Formulation development and characterization of plant-based alternatives to pâté using forest ingredients.

Due to the expanding global population and environmental concerns about meat production from livestock, there is a great demand for alternative ingredients. Beech achene (BA) and sessile oak acorn (SOA) were recently proposed as protein- and carbohydrate-rich novel food ingredients. This study used their roasted kernels to develop and characterize four formulations of spreadable vegetable paste (with 10% BAK, 10% SOAK, 5% SOAK + 5% BAK, and control-just with roasted sunflower kernel). The substitution of sunflower kernel with 10% BAK caused a decrease in the energy value of vegetable paste, while 10% SOAK and 5% SOAK + 5% BAK, an increase. Syneresis was higher in formulations with forest ingredients, most notably in those containing BAK. The SOAK also caused a decrease in the pH of vegetable pastes that included it. All forest formulations had a large total colour difference compared to the control sample, driven by its intensity decrease (less in that with BAK than in the other two). The acceptance rate was reasonable for all formulations, although the overall score was significantly lower (slightly liked) in the vegetable paste formulated only with BAK than in the others (moderately liked); thus, the consumer's purchase intention too (only 4.9% for that with 10% SOAK). Formulation with 10% BAK had a higher hardness, adhesiveness, gumminess, and chewiness than the others, while that with the 5% SOAK and 5% BAK mixture showed the most robust network structure. In conclusion, BA and SOA kernels are suitable for manufacturing plant-based alternatives to pâté if used in proper concentrations. Supplementary Information: The online version contains supplementary material available at 10.1007/s13197-023-05852-7.

Implementation of an Analytical Method for Spectrophotometric Evaluation of Total Phenolic Content in Essential Oils.

Over the past decade, there has been growing interest in polyphenols' research since these compounds, as antioxidants, have several health benefits, such as preventing neurodegenerative diseases, inflammation, cancer, cardiovascular diseases, and type 2 diabetes. This study implements an analytical method to assess the total phenolic content (TPC) in essential oils using Folin-Ciocalteu's phenol reagent and quantifies the individual phenolic compounds by liquid chromatography. Thus, the research design and methodology included: (1) extraction of essential oil from dried thyme leaves by hydrodistillation; (2) spectrophotometric measurement of TPC by Folin-Ciocalteu method; and (3) identification and quantification of individual phenolic compounds by high-performance liquid chromatography-diode array detection/electrospray ionization mass spectrometry (HPLC-DAD-ESI-MS). Results revealed a TPC of 22.62 ± 0.482 mg GAE/100 µL and a polyphenolic profile characterized by phenolic acids (52.1%), flavonoids (16.1%), and other polyphenols (31.8%). Thymol, salvianolic acid A, and rosmarinic acid were the major compounds of thyme essential oil. The proposed analytical procedure has an acceptable level of repeatability, reproducibility, linearity, LOD (limit of detection), and LOQ (limit of quantification).

Wind Turbine Gearbox Condition Monitoring Based on Class of Support Vector Regression Models and Residual Analysis.

The intelligent condition monitoring of wind turbines reduces their downtime and increases reliability. In this manuscript, a feature selection-based methodology that essentially works on regression models is used for identifying faulty scenarios. Supervisory control and data acquisition (SCADA) data with 1009 samples from one year and one month before failure are considered. Gearbox oil and bearing temperatures are treated as target variables with all the other variables used for the prediction model. Neighborhood component analysis (NCA) as a feature selection technique is employed to select the best features and prediction performance for several machine learning regression models is assessed. The results reveal that twin support vector regression (99.91%) and decision trees (98.74%) yield the highest accuracy for gearbox oil and bearing temperatures respectively. It is observed that NCA increases the accuracy and thus reliability of the condition monitoring system. Furthermore, the residuals from the class of support vector regression (SVR) models are tested from a statistical point of view. Diebold-Mariano and Durbin-Watson tests are carried out to establish the robustness of the tested models.

Cognitive evolutionary therapy versus standard cognitive therapy for depression: A single-blinded randomized clinical trial.

