Assessment of ADHD Subtypes Using Motion Tracking Recognition Based on Stroop Color-Word Tests.

Attention-Deficit/Hyperactivity Disorder (ADHD) is a neurodevelopmental disorder known for its significant heterogeneity and varied symptom presentation. Describing the different subtypes as predominantly inattentive (ADHD-I), combined (ADHD-C), and hyperactive-impulsive (ADHD-H) relies primarily on clinical observations, which can be subjective. To address the need for more objective diagnostic methods, this pilot study implemented a Microsoft Kinect-based Stroop Color-Word Test (KSWCT) with the objective of investigating the potential differences in executive function and motor control between different subtypes in a group of children and adolescents with ADHD. A series of linear mixture modeling were used to encompass the performance accuracy, reaction times, and extraneous movements during the tests. Our findings suggested that age plays a critical role, and older subjects showed improvements in KSWCT performance; however, no significant divergence in activity level between the subtypes (ADHD-I and ADHD-H/C) was established. Patients with ADHD-H/C showed tendencies toward deficits in motor planning and executive control, exhibited by shorter reaction times for incorrect responses and more difficulty suppressing erroneous responses. This study provides preliminary evidence of unique executive characteristics among ADHD subtypes, advances our understanding of the heterogeneity of the disorder, and lays the foundation for the development of refined and objective diagnostic tools for ADHD.

Characteristics of Single vs. Multiple Suicide Attempters Among Adult Population: A Systematic Review and Meta-Analysis.

PURPOSE OF REVIEW: We aimed to examine the factors that differentiate single and multiple suicide attempters in adult population. We followed the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines to conduct this review and meta-analysis. The review protocol was registered in PROSPERO. We carried out a systematic literature search in three databases to identify original studies that explored the differences between single and multiple suicide attempters among adult population. RECENT FINDINGS: There might be meaningful differences between those individuals that attempt suicide once in their lifespan and those who make multiple attempts in terms of sociodemographic and clinical characteristics. There are no previous meta-analysis addressing this topic in the adult population. A total of 75 studies were included in the review and 69 were included in the meta-analysis. Multiple attempters were more likely to present certain disorders such as mood and psychotic disorders, as well as personality or substance use disorders. Higher suicide ideation and suicide intent scores also characterized this group. Childhood trauma experiences, stressful life events, and higher rates of hopelessness were statistically significant in multiple attempters. Identifying the factors predicting multiple suicide attempts helps to delineate a high-risk suicidal profile that should be taken into account in the clinical and suicide prevention scenario.

Dual latent tuberculosis screening with tuberculin skin tests and QuantiFERON-TB assays before TNF-α inhibitor initiation in children in Spain.

Tumor-necrosis-factor-α inhibitors (anti-TNF-α) are associated with an increased risk of tuberculosis (TB) disease, primarily due to reactivation of latent TB infection (LTBI). We assessed the performance of parallel LTBI screening with tuberculin skin test (TST) and QuantiFERON-TB Gold In-Tube assays (QFT-GIT) before anti-TNF-α treatment in children with immune-mediated inflammatory disorders in a low TB-burden setting. We conducted a multicenter cohort study involving 17 pediatric tertiary centers in Spain. LTBI was defined as the presence of a positive TST and/or QFT-GIT result without clinical or radiological signs of TB disease. A total of 270 patients (median age:11.0 years) were included, mainly with rheumatological (55.9%) or inflammatory bowel disease (34.8%). Twelve patients (4.4%) were diagnosed with TB infection at screening (LTBI, n = 11; TB disease, n = 1). Concordance between TST and QFT-GIT results was moderate (TST+/QFT-GIT+, n = 4; TST-/QFT-GIT+, n = 3; TST+/QFT-GIT-, n = 5; kappa coefficient: 0.48, 95% CI: 0.36-0.60). Indeterminate QFT-GIT results occurred in 10 patients (3.7%) and were associated with young age and elevated C-reactive protein concentrations. Eleven of 12 patients with TB infection uneventfully completed standard LTBI or TB treatment. During a median follow-up period of 6.4 years, only 2 patients developed TB disease (incidence density: 130 (95% CI: 20-440) per 100,000 person-years), both probable de novo infections. CONCLUSION: A substantial number of patients were diagnosed with LTBI during screening. The dual strategy identified more cases than either of the tests alone, and test agreement was only moderate. Our data show that in children in a low TB prevalence setting, a dual screening strategy with TST and IGRA before anti-TNF-α treatment is effective. WHAT IS KNOWN: • The optimal screening strategy for latent tuberculosis in children with immune-mediated inflammatory disorders remains uncertain. • Children receiving anti-TNF-α drugs are at increased risk of developing severe tuberculosis disease. WHAT IS NEW: • A dual screening strategy, using TST and an IGRA assay, identified more children with latent tuberculosis than either of the tests alone. • Identification and treatment of latent tuberculosis before initiation of anti-TNF-α therapy averted incident tuberculosis cases.

