Association of Vitamin A and D Deficiencies with Infectious Outcomes in Children Undergoing Intensive Induction Therapy for Acute Lymphoblastic Leukemia.

OBJECTIVE: To evaluate the association between deficiency of vitamin A or D at diagnosis of pediatric acute lymphoblastic leukemia (ALL) and subsequent infectious complications during induction therapy. STUDY DESIGN: We conducted an institutional review board-approved, retrospective cohort study of children with newly diagnosed ALL from 2007 to 2017 at St. Jude Children's Research Hospital. We measured vitamin D, vitamin D binding protein, retinol binding protein as a surrogate for vitamin A, and immunoglobulin isotypes in serum obtained at ALL diagnosis, and we assessed the association between vitamin deficiencies or levels and infection-related complications during the 6-week induction phase using Cox regression models. RESULTS: Among 378 evaluable participants, vitamin A and D deficiencies were common (43% and 17%, respectively). Vitamin D deficiency was associated with higher risks of febrile neutropenia (adjusted hazard ratio [aHR], 1.7; P = .0072), clinically documented infection (aHR, 1.73; P = .025), and likely bacterial infection (aHR, 1.86; P = .008). Conversely, vitamin A deficiency was associated solely with a lower risk of sepsis (aHR, 0.19; P = .027). CONCLUSIONS: In this retrospective study, vitamin D deficiency was associated with an increased risk of common infection-related complications during induction therapy for ALL. Additional studies are warranted to evaluate whether vitamin D supplementation could mitigate this effect.

Teachers as first responders: classroom experiences and mental health training needs of Australian schoolteachers.

BACKGROUND: Schoolteachers are often the first to respond when a student presents with a mental health issue in the classroom. This places a burden on schools that impacts school staff, healthcare workers and teachers. More broadly, it places a responsibility on the education system to address students' mental health. This study examines Australian teachers' classroom experiences and the training areas identified by teachers as necessary to manage these issues. METHOD: Interviews were undertaken with 18 in-service teachers between 2020 and 2021 from Catholic, Independent and Public schools. Data were gathered via multiple interviews and analysed using thematic content analysis. RESULTS: The major mental health issues identified by teachers related to mental disorders, depression, anxiety, and a complex range of negative emotional states. Teachers requested training in child and adolescent mental health, counselling skills, early detection and intervention, and training skills to manage the complex relationship with parents and external health and community personnel. Teachers also reported the need to access mental health resources, support and training, which were differentially accessed along socioeconomic status and postcodes. CONCLUSION: The data show that teachers are often placed as first responders when a student has a mental health issue but feel inadequately trained to manage these issues in the classroom. We identified mental health issues presenting in Australian classrooms and documented critical features of mental-health training asked for by teachers in order to address those issues. Given the increasing demands on teachers to address the mental health of children and adolescents, we argue that an urgent review of mental health training for teachers is needed.

Healthcare-Associated Infections Caused by Mycolicibacterium neoaurum.

Mycolicibacterium neoaurum is a rapidly growing mycobacterium and an emerging cause of human infections. M. neoaurum infections are uncommon but likely underreported, and our understanding of the disease spectrum and optimum management is incomplete. We summarize demographic and clinical characteristics of a case of catheter-related M. neoaurum bacteremia in a child with leukemia and those of 36 previously reported episodes of M. neoaurum infection. Most infections occurred in young to middle-aged adults with serious underlying medical conditions and commonly involved medical devices. Overall, infections were not associated with severe illness or death. In contrast to other mycobacteria species, M. neoaurum was generally susceptible to multiple antimicrobial drugs and responded promptly to treatment, and infections were associated with good outcomes after relatively short therapy duration and device removal. Delays in identification and susceptibility testing were common. We recommend using combination antimicrobial drug therapy and removal of infected devices to eradicate infection.

Evaluation of a therapist-guided virtual psychological pain management program when provided as routine care: a prospective pragmatic cohort study.

INTRODUCTION: Numerous randomized controlled trials have evaluated the outcomes of internet-delivered psychological pain management programs (PMPs) as a way of increasing access to care for people with chronic pain. However, there are few reports of the effectiveness of these PMPs when provided as part of routine care. METHODS: The present study sought to report the clinical and demographic characteristics of users (n = 1367) and examine the effectiveness of an established internet-delivered psychological PMP program in improving several pain-related outcomes, when offered at a national digital mental health service over a 5-year period. It also sought to comprehensively explore predictors of treatment commencement, treatment completion, and clinical improvement. RESULTS: Evidence of clinical improvements (% improvement; Hedges g) were found for all outcomes, including pain interference (18.9%; 0.55), depression (26.1%; 0.50), anxiety (23.9%; 0.39), pain intensity (12.8%; 0.41), pain self-efficacy (-23.8%; -0.46) and pain-catastrophizing (26.3%; 0.56). A small proportion of users enrolled but did not commence treatment (13%), however high levels of treatment completion (whole treatment = 63%; majority of the treatment = 75%) and satisfaction (very satisfied = 45%; satisfied = 37%) were observed among those who commenced treatment. There were a number of demographic and clinical factors associated with commencement, completion and improvement, but no decisive or dominant predictors were observed. DISCUSSION: These findings highlight the effectiveness and acceptability of internet-delivered psychological PMPs in routine care and point to the need to consider how best to integrate these interventions into the pathways of care for people with chronic pain.

