Development of CARRA/PReS-endorsed consensus Core and Expanded Datasets in childhood-onset systemic lupus erythematosus for international registry-based research.

OBJECTIVES: Childhood-onset systemic lupus erythematosus (cSLE), representing 15%-20% of individuals with SLE, has been difficult to study globally due to differences between registries. This initiative, supported by Childhood Arthritis Rheumatology Research Alliance (CARRA) and Paediatric Rheumatology European Society (PReS), aims to create Core and Expanded cSLE Datasets to standardise and enhance research worldwide. METHODS: 21 international cSLE experts and 4 patients participated in a Delphi process (questionnaires, 2 topic-specific focus groups and 3 virtual consensus meetings) to create 2 standardised cSLE datasets. The Core cSLE Dataset was designed to include data essential to meaningful clinical research across many settings. The Expanded cSLE Dataset was designed for centres able to consistently collect data to address broader research questions. Final data items for the Core and Expanded datasets were determined by consensus defined as >80% agreement) using an adapted nominal group technique and voting. RESULTS: The resulting Core cSLE Dataset contains 46 items, including demographics, clinical features, laboratory results, medications and significant adverse events. The Expanded cSLE Dataset adds 26 additional items and includes patient-reported outcomes. Consensus was also achieved regarding the frequency and time points for data collection: baseline, quarterly follow-up visits, annually and flare visits. CONCLUSION: Standardised Core and Expanded cSLE Datasets for registry-based international cSLE research were defined through the consensus of global experts and patient/caregiver representatives, endorsed by CARRA and PReS. These datasets incorporate disease-specific and patient-specific features, optimised for diverse settings to facilitate international collaborative research for children and adolescents with SLE worldwide.

Barriers to care in juvenile localized and systemic scleroderma: an exploratory survey study of caregivers' perspectives.

BACKGROUND: Juvenile localized scleroderma (LS) and systemic sclerosis (SSc) are rare pediatric conditions often associated with severe morbidities. Delays in diagnosis are common, increasing the risk for permanent damage and worse outcomes. This study explored caregiver perspectives on barriers they encountered while navigating diagnosis and care for their child's scleroderma. METHODS: In this cross-sectional study, caregivers of juvenile LS or SSc patients were recruited from a virtual family scleroderma educational conference and a juvenile scleroderma online interest group. The survey queried respondents about their child's condition and factors affecting diagnosis and treatment. RESULTS: The response rate was 61% (73/120), with 38 parents of LS patients and 31 parents of SSc patients. Most patients were female (80%) and over half were non-Hispanic white (55%). Most families had at least one person with a college education or higher (87%), traveled ≤ 2 h to see their rheumatologist (83%), and had private insurance (75%). Almost half had an annual household income ≥ $100,000 (46%). Families identified the following factors as barriers to care: lack of knowledge about scleroderma in the medical community, finding reliable information about pediatric scleroderma, long wait times/distances for a rheumatology/specialist appointment, balance of school/work and child's healthcare needs, medication side effects, and identifying effective medications. The barrier most identified as a major problem was the lack of knowledge about juvenile scleroderma in the medical community. Public insurance, household income less than $100,000, and Hispanic ethnicity were associated with specific barriers to care. Lower socioeconomic status was associated with longer travel times to see the rheumatologist/specialist. Diagnosis and systemic treatment initiation occurred at greater than one year from initial presentation for approximately 28% and 36% of patients, respectively. Families of LS patients were commonly given erroneous information about the disease, including on the need and importance of treating active disease with systemic immunosuppressants in patients with deep tissue or rapidly progressive disease. CONCLUSION: Caregivers of children with LS or SSc reported numerous common barriers to the diagnosis, treatment, and ongoing care of juvenile scleroderma. The major problem highlighted was the lack of knowledge of scleroderma within the general medical community. Given that most of the caregiver respondents to the survey had relatively high socioeconomic status, additional studies are needed to reach a broader audience, including caregivers with limited English proficiency, geographical limitations, and financial constraints, to determine if the identified problems are generalizable. Identifying key care barriers will help direct efforts to address needs, reduce disparities in care, and improve patient outcomes.

NMR landscapes for chemical shift prediction.