Characteristics of single vs. multiple suicide attempters among adolescents: a systematic review and meta-analysis.

There might be differential characteristics between those who have attempted suicide once in their lifetime (single attempters) and those who have attempted suicide two or more times (multiple attempters). We aimed to identify the factors that differentiate single and multiple attempters in child and adolescents. This study was conducted following the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines, and the review protocol was registered in PROSPERO. We conducted a systematic literature search in three databases to identify original studies exploring the characteristics of single attempters vs. multiple attempters among adolescents. We considered a wide range for the definition of adolescent, following most recent recommendations: 10-24 years. We carried out a meta-analysis. Fourteen studies were included in the systematic review and 13 in the meta-analysis with a total sample of with a total of 4286 participants. The factors statistically significantly associated with being a multiple attempter in the meta-analysis were: anxiety disorders, depression severity, alcohol abuse, substance abuse, aggressiveness, and hopelessness. Multiple attempters have a more severe clinical profile, with greater severity of symptoms. Knowledge of the risk factors associated with being a multiple attempter could help us to predict which patients are more likely to reattempt suicide and need further monitoring and a tailored treatment. Prevention programs tailored for the adolescent population, along with identification of early risk factors, could help to prevent suicidal behavior among this vulnerable population.

Diagnostic trajectories of mental disorders in children and adolescents: a cohort study.

Mental disorders in children and adolescents may follow different trajectories, such as remission, change of diagnosis, or addition of two or more comorbid diagnoses, showing a heterotypic pattern. This study aims to describe the main diagnostic trajectories across a broad range of mental disorder diagnostic categories, from childhood to adolescence and from adolescence to young adulthood in a clinical population. A prospective study was conducted among a clinical sample of children and adolescents who were aged 3-17 years at the face-to-face baseline interview. Electronic health records of these participants were reviewed 10 years later. The diagnostic stability over time was examined using the kappa coefficient, and factors associated with stability were explored using simple logistic regression. The study included a sample of 691 participants. The kappa coefficient for diagnostic stability across all diagnoses was 0.574 for the transition from childhood to adulthood, 0.614 from childhood to adolescence, and 0.733 from adolescence to adulthood. Neurodevelopmental diagnoses had the highest stability. Factors associated with higher diagnostic stability included family history of mental disorders, receiving psychopharmacological treatment, and symptom severity at baseline. We found a variable diagnostic stability across different diagnoses and age categories. The different life transitions represent complex periods that should not be overlooked from a clinical standpoint. An appropriate transition from child and adolescent mental health services to adult mental health services may have a positive impact on children and adolescents with mental disorders.

Long-term efficacy and safety of canakinumab in patients with mevalonate kinase deficiency: results from the randomised Phase 3 CLUSTER trial.