Integrating digital interventions with clinical practice in youth mental health services.

OBJECTIVE: Integrating digital technologies with clinical practice promises to improve access and enhance care in the context of high service demand and constrained capacity. METHOD: We outline the emerging research in the integration of digital tools in clinical care, known as blended care, and provide case examples of mental health technology platforms currently in use, summarise findings regarding novel technologies such as virtual reality, and outline real-world implementation challenges and potential solutions. RESULTS: Recent evidence shows that blended care approaches are clinically effective and improve service efficiency. Youth-specific technologies such as moderated online social therapy (MOST) are achieving a range of positive clinical and functional outcomes, while emerging technologies like virtual reality have strong evidence in anxiety disorder, and accumulating evidence in psychotic conditions. Implementation science frameworks show promise in helping overcome the common challenges faced in real-world adoption and ongoing use. CONCLUSION: The integrated, blended use of digital mental health technologies with face-to-face clinical care has the potential to improve care quality for young people while helping overcome the growing challenges faced by youth mental health service providers.

Lentiviral Gene Therapy Combined with Low-Dose Busulfan in Infants with SCID-X1.

BACKGROUND: Allogeneic hematopoietic stem-cell transplantation for X-linked severe combined immunodeficiency (SCID-X1) often fails to reconstitute immunity associated with T cells, B cells, and natural killer (NK) cells when matched sibling donors are unavailable unless high-dose chemotherapy is given. In previous studies, autologous gene therapy with γ-retroviral vectors failed to reconstitute B-cell and NK-cell immunity and was complicated by vector-related leukemia. METHODS: We performed a dual-center, phase 1-2 safety and efficacy study of a lentiviral vector to transfer IL2RG complementary DNA to bone marrow stem cells after low-exposure, targeted busulfan conditioning in eight infants with newly diagnosed SCID-X1. RESULTS: Eight infants with SCID-X1 were followed for a median of 16.4 months. Bone marrow harvest, busulfan conditioning, and cell infusion had no unexpected side effects. In seven infants, the numbers of CD3+, CD4+, and naive CD4+ T cells and NK cells normalized by 3 to 4 months after infusion and were accompanied by vector marking in T cells, B cells, NK cells, myeloid cells, and bone marrow progenitors. The eighth infant had an insufficient T-cell count initially, but T cells developed in this infant after a boost of gene-corrected cells without busulfan conditioning. Previous infections cleared in all infants, and all continued to grow normally. IgM levels normalized in seven of the eight infants, of whom four discontinued intravenous immune globulin supplementation; three of these four infants had a response to vaccines. Vector insertion-site analysis was performed in seven infants and showed polyclonal patterns without clonal dominance in all seven. CONCLUSIONS: Lentiviral vector gene therapy combined with low-exposure, targeted busulfan conditioning in infants with newly diagnosed SCID-X1 had low-grade acute toxic effects and resulted in multilineage engraftment of transduced cells, reconstitution of functional T cells and B cells, and normalization of NK-cell counts during a median follow-up of 16 months. (Funded by the American Lebanese Syrian Associated Charities and others; LVXSCID-ND ClinicalTrials.gov number, NCT01512888.).

Clinical staging and the differential risks for clinical and functional outcomes in young people presenting for youth mental health care.

