Co-designing restrictive practice elimination: A systems thinking approach with mental health service users and practitioners in rural/regional Australia.

Elimination of restrictive practices (physical/mechanical restraint and seclusion) from adult acute mental health care services has been demanded internationally for many decades. This study aimed to: (1) Identify priority issues in the elimination of and use of alternative approaches to restrictive practices (seclusion and physical/mechanical restraint) in rural/regional acute adult mental healthcare services, as told by mental healthcare service users and practitioners, (2) identify the community-based, system-level feedback loops that enhance or reduce the use of restrictive practices and viable alternatives and, (3) identify potential action areas to improve system structures to increase regional mental healthcare services' ability to eliminate restrictive practices and use alternative approaches. Group model building (GMB) workshops were held with a small group (n = 9) of mental healthcare practitioners and service users with lived experience of restrictive practice use. This participatory approach enables exploration and visual mapping of local structures causing behaviour patterns of practitioner and service user concern over time - in this case, the barriers, and enablers to alternative approaches to restrictive practices in adult acute mental healthcare services within the Geelong-Barwon region. This is the first study that specifically applies GMB in the discussion of the elimination of restrictive practices in mental health in the non-metropolitan regional/rural context. Participants identified four key priorities in relation to eliminating restrictive practices: (1) self-advocacy, (2) continuity of care, (3) early intervention, and (4) safety for all. The study findings were distilled into a novel preliminary set of mental healthcare practitioner and service user action ideas.

Striving to support the supporters: A mixed methods evaluation of the strive support groups for caregivers of individuals with an eating disorder.

This mixed-methods study evaluated a peer-led support group for ED caregivers; the Eating Disorders Families Australia strive support groups. Quantitatively, 110 past or current strive attendees completed an online survey assessing their own and their care recipients' demographic profiles, strive's impact on caregiving experiences, and caregivers' psychological distress, burden, caregiving skills and self-efficacy. Qualitative assessment comprised open-ended survey questions about caregivers' strive experiences, reinforced by in-depth focus group assessment of nine participants. Quantitative analyses revealed that participants felt more confident and supported, and less isolated in their caregiving since attending strive. Caregivers displayed mid-range psychological distress and caregiver burden, and moderate caregiver skills and self-efficacy. Qualitatively, the most helpful aspects of strive were the shared experience among participants, education, and support. The most difficult elements were emotional distress and overly dominant members. Reflections discussed the necessity of caregiver support and factors impacting strive attendance. Participants recommended resuming face-to-face contact and differentiating groups based on participant characteristics (e.g. care recipients' age/stage of illness). The current findings provide support for the importance and overall positive contribution of support groups led by caregivers, such as strive.

Megakaryocytes possess a STING pathway that is transferred to platelets to potentiate activation.

Platelets display unexpected roles in immune and coagulation responses. Emerging evidence suggests that STING is implicated in hypercoagulation. STING is an adaptor protein downstream of the DNA sensor cyclic GMP-AMP synthase (cGAS) that is activated by cytosolic microbial and self-DNA during infections, and in the context of loss of cellular integrity, to instigate the production of type-I IFN and pro-inflammatory cytokines. To date, whether the cGAS-STING pathway is present in platelets and contributes to platelet functions is not defined. Using a combination of pharmacological and genetic approaches, we demonstrate here that megakaryocytes and platelets possess a functional cGAS-STING pathway. Our results suggest that in megakaryocytes, STING stimulation activates a type-I IFN response, and during thrombopoiesis, cGAS and STING are transferred to proplatelets. Finally, we show that both murine and human platelets contain cGAS and STING proteins, and the cGAS-STING pathway contributes to potentiation of platelet activation and aggregation. Taken together, these observations establish for the first time a novel role of the cGAS-STING DNA sensing axis in the megakaryocyte and platelet lineage.

Mammalian cells internalize bacteriophages and use them as a resource to enhance cellular growth and survival.