OBJECTIVES: To evaluate the long-term efficacy and safety of canakinumab in patients with mevalonate kinase deficiency during the open label extension (weeks 41-113) of the randomized controlled CLUSTER trial. METHODS: During a 72-week period, patients received open-label canakinumab 150 or 300 mg, every 4 or 8 weeks. The disease activity was evaluated every 8 weeks using physician global assessment and counting the number of flares. Concentrations of CRP and serum amyloid A protein were measured. The safety was studied by determination and classification of observed adverse events. The safety and efficacy were analysed separately in three subgroups of patients receiving a cumulative dose of less than <35 mg/kg, ≥35 to <70 mg/kg or ≥70 mg/kg. RESULTS: Of the 74 patients who started the CLUSTER study, 66 entered Epoch 4 and 65 completed it. During the 72-week period, 42 (64%) patients experienced no flares, while 13 (20%) had one flare, as compared with a median of 12 flares per year reported at baseline. Low physician global assessment scores were seen at the end of the study for all groups with >90% reporting minimal disease activity or none at all. Median CRP concentrations were consistently equal or lower than 10 mg/l, while median serum amyloid A concentrations remained only slightly above the normal range of 10 mg/l. The study showed no new or unexpected adverse events. CONCLUSION: Canakinumab proved effective to control disease activity and prevent flares in mevalonate kinase deficiency during the 72-week study period. No new safety concerns were reported. TRIAL REGISTRATION: NCT02059291. https://clinicaltrials.gov.

Video games for the assessment and treatment of attention-deficit/hyperactivity disorder: a systematic review.

Attention-deficit/hyperactivity disorder (ADHD) is a prevalent and serious disorder among children. Video games have shown potential for aiding in child healthcare. Video games could contribute to the assessment and management of ADHD, but there are no previous reviews on this topic. Here, we systematically review the evidence about video game-based assessment tools and interventions for children diagnosed with ADHD. This review followed the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. The review protocol was registered in PROSPERO database. We searched four databases-PubMed, PsycInfo, Embase and clinicaltrials.gov-to identify original studies exploring either video game-based interventions or video game-based assessment tools in children with ADHD. After initial screening, full text revision and study selection, 22 articles were finally included in the review. Most studies used PC as platform, with a minority using a video console, pad, or 3D device. Video game-based assessment tools were generally effective in discriminating ADHD cases from controls, and in discriminating between ADHD subtypes. Video game-based therapeutic interventions were well accepted and generally effective in improving cognitive areas and decreasing ADHD symptoms. Gamification and cognitive training could be the main mechanisms underlying the usefulness and effectiveness of video game-based assessment tools and interventions. Software optimization and greater collaboration between developers and healthcare professionals are some of the priorities for future research in this area.

Genotype FBN1/phenotype relationship in a cohort of patients with Marfan syndrome.

Marfan syndrome (MFS) is a systemic connective tissue disorder caused by mutations in the fibrillin-1 (FBN1) gene, and cardiovascular involvement is the leading cause of mortality. We sought to examine the genotype/phenotype realtionship in 61 consecutive patients with a phenotype and genotype compatible with MFS. The FBN1 gene was analyzed by massive sequencing using a hybridization capture-based target enrichment custom panel. Forty-three different variants of FBN1 were identified, of which 17 have not been previously reported. The causal variants of MFS were grouped into mutations resulting in haploinsufficiency (HI group; 23 patients) and mutations producing a dominant-negative effect (DN group; 38 patients). Patient information was collected from electronic medical records and clinical evaluation. While no significant differences were found between the two groups, the HI group included more cases with aortic dissection and occurring at a younger age that the DN group (34.7% vs. 15.8%; p = 0.160). Irrespective of the mutation group, males presented with a higher probability of aortic involvement (4-fold higher risk than females) and aortic dissections events occurred at younger ages. Patients with DN variants carrying a cysteine substitution had a higher incidence of ectopia lentis.

Ecological Momentary Assessment and Mood Disorders in Children and Adolescents: a Systematic Review.