OBJECTIVE: To compare the efficacy of cognitive evolutionary therapy (CET) with cognitive therapy (CT) for depression. METHODS: Ninety-seven participants (78 females/19 males) were randomized to a single-blinded controlled trial (CET: n = 51 vs. CT: n = 46). Assessments were conducted at baseline, Sessions 4 and 8, posttreatment, and 3-month follow-up. Clinical diagnoses were made with Structured Clinical Interview for DSM-IV (SCID) and self-reports for depression and secondary outcomes. RESULTS: Although both groups showed significant reductions in depressive symptomatology, the overall Time × Treatment group interaction in the intent to treat analysis was not significant (p = .770, posttreatment: d = 0.39). However, CET was superior to CT at increasing engagement in social and enjoyable activities (p = .040, posttreatment: d = 0.83, p = .040) and showed greater reductions than the CT group in behavioral inhibition/avoidance (p = .047, d = 0.62). The between-group differences generally diminished at the 3-month follow-up. CONCLUSIONS: CET is a novel therapy for depression that may add therapeutic benefits beyond those of CT.

Artificial Intelligence and Machine Learning Based Intervention in Medical Infrastructure: A Review and Future Trends.

People in the life sciences who work with Artificial Intelligence (AI) and Machine Learning (ML) are under increased pressure to develop algorithms faster than ever. The possibility of revealing innovative insights and speeding breakthroughs lies in using large datasets integrated on several levels. However, even if there is more data at our disposal than ever, only a meager portion is being filtered, interpreted, integrated, and analyzed. The subject of this technology is the study of how computers may learn from data and imitate human mental processes. Both an increase in the learning capacity and the provision of a decision support system at a size that is redefining the future of healthcare are enabled by AI and ML. This article offers a survey of the uses of AI and ML in the healthcare industry, with a particular emphasis on clinical, developmental, administrative, and global health implementations to support the healthcare infrastructure as a whole, along with the impact and expectations of each component of healthcare. Additionally, possible future trends and scopes of the utilization of this technology in medical infrastructure have also been discussed.

Impact of Lavender Flower Powder as a Flavoring Ingredient on Volatile Composition and Quality Characteristics of Gouda-Type Cheese during Ripening.

This study aimed to formulate a Gouda-type cheese from cow's milk, flavored with lavender flower powder (0.5 g/L matured milk), ripened for 30 days at 14 °C and 85% relative humidity. Physicochemical, microbiological, and textural characteristics, as well as the volatile composition of the control (CC-cheese without lavender) and lavender cheese (LC), were assessed at 10-day intervals of ripening. Consumers' perception, acceptance, and purchase intention were only evaluated for ripened cheeses. Moisture and carbohydrate contents, the pH, cohesiveness, indexes of springiness and chewiness decreased during ripening in both CC and LC; however, protein, ash, and sodium chloride contents, titratable acidity, hardness, lactobacilli, streptococci, and volatiles increased. Fat and fat in dry matter contents, respectively, the energy value did not vary with ripening time in LC and increased in CC; gumminess decreased in CC and did not change in LC. Lavender flower powder significantly affected the cheese's microbiological and sensory characteristics and volatile composition but did not considerably impact physicochemical and textural ones. Populations of lactobacilli and streptococci were substantially higher in LC compared to CC. The volatile profile of LC was dominated by terpene and terpenoids, and that of CC by haloalkanes. Sensory scores were slightly lower for LC than CC, even if it did not considerably affect consumers' acceptance and purchase intention.

Characterization of some Fagaceae kernels nutritional composition for potential use as novel food ingredients.

The present study attempts to characterise Fagaceae kernels as a promising source of nutritional compounds for potential use as novel food ingredients. Thus, the proximate and mineral composition of some kernels (beech achene-BA, sessile oak acorn-SOA, turkey oak acorn-TOA, and red oak acorn-ROA), total phenolic content, individual polyphenols, and cytotoxicity of their aqueous extracts, respectively, the fatty acid composition of kernel oils were investigated using physicochemical and analytical techniques. Results revealed that BAK is rich in lipid and protein, OAKs in carbohydrates. All tested kernels contain high oleic-linoleic acid oils. BAK is abundant in phenolic acids, OAKs in hydrolysable tannins. Only BA and SOA kernels exert cytotoxicity against human fibroblasts. In all kernels, macroelements are dominated by K and microelements by Cu, Mn, and Fe. In conclusion, BA and OA kernels could be alternatively used as protein-rich, respectively, starch-rich ingredients in food.