The ability to reliably predict NMR chemical shifts plays an important role in elucidating the structure of organic molecules. Additionally, an intriguing question is how the multitude of variable factors (structural, electronic, and environmental) correlate with the actual electromagnetic shielding effect that determines the chemical shift value. This work presents NMRscape as a new tool for understanding these correlations by constructing the landscape that describes the relationship between the chemical shift value and the moieties bonded to a molecular scaffold. The scaffold may be as small as a single atom probed by NMR or a larger molecular framework containing the probed atom. NMRscape operates with only a list of the chemical moieties bonded to the scaffold, without utilizing any potentially biasing chemometric descriptors. The corresponding chemical shift landscape is constructed based on fundamental physical principles, which makes NMRscape a credible chemical shift prediction and analysis tool. As an illustration, we demonstrate that NMRscape can predict (13)C chemical shifts with an accuracy exceeding the substituent chemical shift (SCS) increment, hierarchical organization of spherical environments (HOSE), and neural networks (NN), methods for three distinct families of molecules sharing a common scaffold structure with moieties placed at two variable sites. The constructed NMR landscapes confirmed known empirical rules relating chemical shift values to the variation of chemical moieties on a scaffold, as well as uncovered hitherto hidden relationships. The practical importance of NMRscape is discussed.

Exploring constrained quantum control landscapes.

The broad success of optimally controlling quantum systems with external fields has been attributed to the favorable topology of the underlying control landscape, where the landscape is the physical observable as a function of the controls. The control landscape can be shown to contain no suboptimal trapping extrema upon satisfaction of reasonable physical assumptions, but this topological analysis does not hold when significant constraints are placed on the control resources. This work employs simulations to explore the topology and features of the control landscape for pure-state population transfer with a constrained class of control fields. The fields are parameterized in terms of a set of uniformly spaced spectral frequencies, with the associated phases acting as the controls. This restricted family of fields provides a simple illustration for assessing the impact of constraints upon seeking optimal control. Optimization results reveal that the minimum number of phase controls necessary to assure a high yield in the target state has a special dependence on the number of accessible energy levels in the quantum system, revealed from an analysis of the first- and second-order variation of the yield with respect to the controls. When an insufficient number of controls and/or a weak control fluence are employed, trapping extrema and saddle points are observed on the landscape. When the control resources are sufficiently flexible, solutions producing the globally maximal yield are found to form connected "level sets" of continuously variable control fields that preserve the yield. These optimal yield level sets are found to shrink to isolated points on the top of the landscape as the control field fluence is decreased, and further reduction of the fluence turns these points into suboptimal trapping extrema on the landscape. Although constrained control fields can come in many forms beyond the cases explored here, the behavior found in this paper is illustrative of the impacts that constraints can introduce.

Pediatric to Adult Transition Literature: Scoping Review and Rheumatology Research Prioritization Survey Results.

The transition from pediatric to adult care is the focus of growing research. It is important to identify how to direct future research efforts for maximum effect. Our goals were to perform a scoping review of the transition literature, highlight gaps in transition research, and offer stakeholder guidance on the importance and feasibility of research questions designed to fill identified gaps. The transition literature on rheumatic diseases and other common pediatric-onset chronic diseases was grouped and summarized. Based on the findings, a survey was developed and disseminated to pediatric rheumatologists and young adults with rheumatic diseases as well as their caregivers. The transitional care needs of patients, healthcare teams, and caregivers is well described in the literature. While various transition readiness scales exist, no longitudinal posttransfer study confirms their predictive validity. Multiple outcome measures are used alone or in combination to define a successful transition or intervention. Multimodal interventions are most effective at improving transition-related outcomes. How broader health policy affects transition is poorly studied. Research questions that ranked highest for importance and feasibility included those related to identifying and tracking persons with psychosocial vulnerabilities or other risk factors for poor outcomes. Interventions surrounding improving self-efficacy and health literacy were also ranked highly. In contrast to healthcare teams (n = 107), young adults/caregivers (n = 23) prioritized research surrounding improved work, school, or social function. The relevant transition literature is summarized and future research questions prioritized, including the creation of processes to identify and support young adults vulnerable to poor outcomes.

Why is chemical synthesis and property optimization easier than expected?

Identifying optimal conditions for chemical and material synthesis as well as optimizing the properties of the products is often much easier than simple reasoning would predict. The potential search space is infinite in principle and enormous in practice, yet optimal molecules, materials, and synthesis conditions for many objectives can often be found by performing a reasonable number of distinct experiments. Considering the goal of chemical synthesis or property identification as optimal control problems provides insight into this good fortune. Both of these goals may be described by a fitness function J that depends on a suitable set of variables (e.g., reactant concentrations, components of a material, processing conditions, etc.). The relationship between J and the variables specifies the fitness landscape for the target objective. Upon making simple physical assumptions, this work demonstrates that the fitness landscape for chemical optimization contains no local sub-optimal maxima that may hinder attainment of the absolute best value of J. This feature provides a basis to explain the many reported efficient optimizations of synthesis conditions and molecular or material properties. We refer to this development as OptiChem theory. The predicted characteristics of chemical fitness landscapes are assessed through a broad examination of the recent literature, which shows ample evidence of trap-free landscapes for many objectives. The fundamental and practical implications of OptiChem theory for chemistry are discussed.