PURPOSE OF REVIEW: The aim of the present review is to systematically examine published data regarding ecological momentary assessment (EMA) in children and adolescents with mood disorders. RECENT FINDINGS: EMA is increasingly used to collect participant's information in their real environment and in real time. There are multiple studies focused on the evaluation of mood disorders in children and adolescents, but only a few of them used EMA protocols. Results found in this review showed a wide variability of works with different fields of study, methodological approaches, and EMA protocols. More than 60% of EMA studies in children and adolescents with mood disorders were conducted via phone call, showing high completion rates with data missing in 5 to 11.5% of the calls. Length of studies varied from a 4-day EMA protocol to a maximum of 8 weeks. Positive and negative affect, daily activities, and social context were the main EMA measures. Despite the limited number of studies using EMA in children and adolescents with mood disorders, EMA was useful in assessing mood symptoms in the moment and in patients' real-life environment. Studies also showed high completion and satisfaction rates. Although web pages and apps use have been increasing over the past years, the evidence base is still scarce. Future studies can facilitate understanding of EMA methodology among youth with mood disorders.

Personality traits and psychotic symptoms in recent onset of psychosis patients.

OBJECTIVE: Personality in patients with psychosis, and particularly its relation to psychotic symptoms in recent onset of psychosis (ROP) patients, is understudied. The aims of this research were to study the relation between dimensional and categorical clinical personality traits and symptoms, as well as the effects that symptoms, sex and age have on clinically significant personality traits. METHODS: Data for these analyses were obtained from 94 ROP patients. The Millon Clinical Multiaxial Inventory and the Positive and Negative Syndrome Scale were used to assess personality and symptoms. Correlational Analysis, Mann-Whitney test, and, finally, logistic regression were carried out. RESULTS: The negative dimension was higher in patients with schizoid traits. The excited dimension was lower for those with avoidant and depressive traits. The anxiety and depression dimension was higher for patients with dependent traits. The positive dimension was lower for patients with histrionic and higher for patients with compulsive traits. Logistic regression demonstrated that gender and the positive and negative dimensions explained 35.9% of the variance of the schizoid trait. The excited dimension explained 9.1% of the variance of avoidant trait. The anxiety and depression dimension and age explained 31.3% of the dependent trait. Gender explained 11.6% of the histrionic trait, 14.5% of the narcissistic trait and 11.6% of the paranoid trait. Finally gender and positive dimension explained 16.1% of the compulsive trait. CONCLUSIONS: The study highlights the importance of studying personality in patients with psychosis as it broadens understating of the patients themselves and the symptoms suffered.

Microsoft Kinect-based Continuous Performance Test: An Objective Attention Deficit Hyperactivity Disorder Assessment.

BACKGROUND: One of the major challenges in mental medical care is finding out new instruments for an accurate and objective evaluation of the attention deficit hyperactivity disorder (ADHD). Early ADHD identification, severity assessment, and prompt treatment are essential to avoid the negative effects associated with this mental condition. OBJECTIVE: The aim of our study was to develop a novel ADHD assessment instrument based on Microsoft Kinect, which identifies ADHD cardinal symptoms in order to provide a more accurate evaluation. METHODS: A group of 30 children, aged 8-12 years (10.3 [SD 1.4]; male 70% [21/30]), who were referred to the Child and Adolescent Psychiatry Unit of the Department of Psychiatry at Fundación Jiménez Díaz Hospital (Madrid, Spain), were included in this study. Children were required to meet the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) criteria of ADHD diagnosis. One of the parents or guardians of the children filled the Spanish version of the Strengths and Weaknesses of ADHD Symptoms and Normal Behavior (SWAN) rating scale used in clinical practice. Each child conducted a Kinect-based continuous performance test (CPT) in which the reaction time (RT), the commission errors, and the time required to complete the reaction (CT) were calculated. The correlations of the 3 predictors, obtained using Kinect methodology, with respect to the scores of the SWAN scale were calculated. RESULTS: The RT achieved a correlation of -.11, -.29, and -.37 with respect to the inattention, hyperactivity, and impulsivity factors of the SWAN scale. The correlations of the commission error with respect to these 3 factors were -.03, .01, and .24, respectively. CONCLUSIONS: Our findings show a relation between the Microsoft Kinect-based version of the CPT and ADHD symptomatology assessed through parental report. Results point out the importance of future research on the development of objective measures for the diagnosis of ADHD among children and adolescents.