BACKGROUND: Clinical staging proposes that youth-onset mental disorders develop progressively, and that active treatment of earlier stages should prevent progression to more severe disorders. This retrospective cohort study examined the longitudinal relationships between clinical stages and multiple clinical and functional outcomes within the first 12 months of care. METHODS: Demographic and clinical information of 2901 young people who accessed mental health care at age 12-25 years was collected at predetermined timepoints (baseline, 3 months, 6 months, 12 months). Initial clinical stage was used to define three fixed groups for analyses (stage 1a: 'non-specific anxious or depressive symptoms', 1b: 'attenuated mood or psychotic syndromes', 2+: 'full-threshold mood or psychotic syndromes'). Logistic regression models, which controlled for age and follow-up time, were used to compare clinical and functional outcomes (role and social function, suicidal ideation, alcohol and substance misuse, physical health comorbidity, circadian disturbances) between staging groups within the initial 12 months of care. RESULTS: Of the entire cohort, 2093 young people aged 12-25 years were followed up at least once over the first 12 months of care, with 60.4% female and a baseline mean age of 18.16 years. Longitudinally, young people at stage 2+ were more likely to develop circadian disturbances (odds ratio [OR]=2.58; CI 1.60-4.17), compared with individuals at stage 1b. Additionally, stage 1b individuals were more likely to become disengaged from education/employment (OR=2.11, CI 1.36-3.28), develop suicidal ideations (OR=1.92; CI 1.30-2.84) and circadian disturbances (OR=1.94, CI 1.31-2.86), compared to stage 1a. By contrast, we found no relationship between clinical stage and the emergence of alcohol or substance misuse and physical comorbidity. CONCLUSIONS: The differential rates of emergence of poor clinical and functional outcomes between early versus late clinical stages support the clinical staging model's assumptions about illness trajectories for mood and psychotic syndromes. The greater risk of progression to poor outcomes in those who present with more severe syndromes may be used to guide specific intervention packages.

Predicting the emergence of full-threshold bipolar I, bipolar II and psychotic disorders in young people presenting to early intervention mental health services.

BACKGROUND: Predictors of new-onset bipolar disorder (BD) or psychotic disorder (PD) have been proposed on the basis of retrospective or prospective studies of 'at-risk' cohorts. Few studies have compared concurrently or longitudinally factors associated with the onset of BD or PDs in youth presenting to early intervention services. We aimed to identify clinical predictors of the onset of full-threshold (FT) BD or PD in this population. METHOD: Multi-state Markov modelling was used to assess the relationships between baseline characteristics and the likelihood of the onset of FT BD or PD in youth (aged 12-30) presenting to mental health services. RESULTS: Of 2330 individuals assessed longitudinally, 4.3% (n = 100) met criteria for new-onset FT BD and 2.2% (n = 51) met criteria for a new-onset FT PD. The emergence of FT BD was associated with older age, lower social and occupational functioning, mania-like experiences (MLE), suicide attempts, reduced incidence of physical illness, childhood-onset depression, and childhood-onset anxiety. The emergence of a PD was associated with older age, male sex, psychosis-like experiences (PLE), suicide attempts, stimulant use, and childhood-onset depression. CONCLUSIONS: Identifying risk factors for the onset of either BD or PDs in young people presenting to early intervention services is assisted not only by the increased focus on MLE and PLE, but also by recognising the predictive significance of poorer social function, childhood-onset anxiety and mood disorders, and suicide attempts prior to the time of entry to services. Secondary prevention may be enhanced by greater attention to those risk factors that are modifiable or shared by both illness trajectories.

Social and occupational outcomes for young people who attend early intervention mental health services: a longitudinal study.

OBJECTIVE: To identify trajectories of social and occupational functioning in young people during the two years after presenting for early intervention mental health care; to identify demographic and clinical factors that influence these trajectories. DESIGN: Longitudinal, observational study of young people presenting for mental health care. SETTING: Two primary care-based early intervention mental health services at the Brain and Mind Centre (University of Sydney), 1 June 2008 - 31 July 2018. PARTICIPANTS: 1510 people aged 12-25 years who had presented with anxiety, mood, or psychotic disorders, for whom two years' follow-up data were available for analysis. MAIN OUTCOME MEASURES: Latent class trajectories of social and occupational functioning based on growth mixture modelling of Social and Occupational Assessment Scale (SOFAS) scores. RESULTS: We identified four trajectories of functioning during the first two years of care: deteriorating and volatile (733 participants, 49%); persistent impairment (237, 16%); stable good functioning (291, 19%); and improving, but late recurrence (249, 16%). The less favourable trajectories (deteriorating and volatile; persistent impairment) were associated with physical comorbidity, not being in education, employment, or training, having substance-related disorders, having been hospitalised, and having a childhood onset mental disorder, psychosis-like experiences, or a history of self-harm or suicidality. CONCLUSIONS: Two in three young people with emerging mental disorders did not experience meaningful improvement in social and occupational functioning during two years of early intervention care. Most functional trajectories were also quite volatile, indicating the need for dynamic service models that emphasise multidisciplinary interventions and measurement-based care.

Implementing a digital health model of care in Australian youth mental health services: protocol for impact evaluation.