The Feasibility of Shellac Wax Emulsion Oleogels as Low-Fat Spreads Analyzed by Means of Multidimensional Statistical Analysis.

Shellac wax-based oleogel emulsions were studied with a three level two factorial design in order to find an optimal formulation for a spread formulation. Rheological, textural, colorimetry, and stability analysis were conducted to assess the performance of oleogel emulsions. FTIR spectra were also compared. The similarities between the samples were studied using cluster analysis. Analysis of variance (ANOVA) demonstrates that (i) the texture is influenced by the wax concentration, (ii) the rheology and stability by both the considered numeric factors (wax and water concentration) and their interaction, and (iii) the color by both factors. The emulsions containing 7% (m/m) shellac oleogels behaved like the strongest systems, (G' & GLVR > 30,000 Pa) and exhibited the highest value of the G'-G″ cross-over. The lowest oil binding capacity (OBC) was 99.88% for the sample with 3% (m/m) shellac and 20% (m/m) water. The whiteness index (Windex) varied between 58.12 and 78.50. The optimization process indicated that a formulation based on 4.29% (m/m) shellac wax and 24.13% (m/m) water was suitable as a low-fat spread.

Changes in Physicochemical and Microbiological Properties, Fatty Acid and Volatile Compound Profiles of Apuseni Cheese during Ripening.

The evolution during ripening on the quality of Apuseni cheese was studied in this research. The cheese samples were controlled and evaluated periodically (at 4 months) during 16 months of storage (at 2-8 °C) for physicochemical parameters (pH, moisture, fat, fat in dry matter, total protein, ash, NaCl), microbiological (total combined yeasts and molds count (TYMC), total viable count (TVC), Escherichia coli, Staphylococcusaureus, Salmonella, lactic acid bacteria (LAB)), fatty acids (FA) and volatile compounds. For better control of the quality of the cheese, the storage space was evaluated for TYMC and TVC. The ripening period showed improved effects on the quality of the cheese, showing lower values for moisture and pH and an increase in macronutrients. Both the cheese samples and the storage space were kept within the allowed microbiological limits. Lipids are predominant, the predominant FAs being saturated fatty acids (SFAs), which decrease, while monounsaturated fatty acids (MUFAs) increase. During ripening, the microbiological and chemical changes result in the development of flavor. Major volatile compounds such as 2-heptanone show accumulations, while acetophenone, limonene, or thymol show a decrease. In conclusion, Apuseni ripening cheese clearly involves a complex series of transformations, leading to a ripening cheese with improved nutritional and aromatic characteristics.

Hemp (Cannabis sativa L.) Flour-Based Wheat Bread as Fortified Bakery Product.

Hemp flour from Dacia Secuieni and Zenit varieties was added to bread in different proportions (5%, 10%, 15% and 20%) to improve its nutritional properties. The purpose of this paper was to present the advanced nutritional characteristics of these bread samples. The selected varieties of hemp, accepted for human consumption, met the requirements for the maximum accepted level of THC in seeds. The protein content of new products increased from 8.76 to 11.48%, lipids increased from 0.59 to 5.41%, mineral content from 1.33 to 1.62%, and fiber content from 1.17 to 5.84%. Elasticity and porosity decreased from 95.51 to 80% and 78.65 to 72.24%, respectively. K, Mg, Ca, P, Mn and Fe are the main mineral substances in bread with addition of hemp flour from the Dacia Secuieni and Zenit varieties. The total amount of unsaturated fatty acids in the bread samples with hemp flour ranged from 67.93 g/100 g and 69.82 g/100 g. Eight amino acids were identified, of which three were essential (lysine, phenylalanine, histidine). Lysine, the deficient amino acid in wheat bread, increased from 0.003 to 0.101 g/100 g. Sucrose and fructose decreased with the addition of hemp flour, and glucose has not been identified. The amount of yeasts and molds decreased in the first 3 days of storage. Regarding the textural profile, the best results were obtained for the samples with 5% addition. In conclusion, bread with the addition of hemp flour has been shown to have superior nutritional properties to wheat bread.

Textural and Sensory Features Changes of Gluten Free Muffins Based on Rice Sourdough Fermented with Lactobacillus spicheri DSM 15429.

