Factors Associated with Attention Deficit Hyperactivity Disorder Medication Use in Community Care Settings.

OBJECTIVES: To examine patient- and provider-level factors associated with receiving attention-deficit/hyperactivity disorder (ADHD) medication treatment in a community care setting. We hypothesized that the likelihood of ADHD medication receipt would be lower in groups with specific patient sociodemographic (eg, female sex, race other than white) and clinical (eg, comorbid conditions) characteristics as well as physician characteristics (eg, older age, more years since completing training). STUDY DESIGN: A retrospective cohort study was conducted with 577 children (mean age, 7.8 years; 70% male) presenting for ADHD to 50 community-based practices. The bivariate relationship between each patient- and physician-level predictor and whether the child was prescribed ADHD medication was assessed. A multivariable model predicting ADHD medication prescription was conducted using predictors with significant (P < .05) bivariate associations. RESULTS: Sixty-nine percent of children were prescribed ADHD medication in the year after initial presentation for ADHD-related concerns. Eleven of 31 predictors demonstrated a significant (P < .05) bivariate relationship with medication prescription. In the multivariable model, being male (OR, 1.34; 95% CI, 1.01-1.78; P = .02), living in a neighborhood with higher medical expenditures (OR, 1.11 for every $100 increase; 95% CI, 1.03-1.21; P = .005), and higher scores on parent inattention ratings (OR, 1.06; 95% CI, 1.03-1.10; P < .0001) increased the likelihood of ADHD medication prescription. CONCLUSIONS: We found that some children, based on sociodemographic and clinical characteristics, are less likely to receive an ADHD medication prescription. An important next step will be to examine the source and reasons for these disparities in an effort to develop strategies for minimizing treatment barriers.

Synergy between Hematopoietic and Radioresistant Stromal Cells Is Required for Autoimmune Manifestations of DNase II-/-IFNaR-/- Mice.

Detection of endogenous nucleic acids by cytosolic receptors, dependent on STING, and endosomal sensors, dependent on Unc93b1, can provoke inflammatory responses that contribute to a variety of autoimmune and autoinflammatory diseases. In DNase II-deficient mice, the excessive accrual of undegraded DNA leads to both a STING-dependent inflammatory arthritis and additional Unc93b1-dependent autoimmune manifestations, including splenomegaly, extramedullary hematopoiesis, and autoantibody production. In this study, we use bone marrow chimeras to show that clinical and histological inflammation in the joint depends upon DNase II deficiency in both donor hematopoietic cells and host radioresistant cells. Additional features of autoimmunity in these mice, known to depend on Unc93b1 and therefore endosomal TLRs, also require DNase II deficiency in both donor and host compartments, but only require functional TLRs in the hematopoietic cells. Collectively, our data demonstrate a major role of both stromal and hematopoietic cells in all aspects of DNA-driven autoimmunity. These findings further point to the importance of cytosolic nucleic acid sensors in creating an inflammatory environment that facilitates the development of Unc93b1-dependent autoimmunity.

The role of organizational context in the implementation of a statewide initiative to integrate mental health services into pediatric primary care.

BACKGROUND: Although there is evidence that mental health services can be delivered in pediatric primary care with good outcomes, few changes in service delivery have been seen over the past decade. Practices face a number of barriers, making interventions that address determinants of change at multiple levels a promising solution. However, these interventions may need appropriate organizational contexts in place to be successfully implemented. PURPOSE: The objective of this study was to test whether organizational context (culture, climate, structures/processes, and technologies) influenced uptake of a complex intervention to implement mental health services in pediatric primary care. METHODOLOGY/APPROACH: We incorporated our research into the implementation and evaluation of Ohio Building Mental Wellness Wave 3, a learning collaborative with on-site trainings and technical assistance supporting key drivers of mental health care implementation. Simple linear regression was used to test the effects of organizational context and external or fixed organizational characteristics on program uptake. RESULTS: Culture, structure/processes, and technologies scores indicating a more positive organizational context for mental health at the project's start, as well as general cultural values that were more group/developmental, were positively associated with uptake. Patient-centered medical home certification and use of electronic medical records were also associated with greater uptake. Changes in context over the course of Building Mental Wellness did not influence uptake. CONCLUSION: Organizational culture, structures/processes, and technologies are important determinants of the uptake of activities to implement mental health services in pediatric primary care. Interventions may be able to change these aspects of context to make them more favorable to integration, but baseline characteristics more heavily influence the more proximal uptake of program activities. PRACTICE IMPLICATIONS: Pediatric primary care practices would benefit from assessing their organizational context and taking steps to address it prior to or in a phased approach with mental health service implementation.

