Update of evidence- and consensus-based guidelines for the treatment of juvenile idiopathic arthritis (JIA) by the German Society of Pediatric and Juvenile Rheumatic Diseases (GKJR): New perspectives on interdisciplinary care.

BACKGROUND: New therapeutic strategies for juvenile idiopathic arthritis (JIA) have evolved within the past ten years, and as a result, an update of the 2011 recommendations of the German management guidelines was initiated. METHODS: A systemic literature review was performed, overarching principles were proposed and pre-selected via an online survey followed by two multidisciplinary consensus conferences. Pharmacological and non-pharmacological treatments were discussed, statements were proposed and ultimately agreed upon by nominal group technique (NGT). RESULTS: 12 overarching therapeutic principles, as well as 9 recommendations on pharmacological and 5 on non-pharmacological treatments for JIA were agreed upon. CONCLUSION: This report summarizes the recent update of the interdisciplinary, consensus-based German guidelines on the management of JIA. The multi- and interdisciplinary participation of all caregivers was central for this patient-focused update. With these guidelines, physicians can choose an evidence-based approach, which allows better tailored treatment in this vulnerable cohort of children and adolescents.

[Recommendation for standardized medical care for children and adolescents with long COVID]. / Einheitliche Basisversorgung von Kindern und Jugendlichen mit Long COVID: Stellungnahme einer multidisziplinären Arbeitsgruppe der DGKJ-Konvent-Gesellschaften (Stand: Februar 2022).

This current consensus paper for long COVID complements the existing AWMF S1 guidelines for long COVID with a detailed overview on the various clinical aspects of long COVID in children and adolescents. Members of 19 different pediatric societies of the DGKJ convent and collaborating societies together provide expert-based recommendations for the clinical management of long COVID based on the currently available but limited academic evidence for long COVID in children and adolescents. It contains screening questions for long COVID and suggestions for a structured, standardized pediatric medical history and diagnostic evaluation for patients with suspected long COVID. A time and resource-saving questionnaire, which takes the clinical complexity of long COVID into account, is offered via the DGKJ and DGPI websites as well as additional questionnaires suggested for an advanced screening of specific neurocognitive and/or psychiatric symptoms including post-exertional malaise (PEM) and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). According to the individual medical history as well as clinical signs and symptoms a step by step diagnostic procedure and a multidisciplinary therapeutic approach are recommended.

MRP8/14 serum levels as diagnostic markers for systemic juvenile idiopathic arthritis in children with prolonged fever.

OBJECTIVES: Differential diagnosis in children with prolonged fever is challenging. In particular, differentiating systemic-onset JIA (SJIA) from infectious diseases is difficult. Biomarkers are needed that support the diagnostic work-up. The aim of this study was to validate the usefulness of Myeloid-related protein 8/14 (MRP8/14) measurements in the diagnostic work-up of febrile children and to transfer it to clinical practice. METHODS: Data for 1110 paediatric patients were included and divided into two cohorts: (cohort A) for validation of MRP8/14 test performance with three different testing systems: the experimental ELISA, commercial ELISA and an innovative (point-of-care test) lateral flow immunoassay (LFIA); (cohort B) to validate the diagnostic accuracy with the two latter assays. RESULTS: In cohort A (n = 940), MRP8/14 was elevated in SJIA (12 110 ± 2650 ng/ml mean ± 95% CI) compared with other diagnoses (including infections and autoinflammatory diseases; 2980 ± 510 ng/ml) irrespective of fever and anti-inflammatory treatment (P < 0.001). In untreated patients with fever (n = 195) MRP8/14 levels in SJIA (19 740 ± 5080 ng/ml) were even higher compared with other diagnoses (4590 ± 1160 ng/ml) (P < 0.001, sensitivity 73%, specificity 90%). In group B1, the performance of the tests was confirmed in untreated patients with fever (n = 170): commercial ELISA (sensitivity 79%, specificity 89%) and LFIA (sensitivity 84%, specificity 81%). Compared with ferritin, IL-18, ESR, soluble IL-2 receptor and procalcitonin, MRP8/14 showed the best accuracy. CONCLUSION: MRP8/14 serum analyses have been validated as a helpful tool supporting the diagnosis of SJIA in febrile children. The results could be confirmed with commercial ELISA and LFIA enabling a rapid diagnostic point-of-care screening test.