Gluten free products available on the market have a low textural quality associated with high crumbly structure, low-flavor, aroma, poor mouthfeel, less appearance, in comparison with the conventional final baked products. The aim of this study was to assess the influence of rice sourdough fermented with Lactobacillus spicheri DSM 15429 strain on textural, volatile profile, and sensorial properties of gluten free muffins in order to obtain baked goods with improved quality characteristics. Lactobacillus spicheri is a novel strain isolated from industrial rice sourdough but unexploited for bakery products manufacturing. The results showed that Lactobacillus spicheri DSM 15429 was able to growth in the rice flour influencing the texture and the volatile profile of gluten free muffins as well as their sensory characteristics. Both, textural parameters and volatiles recorded significant differences comparing to muffins obtained with a spontaneously fermented rice sourdough. Hardness and cohesiveness decreased while springiness and resilience of gluten free muffins improved their values. The volatile profile of gluten free muffins was significantly improved by utilization of the rice sourdough fermented with Lactobacilus spicheri DSM 15429. 3-methylbutanal, 2-methylbutanal, acetophenone and limonene were the main volatile derivatives responsible for aroma and odor scores of sensory analysis.

Effect of Rice Flour Fermentation with Lactobacillus spicheri DSM 15429 on the Nutritional Features of Gluten-Free Muffins.

Lactobacillus Spicheri DSM 15429 strain was used to ferment rice flour, aiming at exploiting its influence on the amino-acids, minerals, lactic acid, total phenols, and antioxidant activity of the rice sourdough and gluten-free muffins. Gluten-free muffins were prepared by using 15% rice sourdough fermented with the above strain of lactic acid bacteria and compared with rice spontaneous fermentation. Methods like LC-MS (Liquid chromatography-mass spectrometry), AA (atomic absorption), HPLC (High-performance liquid chromatography), Folin-Ciocalteu, and 1,1-Diphenyl-2-picrylhydrazyl radical scavenging activity (DPPH) were used to fulfill the aim of the study. The addition of rice sourdough fermented with LAB was reflected in the chemical composition of the final baked good, improving its amount on bioactive compounds such as amino acids, mineral bioavailability, total phenols, and antioxidant activity. Total phenols and antioxidant activity increased their amount by 70.53% and 73.70%, respectively, meanwhile, lactic acid, minerals, and amino-acids increased their values at least twice. Thus, rice fermented with Lactobacilus spicheri DSM 15429 strain could be a tool to further increase the nutritional value of gluten-free baked products.

Formulation and Characterization of Antimicrobial Edible Films Based on Whey Protein Isolate and Tarragon Essential Oil.

The effects of heat treatment and the addition of tarragon essential oil on physical and mechanical properties of films prepared with 5% whey protein isolate (WPI) and 5% glycerol were investigated in this study. Heat treatment of the film-forming solution caused increases in thickness, moisture content, swelling degree, water vapor permeability (WVP), b*-value, ΔE*-value, transmittance values in the 200-300-nm region, transparency, and puncture resistance of the film, but decreases in water solubility, L*-value, a*-value, transmittance values in the 350-800-nm region, and puncture deformation. When incorporated with tarragon essential oil, heat-treated films have the potential to be used as antimicrobial food packaging. The addition of tarragon essential oil in film-forming solution caused increases in moisture content, solubility in water, WVP, a*-value, b*-value, ΔE*-value, and transparency of the film; decreases in transmittance values in the range of 600-800 nm; and variations in swelling degree, L*-value, transmittance values in the range of 300-550 nm, puncture resistance, and puncture deformation. Nevertheless, different tendencies were noticed in UNT (untreated) and HT (heat-treated) films with regards to transparency, light transmittance, puncture resistance, and puncture deformation. Based on these findings, HT films show improved physical and mechanical properties and, therefore, are more suitable for food-packaging applications.

Use of Pseudocereals Preferment Made with Aromatic Yeast Strains for Enhancing Wheat Bread Quality.

Usually, aromatic yeasts are designed to ferment wheat substrates for baking purposes but identification of new substrates for these strains and consequently new formulations for dough could lead to diversified bakery products with improved nutritional qualities and specific sensorial properties. The purpose of our study was to optimize the fermentation of quinoa and amaranth flours with non-conventional yeast strains in order to obtain a preferment with high potential in enhancing nutritional, textural and sensorial features of white wheat bread. Two biotypes of Saccharomyces cerevisiae yeast-a wine yeast strain and a beer yeast strain-commercialized for their aromatic properties were used. Both aromatic yeast strains revealed good performance on fermenting pseudocereal substrates. Utilization of the obtained preferment in white wheat breadmaking led to bread with higher protein, fibres, mineral, total polyphenols content, with specific texture and aroma profile and high consumers' acceptability.