There is a growing appreciation that the direct interaction between bacteriophages and the mammalian host can facilitate diverse and unexplored symbioses. Yet the impact these bacteriophages may have on mammalian cellular and immunological processes is poorly understood. Here, we applied highly purified phage T4, free from bacterial by-products and endotoxins to mammalian cells and analyzed the cellular responses using luciferase reporter and antibody microarray assays. Phage preparations were applied in vitro to either A549 lung epithelial cells, MDCK-I kidney cells, or primary mouse bone marrow derived macrophages with the phage-free supernatant serving as a comparative control. Highly purified T4 phages were rapidly internalized by mammalian cells and accumulated within macropinosomes but did not activate the inflammatory DNA response TLR9 or cGAS-STING pathways. Following 8 hours of incubation with T4 phage, whole cell lysates were analyzed via antibody microarray that detected expression and phosphorylation levels of human signaling proteins. T4 phage application led to the activation of AKT-dependent pathways, resulting in an increase in cell metabolism, survival, and actin reorganization, the last being critical for macropinocytosis and potentially regulating a positive feedback loop to drive further phage internalization. T4 phages additionally down-regulated CDK1 and its downstream effectors, leading to an inhibition of cell cycle progression and an increase in cellular growth through a prolonged G1 phase. These interactions demonstrate that highly purified T4 phages do not activate DNA-mediated inflammatory pathways but do trigger protein phosphorylation cascades that promote cellular growth and survival. We conclude that mammalian cells are internalizing bacteriophages as a resource to promote cellular growth and metabolism.

Are two occupational therapists better than one? Occupational therapists' perspectives of intra-disciplinary practice within community health.

INTRODUCTION: Intra-disciplinary practice is rarely discussed in occupational therapy and the broader health-care literature. Community-based occupational therapists often work autonomously in clients' homes and consequently have limited access to routine intra-disciplinary practices. Additionally, the community-based role covers a large scope of practice requiring comprehensive expertise. This study aimed to describe occupational therapists' perspectives on intra-disciplinary practice within community health settings. METHODS: This study utilised an online cross-sectional survey design, collecting quantitative and qualitative data to explore perspectives of occupational therapists working within Australian community health services. Quantitative data were analysed using descriptive statistics. Qualitative data were analysed using thematic analysis. Both forms of data were compared and contrasted. RESULTS/FINDINGS: Eighty occupational therapists completed the survey. Seventy-eight participants (97%) previously used or currently use intra-disciplinary practice in their workplace. Participants predominantly consult their peers when client needs are perceived as complex. Participants indicated that intra-disciplinary practice can benefit the client, therapist, and workplace. Enablers and barriers to the use of intra-disciplinary practice had overlapping themes, including access to therapists, attitudes towards intra-disciplinary practice, management support, and funding influences. Most participants expressed a desire to utilise intra-disciplinary practices (n = 70, 87%) and were also likely or extremely likely to incorporate it into their clinical work (n = 73, 91%). Participants who did not want to utilise intra-disciplinary practices or who were unsure provided reasons related to cost, practice inefficiencies, and being uncertain of the benefit. CONCLUSIONS: Occupational therapists perceive intra-disciplinary practice as beneficial for problem-solving and an opportunity for knowledge sharing that supports therapist confidence with clinical reasoning. Conversely, some therapists believe its use may lead to client confusion, a greater need for communication and coordination among therapists, and that power differentials between therapists may discourage equal collaboration. Greater understanding of intra-disciplinary practice will help guide how it is used and supported in community health settings.

One size may not fit all: A mapping review of yoga-based interventions for the treatment of eating disorders.

BACKGROUND: While research investigating the potential benefits of yoga for eating disorders (EDs) has expanded, a systematic approach examining how yoga has been implemented for this cohort has not yet been conducted. This research therefore aimed to synthesize the current understanding of how yoga has been implemented for individuals with EDs, with regards to the feasibility, acceptability, and safety of yoga for this cohort. METHODS: This study utilised mapping review technology. The following electronic databases were searched within the month of September 2021 and December 2022: PsycINFO, MEDLINE, CINAHL, and Embase. Articles that applied and documented the use of yoga for the EDs were selected. RESULTS: The review identified ten unique studies. Details regarding the application, feasibility, acceptability, and safety of these yoga programs were extracted. This resulted in an evidence map or visual summary of how yoga has been applied for the EDs. CONCLUSION: While limited, the current literature suggests that yoga is a safe, acceptable, and feasible transdiagnostic intervention for EDs. These findings provide pragmatic support for safely applying yoga for the EDs into clinical practice to support ED recovery.

Who and how, DNA sensors in NETs-driven inflammation.