BACKGROUND: The World Economic Forum has recently highlighted substantial problems in mental health service provision and called for the rapid deployment of smarter, digitally-enhanced health services as a means to facilitate effective care coordination and address issues of demand. In mental health, the biggest enabler of digital solutions is the implementation of an effective model of care that is facilitated by integrated health information technologies (HITs); the latter ensuring the solution is easily accessible, scalable and sustainable. The University of Sydney's Brain and Mind Centre (BMC) has developed an innovative digital health solution - delivered through the Youth Mental Health and Technology Program - which incorporates two components: 1) a highly personalised and measurement-based (data-driven) model of youth mental health care; and 2) an industrial grade HIT registered on the Australian Register of Therapeutic Goods. This paper describes a research protocol to evaluate the impact of implementing the BMC's digital health solution into youth mental health services (i.e. headspace - a highly accessible, youth-friendly integrated service that responds to the mental health, physical health, alcohol or other substance use, and vocational concerns of young people aged 12 to 25 years) within urban and regional areas of Australia. METHODS: The digital health solution will be implemented into participating headspace centres using a naturalistic research design. Quantitative and qualitative data will be collected from headspace health professionals, service managers and administrators, as well as from lead agency and local Primary Health Network (PHN) staff, via service audits, Implementation Officer logs, online surveys, and semi-structured interviews, at baseline and then three-monthly intervals over the course of 12 months. DISCUSSION: At the time of publication, six headspace centres had been recruited to this study and had commenced implementation and impact evaluation. The first results are expected to be submitted for publication in 2021. This study will focus on the impact of implementing a digital health solution at both a service and staff level, and will evaluate digital readiness of service and staff adoption; quality, usability and acceptability of the solution by staff; staff self-reported clinical competency; overall impact on headspace centres as well as their lead agencies and local PHNs; and social return on investment.

Optimising the integration of technology-enabled solutions to enhance primary mental health care: a service mapping study.

BACKGROUND: Despite the widely acknowledged potential for health information technologies to improve the accessibility, quality and clinical safety of mental health care, implementation of such technologies in services is frequently unsuccessful due to varying consumer, health professional, and service-level factors. The objective of this co-design study was to use process mapping (i.e. service mapping) to illustrate the current consumer journey through primary mental health services, identify barriers to and facilitators of quality mental health care, and highlight potential points at which to integrate the technology-enabled solution to optimise the provision of care based on key service performance indicators. METHODS: Interactive, discussion-based workshops of up to six hours were conducted with representative stakeholders from each participating service, including health professionals, service managers and administrators from Open Arms - Veterans & Families Counselling Service (Sydney), a counselling service for veterans and their families, and five headspace centres in the North Coast Primary Health Network, primary youth mental health services. Service maps were drafted and refined in real time during the workshops. Through both group discussion and the use of post-it notes, participants worked together to evaluate performance indicators (e.g. safety) at each point in the consumer journey (e.g. intake) to indicate points of impact for the technology-enabled solution, reviewing and evaluating differing opinions in order to reach consensus. RESULTS: Participants (n=84 across participating services) created service maps illustrating the current consumer journey through the respective services and highlighting barriers to and facilitators of quality mental health care. By consensus, the technology-enabled solution as facilitated by the InnoWell Platform was noted to enable the early identification of risk, reduce or eliminate lengthy intake processes, enable routine outcome monitoring to revise treatment plans in relation to consumer response, and serve as a personal data record for consumers, driving person-centred, coordinated care. CONCLUSIONS: Service mapping was shown to be an effective methodology to understand the consumer's journey through a service and served to highlight how the co-designed technology-enabled solution can optimise service pathways to improve the accessibility, quality and clinical safety of care relative to key service performance indicators, facilitating the delivery of the right care.

Project Synergy: co-designing technology-enabled solutions for Australian mental health services reform.

Project Synergy aims to test the potential of new and emerging technologies to enhance the quality of mental health care provided by traditional face-to-face services. Specifically, it seeks to ensure that consumers get the right care, first time (delivery of effective mental health care early in the course of illness). Using co-design with affected individuals, Project Synergy has built, implemented and evaluated an online platform to assist the assessment, feedback, management and monitoring of people with mental disorders. It also promotes the maintenance of wellbeing by collating health and social information from consumers, their supportive others and health professionals. This information is reported back openly to consumers and their service providers to promote genuine collaborative care. The online platform does not provide stand-alone medical or health advice, risk assessment, clinical diagnosis or treatment; instead, it supports users to decide what may be suitable care options. Using an iterative cycle of research and development, the first four studies of Project Synergy (2014-2016) involved the development of different types of online prototypes for young people (i) attending university; (ii) in three disadvantaged communities in New South Wales; (iii) at risk of suicide; and (iv) attending five headspace centres. These contributed valuable information concerning the co-design, build, user testing and evaluation of prototypes, as well as staff experiences during development and service quality improvements following implementation. Through ongoing research and development (2017-2020), these prototypes underpin one online platform that aims to support better multidimensional mental health outcomes for consumers; more efficient, effective and appropriate use of health professional knowledge and clinical skills; and quality improvements in mental health service delivery.