Purification of bacterial inulinase in aqueous two-phase systems.

In this study, extracellular inulinase from Bacillus sp. 11/3 was partially purified and concentrated using aqueous two-phase system (ATPS). Two different phase forming salts and four types of polyethylene glycol (PEG) were used. Binodal curves and tie-length lines (TLLs) for eight ATPS were developed. For inulinase purification, concentrations of PEG and salt according to binodal curves (between 17 and 26%) were chosen. All ATPSs for inulinase purification were characterized. An ATPS consisted of 26% PEG1000 and 26% MgSO4 was found to be the most suitable for inulinase purification. This ATPS has 28.47% TLL, 1.03 of volume ratio, purification factor of 4.65 fold and recovery yield of 66.17%. On the SDS-PAGE electrophoresis two protein bands with molecular weight of around 24 and 56 kDa were observed. The partially purified enzymes had optimal activity at pH 8.0 and 6.5, optimal temperature at 30 and 70°C and kinetic parameters Km = 26.32 mmol and Vmax = 526 mmol/min.

Reducing depressive symptomatology with a smartphone app: study protocol for a randomized, placebo-controlled trial.

BACKGROUND: Depression has become one of the leading contributors to the global disease burden. Evidence-based treatments for depression are available, but access to them is still limited in some instances. As technology has become more integrated into mental health care, computerized cognitive behavioral therapy (CBT) protocols have become available and have been recently transposed to mobile environments (e.g., smartphones) in the form of "apps." Preliminary research on some depression apps has shown promising results in reducing subthreshold or mild to moderate depressive symptoms. However, this small number of studies reports a low statistical power and they have not yet been replicated. Moreover, none of them included an active placebo comparison group. This is problematic, as a "digital placebo effect" may explain some of the positive effects documented until now. The aim of this study is to test a newly developed mobile app firmly grounded in the CBT theory of depression to determine whether this app is clinically useful in decreasing moderate depressive symptoms when compared with an active placebo. Additionally, we are interested in the app's effect on emotional wellbeing and depressogenic cognitions. METHODS/DESIGN: Romanian-speaking adults (18 years and older) with access to a computer and the Internet and owning a smartphone are included in the study. A randomized, three-arm clinical trial is being conducted (i.e., active intervention, placebo intervention and delayed intervention). Two hundred and twenty participants with moderate depressive symptoms (i.e., obtaining scores >9 and ≤16 on the Patient Health Questionnaire, PHQ-9) will be randomized to the three conditions. Participants undergoing therapy, presenting serious mental health problems, or legal or health issues that would prevent them from using the app, as well as participants reporting suicidal ideation are excluded. Participants randomized to the active and placebo interventions will use the smartphone app for 6 weeks. A short therapist check-in via phone will take place every week. Participants in the delayed-intervention condition will be given access to the app after 6 weeks from randomization. The primary outcome is the level of depressive symptomatology. The intervention delivered through the app to the active condition includes psychoeducational materials and exercises based on CBT for depression, while the placebo intervention uses a sham version of the app (i.e., similar structure of courses and exercises). DISCUSSION: To our knowledge, this study protocol is the first to test the efficacy of a smartphone app for depressive symptomatology in the form of a randomized controlled trial (RCT) that includes an active placebo condition. As such, this can substantially add to the body of evidence supporting the use of apps designed to decrease depression. TRIAL REGISTRATION: ClinicalTrials.gov, identifier: NCT03060200 . Registered on 1 February 2017. The first participant was enrolled on 17 February 2017.

Using a smartphone app to reduce cognitive vulnerability and mild depressive symptoms: Study protocol of an exploratory randomized controlled trial.

