Paediatrics (RCH) - Theses
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ItemNo Preview AvailableEffectiveness of mass drug administration regimens for the control of scabies( 2022)Scabies is a neglected tropical disease (NTD) of the skin that causes approximately 455 million cases around the world each year. It is most prevalent in low resource, crowded, tropical environments. Scabies is caused by a parasitic mite that burrows into the skin and causes intense itch, which can lead to a break in the skin barrier. Secondary bacterial infection can lead to serious invasive and immune modulated disease. Mass drug administration (MDA) has been used in the control of a number of NTDs and there is evidence that it may be an effective control strategy for scabies in populations with a high prevalence. The first part of this thesis explores the impact of scabies on the community and on individuals, providing evidence for the need for public health control. The impact of scabies on the community was assessed in a survey in Western Province in Solomon Islands. A total of 5239 participants were enrolled across 20 villages. Scabies prevalence was 15% (95% CI 11.8 – 19.1) and impetigo prevalence 5.6% (95% 4.2 – 7.3). Dermatology quality of life interviews were conducted in one-third of participants to assess the impact of scabies on individuals. This study found that scabies has a small, but measurable, impact on quality of life in children and adults, and that the impact increased with the severity of the disease. The second part of this thesis investigates the public health control of scabies. A systematic review and meta-analysis was conducted to assess the impact of MDA on both scabies and impetigo. The meta-analysis included 9 studies and found that MDA with ivermectin or permethrin led to an overall relative reduction of 79% scabies prevalence and 66% impetigo prevalence. A variety of drug and dose regimens were used across the included studies and it was not clear if one regimen was more effective than others. The major study in this thesis is the Regimens of Ivermectin for Scabies Elimination (RISE) trial. RISE was a cluster-randomised non-inferiority study of one versus two doses of ivermectin-based MDA. There were 20 villages included in the study, with 10 villages randomised to each dose group. Participating villages were scattered across 7 different island groups and neighbouring villages did not take part in MDA. The study aim was to assess the prevalence of scabies in one and two dose villages 12 months after MDA, but due to the COVID-19 global pandemic this was delayed to 21 months. At 21 months after MDA there was no change in scabies prevalence in either the one or two dose groups. There was a reduction in the severity of scabies and the prevalence of impetigo in both groups. The results were unexpected. There was considerable movement of people in and out of the study villages between baseline and 21 months which may have contributed to the finding of static scabies prevalence in both groups. Despite the lack of effect seen in the RISE trial the systematic review and meta-analysis demonstrated that MDA can have a substantial impact on scabies prevalence. The RISE trial provided important information about implementation of MDA and the need for neighbouring villages to receive treatment. The question of whether one dose of ivermectin-based MDA is non-inferior to two doses needs further research.
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ItemIvermectin-based mass drug administration for the serious bacterial complications of scabies( 2022)Scabies is a skin disease caused by the mite Sarcoptes scabiei var. hominis, which is especially prevalent in populations experiencing overcrowding and poverty. Recognised as a neglected tropical disease by the World Health Organization in 2017, scabies is characterised through skin lesions and intense itch. The host is made vulnerable to secondary bacterial infection through skin breaches, scratching and inhibition of the complement system via mite secretions. Bacterial infection predominantly caused by Staphylococcus aureus and/or Group A Streptococcus most commonly manifesting as impetigo can complicate scabies. Impetigo can progress to more complicated skin and soft tissue infection, invasive bacterial infection and post streptococcal sequelae which cause significant morbidity and mortality. Previous studies in the Pacific Islands, including in Fiji, demonstrated that ivermectin-based mass drug administration substantially reduces scabies prevalence by approximately 90%, and leads to a concomitant reduction in impetigo prevalence by 60% to 70%. The focus of this thesis was to determine if ivermectin-based mass drug administration also leads to a reduction in the more serious bacterial complications of scabies. The studies and intervention described in this thesis take place in Fiji’s Northern Division (population ~131,914 in 2017). Four studies are reported in the thesis. The first study investigated the burden of hospitalisations for skin and soft tissue infections using prospective surveillance at the referral hospital of the Northern Division, and found a very high population incidence of 647 admissions per 100,000 person-years (95% CI 571-660). The second study investigated the burden of invasive