Policy and practice recommendations for services for disabled children during emergencies: Learning from COVID-19.

AIM: To seek consensus on recommendations for the delivery of services to disabled children in England during future emergencies. METHOD: Candidate recommendations were drafted based on our related mapping review and qualitative research related to experiences during the COVID-19 pandemic. Iterative workshops with professionals and parent carers helped to refine the recommendations. A Delphi survey, rating the importance of each recommendation, was conducted with (1) parent carers of disabled children, (2) disabled young people aged 8 to 19 years, and (3) health, education, and social care professionals. A consensus meeting was convened online to discuss the findings and ratify the recommendations. RESULTS: Twenty-eight recommendations were included in the Delphi survey. There were 141 participants in round 1 and 91 in round 2. Seven recommendations reached the agreed consensus criteria for being critical across all stakeholder groups, while 21 recommendations did not reach consensus across all groups. Fourteen participants ratified 23 recommendations, which when aggregated and refined further produced our final 19 recommendations. INTERPRETATION: Reductions in services for disabled children and their families during the COVID-19 pandemic had serious and lasting consequences. This study enabled parent carers, disabled young people, and health, education, and social care professionals to agree recommendations on services for disabled children during future emergencies.

A lipid-based delivery platform for thermo-responsive delivery of teriparatide.

Teriparatide (and analogue peptides) are the only FDA approved anabolic treatments for osteoporosis. Current therapies are administered as a daily subcutaneous injection, which limits patient adherence and clinical efficacy. To achieve the desired anabolic effect, a controlled delivery system must ensure a pulsatile release profile over a prolonged period. Thermo-responsive formulations (e.g. liposomes) can undergo a temperature-related phase-transition which can allow active control of drug release. Herein, thermo-responsive liposomes were developed to permit control over teriparatide release rate through modulation of temperature. Entrapment of hydrophilic molecules, including peptides, within liposomes remains challenging due to the large volume of hydration. In this work, hydrophobic ion pairing was employed for the first time to enhance peptide entrapment within liposomes. The method resulted in a hydrophobic complex that achieved high teriparatide entrapment (>75 %) in sub-200 nm monodispersed liposomes. Hydrophobic ion pairing outperformed other entrapment approaches. Several liposomal formulations with transition temperatures between 38 and 50 °C were obtained by modulation of the phospholipid composition. In vitro assays demonstrated temperature-dependent release kinetics with faster rates of release observed at/above the transition temperature. The maintenance of biological activity of released teriparatide was demonstrated in a cell-based assay utilising the PTH1 receptor. Overall, this provides the first proof-of-concept of the suitability of thermo-responsive systems for pulsatile delivery of teriparatide and similar peptides.

Ensuring equitable access, engagement and ability of socially and ethnically diverse participants to benefit from health promotion programmes: a qualitative study with parent carers of disabled children.

Background: Equity is fundamental to health promotion programmes. However, unintentional or unseen barriers may exist for some underserved groups. We aimed to identify how to ensure equitable access and engagement for diverse parent carers of disabled children to benefit from health promotion programmes. Methods: We purposively sampled parent carers with potentially intersecting characteristics including those who self-identified as from ethnic groups, whose children were educated other than at school, with sensory impairments, or neurodiversity, and fathers. Participants were recruited through local and national organisations and parent carer networks. Data collection involved semi-structured individual interviews, which were transcribed verbatim and analysed thematically and iteratively alongside data collection. Core researchers performed early analysis independently, followed by research team and advisory group cross-validation. Results: Thirty-six parent carers with intersecting characteristics across the sampled backgrounds participated. We identified various perceived barriers around finding out about, attending and engaging with health programmes. We organised the findings into five themes focused on concepts capturing challenges and potential solutions to contextual barriers to access and participation in health programmes. (i) Reach-judiciously using targeted and universal strategies to ensure equitable distribution; (ii) Credibility-demonstrating trustworthiness of those advertising and/or delivering the programme; (iii) Opportunity-ensuring that the programme is seen as fulfilling a relevant need; (iv) Reservations-addressing barriers of readiness to participate; and (v) Optimisation-tailoring to improve the inclusivity of the programme delivery. Conclusion: We identified modifiable factors that impede members of some social groups from engaging with, and benefiting from, health promotion programmes, and potential solutions. We advocate a multifaceted approach is required from outreach to delivery, tailored to be mindful of extant diverse needs of parent carers in underserved communities. We catalogue key considerations to inform implementation strategies to optimise equity in health programmes for parent carers. The implications are likely transferable to other interventions and contexts.