Randomized trial of tocilizumab in systemic juvenile idiopathic arthritis.

BACKGROUND: Systemic juvenile idiopathic arthritis (JIA) is the most severe subtype of JIA; treatment options are limited. Interleukin-6 plays a pathogenic role in systemic JIA. METHODS: We randomly assigned 112 children, 2 to 17 years of age, with active systemic JIA (duration of ≥6 months and inadequate responses to nonsteroidal antiinflammatory drugs and glucocorticoids) to the anti-interleukin-6 receptor antibody tocilizumab (at a dose of 8 mg per kilogram of body weight if the weight was ≥30 kg or 12 mg per kilogram if the weight was <30 kg) or placebo given intravenously every 2 weeks during the 12-week, double-blind phase. Patients meeting the predefined criteria for nonresponse were offered open-label tocilizumab. All patients could enter an open-label extension. RESULTS: At week 12, the primary end point (an absence of fever and an improvement of 30% or more on at least three of the six variables in the American College of Rheumatology [ACR] core set for JIA, with no more than one variable worsening by more than 30%) was met in significantly more patients in the tocilizumab group than in the placebo group (64 of 75 [85%] vs. 9 of 37 [24%], P<0.001). At week 52, 80% of the patients who received tocilizumab had at least 70% improvement with no fever, including 59% who had 90% improvement; in addition, 48% of the patients had no joints with active arthritis, and 52% had discontinued oral glucocorticoids. In the double-blind phase, 159 adverse events, including 60 infections (2 serious), occurred in the tocilizumab group, as compared with 38, including 15 infections, in the placebo group. In the double-blind and extension periods combined, 39 serious adverse events (0.25 per patient-year), including 18 serious infections (0.11 per patient-year), occurred in patients who received tocilizumab. Neutropenia developed in 19 patients (17 patients with grade 3 and 2 patients with grade 4), and 21 had aminotransferase levels that were more than 2.5 times the upper limit of the normal range. CONCLUSIONS: Tocilizumab was efficacious in severe, persistent systemic JIA. Adverse events were common and included infection, neutropenia, and increased aminotransferase levels. (Funded by Hoffmann-La Roche; ClinicalTrials.gov number, NCT00642460.).

Two randomized trials of canakinumab in systemic juvenile idiopathic arthritis.

BACKGROUND: Interleukin-1 is pivotal in the pathogenesis of systemic juvenile idiopathic arthritis (JIA). We assessed the efficacy and safety of canakinumab, a selective, fully human, anti-interleukin-1ß monoclonal antibody, in two trials. METHODS: In trial 1, we randomly assigned patients, 2 to 19 years of age, with systemic JIA and active systemic features (fever; ≥2 active joints; C-reactive protein, >30 mg per liter; and glucocorticoid dose, ≤1.0 mg per kilogram of body weight per day), in a double-blind fashion, to a single subcutaneous dose of canakinumab (4 mg per kilogram) or placebo. The primary outcome, termed adapted JIA ACR 30 response, was defined as improvement of 30% or more in at least three of the six core criteria for JIA, worsening of more than 30% in no more than one of the criteria, and resolution of fever. In trial 2, after 32 weeks of open-label treatment with canakinumab, patients who had a response and underwent glucocorticoid tapering were randomly assigned to continued treatment with canakinumab or to placebo. The primary outcome was time to flare of systemic JIA. RESULTS: At day 15 in trial 1, more patients in the canakinumab group had an adapted JIA ACR 30 response (36 of 43 [84%], vs. 4 of 41 [10%] in the placebo group; P<0.001). In trial 2, among the 100 patients (of 177 in the open-label phase) who underwent randomization in the withdrawal phase, the risk of flare was lower among patients who continued to receive canakinumab than among those who were switched to placebo (74% of patients in the canakinumab group had no flare, vs. 25% in the placebo group, according to Kaplan-Meier estimates; hazard ratio, 0.36; P=0.003). The average glucocorticoid dose was reduced from 0.34 to 0.05 mg per kilogram per day, and glucocorticoids were discontinued in 42 of 128 patients (33%). The macrophage activation syndrome occurred in 7 patients; infections were more frequent with canakinumab than with placebo. CONCLUSIONS: These two phase 3 studies show the efficacy of canakinumab in systemic JIA with active systemic features. (Funded by Novartis Pharma; ClinicalTrials.gov numbers, NCT00889863 and NCT00886769.).