infections caused by S. aureus and group A Streptococcus, using prospective surveillance also at the referral hospital, and found a high incidence at 45.2 and 12.3 per 100,000 person-years, respectively. The third study investigated the incidence of primary healthcare presentations for scabies and skin and soft tissue infections using a prospective surveillance system established at all primary healthcare facilities in the Northern Division, and found that there were 13,736 presentations over 50 weeks, equivalent to a population incidence of 108 presentations per 1000 person-years. The final major study investigated the impact of ivermectin-based mass drug administration on the bacterial complications of scabies. Ivermectin-based mass drug administration was deployed across the whole of the Northern Division. Coverage of mass drug administration was high – with the first dose achieving 97% and the second dose 87% coverage. The primary outcome measure was the annual incidence of hospitalisations for skin and soft tissue infections, with the study finding that the incidence declined significantly by 17% in the year after mass drug administration (from 467 to 388 per 100,000, incidence rate ratio 0.83 95% confidence intervals 0.74% to 0.94%). This finding was supported by a reduction in the annual incidence of primary healthcare presentations by 21%, and by a reduction in scabies and impetigo prevalence by 29% and 60% respectively. There was no decrease in the incidence of invasive infections and post streptococcal sequelae. Overall, this thesis demonstrates that scabies control through mass drug administration can lead to a reduction in the incidence of bacterial skin and soft tissue infections, measured as a fall in healthcare utilisation and community prevalence. These results are encouraging and provide further evidence of the broader benefits of scabies control via mass drug administration. In settings where scabies is endemic and where resources are limited and health priorities compete, this thesis highlights the underestimated burden of scabies and strengthens the case for policy targeting control of this neglected tropical disease.
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ItemUtilising high resolution impedance manometry to diagnose and manage oesophageal dysfunction in children with oesophageal atresia( 2022)Oesophageal atresia is the most common congenital oesophageal abnormality and requires life-saving surgery in the neonatal period. Despite successful surgery, most patients will have ongoing oesophageal dysmotility. Dysmotility in oesophageal atresia is a life-long risk. Dysmotility results in chronic swallowing dysfunction into adulthood – leading to poor food bolus transport, choking, and even death. We are currently unable to reliably predict which patients will develop dysmotility and require oesophageal dilatations. Therefore, clinical management is reactive, rather than proactive. This research seeks to understand the motility patterns in oesophageal atresia, as well as the dilatation burden and late mortality risk. This research utilises high resolution impedance manometry, which provides accurate and reliable measurements of oesophageal wall compliance, to develop an understanding of how compliance relates to food bolus transport. This will allow for objective characterisation of oesophageal contraction in patients with oesophageal atresia. Simultaneously, patient and carer quality of life will also be assessed. With the largest cohort of patients with oesophageal atresia undergoing high resolution impedance manometry internationally, this research demonstrates that the distinct motility patterns of these patients remain consistent over time. This informs patient management and parental counselling, as well as the development of a strategy for predicting and preventing morbidity and mortality in oesophageal atresia.
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ItemThe use of genomic sequencing technologies to diagnose rare neurological disease( 2022)Background Neurological diseases with presumed genetic aetiology contribute a significant burden of disease in the population, particularly the severe diseases of childhood. Without a genetic diagnosis, families cannot access accurate genetic counselling, prenatal and preimplantation testing, prognostic information, or targeted therapeutics. Genomic sequencing technologies have enabled an unprecedented improvement in the diagnosis of these rare diseases. Aims and Methods The aim of this project is to investigate the use of genomic sequencing technologies to diagnose rare neurological disease. In part 1, a gene panel was applied to a cohort of 124 individuals with polymicrogyria to identify causative variants and determine the genetic mechanism. In part 2, duo exome sequencing was used to investigate the cause of two novel phenotypes affecting siblings in two unrelated families. In part 3, trio genome sequencing was used to investigate the genetic causes underlying a cohort of 26 patients from 22 families with unclassified disorders of white matter. In addition to identifying the genetic basis of these diseases, this project aimed to evaluate the use of three different genomic sequencing strategies, discover novel gene-disease associations and describe expanded gene-disease