Effect of Sarcobesity Index and Body Adipose Tissue Variables on Cardiopulmonary Exercise Testing Performance in Colorectal Surgery Setting: A Retrospective Cohort Study.

Aims/Background The prognostic significance of body composition variables has become a popular area of research over the recent years. This study aimed to determine whether adipose tissue variables and sarcobesity index measured by computed tomography (CT) could predict cardiopulmonary exercise testing (CPET) performance and long-term mortality in patients undergoing major colorectal surgery. Methods The Strengthening the Reporting of Cohort Studies in Surgery (STROCSS) statement standards were followed to conduct a retrospective cohort study of consecutive patients who had CPET prior to major colorectal surgery between January 2011 and January 2017. Receiver Operating Characteristic curve analysis was conducted to assess the discriminative performances of adipose tissue variables. The association between CT-derived adipose tissue variables (sarcobesity index, visceral adipose tissue, subcutaneous adipose tissue, and total adipose tissue) and CPET performance and mortality were assessed using regression analyses. Results 457 patients were included. Total adipose tissue evaluated via 2-dimensional (2D) and 3-dimensional (3D) approaches predicted oxygen uptake (V̇O2) Rest, V̇O2 anaerobic threshold (AT), ventilatory equivalents for carbon dioxide (V̇E/V̇CO2) AT, ventilatory equivalents for oxygen (V̇E/V̇O2) AT, V̇O2 peak, exercise time, maximum work, peak metabolic equivalents (METS), peak respiratory rate (RER), and peak oxygen pulse. Sarcobesity index (2D and 3D) predicted V̇O2 Rest, V̇O2 AT, V̇E/V̇CO2 AT, V̇O2 peak, maximum work, peak METS, maximum heart rate, and peak RER. Neither total adipose tissue nor sarcobesity index (2D and 3D) predicted 1-year, 3-year, or 5-year mortality. There was no difference in the discriminative performance of adipose tissue variables in predicting mortality. Conclusion The CPET performance may be predicted by radiologically measured adipose tissue variables and sarcobesity index. However, the prognostic value of the variables may not be significant in this setting.

Towards 'Formalising' WhatsApp Teledermatology Practice in KZ-N District Hospitals: Key Informant Interviews.

INTRODUCTION: District hospitals in KwaZulu-Natal Province, South Africa, do not have onsite specialist dermatology services. Doctors at these hospitals use WhatsApp instant messaging to informally seek advice from dermatologists and colleagues before possible referral. They have expressed the need to formalise WhatsApp teledermatology. AIM: To determine the views and perspectives of clinicians on the feasibility and practicality of formalising the current WhatsApp-based teledermatology activities within the KwaZulu-Natal Department of Health Dermatology Service. METHODS: Key informant interviews with 12 purposively selected doctors at district hospitals and all 14 dermatologists in the KwaZulu-Natal dermatology service. Their views and perspectives on formalising the current informal use of WhatsApp for teledermatology were recorded, transcribed, and thematically analysed. RESULTS: Five primary themes (communication, usability, utility, process, and poor understanding of legal, regulatory, and ethical issues) and 22 sub-themes were identified. Clinicians wanted WhatsApp teledermatology to continue, be formalised, and be incorporated within the KwaZulu-Natal Department of Health, facilitated by the provision of practical guidelines addressing legal, regulatory, and ethical issues. CONCLUSIONS: These findings will be used to develop a policy brief, providing recommendations and proposed guidelines for formalising the teledermatology service. The findings and methods will be relevant to similar circumstances in other countries.

Long-term outcomes following proton therapy for pediatric spinal low-grade glioma.