Cutting edge: AIM2 and endosomal TLRs differentially regulate arthritis and autoantibody production in DNase II-deficient mice.

Innate immune pattern recognition receptors sense nucleic acids from microbes and orchestrate cytokine production to resolve infection. Inappropriate recognition of host nucleic acids also results in autoimmune disease. In this study, we use a model of inflammation resulting from accrual of self DNA (DNase II(-/-) type I IFN receptor [Ifnar](-/-)) to understand the role of pattern recognition receptor-sensing pathways in arthritis and autoantibody production. Using triple knockout (TKO) mice deficient in DNase II/IFNaR together with deficiency in either stimulator of IFN genes (STING) or absent in melanoma 2 (AIM2), we reveal central roles for the STING and AIM2 pathways in arthritis. AIM2 TKO mice show limited inflammasome activation and, similar to STING TKO mice, have reduced inflammation in joints. Surprisingly, autoantibody production is maintained in AIM2 and STING TKO mice, whereas DNase II(-/-) Ifnar(-/-) mice also deficient in Unc93b, a chaperone required for TLR7/9 endosomal localization, fail to produce autoantibodies to nucleic acids. Collectively, these data support distinct roles for cytosolic and endosomal nucleic acid-sensing pathways in disease manifestations.

An unexpected role for RNA-sensing toll-like receptors in a murine model of DNA accrual.

OBJECTIVES: The goal of this study was to determine whether endosomal Toll-like receptors (TLRs) contribute to the clinical manifestation of systemic autoimmunity exhibited by mice that lack the lysosomal nuclease DNaseII. METHODS: DNaseII/IFNaR double deficient mice were intercrossed with Unc93b13d/3d mice to generate DNaseII-/-mice with non-functional endosomal TLRs. The resulting triple deficient mice were evaluated for arthritis, autoantibody production, splenomegaly, and extramedullary haematopoiesis. B cells from both strains were evaluated for their capacity to respond to endogenous DNA by using small oligonucleotide based TLR9D ligands and a novel class of bifunctional anti-DNA antibodies. RESULTS: Mice that fail to express DNaseII, IFNaR, and Unc93b1 still develop arthritis but do not make autoantibodies, develop splenomegaly, or exhibit extramedullary haematopoiesis. DNaseII-/- IFNaR-/- B cells can respond to synthetic ODNs, but not to endogenous dsDNA. CONCLUSIONS: RNA-reactive TLRs, presumably TLR7, are required for autoantibody production, splenomegaly, and extramedullary haematopoiesis in the DNaseII-/- model of systemic autoimmunity.

Impact of inflammation on the osteoblast in rheumatic diseases.

Normal bone remodeling depends upon a balance between the action of bone-resorbing cells, osteoclasts, and bone-forming cells, osteoblasts. When this balance is disrupted, as is seen in inflammatory diseases such as rheumatoid arthritis (RA) and ankylosing spondylitis (AS), abnormal bone loss or bone formation occurs. In RA, proinflammatory cytokines induce osteoclast differentiation and inhibit osteoblast maturation, leading to articular bone erosions. In contrast, the inflammatory milieu in AS leads to excessive osteoblast activation and bone formation at sites of entheses. While much information exists about the effects of proinflammatory cytokines on osteoclast differentiation and function, more recent studies have begun to elucidate the impact of inflammation on the osteoblast. This review will summarize the mechanisms by which inflammation perturbs bone homeostasis, with a specific focus on the osteoblast.

Child Health Needs and the Developmental-Behavioral Pediatrics Workforce Supply: 2020-2040.