During infections, neutrophil extracellular traps act like a meshwork of molecules that captures microbes. In contrast, during sterile inflammation the presence of NETs is usually associated with tissue damage and uncontrolled inflammation. In this context, DNA acts both as activator of NETs formation and immunogenic molecule fueling inflammation within the injured tissue microenvironment. Pattern recognition receptors that specifically bind to and get activated by DNA such as Toll-like receptor-9 (TLR9), cyclic GMP-AMP synthase (cGAS), Nod-like receptor protein 3 (NLRP3) and Absence in Melanoma-2 (AIM2) have been reported to play a role in NETs formation and detection. However, how these DNA sensors contribute to NETs-driven inflammation is not well understood. Whether these DNA sensors have unique roles or on the contrary they are mostly redundant is still elusive. In this review, we summarize the known contribution of the above DNA sensors to the formation and detection of NETs in the context of sterile inflammation. We also highlight scientific gaps needed to be addressed and propose future direction for therapeutic targets.

Staff perceptions of organisational performance measurement implementation in a health charity.

The non-acute health charity sector forms part of the global health services industry. Organisational Performance Measurement (OPM) is fundamental for modern business to achieve sustained excellence yet is under-utilised by non-acute health charities. The Non-Acute Health Charity Performance Implementation Framework (NCPI Framework) was developed to support non-acute health charities undertaking OPM. A non-acute health charity case study undertook a 12-month OPM implementation process using the NCPI Framework. This study had three aims. Firstly, to understand the perceptions of staff employed by the case study organisation regarding their experience of the 12-month NCPI Framework implementation process, secondly to identify whether an interrelationship existed between the NCPI Framework's implementation elements and the staff's perspectives, and thirdly, identify areas of strength and improvement which could enhance the NCPI Framework's effectiveness. Data were collected post implementation and analysed thematically from open-ended question responses from an anonymous survey and semi-structured interviews. Participants supported the introduction of OPM and valued the NCPI Framework's structured implementation guidelines. Six interrelated themes were identified: clarity, adaptability, alignment, transparent communication, capability and accountability. Participants suggested adaptations to enhance the NCPI Framework's impact. A culture aligned with organisational learning was identified as potentially having a positive impact on the NCPI Framework's implementation. The NCPI Framework may also have relevance and application to the non-profit industry beyond non-acute health care and for use in program development and service quality initiatives.

Setting the top 10 eating disorder research and translation priorities for Australia.

OBJECTIVES: People with eating disorders, as well as their caregivers, experience high symptom burden, reduced quality of life and increased risk of early mortality. A lack of resources, disjointed vision and limited uptake of the evidence have limited the translation and implementation of research into practice. Little is known about what stakeholders (people with a lived experience, caregivers, health care professionals, researchers and policymakers) see as the most important research priorities. This study aimed to identify Australia's top 10 consensus-derived research and translation priorities for eating disorders. METHODS: Participants (n = 606) included people with a lived experience, carers, health care professionals (clinicians) and researchers working in eating disorders. The methodology aligned with the James Lind Alliance priority setting process, which involved oversight by a co-design advisory committee and utilised a national online interim priority setting survey and co-design workshops to identify the top 10 research and translation priorities. RESULTS: The initial national consultations elicited 1210 issues from 480 individuals. From this, 606 participants shortlisted 59 plain language questions in order of personal priority. In total, 16 questions were consistently ranked as important. As a final step, 24 individuals (with equal representation from all 4 stakeholder groups) attended the final prioritisation workshop to co-establish the top 10 research and translation priorities. CONCLUSION: The findings highlight the need for people with a lived experience, carers, health professionals and researchers to work collaboratively to develop co-designed research and translation activities that address the key areas of early intervention, prevention, understanding the aetiology of eating disorders and effective treatment of people experiencing eating disorders.

Psychiatric and medical comorbidities of eating disorders: findings from a rapid review of the literature.