[Prevention of infections by influenza virus and respiratory syncytial virus after removal of the lockdown measures]. / Prävention von Infektionen durch das Influenza- und respiratorische Synzytialvirus nach Aufhebung der Lockdown-Maßnahmen: Gemeinsames Statement der Deutschen Gesellschaft für Pädiatrische Infektiologie (DGPI) und der Gesellschaft für Pädiatrische Pneumologie (GPP).

There have recently been reports of unusual outbreaks of respiratory infections in children due to influenza virus and respiratory syncytial virus (RSV) during the summer in the southern hemisphere. This phenomenon is attributed to the termination of the drastic hygiene measures to contain the pandemic triggered by the coronavirus disease 2019 (COVID-19). The affected children were much older than anticipated. Coincident with the end of the present lockdown in summer, a similar situation could develop in Germany. Physicians and hospitals should be alerted to such a possibility. Interseasonal vaccines are not available for influenza but passive immunization against RSV could help to protect infants for whom appropriate indications exist according to the guidelines.

[Infectious disease-related preventive measures for trainees in healthcare service and welfare]. / Infektiologische Präventivmaßnahmen bei Praktikantinnen und Praktikanten im Gesundheitsdienst und der Wohlfahrtspflege: Aktualisierte Stellungnahme der Kommission für Infektionskrankheiten und Impffragen der DAKJ (April 2021).

Training periods in healthcare and free welfare settings are frequently obligatory. Temporary trainees frequently lack sufficient knowledge regarding hygiene and prevention of infections. Therefore, specific preventive measures for trainees need to be implemented in a standardized fashion, similar to those applied for permanent employees. These are legally regulated by the European Biological Agents Ordinance and the German Standing Committee on Vaccinations (STIKO) recommendations. Criteria regarding immunization against hepatitis A and B, measles, mumps, rubella, varicella, pertussis, diphtheria, tetanus, polio, influenza and COVID-19 are described. Immunization gaps should be closed at any opportunity in general (e.g. in adolescents during regular physician contacts) and specifically in medical students during the first semester and in other healthcare trainees before the start of the training period. Furthermore, individual introduction of trainees to their work areas and in particular education in health measures to protect themselves and also individuals under their care is of high importance. Education should include information on the potential risks of infection, hand hygiene practice and other personal protection measures.

[Fever of unknown origin]. / Fieber unklarer Genese.

Fever of unknown origin is diagnosed when the fever (mostly defined as an elevated body temperature ≥38.3 °C measured by rectal or tympanic route) lasts longer than expected, i.e. 5-10 days after the onset of fever. The search for the cause can be difficult and necessitates the special attention of an experienced general pediatrician in collaboration with specialists in pediatric infectious diseases, rheumatic diseases and oncology, nursing personnel, radiologists and others. In approximately half of the cases an infectious cause is finally found; other causes are primarily inflammatory, malignant and noninflammatory diseases. Individual causes with the imminent threat of a severe course should be treated immediately. For the other cases the diagnostic evaluation is paramount, which is wisely planned and executed with determination and openness. The patient history, physical examination, laboratory and device-based diagnostics, imaging and histological examinations can contribute to the final diagnosis. The parents must be escorted through a period of uncertainty and the child should be comforted wherever possible. Spontaneous recovery is also possible. The probatory administration of antibiotics rarely leads to an improvement. After extensive exclusion of infections and malignancies and increasing suffering from the fever itself, prescription of glucocorticoids may be justified in cases of high inflammatory activity, under the suspicion of a hyperergic state and after detailed informed consent. The management of fever of unknown origin is one of the greatest challenges in pediatrics.

[Recommendations on the approach when unusual neurological symptoms occur in temporal association with vaccinations in childhood and adolescence]. / Empfehlungen zum Vorgehen bei Auftreten ungewöhnlicher neurologischer Symptome in zeitlichem Zusammenhang mit Impfungen im Kindes- und Jugendalter: Aktualisierte Stellungnahme der Kommission für Infektionskrankheiten und Impffragen der DAKJ (Juni 2020).