Developmental-behavioral pediatrics (DBP) subspecialists care for children with complex neurodevelopmental and behavioral health conditions; additional roles include education and training, advocacy, and research. In 2023, there were 1.0 DBP subspecialists per 100 000 US children aged 0 to 17 years (range 0.0-3.8), with wide variability in DBP subspecialist distribution. Given the prevalence of DB conditions, the current workforce is markedly inadequate to meet the needs of patients and families. The American Board of Pediatrics Foundation led a modeling project to forecast the US pediatric subspecialty workforce from 2020 to 2040 using current trends in each subspecialty. The model predicts workforce supply at baseline and across alternative scenarios and reports results in headcount (HC) and HC adjusted for percent time spent in clinical care, termed "clinical workforce equivalent." For DBP, the baseline model predicts HC growth nationally (+45%, from 669 to 958), but these extremely low numbers translate to minimal patient care impact. Adjusting for population growth over time, projected HC increases from 0.8 to 1.0 and clinical workforce equivalent from 0.5 to 0.6 DBP subspecialists per 100 000 children aged 0 to 18 years by 2040. Even in the best-case scenario (+12.5% in fellows by 2030 and +7% in time in clinical care), the overall numbers would be minimally affected. These current and forecasted trends should be used to shape much-needed solutions in education, training, practice, policy, and workforce research to increase the DBP workforce and improve overall child health.

Healthcare reform, quality, and technology: ADHD as a case study.

The concepts of healthcare reform and population health are shifting the emphasis from traditional, volume-based care to a model in which value, or quality, predominates. High quality care will be increasingly rewarded, with financial consequences for poor performance. This shift will be accelerated by the use of healthcare technology, a rapidly growing industry with tools ranging from electronic health records to smart phones and web portals. In this article we highlight pertinent legislative reforms followed by a review of technologies that may play a role in the implementation of these reforms. Pediatric Attention Deficit Hyperactivity Disorder is used as an example given the large number of proposed tools for this condition. While the evidence base is weak for some technologies, research regarding web portals is better developed and will be presented as an example of a technology that may allow practitioners and organizations to improve healthcare quality in several dimensions.

Treatment Using Both Voclosporin and Belimumab in Four Patients With Lupus Nephritis.

Nearly 50% of patients with systemic lupus erythematosus (SLE) will develop lupus nephritis (LN). Current treatment regimens for LN are suboptimal as the majority of patients fail to achieve complete renal response after several months of treatment and there are high rates of relapse. We report outcomes in four LN patients who were treated with both voclosporin and belimumab. These patients had no serious infections, and we were able to taper glucocorticoids and reduce proteinuria.

Descriptive Analysis of Documentation Time for the National Developmental-Behavioral Pediatric Physician Workforce Using a Commercial Electronic Health Record System.

OBJECTIVE: The national developmental-behavioral pediatric (DBP) workforce struggles to meet current service demands because of several factors. Lengthy and inefficient documentation processes are likely to contribute to service demand challenges, but DBP documentation patterns have not been sufficiently studied. Identifying clinical practice patterns may inform strategies to address documentation burden in DBP practice. METHODS: Nearly 500 DBP physicians in the United States use a single commercial electronic health record (EHR) system (EpicCare Ambulatory, Epic Systems Corporation, Verona WI). We evaluated descriptive statistics using the US Epic DBP provider data set. We then compared DBP documentation metrics against those of pediatric primary care and selected pediatric subspecialty providers who provide similar types of care. One-way analyses of variance (ANOVAs) were conducted to determine whether outcomes differed among provider specialties. RESULTS: We identified 4 groups for analysis from November 2019 through February 2020: DBP (n = 483), primary care (n = 76,423), pediatric psychiatry (n = 783), and child neurology (n = 8589). Post hoc pairwise comparisons revealed statistically significant differences between multiple outcome-specialty combinations. Time in notes per appointment and progress note length demonstrated the strongest evidence of an increased burden on DBP providers compared with other similar provider groups. CONCLUSION: DBP providers spend a significant amount of time documenting progress notes both during and outside of normal clinic hours. This preliminary analysis highlights the utility of using EHR user activity data to quantitatively measure documentation burden.

Glucan particles for selective delivery of siRNA to phagocytic cells in mice.