phenotypes. Results In part 1, 25 of 123 individuals with polymicrogyria were identified as having a causative variant. Five individuals with heterozygous variants in keeping with a dominant mechanism had an allele fraction less than 0.33, consistent with mosaicism. The highest diagnostic yield was achieved for patients with an abnormal head size, particularly macrocephaly, and those with the additional brain malformations seen in association with tubulinopathies. In part 2, both families investigated with duo exome sequencing received a diagnosis. One of the diagnoses characterised the neuropathology associated with recessive pathogenic variants in VAC14, and the other resulted in expansion of the clinical and radiological phenotype associated with recessive pathogenic variants in HMBS. In part 3, trio genome sequencing identified a cause in 15 of 22 families with unclassified white matter disease. The phenotypic spectrum associated with known genes was expanded in 11 cases, and for nine, the implicated gene had not previously been associated with white matter disease. Discussion: Advantages and limitations to the different genomic technologies were identified and dependent on the context of study. A gene panel was suitable for investigation of a singleton cohort with a high probability of somatic variants as high sequencing depth is achievable, exome sequencing applied to family studies with multiple affected individuals facilitated a narrowing of the search space for identification of shared variants, and trio genome sequencing was particularly advantageous for its recognition of de novo variants. Conclusions The results of this project have advanced the understanding of the genetic causes of polymicrogyria and white matter diseases and informed the approach to genetic testing for these rare and genetically heterogeneous diseases. Additionally, this research has led to ongoing projects that aim to improve care for patients and families affected by rare neurogenetic diseases.
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ItemInter-arm blood pressure differences at rest and exercise: significance in children and potential mechanisms( 2021)High blood pressure (BP) is one of the leading risk factors for cardiovascular disease and is a key contributor to arterial stiffening, end organ damage, and cognitive decline. Importantly, high BP often begins in childhood, and if left untreated may track into adulthood. However, if diagnosed and treated, reducing high BP lowers the risk of disease. Clinical guidelines for best practice with regards to BP measurement have been established for both adults and children. Although not routinely followed in many settings, a common recommendation for both adult and paediatric populations is to measure BP in both arms. The measurement of bilateral BP holds clinical importance as an inter-arm blood pressure difference (IAD) of greater than or equal to 10 mmHg (IAD+) is associated with cardiovascular disease and premature morbidity and mortality in adults. Additionally, both the magnitude and prevalence of IAD+ has been shown to increase with exercise. While IAD has been investigated in adults, no studies exist on IAD in children despite the recommendation to measure bilateral BP in clinical guidelines. Further, the mechanisms which cause this difference remain unknown. Therefore, the primary purpose of this thesis was to examine IAD in children and adolescents under resting conditions, exercise conditions, and explore a potential mechanism which may result in IAD. Four investigations were performed that 1) quantified the magnitude of IAD and the frequency of IAD+, as well as determined inter-arm BP classification differences, under resting conditions in children and adolescents; 2) generated normative data for exercise BP response in children and adolescents undergoing treadmill exercise stress tests to enable objective assessment of exercise BP classification; 3) quantified the magnitude of IAD and frequency of IAD+ and inter-arm classification differences under exercise conditions in children and adolescents; 4) used a one-dimensional computational model to investigate inter-arm difference in arterial stiffness as a potential mechanism underlying IAD. The frequency of IAD+ in children and adolescents was similar to that of adults under both resting an exercise conditions. The average magnitude of IAD was 5 mmHg under resting conditions and 7 mmHg under exercise conditions.The inter-arm classification difference was ~20% under resting conditions. Normative data generated from treadmill exercise tests was used to determine that ~10% of children and adolescents have an exercising inter-arm classification difference. Lastly, the modelling study supported the hypothesis that inter-arm differences in regional arterial stiffness may contribute to IAD. Data presented in this thesis supports the recommendation to measure BP in both arms and provides a strong rationale for conducting this measurement in apparently healthy children. Measuring BP in both arms under both resting and exercise conditions may be important for detecting high BP in children and adolescents. Lastly, it was shown that mechanistic investigations with regards to IAD can be performed using 1D models and may be useful where in-vivo studies are not physiologically possible.