BACKGROUND: Eating disorders (EDs) are potentially severe, complex, and life-threatening illnesses. The mortality rate of EDs is significantly elevated compared to other psychiatric conditions, primarily due to medical complications and suicide. The current rapid review aimed to summarise the literature and identify gaps in knowledge relating to any psychiatric and medical comorbidities of eating disorders. METHODS: This paper forms part of a rapid review) series scoping the evidence base for the field of EDs, conducted to inform the Australian National Eating Disorders Research and Translation Strategy 2021-2031, funded and released by the Australian Government. ScienceDirect, PubMed and Ovid/Medline were searched for English-language studies focused on the psychiatric and medical comorbidities of EDs, published between 2009 and 2021. High-level evidence such as meta-analyses, large population studies and Randomised Control Trials were prioritised. RESULTS: A total of 202 studies were included in this review, with 58% pertaining to psychiatric comorbidities and 42% to medical comorbidities. For EDs in general, the most prevalent psychiatric comorbidities were anxiety (up to 62%), mood (up to 54%) and substance use and post-traumatic stress disorders (similar comorbidity rates up to 27%). The review also noted associations between specific EDs and non-suicidal self-injury, personality disorders, and neurodevelopmental disorders. EDs were complicated by medical comorbidities across the neuroendocrine, skeletal, nutritional, gastrointestinal, dental, and reproductive systems. Medical comorbidities can precede, occur alongside or emerge as a complication of the ED. CONCLUSIONS: This review provides a thorough overview of the comorbid psychiatric and medical conditions co-occurring with EDs. High psychiatric and medical comorbidity rates were observed in people with EDs, with comorbidities contributing to increased ED symptom severity, maintenance of some ED behaviours, and poorer functioning as well as treatment outcomes. Early identification and management of psychiatric and medical comorbidities in people with an ED may improve response to treatment and overall outcomes.

The mortality rate of eating disorders is significantly elevated compared to other psychiatric conditions, primarily due to medical complications and suicide. Further, individuals with eating disorders often meet the diagnostic criteria of at least one comorbid psychiatric or medical disorder, that is, the individual simultaneously experiences both an ED and at least one other condition. This has significant consequences for researchers and health care providers ­ medical and psychiatric comorbidities impact ED symptoms and treatment effectiveness. The current review is part of a larger Rapid Review series conducted to inform the development of Australia's National Eating Disorders Research and Translation Strategy 2021­2031. A Rapid Review is designed to comprehensively summarise a body of literature in a short timeframe, often to guide policymaking and address urgent health concerns. The Rapid Review synthesises the current evidence base and identifies gaps in eating disorder research and care. This paper gives a critical overview of the scientific literature relating to the psychiatric and medical comorbidities of eating disorders. It covers recent literature regarding psychiatric comorbidities including anxiety disorders, mood disorders, substance use disorders, trauma and personality disorders and neurodevelopmental disorders. Further, the review discusses the impact and associations between EDs and medical comorbidities, some of which precede the eating disorder, occur alongside, or as a consequence of the eating disorder.

Genistein Targets STING-Driven Antiviral Responses.

Cytoplasmic detection of DNA by cyclic GMP-AMP (cGAMP) synthase (cGAS) is an essential component of antiviral responses. Upon synthesis, cGAMP binds to the stimulator of interferon (IFN) genes (STING) in infected and adjacent cells through intercellular transfer by connexins forming gap-junctions, eliciting a strong IFN-ß-driven antiviral response. We demonstrate here that Genistein, a flavonoid compound naturally occurring in soy-based foods, inhibits cGAS-STING antiviral signaling at two levels. First, Genistein pretreatment of cGAMP-producing cells inhibited gap-junction intercellular communication, resulting in reduced STING responses in adjacent cells. In addition, Genistein directly blocked STING activation by the murine agonist DMXAA, by decreasing the interaction of STING with TBK1 and IKKε. As a result, Genistein attenuated STING signaling in human and mouse cells, dampening antiviral activity against Semliki Forest Virus infection. Collectively, our findings identify a previously unrecognized proviral activity of Genistein mediated via its inhibitory effects at two levels of cGAS-STING signaling. IMPORTANCE Several reports suggest that Genistein exhibits antiviral activities against DNA viruses. Our work uncovers a previously unrecognized proviral effect of Genistein, through inhibition of the cGAS-STING pathway at the level of cGAMP transfer and its sensing by STING. This suggests that the use of Genistein as an antiviral should be taken with caution as it may reduce the protective antiviral effects elicited by host STING activation.

Type-I Interferon Signaling in Fanconi Anemia.