Clinical Characteristics and Factors Associated With Disability and Impaired Quality of Life in Children With Juvenile Systemic Sclerosis: Results From the Childhood Arthritis and Rheumatology Research Alliance Legacy Registry.

OBJECTIVE: To investigate clinical manifestations of juvenile systemic sclerosis (SSc; scleroderma), including disease characteristics and patient quality of life, using the multinational Childhood Arthritis and Rheumatology Research Alliance (CARRA) Legacy Registry. METHODS: Patients with juvenile SSc were prospectively enrolled between 2010 and 2013. The diagnosis of juvenile SSc was determined by the enrolling pediatric rheumatologist, with the requirement for disease onset prior to age 18 years. Collected data included demographics, disease characteristics, medication exposure, and quality of life metrics. RESULTS: In total, 64 patients with juvenile SSc were enrolled a median of 3.6 years after disease onset, which occurred at a median age of 10.3 years. The most common organ manifestations were dermatologic and vascular, followed by musculoskeletal, gastrointestinal, and pulmonary; in 38% of patients, ≥4 organ systems were affected. Patients with juvenile SSc had significantly more disability at enrollment compared with CARRA Legacy Registry patients with juvenile idiopathic arthritis, dermatomyositis, or systemic lupus erythematosus. Although physician-reported measures correlated most closely with arthritis, dermatologic manifestations, and pulmonary manifestations, poor patient-reported measures were associated with gastrointestinal involvement. During >50 person-years of follow-up, most organ manifestations remained stable, and no mortality or development of new solid organ involvement after enrollment was reported. CONCLUSION: In the first multicenter prospective cohort of patients with juvenile SSc in North America, the disease burden was high: multiorgan manifestations were common, and functional disability was greater than that observed in patients with other childhood-onset rheumatic diseases. Gastrointestinal involvement had the greatest impact on quality of life.

Association analysis of CHMP1.5 genetic variation and bipolar disorder.

OBJECTIVES: The18p11.2 region surrounding the G-olf gene has been linked in several independent studies to bipolar disorder and schizophrenia, yet association studies between G-olf genetic variations and bipolar disorder have been negative. We hypothesized that the linkage in this region might be due to a gene in close physical proximity to G-olf, and we examined variations in the CHMP1.5 gene within intron 5 of G-olf for association with bipolar disorder. METHODS: Two single-nucleotide polymorphisms, rs1786581 and rs1249624, were analyzed for association with bipolar disorder in 402 unrelated bipolar individuals and 181 unrelated controls. Genotyping was performed via pyrosequencing and restriction fragment length polymorphism analysis; results were compared by chi2 contingency analysis. RESULTS: No evidence was found for association of either allele at rs1249624 with bipolar disorder (chi2=1.25, degrees of freedom=1, P=0.26); however, a trend towards association with the 'T' allele at rs1786581 and with the 'T/T' 1786581/1249624 haplotype was observed. The chi2 for the haplotype was 7.16, (degrees of freedom=3, P=0.067) and for rs1786581 chi2=3.56, degrees of freedom=1, P=0.060; these differences are not statistically significant. CONCLUSIONS: Variation in the CHMP1.5 gene does not appear to be associated with bipolar disorder. A systematic assessment of genetic variation in the region using association studies will be necessary.

AuICl-bound N-heterocyclic carbene ligands form MII4(LAuCl)6 integrally gilded cages.

The incorporation of an N-heterocyclic carbene (NHC) moiety into a self-assembled MII4L6 cage framework required the NHC first to be metallated with gold(i). Bimetallic cages could then be constructed using zinc(ii) and cadmium(ii) templates, showing weak luminescence. The cages were destroyed by the addition of further gold(i) in the form of AuI(2,4,6-trimethoxybenzonitrile)2SbF6, which caused the reversibly-formed cages to disassemble and controllably release the AuI-NHC subcomponent into solution. This release in turn induced the growth of gold nanoparticles. The rate of dianiline release could be tuned by capsule design or through the addition of chemical stimuli, with different release profiles giving rise to different nanoparticle morphologies.

Autoantibodies to Dense Fine Speckles in Pediatric Diseases and Controls.