Efficacy and safety of tocilizumab in patients with polyarticular-course juvenile idiopathic arthritis: results from a phase 3, randomised, double-blind withdrawal trial.

OBJECTIVE: To evaluate the interleukin-6 receptor inhibitor tocilizumab for the treatment of patients with polyarticular-course juvenile idiopathic arthritis (pcJIA). METHODS: This three-part, randomised, placebo-controlled, double-blind withdrawal study (NCT00988221) included patients who had active pcJIA for ≥6 months and inadequate responses to methotrexate. During part 1, patients received open-label tocilizumab every 4 weeks (8 or 10 mg/kg for body weight (BW) <30 kg; 8 mg/kg for BW ≥30 kg). At week 16, patients with ≥JIA-American College of Rheumatology (ACR) 30 improvement entered the 24-week, double-blind part 2 after randomisation 1:1 to placebo or tocilizumab (stratified by methotrexate and steroid background therapy) for evaluation of the primary end point: JIA flare, compared with week 16. Patients flaring or completing part 2 received open-label tocilizumab. RESULTS: In part 1, 188 patients received tocilizumab (<30 kg: 10 mg/kg (n=35) or 8 mg/kg (n=34); ≥30 kg: n=119). In part 2, 163 patients received tocilizumab (n=82) or placebo (n=81). JIA flare occurred in 48.1% of patients on placebo versus 25.6% continuing tocilizumab (difference in means adjusted for stratification: -0.21; 95% CI -0.35 to -0.08; p=0.0024). At the end of part 2, 64.6% and 45.1% of patients receiving tocilizumab had JIA-ACR70 and JIA-ACR90 responses, respectively. Rates/100 patient-years (PY) of adverse events (AEs) and serious AEs (SAEs) were 480 and 12.5, respectively; infections were the most common SAE (4.9/100 PY). CONCLUSIONS: Tocilizumab treatment results in significant improvement, maintained over time, of pcJIA signs and symptoms and has a safety profile consistent with that for adults with rheumatoid arthritis. TRIAL REGISTRATION NUMBER: NCT00988221.

Somatic NLRP3 mosaicism in Muckle-Wells syndrome. A genetic mechanism shared by different phenotypes of cryopyrin-associated periodic syndromes.

UNLABELLED: : Familial cold autoinflammatory syndrome, Muckle-Wells syndrome (MWS), and chronic, infantile, neurological, cutaneous and articular (CINCA) syndrome are dominantly inherited autoinflammatory diseases associated to gain-of-function NLRP3 mutations and included in the cryopyrin-associated periodic syndromes (CAPS). A variable degree of somatic NLRP3 mosaicism has been detected in ≈35% of patients with CINCA. However, no data are currently available regarding the relevance of this mechanism in other CAPS phenotypes. OBJECTIVE: To evaluate somatic NLRP3 mosaicism as the disease-causing mechanism in patients with clinical CAPS phenotypes other than CINCA and NLRP3 mutation-negative. METHODS: NLRP3 analyses were performed by Sanger sequencing and by massively parallel sequencing. Apoptosis-associated Speck-like protein containing a CARD (ASC)-dependent nuclear factor kappa-light chain-enhancer of activated B cells (NF-κB) activation and transfection-induced THP-1 cell death assays determined the functional consequences of the detected variants. RESULTS: A variable degree (5.5-34.9%) of somatic NLRP3 mosaicism was detected in 12.5% of enrolled patients, all of them with a MWS phenotype. Six different missense variants, three novel (p.D303A, p.K355T and p.L411F), were identified. Bioinformatics and functional analyses confirmed that they were disease-causing, gain-of-function NLRP3 mutations. All patients treated with anti-interleukin1 drugs showed long-lasting positive responses. CONCLUSIONS: We herein show somatic NLRP3 mosaicism underlying MWS, probably representing a shared genetic mechanism in CAPS not restricted to CINCA syndrome. The data here described allowed definitive diagnoses of these patients, which had serious implications for gaining access to anti-interleukin 1 treatments under legal indication and for genetic counselling. The detection of somatic mosaicism is difficult when using conventional methods. Potential candidates should benefit from the use of modern genetic tools.