Fanconi Anemia (FA) is a genome instability syndrome caused by mutations in one of the 23 repair genes of the Fanconi pathway. This heterogenous disease is usually characterized by congenital abnormalities, premature ageing and bone marrow failure. FA patients also show a high predisposition to hematological and solid cancers. The Fanconi pathway ensures the repair of interstrand crosslinks (ICLs) DNA damage. Defect in one of its proteins prevents functional DNA repair, leading to the accumulation of DNA breaks and genome instability. Accumulating evidence has documented a close relationship between genome instability and inflammation, including the production of type-I Interferon. In this context, type-I Interferon is produced upon activation of pattern recognition receptors by nucleic acids including by the cyclic GMP-AMP synthase (cGAS) that detects DNA. In mouse models of diseases displaying genome instability, type-I Interferon response is responsible for an important part of the pathological symptoms, including premature aging, short stature, and neurodegeneration. This is illustrated in mouse models of Ataxia-telangiectasia and Aicardi-Goutières Syndrome in which genetic depletion of either Interferon Receptor IFNAR, cGAS or STING relieves pathological symptoms. FA is also a genetic instability syndrome with symptoms such as premature aging and predisposition to cancer. In this review we will focus on the different molecular mechanisms potentially leading to type-I Interferon activation. A better understanding of the molecular mechanisms engaging type-I Interferon signaling in FA may ultimately lead to the discovery of new therapeutic targets to rescue the pathological inflammation and premature aging associated with Fanconi Anemia.

Biological Investigation of Amaryllidaceae Alkaloid Extracts from the Bulbs of Pancratium trianthum Collected in the Senegalese Flora.

Amaryllidaceae plants are rich in alkaloids with biological properties. Pancratium trianthum is an Amaryllidaceae species widely used in African folk medicine to treat several diseases such as central nervous system disorders, tumors, and microbial infections, and it is used to heal wounds. The current investigation explored the biological properties of alkaloid extracts from bulbs of P. trianthum collected in the Senegalese flora. Alkaloid extracts were analyzed and identified by chromatography and mass spectrometry. Alkaloid extracts from P. trianthum displayed pleiotropic biological properties. Cytotoxic activity of the extracts was determined on hepatocarcinoma Huh7 cells and on acute monocytic leukemia THP-1 cells, while agar diffusion and microdilution assays were used to evaluate antibacterial activity. Antiviral activity was measured by infection of extract-treated cells with dengue virus (DENVGFP) and human immunodeficiency virus-1 (HIV-1GFP) reporter vectors. Cytotoxicity and viral inhibition were the most striking of P. trianthum's extract activities. Importantly, non-cytotoxic concentrations were highly effective in completely preventing DENVGFP replication and in reducing pseudotyped HIV-1GFP infection levels. Our results show that P. trianthum is a rich source of molecules for the potential discovery of new treatments against various diseases. Herein, we provide scientific evidence to rationalize the traditional uses of P. trianthum for wound treatment as an anti-dermatosis and antiseptic agent.

Amaryllidaceae Alkaloid Cherylline Inhibits the Replication of Dengue and Zika Viruses.

Dengue fever, caused by dengue virus (DENV), is the most prevalent arthropod-borne viral disease and is endemic in many tropical and subtropical parts of the world, with an increasing incidence in temperate regions. The closely related flavivirus Zika virus (ZIKV) can be transmitted vertically in utero and causes congenital Zika syndrome and other birth defects. In adults, ZIKV is associated with Guillain-Barré syndrome. There are no approved antiviral therapies against either virus. Effective antiviral compounds are urgently needed. Amaryllidaceae alkaloids (AAs) are a specific class of nitrogen-containing compounds produced by plants of the Amaryllidaceae family with numerous biological activities. Recently, the AA lycorine was shown to present strong antiflaviviral properties. Previously, we demonstrated that Crinum jagus contained lycorine and several alkaloids of the cherylline, crinine, and galanthamine types with unknown antiviral potential. In this study, we explored their biological activities. We show that C. jagus crude alkaloid extract inhibited DENV infection. Among the purified AAs, cherylline efficiently inhibited both DENV (50% effective concentration [EC50], 8.8 µM) and ZIKV replication (EC50, 20.3 µM) but had no effect on HIV-1 infection. Time-of-drug-addition and -removal experiments identified a postentry step as the one targeted by cherylline. Consistently, using subgenomic replicons and replication-defective genomes, we demonstrate that cherylline specifically hinders the viral RNA synthesis step but not viral translation. In conclusion, AAs are an underestimated source of antiflavivirus compounds, including the effective inhibitor cherylline, which could be optimized for new therapeutic approaches.