Right care, first time: a highly personalised and measurement-based care model to manage youth mental health.

Mood and psychotic syndromes most often emerge during adolescence and young adulthood, a period characterised by major physical and social change. Consequently, the effects of adolescent-onset mood and psychotic syndromes can have long term consequences. A key clinical challenge for youth mental health is to develop and test new systems that align with current evidence for comorbid presentations and underlying neurobiology, and are useful for predicting outcomes and guiding decisions regarding the provision of appropriate and effective care. Our highly personalised and measurement-based care model includes three core concepts: ▶ A multidimensional assessment and outcomes framework that includes: social and occupational function; self-harm, suicidal thoughts and behaviour; alcohol or other substance misuse; physical health; and illness trajectory. ▶ Clinical stage. ▶ Three common illness subtypes (psychosis, anxious depression, bipolar spectrum) based on proposed pathophysiological mechanisms (neurodevelopmental, hyperarousal, circadian). The model explicitly aims to prevent progression to more complex and severe forms of illness and is better aligned to contemporary models of the patterns of emergence of psychopathology. Inherent within this highly personalised approach is the incorporation of other evidence-based processes, including real-time measurement-based care as well as utilisation of multidisciplinary teams of health professionals. Data-driven local system modelling and personalised health information technologies provide crucial infrastructure support to these processes for better access to, and higher quality, mental health care for young people. CHAPTER 1: MULTIDIMENSIONAL OUTCOMES IN YOUTH MENTAL HEALTH CARE: WHAT MATTERS AND WHY?: Mood and psychotic syndromes present one of the most serious public health challenges that we face in the 21st century. Factors including prevalence, age of onset, and chronicity contribute to substantial burden and secondary risks such as alcohol or other substance misuse. Mood and psychotic syndromes most often emerge during adolescence and young adulthood, a period characterised by major physical and social change; thus, effects can have long term consequences. We propose five key domains which make up a multidimensional outcomes framework that aims to address the specific needs of young people presenting to health services with emerging mental illness. These include social and occupational function; self-harm, suicidal thoughts and behaviours; alcohol or other substance misuse; physical health; and illness type, stage and trajectory. Impairment and concurrent morbidity are well established in young people by the time they present for mental health care. Despite this, services and health professionals tend to focus on only one aspect of the presentation - illness type, stage and trajectory - and are often at odds with the preferences of young people and their families. There is a need to address the disconnect between mental health, physical health and social services and interventions, to ensure that youth mental health care focuses on the outcomes that matter to young people. CHAPTER 2: COMBINING CLINICAL STAGE AND PATHOPHYSIOLOGICAL MECHANISMS TO UNDERSTAND ILLNESS TRAJECTORIES IN YOUNG PEOPLE WITH EMERGING MOOD AND PSYCHOTIC SYNDROMES: Traditional diagnostic classification systems for mental disorders map poorly onto the early stages of illness experienced by young people, and purport categorical distinctions that are not readily supported by research into genetic, environmental and neurobiological risk factors. Consequently, a key clinical challenge in youth mental health is to develop and test new classification systems that align with current evidence on comorbid presentations, are consistent with current understanding of underlying neurobiology, and provide utility for predicting outcomes and guiding decisions regarding the provision of appropriate and effective care. This chapter outlines a transdiagnostic framework for classifying common adolescent-onset mood and psychotic syndromes, combining two independent but complementary dimensions: clinical staging, and three proposed pathophysiological mechanisms. Clinical staging reflects the progression of mental disorders and is in line with the concept used in general medicine, where more advanced stages are associated with a poorer prognosis and a need for more intensive interventions with a higher risk-to-benefit ratio. The three proposed pathophysiological mechanisms are neurodevelopmental abnormalities, hyperarousal and circadian dysfunction, which, over time, have illness trajectories (or pathways) to psychosis, anxious depression and bipolar spectrum disorders, respectively. The transdiagnostic framework has been evaluated in young people presenting to youth mental health clinics of the University of Sydney's Brain and Mind Centre, alongside a range of clinical and objective measures. Our research to date provides support for this framework, and we are now exploring its application to the development of more personalised models of care. CHAPTER 3: A COMPREHENSIVE ASSESSMENT FRAMEWORK FOR YOUTH MENTAL HEALTH: GUIDING HIGHLY PERSONALISED AND MEASUREMENT-BASED CARE USING MULTIDIMENSIONAL AND OBJECTIVE MEASURES: There is an urgent need for improved care for young people with mental health problems, in particular those with subthreshold mental disorders that are not sufficiently severe to meet traditional diagnostic criteria. New comprehensive assessment frameworks are needed to capture the biopsychosocial profile of a young person to drive highly personalised and measurement-based mental health care. We present a range of multidimensional measures involving five key domains: social and occupational function; self-harm, suicidal thoughts and behaviours; alcohol or other substance misuse; physical health; and illness type, stage and trajectory. Objective measures include: neuropsychological function; sleep-wake behaviours and circadian rhythms; metabolic and immune markers; and brain structure and function. The recommended multidimensional measures facilitate the development of a comprehensive clinical picture. The objective measures help to further develop informative and novel insights into underlying pathophysiological mechanisms and illness trajectories to guide personalised care plans. A panel of specific multidimensional and objective measures are recommended as standard clinical practice, while others are recommended secondarily to provide deeper insights with the aim of revealing alternative clinical paths for targeted interventions and treatments matched to the clinical stage and proposed pathophysiological mechanisms of the young person. CHAPTER 4: PERSONALISING CARE OPTIONS IN YOUTH MENTAL HEALTH: USING MULTIDIMENSIONAL ASSESSMENT, CLINICAL STAGE, PATHOPHYSIOLOGICAL MECHANISMS, AND INDIVIDUAL ILLNESS TRAJECTORIES TO GUIDE TREATMENT SELECTION: New models of mental health care for young people require that interventions be matched to illness type, clinical stage, underlying pathophysiological mechanisms and individual illness trajectories. Narrow syndrome-focused classifications often direct clinical attention away from other key factors such as functional impairment, self-harm and suicidality, alcohol or other substance misuse, and poor physical health. By contrast, we outline a treatment selection guide for early intervention for adolescent-onset mood and psychotic syndromes (ie, active treatments and indicated and more specific secondary prevention strategies). This guide is based on experiences with the Brain and Mind Centre's highly personalised and measurement-based care model to manage youth mental health. The model incorporates three complementary core concepts: ▶A multidimensional assessment and outcomes framework including: social and occupational function; self-harm, suicidal thoughts and behaviours; alcohol or other substance misuse; physical health; and illness trajectory. ▶Clinical stage. ▶Three common illness subtypes (psychosis, anxious depression, bipolar spectrum) based on three underlying pathophysiological mechanisms (neurodevelopmental, hyperarousal, circadian). These core concepts are not mutually exclusive and together may facilitate improved outcomes through a clinical stage-appropriate and transdiagnostic framework that helps guide decisions regarding the provision of appropriate and effective care options. Given its emphasis on adolescent-onset mood and psychotic syndromes, the Brain and Mind Centre's model of care also respects a fundamental developmental perspective - categorising childhood problems (eg, anxiety and neurodevelopmental difficulties) as risk factors and respecting the fact that young people are in a period of major biological and social transition. Based on these factors, a range of social, psychological and pharmacological interventions are recommended, with an emphasis on balancing the personal benefit-to-cost ratio. CHAPTER 5: A SERVICE DELIVERY MODEL TO SUPPORT HIGHLY PERSONALISED AND MEASUREMENT-BASED CARE IN YOUTH MENTAL HEALTH: Over the past decade, we have seen a growing focus on creating mental health service delivery models that better meet the unique needs of young Australians. Recent policy directives from the Australian Government recommend the adoption of stepped-care services to improve the appropriateness of care, determined by severity of need. Here, we propose that a highly personalised approach enhances stepped-care models by incorporating clinical staging and a young person's current and multidimensional needs. It explicitly aims to prevent progression to more complex and severe forms of illness and is better aligned to contemporary models of the patterns of emergence of psychopathology. Inherent within a highly personalised approach is the incorporation of other evidence-based processes, including real-time measurement-based care and use of multidisciplinary teams of health professionals. Data-driven local system modelling and personalised health information technologies provide crucial infrastructure support to these processes for better access to, and higher quality of, mental health care for young people.