BACKGROUND: Due to its rarity, no standard treatment guidelines exist for pediatric spinal low-grade glioma (LGG-S). Proton therapy (PT) offers an attractive modality to minimize toxicity. Herein, we present the first published series of pediatric patients who received PT for progressive LGG-S. PROCEDURES: We identified eight consecutive patients with nonmetastatic LGG-S treated with PT. Cumulative incidence method was used to estimate local control (LC), freedom from distant metastases (FFDM), and freedom from progression (FFP). The Kaplan-Meier product limit method assessed overall survival (OS). Toxicity was assessed according to the Common Terminology Criteria for Adverse Events Version 5.0. RESULTS: Median age at diagnosis was 4 years. All patients underwent attempted resection and developed recurrence/progression prior to referral for PT, with median duration between initial surgery and PT of 4.4 years. Median age at the start of PT was 8 years. Most patients (n = 5) received PT as ≥third line treatment. Seven patients were treated with PT to the primary tumor. Most patients (n = 7) received between 45-50.4 CGE. Median follow up was 7.8 years. The 10-year estimates for LC, FFDM, FFP, and OS were 85, 88, 73, and 55%, respectively. One patient experienced malignant transformation and two developed pseudoprogression following PT. No pulmonary, gastrointestinal, or musculoskeletal toxicities were observed during or after PT. CONCLUSIONS: Despite negative selection bias our experience suggests PT for pediatric LGG-S offers long-term disease control with limited toxicity. The favorable therapeutic ratio of PT suggests it should be considered among first-line therapy in children with nonmetastatic, unresectable LGG-S.

Evaluating Scholastic Achievement in Pediatric Brain Tumor Survivors Compared With Healthy Controls.

PURPOSE: Radiation therapy (RT) causes cognitive deficits in pediatric brain tumor survivors (PBTS). Traditionally, this is measured using neuropsychological testing, which lack prediagnosis baseline and do not necessarily trigger action. This pilot project investigated a novel patient-centered outcome of scholastic performance using state-collected educational data. METHODS AND MATERIALS: We retrospectively analyzed scholastic achievements in children residing in Florida. Eligibility in the treatment group received brain-directed RT between 2007 and 2020 at our institution. Controls were matched at a 3:1 ratio by age, grade, district, and free or reduced lunch eligibility. The Florida Department of Education provided educational records for both groups. Generalized linear mixed-effects models were used to predict scholastic outcomes with covariates age, time (binary value of pre- or post-RT), treatment group, and the primary independent variable as the interaction term between time and treatment. Scholastic data were matched with institutional clinical data. RESULTS: A total of 50 PBTS and 150 matched controls were included for analysis. The median age of PBTS was 12, 12% identified as Black, and 18% identified as Hispanic. Fifty-two percent were eligible for free or reduced lunch. Forty percent received craniospinal irradiation, and 56% received chemotherapy. Post-RT PBTS had 21 times the odds of receiving accommodations (P = .006), twice the odds of being retained (P = .010), and 42% lower odds than controls receiving a passing mathematics score (P = .068). CONCLUSIONS: To our knowledge, this is the first American experience to successfully link individual scholastic and clinical data. Scholastic performance serves as a meaningful patient-centered outcome complementing the existing suite of neuropsychological testing.

A microtubule stability switch alters isolated vascular smooth muscle calcium flux in response to matrix rigidity.

During ageing, the extracellular matrix of the aortic wall becomes more rigid. In response, VSMCs generate enhanced contractile forces. Our previous findings demonstrate that VSMC volume is enhanced in response to increased matrix rigidity, but our understanding of mechanisms regulating this process remain incomplete. In this current study, we show that microtubule stability in VSMCs is reduced in response to enhanced matrix rigidity via piezo1-mediated Ca2+ influx. Moreover, VSMC volume and Ca2+ flux was regulated by microtubule dynamics; microtubule stabilising agents reduced both VSMC volume and Ca2+ flux on rigid hydrogels, whereas microtubule destabilising agents increased VSMC volume and Ca2+ flux on pliable hydrogels. Finally, we show that disruption of the microtubule deacetylase HDAC6 uncoupled these processes and increased K40 alpha tubulin acetylation, VSMC volume and Ca2+ flux on pliable hydrogels, but did not alter VSMC microtubule stability. These findings uncover a microtubule stability switch that controls VSMC volume by regulating Ca2+ flux. Together, these data demonstrate that manipulation of microtubule stability can modify VSMC response to matrix stiffness.