Multi-system involvement in a severe variant of fibrodysplasia ossificans progressiva (ACVR1 c.772G>A; R258G): A report of two patients.

Severe variants of fibrodysplasia ossificans progressiva (FOP) affect <2% of all FOP patients worldwide, but provide an unprecedented opportunity to probe the phenotype-genotype relationships that propel the pathology of this disabling disease. We evaluated two unrelated children who had severe reduction deficits of the hands and feet with absence of nails, progressive heterotopic ossification, hypoplasia of the brain stem, motor and cognitive developmental delays, facial dysmorphology, small malformed teeth, and abnormal hair development. One child had sensorineural hearing loss, microcytic anemia, and a tethered spinal cord and the other had a patent ductus arteriosus and gonadal dysgenesis with sex reversal (karyotype 46, XY female). Both children had an identical mutation in ACVR1 c.772A>G; p.Arg258Gly (R258G), not previously described in FOP. Although many, if not most, FOP mutations directly perturb the structure of the GS regulatory subdomain and presumably the adjacent αC helix, substitution with glycine at R258 may directly alter the position of the helix in the kinase domain, eliminating a key aspect of the autoinhibitory mechanism intrinsic to the wild-type ACVR1 kinase. The high fidelity phenotype-genotype relationship in these unrelated children with the most severe FOP phenotype reported to date suggests that the shared features are due to the dysregulated activity of the mutant kinase during development and postnatally, and provides vital insight into the structural biology and function of ACVR1 as well as the design of small molecule inhibitors.

Efficacy and safety of canakinumab in cryopyrin-associated periodic syndromes: results from a Spanish cohort.

OBJECTIVES: Cryopyrin-associated periodic syndromes (CAPS) are dominantly-inherited autoinflammatory diseases. The uncontrolled IL-1ß overproduction observed in these patients is the rational basis to treat them with anti-IL-1 drugs. The objective of this study was to evaluate the efficacy and safety of treatment with the long-lasting fully humanised anti-IL-1ß monoclonal antibody canakinumab in a Spanish cohort of patients with CAPS. METHODS: Clinical and laboratory data of CAPS patients carrying a heterozygous germline NLRP3 mutation were obtained. The initial treatment scheme with canakinumab was 150 mg/8 weeks administered subcutaneously in adult patients and 2 mg/kg/8 weeks in paediatric patients. RESULTS: Eight unrelated patients were enrolled. Canakinumab was the first anti-IL-1 drug used in three of them; five were already receiving anakinra. The clinical response to the initial canakinumab scheme was positive in all patients, and was quickly observed in the first 24-72 hours. Four required increasing the frequency and/or dose of canakinumab. A limited or no efficacy in those symptoms related to consequence of the deforming arthropathy and neurosensorial deafness was observed. The adverse side effects were restricted to infectious complications in a small percentage of patients. The treatment was well tolerated by all patients, with no reactions at drug site injections. CONCLUSIONS: Canakinumab caused fast and sustained remissions in most clinical and biochemical manifestations in all enrolled patients, with a limited efficacy in the structural lesions. Dose adjustments seem to be necessary for children and/or for patients with the most severe CAPS phenotypes. Treatment was well tolerated with a low incidence of adverse effects.

Clinical management algorithm of uveitis associated with juvenile idiopathic arthritis: interdisciplinary panel consensus.