Managing local-regional failure in children with high-risk neuroblastoma: A single institution experience.

BACKGROUND: Intensification of systemic therapy for high-risk neuroblastoma (HRNB) has resulted in improved local control and overall survival (OS) leaving potential for de-escalation of primary site radiotherapy. The utility of primary site de-escalation should be evaluated in the context of potential for successful local-regional salvage. We evaluated salvage strategies and outcomes in patients with HRNB with local-regional recurrence as a component of first failure. METHODS: Twenty of 89 patients with HRNB experienced local-regional recurrence as a component of first relapse after chemotherapy, radiotherapy, surgery, and stem cell transplant from 1997 to 2013. We reviewed salvage therapy strategies and disease control, and report on the impact of local therapy as salvage for local-regional relapse. RESULTS: Six of 20 patients with local-regional failure (LRF) were alive after a median follow-up of 13 years (range, 0.9-25.2 years). Median OS was 4.6 years (95% CI, 0.6 to not reached) versus 0.6 years (95% CI, 0.05-2.6) after LRF with and without distant failure, respectively (P = 0.03). OS in patients receiving salvage radiotherapy was comparable to those receiving initial adjuvant but no salvage radiotherapy. Time to first failure and death was significantly impacted by the intensity of frontline systemic therapy (P = 0.03). Salvage radiotherapy reduced the hazard for subsequent LRF (hazard ratio 0.3, 95% CI 0.1-0.9, P = 0.04) but not OS (P = 0.07). CONCLUSIONS: Our study highlights the potential of local control strategies at first failure in patients with LRF when primary site radiotherapy was initially omitted, and delineates potential selection factors which may further improve the therapeutic ratio.