Experiences of families post treatment for childhood brain tumours during medical clinic consultations regarding health-related quality of life, unmet needs and communication barriers: A qualitative exploration.

BACKGROUND: Many studies highlight poor health-related quality of life (HRQoL) in children treated for brain tumours and their parents. However, little is known about the extent to which their informational, healthcare and communication needs regarding HRQoL are met during medical outpatient consultations. AIM: To explore the experiences of families regarding communication with physicians about HRQoL issues during consultations after treatment for childhood brain tumours. METHODS: Interviews were conducted with 18 families of children and adolescents aged 8-17 years after completion of brain tumour treatment. Participants had completed treatment within the last 5 years and were receiving regular outpatient follow-up care. Thematic analysis was undertaken using the Framework Method. RESULTS: Five main themes were identified: (i) unmet emotional and mental health needs; (ii) double protection; (iii) unmet information needs; (iv) communication barriers within consultations; and (v) finding a new normal. CONCLUSION: There was a need to improve communication between clinicians and these families, improve information provision, and overcome barriers to conversing with children within these outpatient consultations. Children and their parents should be supported to voice their current needs and concerns regarding their HRQoL. These findings will inform further development of the UK version of the 'KLIK' patient- and parent-reported outcome (PROM) portal.

Restoration of Strength in Polyamide Woven Glass Fiber Organosheets by Hot Pressing: Case Study of Impact and Compression after Impact.

Thermoplastic composite organosheets (OSs) are increasingly recognized as a viable solution for automotive and aerospace structures, offering a range of benefits including cost-effectiveness through high-rate production, lightweight design, impact resistance, formability, and recyclability. This study examines the impact response, post-impact strength evaluation, and hot-pressing repair effectiveness of woven glass fiber nylon composite OSs across varying impact energy levels. Experimental investigations involved subjecting composite specimens to impact at varying energy levels using a drop-tower test rig, followed by compression-after-impact (CAI) tests. The results underscore the exceptional damage tolerance and improved residual compressive strength of the OSs compared to traditional thermoset composites. This enhancement was primarily attributed to the matrix's ductility, which mitigated transverse crack propagation and significantly increased the amount of absorbed energy. To mitigate impact-induced damage, a localized hot-pressing repair approach was developed. This allowed to restore the post-impact strength of the OSs to pristine levels for impact energies below 40 J and by 83.6% for higher impact energies, when OS perforation was observed. The measured levels of post-repair strength demonstrate a successful restoration of OS strength over a wide range of impact energies, and despite limitations in achieving complete strength recovery above 40 J, hot-pressing repair emerges as a promising strategy for ensuring the longevity of thermoplastic composites through repairability.

Professional perspectives on facilitators and barriers for high quality provision of health, education and social care services to disabled children in England during the COVID-19 pandemic: a qualitative study.

OBJECTIVES: To understand how health, education and social care services for disabled children changed during the COVID-19 pandemic, what did or did not work well and what the impacts of service changes were on both professionals and families. DESIGN: Qualitative study using semistructured interviews. SETTING: Telephone and video call interviews and focus groups with professionals working in one of five local authority areas in England. PARTICIPANTS: 78 health, education and social care professionals working with children in one of five local authority areas in England. RESULTS: There was a significant disruption to services and reduced contact with families during the early stages of the pandemic; nevertheless, professionals were able to reflect on innovative ways they interacted with and sought to support and maintain health, education and social care provision to disabled children and their families. As waitlists have substantially increased, this and the longevity of the pandemic were perceived to have had negative consequences for staff health and well-being, the health and psychosocial outcomes of children and young people, and their parent carers. CONCLUSIONS: Key learning from this study for service recovery and planning for future emergencies is the need to be able to identify disabled children, classify their level of need and risk, assess the impact of loss of services and maintain clear communication across services to meet the needs of disabled children. Finally, services need to work collaboratively with families to develop child-centred care to strengthen resilience during service disruption.