Vaccinations are often administered at an age when many neurological diseases of childhood and adolescence also occur. Febrile seizures may occur following vaccination in patients with an appropriate genetic predisposition. The occurrence of narcolepsy has been described more frequently after pandemic influenza A-H1N1 vaccinations. The causality has not been proven. Data regarding an association between Guillain-Barré syndrome and influenza vaccinations are inconclusive. It was conclusively shown that vaccinations do not cause neurological disorders, such as autism and do not trigger multiple sclerosis. In summary, there is currently no confirmed evidence for the occurrence of chronic neurological diseases as a consequence of generally recommended vaccinations in Germany. If unusual neurological symptoms are observed in temporal association with vaccinations, a comprehensive evaluation is necessary to exclude a causal relationship and to diagnose the underlying neurological disease independent of the vaccination. This statement gives specific recommendations for the practical approach when neurological symptoms are observed in temporal association with vaccinations with respect to taking the patient history, initial diagnostic procedures, accurate and prompt documentation and the obligation to report the event. The committee also proposes procedures for further clarification and differential diagnostics of causal neurological diseases in childhood and adolescence.

[Use of masks by children to prevent infection with SARS-CoV-2]. / Verwendung von Masken bei Kindern zur Verhinderung der Infektion mit SARS-CoV-2: Stellungnahme der Deutschen Gesellschaft für Pädiatrische Infektiologie (DGPI), des Berufsverbandes der Kinder- und Jugendärzte (bvkj e. V.), der Deutschen Gesellschaft für Kinder- und Jugendmedizin (DGKJ), der Gesellschaft für Pädiatrische Pneumologie (GPP), der Deutschen Gesellschaft für Sozialpädiatrie und Jugendmedizin (DGSPJ), der Süddeutschen Gesellschaft für Kinder- und Jugendmedizin (SGKJ) und der Deutschen Gesellschaft für Kinder- und Jugendpsychiatrie, Psychosomatik und Psychotherapie (DGKJP).

After initial reluctance masks have emerged as an important means of restricting the spread of SARS-CoV­2, the new coronavirus causing COVID-19. Other simple measures are keeping a distance of at least 1 ½â€¯m from other persons and observing hygiene recommendations, including washing or even disinfecting the hands, coughing into the crook of the arm and remaining at home when sick. Combining the initial letters of the German words for the three measures (Abstand-Hygiene-Alltagsmaske, distance-hygiene-face mask) the acronym AHA was formed, a colloquial German word meaning that the speaker understood the information presented. This acronym was later extended by the letter "L", initial letter of "Lüften" meaning air ventilation for indoor rooms and arriving at AHA­L, recommended by the federal German Health Institute the Robert Koch Institute. In fact, masks including surgical masks and face coverings can form an effective barrier against the spread of the virus: protecting other people from droplets expelled from the throat of the speaker wearing a mask and even in part protecting the wearer from inhaling droplets emanating from other peoples' throats. Studies to find out if wearing masks might impose risks did not find essential problems: alterations of respiratory parameters due to an increased airway resistance remained within normal limits in healthy adults and even in asthmatics whose disease was well controlled; however, many adults expressed their unease with masks describing them as cumbersome and inconvenient. Emotional resistance against masks made it increasingly more difficult for them to use a mask. Efficient application of masks requires, in addition to a logical explanation of its effect, the evocation of empathy for vulnerable people who can be protected from catching a possibly deadly disease. In children there are very few data on adverse effects of wearing a mask although there is ample experience in children with serious diseases compromising defense against infectious agents acquired via respiratory mucus membranes; however, when using masks appropriately in children relevant adverse effects have not been reported and are not to be expected. Masks should only be used in children when they are healthy and awake and can remove the masks themselves anytime they like. Children 10 years or older can use masks efficiently when they have been informed beforehand appropriate to their age. Under these conditions they can also be obliged to wear masks in certain situations, for example while walking through the school building to their desk in class. To limit the period of wearing a mask normally they will be allowed to remove the mask when sitting in class and keeping their distance. Children in primary schools may use masks, but they should not be obliged to wear them and children in kindergartens should not use masks. This exemption of younger children does not expose school and kindergarten teachers to additional risks since the infectivity with SARS-CoV­2 is age-dependent and increases with age reaching adult values only after 12 years of age.

[Children with acute respiratory tract infections in pediatric hospitals in autumn/winter 2020/2021]. / Kinder mit akuter Atemwegsinfektion in Kinderkliniken im Herbst/Winter 2020/21: Empfehlungen der Deutschen Gesellschaft für Pädiatrische Infektiologie (DGPI) und der Deutschen Gesellschaft für Krankenhaushygiene (DGKH) (Stand 14.10.2020).