Selective T-cell depletion targeting CD45RA reduces viremia and enhances early T-cell recovery compared with CD3-targeted T-cell depletion.

BACKGROUND: T-cell depletion (TCD) effectively reduces severe graft-versus-host disease in recipients of HLA-mismatched allografts. However, TCD is associated with delayed immune recovery and increased infections. We hypothesized that specific depletion of CD45RA+ naive T cells, rather than broad depletion of CD3+ T cells, can preserve memory-immunity in the allografts and confer protection against important viral infections in the early post-transplant period. METHODS: Sixty-seven patients who received TCD haploidentical donor transplantation for hematologic malignancy on 3 consecutive trials were analyzed. RESULTS: Patients receiving CD45RA-depleted donor grafts had 2000-fold more donor T cells infused, significantly higher T-cell counts at Day +30 post transplant (550/µL vs 10/µL; P < .001), and higher T-cell diversity by Vbeta spectratyping at Day +100 (P < .001). Importantly, these recipients experienced a significant reduction in both the incidence (P = .002) and duration (P = .02) of any viremia (cytomegalovirus, Epstein-Barr virus, or adenovirus) in the first 6 months post transplant. Specifically, recipients of CD3-depleted grafts were more likely to experience adenovirus viremia (27% vs 4%, P = .02). CONCLUSION: CD45RA-depletion provided a large number of donor memory T cells to the recipients and was associated with enhanced early T-cell recovery and protection against viremia.

Haploidentical Donor Transplantation Using a Novel Clofarabine-containing Conditioning Regimen for Very High-risk Hematologic Malignant Neoplasms.

Recurrent/refractory hematologic malignancies have a poor prognosis, and there is a need for novel treatment regimens that can be tolerated by this heavily pretreated patient group. Clofarabine has antileukemic activity with an acceptable toxicity profile. In a phase I clinical trial (NCT00824135), we substituted clofarabine for fludarabine in a well-established reduced-intensity conditioning regimen for a T cell-depleted, mismatched-related (haploidentical) donor transplant backbone and explored the maximum tolerated dose of clofarabine in this combination in 15 patients undergoing hematopoietic cell transplantation for recurrent/refractory or secondary leukemia. Clofarabine was well tolerated at a dose of 50 mg/m/d for 5 days in this regimen, with minimal treatment-related mortality in a heavily pretreated group of high-risk patients. All patients exhibited quick hematopoietic recovery, with median times to neutrophil and platelet engraftment being 11 and 16 days, respectively. Transient elevation of transaminases was the most common toxicity-observed in 13 patients (86.7%), with 6 (40%) grade III or above. Three patients (20%) developed hepatic veno-occlusive disease. Eleven patients (73.3%) died, with the most common cause of death being disease relapse (in 9 patients [60%]), followed by treatment-related mortality (in 2 patients [13.3%]). Four (26.6%) of the patients are long-term survivors.

Using New and Innovative Technologies to Assess Clinical Stage in Early Intervention Youth Mental Health Services: Evaluation Study.