Informing creation of the FEEDS Toolkit to support parent-delivered interventions for eating, drinking and swallowing difficulties in young children with neurodisability: intervention use by neurodevelopmental diagnosis and healthcare professional role.

BACKGROUND: The FEEDS (Focus on Early Eating, Drinking and Swallowing) study focused on interventions used to improve feeding for children with neurodisability and eating, drinking and swallowing difficulties (EDSD), and the outcomes viewed as important by healthcare professionals (HPs) and parent carers. The FEEDS Toolkit was created subsequently as an intervention decision aid to be used collaboratively by parent carers and HPs. This study aimed to inform on current intervention practices and influence toolkit design by ascertaining whether specific intervention use varied by a child's main diagnosis and by specific HP role. METHODS: FEEDS survey data were grouped by child's main diagnosis and HP role. Main diagnoses included autism spectrum disorder (ASD) n=183; Down syndrome (DS) n=69; cerebral palsy (CP) n=30). HPs included were speech and language therapists (SLT) n=131; occupational therapists (OT) n=63; physiotherapists (PT) n=57; paediatricians n=50; dieticians n=40; nurses n=32 and health visitors n=14. RESULTS: Most interventions were used commonly across diagnoses. However, some interventions were used more commonly with specific conditions, for example, positioning (CP 85%, DS 70%, ASD 23%, strategies/programmes aimed at changing behaviour at mealtimes (ASD 52%, CP 8%, DS 11%); visual supports (ASD 58%, CP 0%, DS 21%). HPs reported using a broad range of interventions, SLTs (mean=13.9), dieticians (12.3), OTs (12.7) and paediatricians (11.1). There was overlap between intervention use and HP role, for example, positioning (100% PT, 97% SLT, 94% OT, 73% paediatricians and 69% nurses). CONCLUSIONS: Interdisciplinary working is common when managing EDSD, with all HP types using multiple interventions. A child's main diagnosis does not substantially influence intervention use, and the individual context of each child requires consideration in intervention selection. Study findings have supported development of the FEEDS Toolkit for use in feeding services.

Structural insights into i-motif DNA structures in sequences from the insulin-linked polymorphic region.

The insulin-linked polymorphic region is a variable number of tandem repeats region of DNA in the promoter of the insulin gene that regulates transcription of insulin. This region is known to form the alternative DNA structures, i-motifs and G-quadruplexes. Individuals have different sequence variants of tandem repeats and although previous work investigated the effects of some variants on G-quadruplex formation, there is not a clear picture of the relationship between the sequence diversity, the DNA structures formed, and the functional effects on insulin gene expression. Here we show that different sequence variants of the insulin linked polymorphic region form different DNA structures in vitro. Additionally, reporter genes in cellulo indicate that insulin expression may change depending on which DNA structures form. We report the crystal structure and dynamics of an intramolecular i-motif, which reveal sequences within the loop regions forming additional stabilising interactions that are critical to formation of stable i-motif structures. The outcomes of this work reveal the detail in formation of stable i-motif DNA structures, with potential for rational based drug design for compounds to target i-motif DNA.

Nanoscale synchrotron x-ray analysis of intranuclear iron in melanised neurons of Parkinson's substantia nigra.

Neuromelanin-pigmented neurons of the substantia nigra are selectively lost during the progression of Parkinson's disease. These neurons accumulate iron in the disease state, and iron-mediated neuron damage is implicated in cell death. Animal models of Parkinson's have evidenced iron loading inside the nucleoli of nigral neurons, however the nature of intranuclear iron deposition in the melanised neurons of the human substantia nigra is not understood. Here, scanning transmission x-ray microscopy (STXM) is used to probe iron foci in relation to the surrounding ultrastructure in melanised neurons of human substantia nigra from a confirmed Parkinson's case. In addition to the expected neuromelanin-bound iron, iron deposits are also associated with the edge of the cell nucleolus. Speciation analysis confirms these deposits to be ferric (Fe3+) iron. The function of intranuclear iron in these cells remains unresolved, although both damaging and protective mechanisms are considered. This finding shows that STXM is a powerful label-free tool for the in situ, nanoscale chemical characterisation of both organic and inorganic intracellular components. Future applications are likely to shed new light on incompletely understood biochemical mechanisms, such as metal dysregulation and morphological changes to cell nucleoli, that are important in understanding the pathogenesis of Parkinson's.