Phagocytic macrophages and dendritic cells are desirable targets for potential RNAi (RNA interference) therapeutics because they often mediate pathogenic inflammation and autoimmune responses. We recently engineered a complex 5 component glucan-based encapsulation system for siRNA (small interfering RNA) delivery to phagocytes. In experiments designed to simplify this original formulation, we discovered that the amphipathic peptide Endo-Porter forms stable nanocomplexes with siRNA that can mediate potent gene silencing in multiple cell types. In order to restrict such gene silencing to phagocytes, a method was developed to entrap siRNA-Endo-Porter complexes in glucan shells of 2-4 µm diameter in the absence of other components. The resulting glucan particles containing fluorescently labelled siRNA were readily internalized by macrophages, but not other cell types, and released the labelled siRNA into the macrophage cytoplasm. Intraperitoneal administration of such glucan particles containing siRNA-Endo-Porter complexes to mice caused gene silencing specifically in macrophages that internalized the particles. These results from the present study indicate that specific targeting to phagocytes is mediated by the glucan, whereas Endo-Porter peptide serves both to anchor siRNA within glucan particles and to catalyse escape of siRNA from phagosomes. Thus we have developed a simplified siRNA delivery system that effectively and specifically targets phagocytes in culture or in intact mice.

Defining Developmental-Behavioral Pediatrics.

There is an insufficient number of specialty developmental-behavioral pediatrics (DBP) physicians, despite nearly 25% of children and adolescents having a developmental, learning, behavioral, or emotional problem. In the nearly 20 years since becoming a board-certified subspecialty, the definition of DBP clinical practice remains somewhat unclear. This lack of clarity likely contributes to recruitment challenges and workforce issues, and limited visibility of DBP among parents, other professionals, payors, and administrators. Defining DBP is therefore an important step in the survival and growth of the field. In this paper, we describe the methodology used to develop this definition along with the origins of DBP, the persistent challenges to defining its scope, what training in DBP involves, and what distinguishes DBP from other overlapping fields of medicine. We propose the following definition of DBP: developmental-behavioral pediatrics (DBP) is a board-certified, medical subspecialty that cares for children with complex and severe DBP problems by recognizing the multifaceted influences on the development and behavior of children and addressing them through systems-based practice and a neurodevelopmental, strength-based approach that optimizes functioning. Developmental behavioral pediatricians care for children from birth through young adulthood along a continuum including those suspected of, at risk for, or known to have developmental and behavioral disorders.

Chemoresistant hepatoblastoma in a patient with mosaic trisomy 18 treated with orthotopic liver transplantation.

We present a 9-month-old male with mosaic trisomy 18 with a right hepatic lobe mass. The tumor was completely resected and identified as pure fetal histology hepatoblastoma but contained increased mitotic activity. Adjuvant chemotherapy consisted of cisplatin, vincristine, and 5-fluorouracil. After the first and fourth cycles of chemotherapy, recurrent tumor developed. The patient underwent rescue orthotopic liver transplantation, and is currently alive without evidence of hepatoblastoma 28 months after transplantation. This report demonstrates the use of orthotopic liver transplantation in a child with mosaic trisomy 18 and hepatoblastoma.

Changes in Provider Type and Prescription Refills Among Privately Insured Children and Youth With ADHD.

OBJECTIVE: The aim of this paper is to understand associations between age and health care provider type in medication continuation among transition-aged youth with ADHD. METHOD: Using an employer-sponsored insurance claims database, we identified patients with likely ADHD and receipt of ADHD medications. Among patients who had an outpatient physician visit at baseline and maintained enrollment at follow-up 3 years later, we evaluated which ones continued to fill prescriptions for ADHD medications. RESULTS: Patients who were younger at follow-up more frequently continued medication (77% of 11-12 year-olds vs. 52% of 19-20 year-olds). Those who saw a pediatric provider at baseline and follow-up more frequently continued to fill ADHD medication prescriptions than those who saw a pediatric provider at baseline and non-pediatric providers at follow-up (71% vs. 53% among those ages 15-16 years at follow-up). CONCLUSION: Adolescents and young adults with ADHD who changed from pediatric to exclusively non-pediatric providers less frequently continued to receive ADHD medications.

Suppression of autophagy in skeletal muscle uncovers the accumulation of ubiquitinated proteins and their potential role in muscle damage in Pompe disease.