BACKGROUND: Globally there is increasing recognition that new strategies are required to reduce disability due to common mental health problems. As 75% of mental health and substance use disorders emerge during the teenage or early adulthood years, these strategies need to be readily accessible to young people. When considering how to provide such services at scale, new and innovative technologies show promise in augmenting traditional clinic-based services. OBJECTIVE: The aim of this study was to test new and innovative technologies to assess clinical stage in early intervention youth mental health services using a prototypic online system known as the Mental Health eClinic (MHeC). METHODS: The online assessment within the MHeC was compared directly against traditional clinician assessment within 2 Sydney-based youth-specific mental health services (headspace Camperdown and headspace Campbelltown). A total of 204 young people were recruited to the study. Eligible participants completed both face-to-face and online assessments, which were randomly allocated and counterbalanced at a 1-to-3 ratio. These assessments were (1) a traditional 45- to 60-minute headspace face-to-face assessment performed by a Youth Access Clinician and (2) an approximate 60-minute online assessment (including a self-report Web-based survey, immediate dashboard of results, and a video visit with a clinician). All assessments were completed within a 2-week timeframe from initial presentation. RESULTS: Of the 72 participants who completed the study, 71% (51/72) were female and the mean age was 20.4 years (aged 16 to 25 years); 68% (49/72) of participants were recruited from headspace Camperdown and the remaining 32% (23/72) from headspace Campbelltown. Interrater agreement of participants' stage, as determined after face-to-face assessment or online assessment, demonstrated fair agreement (kappa=.39, P<.001) with concordance in 68% of cases (49/72). Among the discordant cases, those who were allocated to a higher stage by online raters were more likely to report a past history of mental health disorders (P=.001), previous suicide planning (P=.002), and current cannabis misuse (P=.03) compared to those allocated to a lower stage. CONCLUSIONS: The MHeC presents a new and innovative method for determining key clinical service parameters. It has the potential to be adapted to varied settings in which young people are connected with traditional clinical services and assist in providing the right care at the right time.

Derivation of new equations to estimate glomerular filtration rate in pediatric oncology patients.

BACKGROUND AND OBJECTIVE: Monitoring renal function is critical in treating pediatric patients, especially when dosing nephrotoxic agents. We evaluated the validity of the bedside Schwartz and Brandt equations in pediatric oncology patients and developed new equations for estimated glomerular filtration rate (eGFR) in these patients. METHODS: A retrospective analysis was conducted comparing eGFR using the bedside Schwartz and Brandt equations to measured GFR (mGFR) from technetium-99m diethylenetriamine pentaacetic acid (99mTc-DTPA) between January 2007 and August 2013. An improved equation to estimate GFR was developed, simplified, and externally validated in a cohort of patients studied from September 2013 to June 2015. Carboplatin doses calculated from 99mTc-DTPA were compared with doses calculated by GFR-estimating equations. RESULTS: Overall, the bedside Schwartz and Brandt equations did not precisely or accurately predict measured GFR (mGFR). Using a data subset, we developed a five-covariate equation, which included height, serum creatinine, age, blood urea nitrogen (BUN), and gender, and a simplified version (two-covariates), which contained height and serum creatinine. These equations were used to estimate GFR in 2036 studies, resulting in precise and accurate predictors of mGFR values. Equations were validated in an external cohort of 570 studies; both new equations were more accurate in calculating carboplatin doses than either the bedside Schwartz or Brandt equation. CONCLUSIONS: Two new equations were developed to estimate GFR in pediatric oncology patients, both of which did a better job at estimating mGFR than published equations.

Using New and Emerging Technologies to Identify and Respond to Suicidality Among Help-Seeking Young People: A Cross-Sectional Study.

BACKGROUND: Suicidal thoughts are common among young people presenting to face-to-face and online mental health services. The early detection and rapid response to these suicidal thoughts and other suicidal behaviors is a priority for suicide prevention and early intervention efforts internationally. Establishing how best to use new and emerging technologies to facilitate person-centered systematic assessment and early intervention for suicidality is crucial to these efforts. OBJECTIVE: The aim of this study was to examine the use of a suicidality escalation protocol to respond to suicidality among help-seeking young people. METHODS: A total of 232 young people in the age range of 16-25 years were recruited from either a primary mental health care service or online in the community. Each young person used the Synergy Online System and completed an initial clinical assessment online before their face-to-face or online clinical appointment. A suicidality escalation protocol was used to identify and respond to current and previous suicidal thoughts and behaviors. RESULTS: A total of 153 young people (66%, 153/232) reported some degree of suicidality and were provided with a real-time alert online. Further levels of escalation (email or phone contact and clinical review) were initiated for the 35 young people (15%, 35/232) reporting high suicidality. Higher levels of psychological distress (P<.001) and a current alcohol or substance use problem (P=.02) predicted any level of suicidality compared with no suicidality. Furthermore, predictors of high suicidality compared with low suicidality were higher levels of psychological distress (P=.01), psychosis-like symptoms in the last 12 months (P=.01), a previous mental health problem (P=.01), and a history of suicide planning or attempts (P=.001). CONCLUSIONS: This study demonstrates the use of new and emerging technologies to facilitate the systematic assessment and detection of help-seeking young people presenting with suicidality. This protocol empowered the young person by suggesting pathways to care that were based on their current needs. The protocol also enabled an appropriate and timely response from service providers for young people reporting high suicidality that was associated with additional comorbid issues, including psychosis-like symptoms, and a history of suicide plans and attempts.

Correction of: Using New and Emerging Technologies to Identify and Respond to Suicidality Among Help-Seeking Young People: A Cross-Sectional Study.

[This corrects the article DOI: 10.2196/jmir.7897.].