OBJECTIVE: Autoantibodies to the dense fine speckled 70 kDa antigen (DFS70) are reported to be more common in individuals who do not have an antinuclear antibody (ANA)-associated rheumatic disease (AARD) than in patients with AARD. The frequency of anti-DFS70 antibodies has been thoroughly studied in adult but not in pediatric populations. The primary objective of this observational study was to determine the frequency of anti-DFS70 in pediatric AARD and reference cohorts. METHODS: Sera from 743 children with AARD and related conditions, and 345 samples from reference cohorts (healthy children and those being investigated for AARD) were studied for anti-DFS70 autoantibodies as measured by a chemiluminescence immunoassay. A de-identified administrative database was used to retrieve demographic, serologic, and clinical data. RESULTS: Anti-DFS70 antibodies were seen in 2.1% of healthy children and in 4.5% of sera from pediatric individuals referred for ANA testing. The frequency of anti-DFS70 was highest in juvenile localized scleroderma (LS; 4/29, 13.8%), juvenile dermatomyositis (JDM; 2/11, 18.2%), childhood systemic lupus erythematosus (cSLE; 19/331, 5.7%), diffuse cutaneous systemic sclerosis (1/22, 4.5%), celiac disease (2/49, 4.1%), and juvenile idiopathic arthritis (JIA; 5/202, 2.5%). Of note, anti-DFS70 antibodies were observed in 3/26 children (11.5%) with uveitis and JIA-associated uveitis. CONCLUSION: The frequency of anti-DFS70 autoantibodies in healthy pediatric subjects is within the lower range of that reported in adults. Anti-DFS70 antibodies can be found in childhood SSc and cSLE, but has a remarkably high frequency in children with LS, JDM, and uveitis.

Sampling nanoparticles for chemical analysis by low resolution electrical mobility classification.

The use of electrostatic classification to collect samples of aerosol nanoparticles for chemical analysis is discussed. Our technique exposes the aerosol to negative ions in a unipolar charger with subsequent mobility classification at low resolution and high sampling rate. The negative unipolar charger produces high charged fractions. The low-resolution mobility classifier enables the delivery of high mass concentrations in a well-defined mobility range. The mobility-classified particles are collected by electrostatic precipitation. We summarize experimental and computational work on the performance of the unipolar charger, and we describe the performance of the overall system when used to sample atmospheric particles. For a size distribution measured in Atlanta during a new particle formation event, calculated mass sampling rates of approximately 8 nm particles were about 150 pg/h.

On the relationship between quantum control landscape structure and optimization complexity.

It has been widely observed in optimal control simulations and experiments that state preparation is surprisingly easy to achieve, regardless of the dimension N of the system Hilbert space. In contrast, simulations for the generation of targeted unitary transformations indicate that the effort increases exponentially with N. In order to understand such behavior, the concept of quantum control landscapes was recently introduced, where the landscape is defined as the physical objective, as a function of the control variables. The present work explores how the local structure of the control landscape influences the effectiveness and efficiency of quantum optimal control search efforts. Optimizations of state and unitary transformation preparation using kinematic control variables (i.e., the elements of the action matrix) are performed with gradient, genetic, and simplex algorithms. The results indicate that the search effort scales weakly, or possibly independently, with N for state preparation, while the search effort for the unitary transformation objective increases exponentially with N. Analysis of the mean path length traversed during a search trajectory through the space of action matrices and the local structure along this trajectory provides a basis to explain the difference in the scaling of the search effort with N for these control objectives. Much more favorable scaling for unitary transformation preparation arises upon specifying an initial action matrix based on state preparation results. The consequences of choosing a reduced number of control variables for state preparation is also investigated, showing a significant reduction in performance for using fewer than 2N-2 variables, which is consistent with the topological analysis of the associated landscape.

Daily variation in chemical characteristics of urban ultrafine aerosols and inference of their sources.

A summer air quality monitoring campaign focusing on daily variation of ultrafine (<180 nm in diameter) particle chemical characteristics was conducted in a typical urban site in Los Angeles during June-July 2006. Ultrafine particles (UFP) were collected weekly for two 3 h periods each day, one to capture the morning commute (06:00-09:00 PDT) (Pacific Daylight Time) and one to investigate photochemically altered particles (13:00-16:00 PDT). Samples were analyzed for ionic compounds, metals, trace elements, elemental carbon, and organic carbon. In addition, measurements of individual organic species and their variation with time of day at the urban site were conducted. The relative abundances of alkanes, PAH, and hopanes in the morning denote a strong influence of commute traffic emissions on ultrafine particle concentrations. By contrast, afternoon concentrations of oxygenated organic acids and sulfate rose, while other species were diluted by increased mixing height or lost due to increasing temperature. These are clear indicators that secondary photochemical reactions are a major formation mechanism of ultrafine aerosols in the afternoon. The concentrations of organic species originating from vehicular emissions measured in this study compare favorably to those from freeway-adjacent measurements by using CO2 concentrations to adjust for dilution, demonstrating the effectiveness of this tool for relating sites affected by vehicular emissions.