Sequence-dependent inhibition of cGAS and TLR9 DNA sensing by 2'-O-methyl gapmer oligonucleotides.

Oligonucleotide-based therapeutics have the capacity to engage with nucleic acid immune sensors to activate or block their response, but a detailed understanding of these immunomodulatory effects is currently lacking. We recently showed that 2'-O-methyl (2'OMe) gapmer antisense oligonucleotides (ASOs) exhibited sequence-dependent inhibition of sensing by the RNA sensor Toll-Like Receptor (TLR) 7. Here we discovered that 2'OMe ASOs can also display sequence-dependent inhibitory effects on two major sensors of DNA, namely cyclic GMP-AMP synthase (cGAS) and TLR9. Through a screen of 80 2'OMe ASOs and sequence mutants, we characterized key features within the 20-mer ASOs regulating cGAS and TLR9 inhibition, and identified a highly potent cGAS inhibitor. Importantly, we show that the features of ASOs inhibiting TLR9 differ from those inhibiting cGAS, with only a few sequences inhibiting both pathways. Together with our previous studies, our work reveals a complex pattern of immunomodulation where 95% of the ASOs tested inhibited at least one of TLR7, TLR9 or cGAS by ≥30%, which may confound interpretation of their in vivo functions. Our studies constitute the broadest analysis of the immunomodulatory effect of 2'OMe ASOs on nucleic acid sensing to date and will support refinement of their therapeutic development.

Australian adolescent population norms for the child health utility index 9D-results from the young minds matter survey.

OBJECTIVE: Patient-reported outcomes of health-related quality-of-life (HRQoL) are important descriptors of population health. A recent Australian adolescent population survey provided a unique opportunity to derive preference-based HRQoL. METHODS: Data from 2967 adolescents aged 11-17 years were analysed. An interviewer-led parent/carer questionnaire was administered for demographic variables and mental disorders of adolescents during previous 12 months using the Diagnostic Interview Schedule for Children. A self-report survey was administered to derive HRQoL using the child health utility nine-dimensions instrument (CHU-9D). Weighted HRQoL was derived for several demographic groups, mental disorder diagnosis, and youth risk behaviours. RESULTS: The total population had a mean utility of 0.78 [standard deviation (SD): 0.20]. Males had a significantly higher mean utility (0.81, SD 0.18) than females (0.76, SD: 0.21) (Cohen's d = 0.23, p < 0.001), and utility decreased with age for both males and females (p < 0.001). Family type and some parent/carer variables were associated with significant lower HRQoL scores with small effect size. Youth risk behaviours were associated with reduced HRQoL with moderate effect sizes. Adolescents who self-harmed, had suicidal ideation, or had a mental disorder had significantly lower utilities scores with moderate to large effect sizes compared to those who did not have such conditions. CONCLUSIONS: This study has provided contemporary Australian population norms for HRQoL in adolescents that may be used as cross comparison between studies as well as indicators allowing estimation of population health (e.g. estimation of the burden of disease) and can be used to populate future economic models.

The cost of Medicare-funded medical and pharmaceutical services for mental disorders in children and adolescents in Australia.

OBJECTIVE: To examine the health care costs associated with mental disorders and subthreshold mental disorders within a nationally representative sample of children and adolescents in Australia. METHOD: Data were derived from the Young Minds Matter Survey (N = 6,310). Mental disorders were classified using the Diagnostic Interview Schedule for Children Version IV. Participant data were linked to administrative data on health care costs. Adjusted generalized linear regression models and two-part models were used to estimate mean differences in costs between those with a mental disorder or subthreshold disorder and those without. RESULTS: Costs associated with health care attendances and medications were higher for children and adolescents with mental disorders and subthreshold mental disorders compared to those without a mental disorder. The additional population health care costs due to mental disorders amounted to AUD$234 million annually in children and adolescents, of which approximately 16% was attributed to out-of-pocket costs. Findings showed that those with subthreshold mental disorders or comorbid mental disorders have substantial additional costs of Medicare-funded medical and pharmaceutical services. CONCLUSION AND IMPLICATION: Mental disorders in children and adolescents are associated with significant health care costs. Further research is needed to ensure that this population is receiving effective and efficient care.