Due to the shortage of pediatric hospital beds in general and due to the large annual burden of hospital admissions for common respiratory tract infections, such as influenza or RSV [respiratory syncytial virus] in particular, it can be expected that hospitalization of children with suspected or confirmed SARS-CoV­2 infections will face hospitals with an even more tense situation than usual in the winter 2020/2021. This tenuous shortage may touch various aspects but in the first place it will affect isolation and cohorting. In addition, this shortage will not only apply to acutely ill children with viral respiratory tract infections but all children with need for hospital care, either chronically ill or e.g. being premature babies or newborns. Therefore, approaches are required which on the one hand are based on pragmatic grounds but on the other hand fulfill the basics of hygiene and infection control. The recommendations proposed in this statement are intended to give assistance to hospitals for the management of testing, isolation and cohorting of pediatric patients with suspected or confirmed SARS-CoV­2 infections. The most important factor navigating the essential measures is the cumulative incidence of newly diagnosed infections per 100,000 over the last 7 days, which is given by the RKI or the local public health authorities. In the situation of low (<25/100,000) or medium (25-50/100,000) incidence the respective diagnostic measures and hospital admission can be performed under standard hygiene precautions and the children will be cohorted according to their clinical presentation until the results of SARS-CoV­2 test (or RSV [respiratory syncytial virus] or influenza test) are available. In the situation of high (>50/100,000) incidence the respective diagnostic measures and the admission have to be performed under SARS-CoV­2 precautions as specified by the RKI, and the children have to be isolated until the results of SARS-CoV­2 test are available. The assessment of the incidence figures and the respective measures may be adapted by the local public health authorities on an individual basis. In case of shortfalls in admission capacities, the requirement of acute emergency care may necessitate that isolation and cohorting in the hospital will have to be performed temporarily in a less restrictive way than recommended here for standard.

Measures to maintain regular operations and prevent outbreaks of SARS-CoV-2 in childcare facilities or schools under pandemic conditions and co-circulation of other respiratory pathogens.

After the lockdown and the end of the summer holidays, day-cares and schools need to be reopened and (despite the continued circulation of the new coronavirus SARS-CoV-2) kept open. The need for opening up arises from the right of children to education, participation, support and care. This is possible if appropriate hygiene measures are implemented and community transmission remains stable. In addition, the safety of educators, teachers and carers must be a priority and needs to be addressed by appropriate measures. Finally, the needs of families must also be taken into account. The following document describes in detail how these objectives can be achieved.

Treat-to-target study for improved outcome in polyarticular juvenile idiopathic arthritis.

BACKGROUND: Juvenile idiopathic arthritis is one of the most prevalent chronic inflammatory diseases in children. Evidence suggests that early effective treatment minimises the burden of disease during childhood and in further life. We hypothesise that a guided treat-to-target (T2T) approach is superior to routine care in polyarticular juvenile idiopathic arthritis (pJIA) in terms of reaching a clinical remission after 12 months of treatment. METHODS: Patients with early and active pJIA were enrolled. Targets for treatment were the following: Recognisable Juvenile Arthritis Disease Activity Score (JADAS) improvement after 3 months, acceptable disease at 6 months, minimal disease activity at 9 months and as primary endpoint remission after 12 months. Initially, patients received methotrexate. Failure to meet a defined target required treatment modification at the specified intervals. The choice of biologics was not influenced by the protocol. Finally, T2T patients were compared with a cohort of matched controls of patients with pJIA with unguided therapy documented by BIKER. RESULTS: Sixty-three patients were enrolled. Treatment targets after 3/6/9 and 12 months were reached by 73%/75%/77% and 48% of patients. Fifty-four patients completed the protocol. Compared with matched controls, on T2T guidance significantly more patients reached JADAS remission (48% vs 32%; OR 1.96 (1.1-3.7); p=0.033) and JADAS minimal disease activity (JADAS-MDA) (76% vs 59%; OR 2.2 (1.1-4.4); p=0.028). Patients from the T2T cohort received a biologic significantly more frequent (50% vs 9% after 12 months; OR 9.8 (4.6-20.8); p<0.0001). CONCLUSION: The T2T concept was feasible and superior to unguided treatment. High rates of patients reached JADAS-MDA and JADA remission after 12 months. Approximately half of the patients achieved their therapy goals without a biologic.