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ItemExome sequencing in infants with congenital deafness, a model for genomic newborn screening( 2021)Background Genomic technology is emerging as a powerful diagnostic tool to provide precision management and personalised care. It also has potential to be used at a population level to provide predictive and tailored health information, including as part of newborn screening (NBS). NBS traditionally detects serious and treatable childhood conditions, including congenital hearing impairment. As the majority of childhood hearing impairment has an underlying genetic cause, genomics is the ideal technology to investigate this condition. Aims and Methods The aims of this research were to: a) characterise the genetic causes of congenital hearing impairment in the population; b) understand the impact genomic testing has on the pathway of care following this diagnosis; and c) examine the factors that may influence the uptake and success of a genomic NBS tool. The methods used to investigate these aims were: 1. Offering diagnostic genomic testing to a cohort of infants with hearing impairment and observing the effect of this investigation on their healthcare journey; 2. Determining the cost-effectiveness of this genomic testing pathway when compared with the standard of care; 3. Offering parents additional analysis of non-deafness genes and investigating what factors influence their choices around seeking predictive health information for their infant; 4. Undertaking a systematic literature review to understand the current status of the field of genomics as a potential tool for NBS. Results Genomic sequencing was performed on 106 infants diagnosed with congenital deafness through newborn screening. Fifty-nine infants (56%) had a genetic cause for their hearing impairment. The majority (n=38, 36%) had a diagnosis that indicated their hearing impairment was isolated, such that they did not need to undertake surveillance for other health conditions. Those who received a syndrome diagnosis (n=21, 20%) were able to access accurate prognostic information, support and tailored healthcare. Streamlining the care of this cohort according to their underlying diagnosis was cost-effective when compared to standard of care, where most infants do not have a cause for their hearing impairment identified. Genomic testing also had non-health related benefits for families, i.e., personal utility. Parents made varying choices regarding receiving predictive information from the testing. Seventy-two parents (68%) accepted the offer of additional information. These findings are consistent with those identified in our systematic review of the literature – that “one size does not fit all”. Conclusion Offering genomic sequencing to a cohort of infants with congenital hearing impairment served as an ideal model to investigate genomic NBS. It re-enforced the diagnostic power of the test for congenital hearing impairment, translating into a cost-effectiveness analysis and an application for a Medicare item number. More broadly, this research identified the key elements required for genomic NBS to be acceptable and successful at a population level. Areas for future work are to refine the scope of testing with a strategy for gene list composition, and to identify the optimum timing and consent process. Getting these elements right will enhance newborn screening by increasing its scope and sensitivity, not just for congenital hearing impairment, but for improving the health of many children and their families.
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ItemDevelopment of functional and structural brain connectivity supporting sustained attention in ADHD( 2022)Sustained attention is an important cognitive ability which supports success in everyday life. Sustained attention gradually matures over childhood and adolescence and initial work has hinted at the brain areas in grey and white matter which may be most critical for sustained attention. However, no studies have used longitudinal data to establish how the strength of connections within grey and white matter may influence attention improvements within individuals over development. Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder in which impaired sustained attention is common, however understanding of sustained attention trajectories in ADHD and their neural underpinnings is also currently limited. This work establishes how sustained attention develops over the ages 9-14 years in a longitudinal, community sample of children with and without ADHD. Progress has been made in recent years in advancing the techniques used in the sustained attention field — sustained attention tasks and measures with strong reliability and validity have been identified, the overall organization of the brain into several functional networks has been established, and advanced diffusion imaging techniques now offer more precise and interpretable measures of structural white matter properties. This thesis takes advantage of these developments to map associations between sustained attention and brain properties over childhood and adolescence. The first study investigates the typical developmental trajectory of sustained attention and how this trajectory differs in children with persistent or remitted ADHD. Results show that although sustained attention improves in all groups over the transition from late childhood to early adolescence, participants with ADHD have consistently poorer sustained attention regardless of remission status. The second study quantifies the functional connectivity within and between established brain networks and demonstrates how this connectivity is associated with sustained attention over the studied age period. Findings reveal that adolescents who have reduced functional connectivity between the frontoparietal network and other brain networks display better sustained attention, supporting the proposed role of the frontoparietal network in attention maintenance. Although participants with ADHD exhibit generally poorer sustained attention at all timepoints, adolescents with ADHD who have reduced functional connectivity between frontoparietal and dorsal attention networks display attention performance comparable to neurotypical peers. Finally, the third study estimates micro- and macrostructural properties of white matter fiber bundles that underpin important functional networks and examines how these white matter properties relate to sustained attention in neurotypical control and ADHD groups. The study demonstrates the fiber bundle size of the superior longitudinal fasciculus is associated with sustained attention performance across late childhood to early adolescence. The density of fibers in the dorsal and middle superior longitudinal fasciculus is not associated with sustained attention in the ADHD group, which may be due to altered white matter in participants with ADHD. Overall, the findings of this thesis establish a strong basis from which to understand how brain connectivity contributes to the development of sustained attention over childhood and adolescence, and how this may differ between neurotypical children and individuals with ADHD. Results contribute to new research aimed at establishing effective interventions for children with sustained attention deficits.
