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.

Axillary Surgery for Chemoresidual (ypN-Positive) Nodal Disease.

This cohort study using pooled data from 2 randomized clinical trials examines whether removing more lymph nodes with axillary lymph node dissection improved outcomes over sentinel lymph node biopsy when most patients received adjuvant radiation therapy or regional nodal irradiation.

Common Comorbidities in Patients with Remitting Seronegative and Symmetrical Synovitis with Pitting Edema (RS3PE).

OBJECTIVES: Remitting seronegative symmetrical synovitis with pitting edema (RS3PE) is considered a rare inflammatory rheumatologic disorder that is seen primarily in older adult men. Patients present with arthralgias of large joints accompanied by painful pitting edema of the hands and feet. Few studies have reported the prevalence of metabolic syndromes, including diabetes mellitus and hyperlipidemia in these patients. METHODS: This case series reviewed 25 patients who were diagnosed as having RS3PE in a private outpatient clinic. RESULTS: Nearly half of the patients (48%) had diabetes mellitus, predominantly type 2, and more than half of the patients (60%) had hyperlipidemia. CONCLUSIONS: We believe that future case studies on RS3PE should include an assessment of various comorbidities that can be seen in patients with this autoinflammatory disorder. The increased availability of musculoskeletal ultrasound provides a potential area of study to differentiate this disorder from other inflammatory arthritis and improve reaching the correct diagnosis.

Long-Term Outcomes Following Definitive or Adjuvant Proton Radiotherapy for Adenoid Cystic Carcinoma.

Purpose: Adenoid cystic carcinoma (ACC) is a rare malignancy accounting for 1% of all head and neck cancers. Treatment for ACC has its challenges and risks, yet few outcomes studies exist. We present long-term outcomes of patients with ACC of the head and neck treated with proton therapy (PT). Materials and Methods: Under an institutional review board-approved, single-institutional prospective outcomes registry, we reviewed the records of 56 patients with de novo, nonmetastatic ACC of the head and neck treated with PT with definitive (n = 9) or adjuvant PT (n = 47) from June 2007 to December 2021. The median dose to the primary site was 72.6 gray relative biological equivalent (range, 64-74.4) delivered as either once (n = 19) or twice (n = 37) daily treatments. Thirty patients received concurrent chemotherapy. Thirty-one patients received nodal radiation, 30 electively and 1 for nodal involvement. Results: With a median follow-up of 6.2 years (range, 0.9-14.7), the 5-year local-regional control (LRC), disease-free survival, cause-specific survival, and overall survival rates were 88%, 85%, 89%, and 89%, respectively. Intracranial extension (P = .003) and gross residual tumor (P = .0388) were factors associated with LRC rates. While the LRC rate for those with a gross total resection was 96%, those with subtotal resection or biopsy alone were 81% and 76%, respectively. The 5-year cumulative incidence of clinically significant grade ≥3 toxicity was 15%, and the crude incidence at the most recent follow-up was 23% (n = 13). Conclusion: This is the largest sample size with the longest median follow-up to date of patients with ACC treated with PT. PT can provide excellent disease control for ACC of the head and neck with acceptable toxicity. T4 disease, intracranial involvement, and gross residual disease at the time of PT following either biopsy or subtotal resection were significant prognostic features for worse outcomes.

The adverse inpatient medication event and frailty (AIME-frail) risk prediction model.

