = 0.05). This exploratory analysis did not reveal significant impact of aspirin resistance on outcomes among patients undergoing CABG. Further, sufficiently powered studies are needed in order to evaluate clinical relevance of AR in patients undergoing CABG.

Activated coagulation time vs. intrinsically activated modified rotational thromboelastometry in assessment of hemostatic disturbances and blood loss after protamine administration in elective cardiac surgery: analysis from the clinical trial (NCT01281397).

BACKGROUND: Excessive bleeding after cardiopulmonary bypass (CPB) is risk factor for adverse outcomes after elective cardiac surgery (ECS). Although many different point-of-care devices to diagnose hemostatic disturbances after CPB are available, the best test is still unclear. The study aim was to compare the accuracy of hemostatic disorder detection between two point-of-care devices. METHODS: We enrolled 148 patients (105 male and 43 female) undergoing ECS in a prospective observational study. Rotational thromboelastometry (TEM, with InTEM test), and Activated coagulation time (ACT) measurement were performed 15 min after protamine administration. The cohort group was divided into two subgroups according to occurrence of excessive postoperative bleeding. Endpoints were defined in two ways: as total amount of chest tube output (CTO) and blood product transfusion requirements. RESULTS: Total amount of CTO value of 1507,50 mL presented 75th percentile of distribution, thus cut-off value for bleeder category. InTEM parameters, but not ACT, correlated significantly with CTO. InTEM parameters with the strongest correlation to CTO were tested for accuracy in predicting excessive postoperative bleeding using ROC analysis. InTEM A 10 value of 38 mm, InTEM A 20 value of 49 mm and InTEM A 30 value of 51 mm delineated bleeding tendency. Patients with total amount of CTO exceeding 75th percentile were more frequently transfused with fresh frozen plasma (51.4% vs. 9.9%, p < 0.001), fibrinogen concentrate (21.6% vs. 2.7%, p = 0.001) and platelet concentrate (13.5% vs. 0.9%, p = 0.004). CONCLUSION: Our study showed that InTEM test, but not ACT is useful in prediction of bleeding tendency after protamine administration following weaning from CPB. InTEM test could be used as a first line test in screening of possible hemostatic disorder following protamine administration.

Impact of dual antiplatelet therapy on outcomes among aspirin-resistant patients following coronary artery bypass grafting.

Coronary artery bypass grafting is pivotal in the contemporary management of complex coronary artery disease. Interpatient variability to antiplatelet agents, however, harbors the potential to compromise the revascularization benefit by increasing the incidence of adverse events. This study was designed to define the impact of dual antiplatelet therapy (dAPT) on clinical outcomes among aspirin-resistant patients who underwent coronary artery surgery. We randomly assigned 219 aspirin-resistant patients according to multiple electrode aggregometry to receive clopidogrel (75 mg) plus aspirin (300 mg) or aspirin-monotherapy (300 mg). The primary end point was a composite outcome of all-cause death, nonfatal myocardial infarction, stroke, or cardiovascular hospitalization assessed at 6 months postoperatively. The primary end point occurred in 6% of patients assigned to dAPT and 10% of patients randomized to aspirin-monotherapy (relative risk 0.61, 95% confidence interval 0.25 to 1.51, p = 0.33). No significant treatment effect was noted in the occurrence of the safety end point. The total incidence of bleeding events was 25% and 19% in the dAPT and aspirin-monotherapy groups, respectively (relative risk 1.34, 95% confidence interval 0.80 to 2.23, p = 0.33). In the subgroup analysis, dAPT led to lower rates of adverse events in patients with a body mass index >30 kg/m(2) (0% vs 18%, p <0.01) and those <65 years (0% vs 10%, p = 0.02). In conclusion, the addition of clopidogrel in patients found to be aspirin resistant after coronary artery bypass grafting did not reduce the incidence of adverse events, nor did it increase the number of recorded bleeding events. dAPT did, however, lower the incidence of the primary end point in obese patients and those <65 years.

Pretransplant and perioperative predictors of early heart transplantation outcomes.