The role of autophagy, a catabolic lysosome-dependent pathway, has recently been recognized in a variety of disorders, including Pompe disease, the genetic deficiency of the glycogen-degrading lysosomal enzyme acid-alpha glucosidase. Accumulation of lysosomal glycogen, presumably transported from the cytoplasm by the autophagic pathway, occurs in multiple tissues, but pathology is most severe in skeletal and cardiac muscle. Skeletal muscle pathology also involves massive autophagic buildup in the core of myofibers. To determine if glycogen reaches the lysosome via autophagy and to ascertain whether autophagic buildup in Pompe disease is a consequence of induction of autophagy and/or reduced turnover due to defective fusion with lysosomes, we generated muscle-specific autophagy-deficient Pompe mice. We have demonstrated that autophagy is not required for glycogen transport to lysosomes in skeletal muscle. We have also found that Pompe disease involves induction of autophagy but manifests as a functional deficiency of autophagy because of impaired autophagosomal-lysosomal fusion. As a result, autophagic substrates, including potentially toxic aggregate-prone ubiquitinated proteins, accumulate in Pompe myofibers and may cause profound muscle damage.

Differences in the predominance of lysosomal and autophagic pathologies between infants and adults with Pompe disease: implications for therapy.

Pompe disease is a lysosomal storage disorder caused by the deficiency of acid alpha-glucosidase, the enzyme that degrades glycogen in the lysosomes. The disease manifests as a fatal cardiomyopathy and skeletal muscle myopathy in infants; in milder late-onset forms skeletal muscle is the major tissue affected. We have previously demonstrated that autophagic inclusions in muscle are prominent in adult patients and the mouse model. In this study we have evaluated the contribution of the autophagic pathology in infants before and 6 months after enzyme replacement therapy. Single muscle fibers, isolated from muscle biopsies, were stained for autophagosomal and lysosomal markers and analyzed by confocal microscopy. In addition, unstained bundles of fixed muscles were analyzed by second harmonic imaging. Unexpectedly, the autophagic component which is so prominent in juvenile and adult patients was negligible in infants; instead, the overwhelming characteristic was the presence of hugely expanded lysosomes. After 6 months on therapy, however, the autophagic buildup becomes visible as if unmasked by the clearance of glycogen. In most fibers, the two pathologies did not seem to coexist. These data point to the possibility of differences in the pathogenesis of Pompe disease in infants and adults.

Using Practice Facilitation to Improve Depression Management in Rural Pediatric Primary Care Practices.

INTRODUCTION: Depression is a common and serious mental health condition frequently encountered in pediatric primary care. Pediatricians report discomfort in managing depression due in part to limited training and limited access to mental health care, which is accentuated in rural areas. METHODS: We developed an evidence-based, quality improvement project designed to help pediatricians increase screening and initial management of depression in the primary care setting. We recruited practices from a pediatric accountable care organization as part of a larger quality improvement portfolio that used a practice facilitation model to support practices with data collection and project management. Practitioners received training on quality improvement, depression screening, and a depression management plan (referred to as the depression management bundle). Practices completed Plan-Do-Study-Act cycles to improve their performance. RESULTS: We recruited 4 practices in rural Ohio to participate. Screening increased from 0% to 81% within 6 months. All 4 practices measured documentation of the depression management bundle for patients diagnosed with depression. Composite data from these practices showed an increase in documentation from 59% to 86% by month 6. CONCLUSIONS: This study provides preliminary support for the use of practice facilitation combined with skills training to increase screening and improve documentation of depression management in rural primary care practices, where specialty mental health resources may be limited. Further research is needed to determine if this approach can be successfully disseminated and if patient outcomes improved.

When to Raise Our White Flag-A Discussion of Scope of Practice in a Resource Scarce World.