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ItemModelling development of the human adaptive immune system in vitro( 2021)The human adaptive immune system provides a specialized function in the defense of the body against invading pathogens. Abnormal development of the adaptive immune system is thought to cause autoimmune disorders. Its development requires spatiotemporal coordination of multiple embryonic activities, including hematopoiesis, development of lymphoid organs, and hematopoietic colonization. Here, we focus on T cell and thymus development and use pluripotent stem cells (PSCs) to create multiple cell types that are known to contribute to thymus ontogeny. We demonstrate new methods for generating human hematopoietic cells, endothelial cells and thymic epithelial cells from PSCs in vitro, supported by three results chapters. Chapter 3 describes the generation of macrophages from PSCs and comprises a submitted manuscript in the journal format. The manuscript describes a novel streamlined protocol that enables the differentiation of macrophages from different PSC lines and shows that these PSC-derived macrophages can be infected with Mycobacterium abscessus. This submitted manuscript also includes a proof-of-principle demonstrating that this platform can be used to assess antibiotic sensitivities. Chapter 4 describes the derivation and characterization of thymic epithelial cells from PSCs and primary human thymus. This work comprises a manuscript which has been peer-reviewd and published in the journal Frontiers in Immunology; the published version is included in Chapter 4. The manuscript shows the identification of a new CD90 (THY1) + thymic epithelial cell population expressing genes associated with both epithelial and mesenchymal cell profiles, highlighting the ambiguous cell identity of thymic epithelial cells. Chapter 5 describes the derivation of arterial-like endothelial cells expressing DLL4, a ligand that is important for inducing hematopoietic stem cells to commit to the T cell lineage. Additional experiments explored the effects of different concentrations of SCF and IL7 on the production of CD4+CD8+ T cell progenitors, assessed by expression of RAG1:GFP, CD7 and IL7R, and CD4 and CD8. These experiments suggest opposing functions of SCF and IL7 in lymphoid cell production. This chapter also describes a pilot coculture experiment aimed at assembling an artificial thymus using the above materials. This thesis examined multiple lineages that are known to be important during the ontogeny of the human adaptive immune system, with a particular emphasis on events related to thymus development. This work lays a foundation for future studies aimed at understanding and manipulating the generation of human immune cells. This thesis also includes three scientific blog articles in the Appendix, written and published for the International Society for Stem Cell Research for scientific communication and public engagement.
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ItemEarly life oral exposures as risk factors for food allergy and the impact of infant feeding guidelines( 2021)Food allergy is a severe immune reaction affecting around 10% of infants. The recent rise in food allergy is a growing public health concern. Susceptibility to food allergy is affected by environmental exposures that affect infant gut immunity, including oral food and microbial exposures. Changes in infant feeding guidelines recommending introduction of allergenic foods in the first year were the first public health measure introduced specifically to prevent food allergy. I aimed to evaluate their impact on timing of allergenic food introduction and prevalence of food allergy, as well as investigating oral microbial exposure as a potential food allergy risk factor. The effect of 2016 updates to infant feeding guidelines on food allergy was evaluated using two large population-based cross-sectional studies (n=5,300 and n=1,933) that recruited 12-month-old infants in Melbourne, Australia 10-years apart (2007-2011 and 2018-2019) to study allergenic food introduction and peanut allergy. Microbial exposure was investigated in relation to food allergy using data from a cohort study (n=1,072) based in south-east Australia which measured pacifier cleaning methods in the first year of life. Data were analyzed using multivariable logistic regression models and direct standardization. Regression models were adjusted for known food allergy risk factors, depending on the exposure. An overview of systematic reviews searched systematic reviews in four databases to examine age of complementary feeding in relation to other health outcomes. These studies are the first report that peanut introduction by 12 months of age (inclusive) in the population increased (88% in 2018-2019 vs 28% in 2007-2011) following the implementation of 2016 infant feeding guidelines. Despite this massive shift, peanut allergy prevalence did not decrease as much as expected (3.1% to 2.6%). However, the increase in peanut introduction