Aim. To identify predictors of 3-month mortality after heart transplantation in a Croatian academic center. Methods. A retrospective review of institutional database identified 117 heart transplantations from January 2008 to July 2014. Two children <14 years were excluded from the study. The remaining 115 patients were dichotomized into survivors and non-survivors adjudicated at 3-months postoperatively, and their demographic, clinical, and longitudinal hemodynamic data were analyzed. Results. 3-month survival after heart transplantation was 86%. Non-survivors were older (59±8 vs 50±14 years, P=0.009), more likely to have previous cardiac surgery (44% vs 19%; odds ratio [OR] 3.28, 95% confidence interval [CI] 1.08-9.90; P=0.029), lower body mass index (BMI) (25±4 vs 28±2 kg/m(2), P=0.001), and be diabetics (44% vs 23%; OR 2.57, 95% CI 0.86-7.66; P=0.083). Creatinine clearance was marginally superior among survivors (59=19 vs 48 ± 20 mL/min, P=0.059). Donor age and sex did not affect outcomes. Non-survivors were more likely to have had ischemic cardiomyopathy (69% vs 32%, P=0.010). Postoperative utilization of epinephrine as a second line inotropic agent was a strong predictor of mortality (63% vs 7%; OR 21.91; 95% CI 6.15-78.06; P<0.001). Serum lactate concentrations were consistently higher among non-survivors, with the difference being most pronounced 2 hours after cardiopulmonary bypass (9.8±3.5 vs 5.2±3.2 mmol/L, P<0.001). The donor hearts exhibited inferior early hemodynamics in non-survivors (cardiac index 3.0±1.0 vs 4.0±1.1 L/min/m(2), P=0.001), stroke volume (49±24 vs 59±19 mL, P=0.063), and left and right ventricular stroke work indices (18±8 vs 30±11 g/beat/m(2), P<0.001 and 5±3 vs 7±4 g/beat/m(2), P=0.060, respectively). Non-survivors were more likely to require postoperative re-sternotomy (50% vs 12%; OR 7.25, 95% CI 2.29-22.92; P<0.001), renal replacement therapy (RRT) (69% vs 9%; OR 22.00, 95% CI 6.24-77.54; P<0.001), and mechanical circulatory assistance (MCS) (44% vs 5%; OR 14.62, 95% CI 3.84-55.62; P<0.001). Binary logistic regression revealed recipient age (P=0.024), serum lactates 2 hours after CPB (P=0.007), and epinephrine use on postoperative day 1 (P=0.007) to be independently associated with 3-month mortality. Conclusion. Pretransplant predictors of adverse outcome after heart transplantation were recipient age, lower BMI, ischemic cardiomyopathy, reoperation and diabetes. Postoperative predictors of mortality were inferior donor heart hemodynamics, epinephrine use, and serum lactate concentrations. Non-survivors were more likely to require re-sternotomy, MCS, and RRT.

Results of extracorporeal life support implementation in routine clinical practice: single center experience.

AIM: To describe our experience in the clinical application of extracorporeal life support (ECLS) and analyze whether ECLS leads to acceptable clinical outcomes in patients with cardiac failure. METHODS: Data from clinical database of University Hospital Center Zagreb, Croatia, on 75 patients undergoing ECLS support from 2009 to 2014 due to cardiac failure were retrospectively analyzed. Outcomes were defined as procedural and clinical outcomes. ECLS as a primary procedure and ECLS as a postcardiotomy procedure due to inability to wean from cardiopulmonary bypass were analyzed. RESULTS: ECLS was used in 75 adult patients, and in 24 (32%) of those procedural success was noted. ECLS was implemented as a primary procedure in 36 patients and as a postcardiotomy procedure in 39 patients. Nine out of 39 (23.08%) patients had postcardiotomy ECLS after heart transplantation. Bleeding complications occurred in 30 (40%) patients, both in primary (11/36 patients) and postcardiotomy group (19/39 patients). ECLS was established by peripheral approach in 46 patients and by central cannulation in 27 patients. In 2 patients, combined cannulation was performed, with an inflow cannula placed into the right atrium and an outflow cannula placed into the femoral artery. Eleven patients treated with peripheral approach had ischemic complications. CONCLUSION: ECLS is a useful tool in the treatment of patients with refractory cardiac failure and its results are encouraging in patients who otherwise have an unfavorable prognosis. Patient outcomes may be further improved by technological advances, more clinical experience in application of the technique, careful patient selection, and multidisciplinary approach in patient management.

Definition of acetylsalicylic acid resistance using whole blood impedance aggregometry in patients undergoing coronary artery surgery.