BACKGROUND: Depression is a major challenge worldwide, with significant increasing personal, economic, and societal costs. Although empirically supported treatments have been developed, they are not always available for patients in routine clinical care. Therefore, we need effective and widely accessible strategies to prevent the onset of the very first depressive symptoms. Mental health apps could prove a valuable solution for this desideratum. Although preliminary research has indicated that such apps can be useful in treating depression, no study has attempted to test their utility in preventing depressive symptoms. The aim of this exploratory study is to contrast the efficacy of a smartphone app in reducing cognitive vulnerability and mild depressive symptoms, as risk factors for the onset of depression, against a wait-list condition. More specifically, we aim to test an app designed to (1) decrease general cognitive vulnerability and (2) promote engagement in protective, adaptive activities, while (3) counteracting (through gamification and customization) the tendency of premature dropout from intervention. METHODS/DESIGN: Romanian-speaking adults (18 years and older) with access to a computer and the Internet and who own a smartphone are included in the study. Two parallel randomized clinical trials are conducted: in the first one, 50 participants free of depressive symptoms (i.e., who obtain scores ≤4 on the Patient Health Questionnaire, PHQ-9) will be included, while in the second one 50 participants with minimal depressive symptoms (i.e., who obtain PHQ-9 scores between 5 and 9) will be included. Participants undergoing therapy, presenting with substance abuse problems, psychotic symptoms, and organic brain disorders, or serious legal or health issues that would prevent them from using the app, as well as participants reporting suicidal ideation are excluded. Participants randomized to the active intervention will autonomously use the smartphone app for 4 weeks, while the others will be given access to the app after 4 weeks from randomization. The primary outcomes are (1) cognitive vulnerability factors as defined within the cognitive behavioral therapy (CBT) paradigm (i.e., dysfunctional cognitions, irrational beliefs, and negative automatic thoughts) (for the first trial), and (2) level of depressive symptomatology (for the second trial). The app includes self-help materials and exercises based on CBT for depression, presented in a tailored manner and incorporating gamification elements aimed at boosting motivation to use the app. DISCUSSION: This study protocol is the first to capitalize on the ubiquity of smartphones to large-scale dissemination of CBT-based strategies aimed at preventing depression in non-clinical populations. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02783118 . Registered on 26 May 2016.

Cognitive evolutionary therapy for depression: a case study.

KEY CLINICAL MESSAGE: We present an evolutionary-driven cognitive-behavioral intervention for a moderately depressed patient. Standard cognitive and behavioral therapy techniques focused on the patient's perfectionistic and self-downing beliefs, while novel, evolutionary-informed techniques were used to guide behavioral activation and conceptualize secondary emotional problems related to anger. The treatment reduced depressive symptomatology and increased evolutionary fitness.

Evolutionary cognitive therapy versus standard cognitive therapy for depression: a protocol for a blinded, randomized, superiority clinical trial.

BACKGROUND: Depression is estimated to become the leading cause of disease burden globally by 2030. Despite existing efficacious treatments (both medical and psychotherapeutic), a large proportion of patients do not respond to therapy. Recent insights from evolutionary psychology suggest that, in addition to targeting the proximal causes of depression (for example, targeting dysfunctional beliefs by cognitive behavioral therapy), the distal or evolutionary causes (for example, inclusive fitness) should also be addressed. A randomized superiority trial is conducted to develop and test an evolutionary-driven cognitive therapy protocol for depression, and to compare its efficacy against standard cognitive therapy for depression. METHODS/DESIGN: Romanian-speaking adults (18 years or older) with elevated Beck Depression Inventory (BDI) scores (>13), current diagnosis of major depressive disorder or major depressive episode (MDD or MDE), and MDD with comorbid dysthymia, as evaluated by the Structured Clinical Interview for DSM-IV (SCID), are included in the study. Participants are randomized to one of two conditions: 1) evolutionary-driven cognitive therapy (ED-CT) or 2) cognitive therapy (CT). Both groups undergo 12 psychotherapy sessions, and data are collected at baseline, mid-treatment, post-treatment, and the 3-month follow-up. Primary outcomes are depressive symptomatology and a categorical diagnosis of depression post-treatment. DISCUSSION: This randomized trial compares the newly proposed ED-CT with a classic CT protocol for depression. To our knowledge, this is the first attempt to integrate insights from evolutionary theories of depression into the treatment of this condition in a controlled manner. This study can thus add substantially to the body of knowledge on validated treatments for depression. TRIAL REGISTRATION: Current Controlled Trials ISRCTN64664414The trial was registered in June 2013. The first participant was enrolled on October 3, 2012.