'There was nothing, just absolute darkness': Understanding the needs of those caring for children and young people with complex neurodisability in a diverse UK context: A qualitative exploration in the ENCOMPASS study.

BACKGROUND: Children and young people (CYP) with complex neurodisability experience multiple physical, communication, educational and social challenges, which require complex packages of multidisciplinary care. Part of the holistic care required includes supporting the families and parents/caregivers. The aim of the wider study was to introduce a new programme ('Ubuntu') to parents/caregivers and healthcare professionals (HCPs) in order to test the feasibility and acceptability of the concept and content, with the goal of potential adaptation for the UK in mind. Data collection and analysis uncovered rich data on caregiving journeys, navigation of health services, and perceived service gaps. This paper focuses solely on these topics. Further papers will report on the feasibility and adaptation data. METHODS: Two rounds of semi-structured interviews were conducted with 12 caregivers of CYP with complex neurodisability and six HCPs from a variety of disciplines, recruited from a community child health service in London Borough of Newham, UK in 2020. The interviews included open-ended questions to explore caregiving journeys, experiences of navigating health services and perceived service gaps. Transcripts were analysed using a data-driven inductive thematic analysis. RESULTS: Three themes were identified that related to the aim of understanding caregivers' experiences and unmet needs relating to current service provision. These were (1) Caregiver Mental Health, (2) The Information Gap and (3) The Need for Holistic Support. Mental health difficulties were reported, particularly around the period of diagnosis. Priority needs included the provision of clear information about the diagnosis and services offered, opportunities to forge peer support networks and for services across the community to collaborate. CONCLUSIONS: The delivery of health services for CYP with neurodisability should encompass the broad needs of the family as well as meeting the clinical needs of the CYP.

Effect of Post-Cured through Thickness Reinforcement on Disbonding Behavior in Skin-Stringer Configuration.

An experimental investigation of interlaminar toughness for post-cured through-thickness reinforcement (PTTR) skin-stringer sub-element is presented. The improvement in the crack resistance capability of skin-stringer samples was shown through experimental testing and finite element analysis (FEA) modeling. The performance of PTTR was evaluated on a pristine and initial-disbond of the skin-stringer specimen. A macro-scale pin-spring modeling approach was employed in FEA using a non-linear spring to capture the pin failure under the mixed-mode load. The experimental results showed a 15.5% and 20.9% increase in strength for the pristine-PTTR and initial-disbond PTTR specimens, respectively. The modeling approach accurately represents the overall structural response of PTTR laminate, including stiffness, adhesive strength, crack extension scenarios and progressive pin failure modes. This modeling approach can be beneficial for designing damage-tolerant structures by exploring various PTTR arrangements for achieving improved structural responses.

What aspects of health and wellbeing are most important to parent carers of children with disabilities?

INTRODUCTION: Parent carers of children with special educational needs or disabilities are at risk of poorer health and wellbeing outcomes because of the distinct and challenging circumstances they face. Evaluations of interventions promoting the health of parent carers should focus on measuring the aspects of health and wellbeing which are most relevant to this group. As part of a programme of research on parent carer-focused interventions, this study aimed to understand which aspects of health and wellbeing are perceived by parent carers as most meaningful and important. METHODS: A qualitative study using semistructured online interviews was conducted. A purposive sample of parent carers was interviewed about relevant health and wellbeing outcomes. Transcripts were analysed thematically. RESULTS: Thirty parent carers were interviewed, 19 of whom had experienced a health-promoting intervention, either as participants (n = 14) or facilitators (n = 5). Three main themes were identified: 'self, identity and beliefs'; 'social connections and support' and 'health-promoting practices and outcomes.' Each theme encompassed the challenges participants faced, and the changes that helped them overcome these challenges. 'Self-identity' challenges focused on the overwhelming nature of the parental care role and the emotional impact of this. Changes were brought about by developing a positive mindset, increasing confidence, and reconnecting with aspects of their identity which were important to them before they became parent carers. Challenges related to 'social connections' reflected parent carers' isolation. Change was brought about through increased peer support and peer interactions. Parent carers experienced challenges in terms of 'health-promoting activities' because they lacked free time and experienced poor physical health. Changes were brought about by engagement in health-promoting activities of various kinds. CONCLUSION: Parent carers view health and wellbeing in terms of overcoming the common challenges they face as a group. These challenges reflect the ways in which their physiological and psychological needs are often unmet. Researchers interested in measuring parent carer health and wellbeing should consider the specific challenges this group face, as well as theoretical frameworks which can make sense of these challenges, such as self-determination theory. PATIENT OR PUBLIC CONTRIBUTION: Our team carries out patient and public involvement (PPI) through a Family Faculty group facilitated by a Family Involvement Co-ordinator (A. McD.) who is herself a parent carer. A study-specific PPI working group was established which included members of the Family Faculty. The PPI group advised on various aspects of the research as reported in the paper. The manuscript was co-authored by the team's Family Involvement Co-ordinator (A. McD.).