Guidelines for diagnosis and treatment in neurology - Lyme neuroborreliosis.

Lyme borreliosis is the most common tick-borne infectious disease in Europe. A neurological manifestation occurs in 3-15% of infections and can manifest as polyradiculitis, meningitis and (rarely) encephalomyelitis. This S3 guideline is directed at physicians in private practices and clinics who treat Lyme neuroborreliosis in children and adults. Twenty AWMF member societies, the Robert Koch Institute, the German Borreliosis Society and three patient organisations participated in its development. A systematic review and assessment of the literature was conducted by the German Cochrane Centre, Freiburg (Cochrane Germany). The main objectives of this guideline are to define the disease and to give recommendations for the confirmation of a clinically suspected diagnosis by laboratory testing, antibiotic therapy, differential diagnostic testing and prevention.

Opportunistic infections in immunosuppressed patients with juvenile idiopathic arthritis: analysis by the Pharmachild Safety Adjudication Committee.

BACKGROUND: To derive a list of opportunistic infections (OI) through the analysis of the juvenile idiopathic arthritis (JIA) patients in the Pharmachild registry by an independent Safety Adjudication Committee (SAC). METHODS: The SAC (3 pediatric rheumatologists and 2 pediatric infectious disease specialists) elaborated and approved by consensus a provisional list of OI for use in JIA. Through a 5 step-procedure, all the severe and serious infections, classified as per MedDRA dictionary and retrieved in the Pharmachild registry, were evaluated by the SAC by answering six questions and adjudicated with the agreement of 3/5 specialists. A final evidence-based list of OI resulted by matching the adjudicated infections with the provisional list of OI. RESULTS: A total of 772 infectious events in 572 eligible patients, of which 335 serious/severe/very severe non-OI and 437 OI (any intensity/severity), according to the provisional list, were retrieved. Six hundred eighty-two of 772 (88.3%) were adjudicated as infections, of them 603/682 (88.4%) as common and 119/682 (17.4%) as OI by the SAC. Matching these 119 opportunistic events with the provisional list, 106 were confirmed by the SAC as OI, and among them infections by herpes viruses were the most frequent (68%), followed by tuberculosis (27.4%). The remaining events were divided in the groups of non-OI and possible/patient and/or pathogen-related OI. CONCLUSIONS: We found a significant number of OI in JIA patients on immunosuppressive therapy. The proposed list of OI, created by consensus and validated in the Pharmachild cohort, could facilitate comparison among future pharmacovigilance studies. TRIAL REGISTRATION: Clinicaltrials.gov NCT01399281; ENCePP seal: awarded on 25 November 2011.

[Lyme Borreliosis: Cutaneous and Neurologic Manifestations, Case Definitions and Therapy]. / Lyme-Borreliose: Kutane und neurologische Manifestationen, Falldefinitionen und Therapie.

Lyme borreliosis is the most common zoonosis in Germany with an incidence of up to 138/100 000. More than 90 % of all cases show dermatological manifestations. Early manifestations are erythema migrans, multiple erythemata migrantia, and (less frequently) borrelial lymphocytoma. A typical late manifestation is acrodermatitis chronica atrophicans. Lyme neuroborreliosis is much less common with an incidence of about 0.8/100 000 inhabitants in Germany. Bannwarth's syndrome (painful radiculoneuritis) is the most common manifestation of Lyme neuroborreliosis in adults followed by meningitis. International case definitions exist regarding the likelihood of Lyme neuroborreliosis on the basis of diagnostic test results. A CSF analysis should be performed in patients with suspected Lyme neuroborreliosis. The first line treatment for dermatological manifestations of Lyme borreliosis is doxycycline, in children and pregnant women amoxicillin. Doxycycline and beta-lactam antibiotics show similar efficacy regarding neurological symptoms and adverse effects for treatment of neurological manifestations. Treatment duration for early manifestations is 10 to 14 days, in Lyme neuroborreliosis it should not exceed 21 days. All manifestations, also Lyme neuroborreliosis, usually show a favourable prognosis after antibiotic treatment. Antibiotic treatment does not show any efficacy in patients with unspecific symptoms and concurrent positive anti-borrelial serology.