A beneficial effect of acetylsalicylic acid (ASA) on vein graft patency has been described, but some patients experience adverse cardiac events despite appropriate ASA treatment. Study aim was to define ASA resistance using Multiple electrode aggregometry (MEA) preoperatively in group of patients undergoing coronary artery bypass grafting (CABG). Prospective observational trial at University Hospital Center Zagreb enrolled 131 patients scheduled for CABG, and divided them into 4 groups with respect to preoperative antiplatelet therapy (APT). Group 1 received 100 mg ASA per day, Group 2 100 mg ASA + 75 mg clopidogrel per day, Group 3 75 mg clopidogrel per day, and Group 4 did not receive any APT. MEA with ASPI test (sensitive to ASA) and ADP test (sensitive to clopidogrel) was performed prior to surgery. In Group 1, patients were characterized as ASA resistant if their ASPI test value exceeded the 75th percentile distribution. Study enrolled 131 patients. Significant differences both in the ASPI (p < 0.001) and the ADP test (p = 0.038) were observed between patients in different APT groups. In Group (1) ASPI test value of 30 AUC presented 75th percentile of distribution, thus indicating ASA resistance. Group 2 patients had slightly lower ADP test values, but no significant difference occurred (mean 60.05 vs. 63.32 AUC, p = 0.469). In Group 1 and 2, significant correlations between the ADP test and both, platelet count (r = 0.347, p < 0.001) and fibrinogen level (r = 0.364, p < 0.001) were observed. Association between low response to ASA and post-CABG major adverse ischemic events risk increase has been described thus indicating need for ASA resistant patients detection. In patients with preoperative ASPI test exceeding 30 AUC postoperative, ASA dose adjustment or clopidogrel addition according to MEA results should be considered.

Bleeding risk assessment using whole blood impedance aggregometry and rotational thromboelastometry in patients following cardiac surgery.

Excessive bleeding after cardiopulmonary bypass (CPB) is risk factor for adverse outcomes after elective cardiac surgery (ECS). Differentiating between patients who bleed due to surgical issues and those whose excessive chest tube output (CTO) is due to coagulopathy, remains challenging. Bedside suitable tests to identify hemostatic disturbances and predict excessive bleeding are desirable. The study sought to evaluate prediction of excessive bleeding after ECS using two bedside suitable devices for platelet function and viscoelastic blood clot properties assessment. We enrolled 148 patients (105 male and 43 female) undergoing ECS in a prospective observational study. Patients were characterized as bleeders if their 24 h CTO exceeded the 75th percentile of distribution. Multiple electrode aggregometry (MEA, with ASPI, ADP and the TRAP test) and rotational thromboelastometry (TEM, with ExTEM, HepTEM and FibTEM test), were performed at three time points: preoperatively (T1), during CPB (T2), and after protamine administration (T3). The primary endpoint was CTO and the secondary endpoint was administration of blood products, 30-day and 1 year mortality. The best predictors of increased bleeding tendency were the tests performed after protamine administration (T3). At T3, patients characterized as bleeders had significantly lower MEA ASPI (median, 14 vs. 27 AUC, p = 0.004) and ADP test values (median, 22 vs. 41 AUC, p = 0.002) as well as TEM values expressed in maximum clot firmness after 30 min (MCF 30) for ExTEM (53 vs. 56 mm, p = 0.005), HepTEM (48 vs. 52 mm, p = 0.003) and FibTEM (8 vs. 11 mm, p < 0.001) test. 24 h CTO inversely correlated with both the MEA (ASPI test: r = -0.236, p = 0.004; ADP test: r = -0.299, p < 0.001), and TEM MCF 30 (ExTEM: r = -0.295, p < 0.001; HepTEM: -0.329, p < 0.001; FibTEM: -0.377, p < 0.001) test values. Our study showed that MEA and TEM are useful methods for prediction of excessive bleeding after ECS. In order to prevent excessive postoperative CTO, hemostatic interventions with timely and targeted blood component therapy according to MEA and TEM results should be considered.

Dual antiplatelet therapy in patients with aspirin resistance following coronary artery bypass grafting: study protocol for a randomized controlled trial [NCT01159639].

BACKGROUND: Coronary artery disease remains the dominant cause of mortality in developed countries. While platelets have been recognized to play a pivotal role in atherothrombosis, the ideal antiplatelet regime after coronary artery surgery remains elusive. The evolution of CABG has presently moved beyond technical improvements to involve modulation of pharmacologic management designed to improve patient outcomes. The aim of this trial will be to test the hypothesis that the addition of clopidogrel to patients with documented postoperative aspirin resistance will reduce the incidence of major cardiovascular events. METHODS: Patients scheduled for isolated coronary artery surgery will be eligible for the study. Patients in whom postoperative multiple electrode aggregometry documents aspirin resistance will be randomized into two groups. The control group will receive 300 mg of aspirin. The dual antiplatelet group will receive 75 mg of clopidogrel in addition to 300 mg of aspirin. Patients will be followed for 6 months. Major adverse cardiac and cerebrovascular events (death from any cause, myocardial infarction, stroke, hospitalization due to cardiovascular pathology) as well as bleeding events will be recorded. DISCUSSION: This will be the first trial that will specifically address the issue of dual antiplatelet therapy in patients undergoing coronary artery surgery who have been found to be aspirin resistant. In the event that the addition of clopidogrel proves to be beneficial in this subset of surgical patients, this study could significantly impact their future antiplatelet management. This randomized controlled trial has been registered at the ClinicalTrials.gov website (Identifier NCT01159639).