CASE: Thomas is a 13-year-old boy with autism spectrum disorder, attention deficit hyperactivity disorder (ADHD), generalized anxiety disorder, separation anxiety disorder, and major depressive disorder who presented for a follow-up to his developmental and behavioral pediatrician (DBP). His mother describes an increase in symptoms of anxiety and depression for the last 6 weeks, accompanied by suicidal ideation and thoughts of self-mutilation.Before this increase in symptoms, he had been doing well for the last several months with the exception of increasing weight gain, and Abilify was decreased from 5 mg to 2.5 mg at his last visit. Other medications at that time included Zoloft 100 mg twice daily, Focalin XR 40 mg every morning, and Focalin 5 mg every night. Without seeking the guidance of our developmental and behavioral pediatrics clinic, his mother increased his intake of Zoloft to 150 mg each morning and continued 100 mg each evening because of worsening anxiety and depression.Religion is very important to Thomas and his family. He acknowledges that he does not want to die and feels badly because "suicide is against our religion."Helping Thomas receive appropriate care has been a challenge. He was diagnosed with ADHD and Asperger disorder at the age of 5. Thomas is homeschooled and is very attached to his mother. His parents have very different parenting styles, with his mother being more permissive and his father more authoritarian. At the time of initial diagnosis, the behavioral health services (BHS) in Thomas' community, which is about an hour away from the DBP, were limited to older children, and he was followed by a DBP for ADHD medication management. At the age of 11, he expressed passive suicidal ideation and described that he imagined his mother as "the devil with fire coming out of her eyes" when she corrected him. He was evaluated by BHS, diagnosed with anxiety disorder, and started on Lexapro. BHS linked to the DBP were out of network for his insurance. The family was unable to pay out of pocket, so care was subsequently transferred to a DBP clinic that was in network. Soon after, Thomas developed auditory hallucinations, and Abilify was added after consultation with BHS.Over the last few years, Thomas' symptoms have waxed and waned. He did well for a short time and then again developed auditory hallucinations, worsening symptoms of anxiety and depression, and increasing somatic symptoms including vomiting and penile pain. Medications were adjusted with input from BHS, and further attempts were made to link him to local BHS but were unsuccessful. With his current concerns of suicidal ideation and self-mutilation, what would be your next steps?

Interplay of Cyclic GMP-AMP Synthase/Stimulator of IFN Genes and Toll-Like Receptor Nucleic Acid Sensing Pathways in Autoinflammation and Abnormal Bone Formation due to DNaseII-Deficiency.

Nucleic acid (NA) sensing receptors were first described in the context of host defense. We now know that some endosomal NA sensors play a critical role in the development of systemic autoimmune diseases such as systemic lupus erythematosus, whereas cytosolic Cyclic GMP-AMP Synthase/Stimulator of IFN Genes (cGAS/STING) DNA-detecting pathway has been associated with monogenic autoinflammatory interferonopathies such as Aicardi-Goutieres and Education; collaboration; communication STING-associated vasculopathy with onset in infancy (SAVI). DNaseII hypomorphic patients and DNase-/- IFNaR-/- (double knockout [DKO]) mice also develop an autoinflammatory syndrome associated with an interferon signature. We now add to the description of an unusual clinical manifestation of DKO mice that involves the accrual of trabecular bone in long bone marrow and the formation of ectopic bone within the spleen. This aberrant bone formation is lost not only in STING-deficient but also in Unc93b1-deficient mice and, therefore, depends on the interplay of cells expressing cytosolic and endosomal NA sensing receptors.

Comparison of Performance on ADHD Quality of Care Indicators: Practitioner Self-Report Versus Chart Review.

Objective: This study compared practitioner self-report of ADHD quality of care measures with actual performance, as documented by chart review. Method: In total, 188 practitioners from 50 pediatric practices completed questionnaires in which they self-reported estimates of ADHD quality of care indicators. A total of 1,599 charts were reviewed. Results: The percentage of patients for whom practitioners self-reported that they used evidence-based care was higher in every performance category when compared with chart review, including higher use of parent and teacher rating scales during assessment and treatment compared with chart review. Self-reported use of Diagnostic and Statistical Manual of Mental Disorders (4th ed.; DSM-IV) criteria during assessment was also higher than by chart review. The actual number of days until the first contact after starting medication was nearly three times longer than self-report estimates. Conclusion: Practitioners overreport performance on quality of care indicators. These differences were large and consistent across ADHD diagnostic and treatment monitoring practices. Practitioner self-report of ADHD guideline adherence should not be considered a valid measure of performance.