Growth and Puberty in Juvenile Dermatomyositis: A Longitudinal Cohort Study.

OBJECTIVE: To study growth and puberty in a multinational longitudinal prospective cohort of children with juvenile dermatomyositis (DM). METHODS: Children from 31 countries who were ages <18 years and had juvenile DM in active phase were studied, and analyses of height, weight, and pubertal development were conducted in those who had follow-up visits during a 2-year period and for whom anthropometric data was available. RESULTS: A total of 196 of 275 children (71%) were included. We found a significant reduction in parent-adjusted height Z score over time in female patients (P < 0.0001) and male patients (P = 0.001), but with catch-up growth at the final study visit. Median body mass index Z score peaked at 6 months (P < 0.0001) and was still significantly above baseline at the final study visit, which was at a median of 26 months after baseline (P = 0.007), with no difference between sexes. Female patients with a disease duration ≥12 months after onset had significantly lower parent-adjusted height Z score (P = 0.002) and no 2-year catch-up growth. At the final study visit, growth failure was seen in 20 of 97 female patients (21%) and in 11 of 73 male patients (15%). Height deflection (∆height Z score less than -0.25/year) was observed in 29 of 116 female patients (25%) and 25 of 80 male patients (31.3%). Delayed puberty was seen in 20 of 55 female patients (36.4%) and in 11 of 31 male patients (35.5%). Children in early pubertal stage at baseline had the highest risk of growth failure. CONCLUSION: Juvenile DM in the active phase and/or its treatment has a significant impact on growth and puberty in affected children. Children with recent onset of puberty or previous growth failure have the highest risk of delayed pubertal development and further growth retardation.

Intravenous dosing of tocilizumab in patients younger than two years of age with systemic juvenile idiopathic arthritis: results from an open-label phase 1 clinical trial.

BACKGROUND: The anti-interleukin-6 receptor-alpha antibody tocilizumab was approved for intravenous (IV) injection in the treatment of patients with systemic juvenile idiopathic arthritis (sJIA) aged 2 to 17 years based on results of a randomized controlled phase 3 trial. Tocilizumab treatment in systemic juvenile idiopathic arthritis (sJIA) patients younger than 2 was investigated in this open-label phase 1 trial and compared with data from the previous trial in patients aged 2 to 17 years. METHODS: Patients younger than 2 received open-label tocilizumab 12 mg/kg IV every 2 weeks (Q2W) during a 12-week main evaluation period and an optional extension period. The primary end point was comparability of pharmacokinetics during the main evaluation period to that of the previous trial (in patients aged 2-17 years), and the secondary end point was safety; pharmacodynamics and efficacy end points were exploratory. Descriptive comparisons for pharmacokinetics, pharmacodynamics, safety, and efficacy were made with sJIA patients aged 2 to 17 years weighing < 30 kg (n = 38) who received tocilizumab 12 mg/kg IV Q2W in the previous trial (control group). RESULTS: Eleven patients (mean age, 1.3 years) received tocilizumab during the main evaluation period. The primary end point was met: tocilizumab exposures for patients younger than 2 were within the range of the control group (mean [±SD] µg/mL concentration at the end-of-dosing interval [Cmin]: 39.8 [±14.3] vs 57.5 [±23.3]; maximum concentration [Cmax] postdose: 288 [±40.4] vs 245 [±57.2]). At week 12, pharmacodynamic measures were similar between patients younger than 2 and the control group; mean change from baseline in Juvenile Arthritis Disease Activity Score-71 was - 17.4 in patients younger than 2 and - 28.8 in the control group; rash was reported by 14.3 and 13.5% of patients, respectively. Safety was comparable except for the incidence of serious hypersensitivity reactions (27.3% in patients younger than 2 vs 2.6% in the control group). CONCLUSIONS: Tocilizumab 12 mg/kg IV Q2W provided pharmacokinetics, pharmacodynamics, and efficacy in sJIA patients younger than 2 comparable to those in patients aged 2 to 17 years. Safety was comparable except for a higher incidence of serious hypersensitivity events in patients younger than 2 years. CLASSIFICATION: Juvenile idiopathic arthritis. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01455701 . Registered, October 20, 2011, Date of enrollment of first participant: October 26, 2012.