seems to have halted the rise of peanut allergy in one-year-old infants. The systematic review found 27 reviews on age of complementary or allergenic food introduction on multiple outcomes. There was no evidence of a detrimental effect on other health outcomes of the recommended introduction of solids and allergenic foods starting around 6 months of age, though solids introduced earlier than 4 months could increase the risk of overweight. Furthermore, sanitization of infant pacifier with antiseptics at 6 months of age increased the risk of food allergy at age one, possibly an effect of the chemicals on oral or gut microbiome. An increase in early introduction following 2016 guideline changes has halted the overall rise in peanut allergy. Nevertheless, peanut allergy is still high in Melbourne, thus additional prevention strategies are required. Reassuringly, other health outcomes are not risked by the recommended age of allergenic food introduction. The findings on cleaning pacifiers with antiseptics suggests that suggests microbial exposure can protect against food allergy. This warrants further interventional studies to determine if microbial exposures could prevent food allergy. Moreover, early life risk factors, prior to food introduction, need to be explored further.
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ItemEffect of a high-level mobility skills training programme on sustained physical activity participation among ambulant children with cerebral palsy( 2021)Abstract: Objective: Sustained participation in physical activity is important for everyone. This thesis (i) systematically reviewed the evidence for the ability of physical activity interventions to enhance attendance and involvement in physical activity (study 1); (ii) assessed the effect of a community-based high-level mobility skills programme (HLMP) on participation in physical activity among ambulant children with cerebral palsy (study 2); and (iii) explored the children and their parents’ experiences of being active (study 3). Methods: Study 1 consisted of a systematic literature review. Seven databases were searched using PRISMA guidelines (2001-2020). Study 2 used a single-subject research design (SSRD) to evaluate quantitative outcomes after implementation of the HLMP. Ambulant children with cerebral palsy (aged 7–18 years) were invited to participate in a 12-week community-based HLMP that provided task-specific training of running skills. Each study participant set personal participation attendance, involvement, and physical competency goals and completed activity diaries for 56–58 weeks. Outcomes were collected during a baseline phase (4–6 weeks), an intervention phase (12 weeks), and during a nine-month follow-up phase that included a COVID lockdown. In study 3, semi-structured interviews were conducted at baseline, post-intervention, and at the end of follow-up with child-parent pairs. An interpretive description approach was used and guided coding and development of themes. Results: The systematic review included 11 randomised controlled trials and two cohort studies, all of which included only short-term follow-up. Two studies reported short-term gains in attendance in the 4–14 weeks following the physical activity intervention and one study reported an improvement in involvement during a follow-up period of one month. Eight ambulant children with cerebral palsy (aged 11–16 years, seven male) were recruited for study 2. Seven of the eight participants attended a median 23 of 24 HLMP sessions over 12 weeks, attained their involvement goal in at least two study phases and achieved at least one physical goal during the HLMP (11/15 goals), with continued attainment over the next 9 months (9/16 goals achieved). The frequency of attendance varied, with participant’s diaries indicating 0–17 sessions of being active per week during all study phases. Diversity of physical activities (variety and range of formal and informal physical activities) remained stable at 1–4 different activities per week (range 0–7). On testing, physical capacity increased post-intervention in the seven children who attended the HLMP and skill competency increased in six participants at the 6-month follow-up. Children and their parents valued being active now and into adulthood, reporting improved motivation, confidence, and physical well-being following the HLMP. Core themes were developed: ‘just doing it’, ‘getting the mix right’ (right people, right place, right time), ‘balancing the continua’ and ‘navigating the systems’. Co-designing, connecting and collaborating were seen as important to promote sustained participation for life. Conclusion: Children with cerebral palsy can achieve participation and physical goals, be highly involved in their chosen physical activities, and improve their physical competency. The community-based, task-specific goal-directed HLMP was able to keep some, but not all, children “on track” to achieve sustained participation in physical activity. Each child’s journey was complex and dynamic.