The WD Domain of Atg16l1 Crucial for LC3-Associated Phagocytosis Is Not Required for Preserving Skin Barrier Function in Mice.

The skin is a multifunctional organ, forming a barrier between the external and internal environment, thereby functioning as a safeguard against extrinsic factors. Autophagy has been implicated in epidermal differentiation and in preserving skin homeostasis. LC3-associated phagocytosis (LAP) uses some but not all components of autophagy. The Atg16l1 (Δ WD) mouse model lacks the WD40 domain required for LAP and has been widely used to study the effects of LAP deficiency and autophagy on tissue homeostasis and response to infection. In this study, the Δ WD model was used to study the relationship between LAP and skin homeostasis by determining whether LAP-deficient mice display a cutaneous phenotype. Skin histology of wild-type and Δ WD mice aged 1 year revealed minor morphological differences in the tail skin dermal layer. RT-qPCR and western blot analysis showed no differences in key keratin expression between genotypes. Skin barrier formation, assessed by dye permeation assays, demonstrated full and proper formation of the skin barrier at embryonic day 18.5 in both genotypes. Biomechanical analysis of the skin showed decreased skin elasticity in aged Δ WD but not wild-type mice. In summary, the LAP-deficient Δ WD mice displayed subtle alterations in dermal histology and age-related biomechanical changes.

Long-term outcomes following proton therapy for non-metastatic central nervous system germinoma in children and adolescents.

BACKGROUND/PURPOSE: Radiation is a key component in the treatment of central nervous system pure germinoma (PG) in children and adolescents. Proton therapy (PT) improves normal tissue sparing and potentially reduces adverse effects (AE). The aim of this study was to present the largest single institution experience utilizing PT for the management of PG. MATERIALS METHODS: We enrolled 35 non-metastatic patients with PG that were treated with PT at our institution between July 2007 - September 2021. Most received induction chemotherapy (n = 31, 89 %) and whole ventricular irradiation with an involved field boost (n = 29, 83 %). The most common total dose was 30 CGE (n = 18, 51.4 %). We utilized the cumulative incidence method to estimate local control (LC), freedom from distant metastases (FFDM), freedom from progression (FFP), and overall survival (OS). Treatment related toxicity was assessed per CTCAE version 5. RESULTS: Median follow-up was 6.2 years (range, 0.9---15.2). The 10-year Kaplan-Meier estimates for LC, FFDM, FFP, and OS were 100 %, 100 %, 100 %, and 94 % respectively. The most common AE were hearing impairment requiring hearing aids (n = 3), transient hypersomnia requiring medication (n = 3), and new onset endocrinopathy (n = 1). Of the 23 evaluable patients ≥ 18 years old at last follow-up, 8 were high school graduates/in college, 8 college graduates, and 7 others gainfully employed. CONCLUSIONS: When utilized in modern multimodality treatment of non-metastatic PG, the precise dosimetry of PT does not compromise disease control. Although serious radiation side effects are rare, the 100% cure rate supports further investigation into selective radiation dose and volume de-escalation.