Uveitis associated with juvenile idiopathic arthritis (JIA) typically involves the anterior chamber segment, follows an indolent chronic course, and presents a high rate of uveitic complications and a worse outcome as compared to other aetiologies of uveitis. Disease assessment, treatment, and outcome measures have not been standardized. Collaboration between pediatric rheumatologists and ophthalmologists is critical for effective management and prevention of morbidity, impaired vision, and irreparable visual loss. Although the Standardization of Uveitis Nomenclature Working Group recommendations have been a great advance to help clinicians to improve consistency in grading and reporting data, difficulties arise at the time of deciding the best treatment approach in the individual patient in routine daily practice. For this reason, recommendations for a systematized control and treatment strategies according to clinical characteristics and disease severity in children with JIA-related uveitis were developed by a panel of experts with special interest in uveitis associated with JIA. A clinical management algorithm organized in a stepwise regimen is here presented.

Consensus of the Spanish society of pediatric rheumatology for transition management from pediatric to adult care in rheumatic patients with childhood onset.

To develop recommendations on the transition from pediatric care to adult care in patients with chronic inflammatory rheumatic diseases with childhood onset based. Recommendations were generated following nominal group methodology and Delphi technique. A panel of 16 experts was established. A systematic literature review (on transitional care) and a narrative review were performed and presented to the panel in the first panel meeting to be discussed. A first draft of recommendations was generated and circulated. Focal groups with adolescents, young adults and parents were organized. In a second meeting, the focus group results along with the input from invited psychologist were used to establish definitive recommendations. Then, a Delphi process (two rounds) was carried out. A group of 72 pediatric and adult rheumatologists took part. Recommendations were voted from 1 (total disagreement) to 10 (total agreement). We defined agreement if at least 70 % voted ≥7. The level of evidence and grade or recommendation was assessed using the Oxford center for evidence-based medicine levels of evidence. Transition care was defined as a purposeful, planned process that addresses the medical, psychosocial and educational/vocational needs of adolescents and young adults with chronic inflammatory rheumatic diseases with childhood onset as they move from child-centered to adult-oriented healthcare systems. The consensus covers: transition needs, barriers and facilitators, transitional issues (objectives, participants, content, phases, timing, plans, documentation and responsibilities), physicians' and other health professionals' knowledge and skill requirements, models/programs, and strategies and guideline for implementation. Preliminary recommendations and agreement grade are shown in the Table (first Delphi round). These recommendations are intended to provide health professionals, patients, families and other stakeholders with a consensus on the transition process from pediatric to adult care.

Current situation of osteogenesis imperfecta in Spain: results from a Delphi study.

BACKGROUND: Osteogenesis imperfecta (OI) is a rare disease characterized by low bone mass and bone fragility, associated with an increased risk of fractures, and skeletal and extra-skeletal symptoms that results in an impairment of health-related quality of life of OI patients. Since published studies on OI in Spain are limited, this study aimed to determine the epidemiology, assessed the disease burden, management and unmet needs of OI patients in Spain. Thirty-four experts in the management of patients with osteogenesis imperfecta completed two rounds of online consultation and reported real-life experience and data from Spanish hospitals. Delphi study questionnaires were based on literature review. A working group of nationally recognized clinical experts supported the development of the study questionnaires and the final validation of results. RESULTS: The estimated prevalence of patients diagnosed with OI in Spain is 0.56:10,000 inhabitants (95%CI: 0.54-0.59), which represents that, approximately, 2,669 OI patients are currently managed in Spanish hospitals. It is estimated that approximately 269 new patients would be diagnosed with OI each year in Spain, representing an estimated incidence of 0.06 (95%CI: 0.05-0.06) per 10,000 inhabitants per year. Clinical management of OI in Spain is performed by a range of medical specialists; however, multidisciplinary care is not fully implemented. The absence of an approved curative treatment or a treatment to reduce the clinical features of the disease remains the main unmet need. CONCLUSIONS: This study provides a snapshot of the current situation of patients with OI in Spain reported by clinical experts. The results provide an estimation of the epidemiology of the disease, and complement the available evidence on disease burden, clinical management, and unmet needs of these patients in Spain.