BACKGROUND: Medication harm affects between 5 and 15% of hospitalised patients, with approximately half of the harm events considered preventable through timely intervention. The Adverse Inpatient Medication Event (AIME) risk prediction model was previously developed to guide a systematic approach to patient prioritisation for targeted clinician review, but frailty was not tested as a candidate predictor variable. AIM: To evaluate the predictive performance of an updated AIME model, incorporating a measure of frailty, when applied to a new multisite cohort of hospitalised adult inpatients. METHODS: A retrospective cohort study was conducted at two tertiary Australian hospitals on patients discharged between 1st January and April 31, 2020. Data were extracted from electronic medical records (EMRs) and clinical coding databases. Medication harm was identified using ICD-10 Y-codes and confirmed by senior pharmacist review of medical records. The Hospital Frailty Risk Score (HFRS) was calculated for each patient. Logistic regression analysis was used to construct a modified AIME model. Candidate variables of the original AIME model, together with new variables including HFRS were tested. Performance of the final model was reported using area under the curve (AUC) and decision curve analysis (DCA). RESULTS: A total of 4089 patient admissions were included, with a mean age ± standard deviation (SD) of 64 years (±19 years), 2050 patients (50%) were males, and mean HFRS was 6.2 (±5.9). 184 patients (4.5%) experienced one or more medication harm events during hospitalisation. The new AIME-Frail risk model incorporated 5 of the original variables: length of stay (LOS), anti-psychotics, antiarrhythmics, immunosuppressants, and INR greater than 3, as well as 5 new variables: HFRS, anticoagulants, antibiotics, insulin, and opioid use. The AUC was 0.79 (95% CI: 0.76-0.83) which was superior to the original model (AUC = 0.70, 95% CI: 0.65-0.74) with a sensitivity of 69%, specificity of 81%, positive predictive value of 0.14 (95% CI: 0.10-0.17) and negative predictive value of 0.98 (95% CI: 0.97-0.99). The DCA identified the model as having potential clinical utility between the probability thresholds of 0.05-0.4. CONCLUSION: The inclusion of a frailty measure improved the predictive performance of the AIME model. Screening inpatients using the AIME-Frail tool could identify more patients at high-risk of medication harm who warrant timely clinician review.

Association between psoas major muscle mass and CPET performance and long-term survival following major colorectal surgery: A retrospective cohort study.

OBJECTIVES: To evaluate whether computed tomography (CT)-derived psoas major muscle measurements could predict preoperative cardiopulmonary exercise testing (CPET) performance and long-term mortality in patients undergoing major colorectal surgery and to compare predictive performance of psoas muscle measurements using 2D approach and 3D approach. METHODS: A retrospective cohort study compliant with STROCSS standards was conducted. Consecutive patients undergoing major colorectal surgery between January 2011 and January 2017 following CPET as part of their preoperative assessment were included. Regression analyses were modelled to investigate association between the CT-derived psoas major muscle mass variables [total psoas muscle area (TPMA), total psoas muscle volume (TPMV) and psoas muscle index (PMI)] and CPET performance and mortality (1-year and 5-year). Discriminative performances of the variables were evaluated using Receiver Operating Characteristic (ROC) curve analysis. RESULTS: A total of 457 eligible patients were included. The median TPMA and TPMV were 21 â€‹cm2 (IQR: 15-27) and 274 â€‹cm3 (IQR: 201-362), respectively. The median PMI measured via 2D and 3D approaches were 7 â€‹cm2/m2 (IQR: 6-9) and 99 â€‹cm3/m2 (IQR: 76-120), respectively. The risks of 1-year and 5-year mortality were 7.4% and 27.1%, respectively. Regression analyses showed TPMA, TPMV, and PMI can predict preoperative CPET performance and long-term mortality. However, ROC curve analyses showed no significant difference in predictive performance amongst TPMA, TPMV, and PMI. CONCLUSION: Radiologically-measured psoas muscle mass variables may predict preoperative CPET performance and may be helpful with informing more objective selection of patients for preoperative CPET and prehabilitation.

MAPT H2 haplotype and risk of Pick's disease in the Pick's disease International Consortium: a genetic association study.

BACKGROUND: Pick's disease is a rare and predominantly sporadic form of frontotemporal dementia that is classified as a primary tauopathy. Pick's disease is pathologically defined by the presence in the frontal and temporal lobes of Pick bodies, composed of hyperphosphorylated, three-repeat tau protein, encoded by the MAPT gene. MAPT has two distinct haplotypes, H1 and H2; the MAPT H1 haplotype is the major genetic risk factor for four-repeat tauopathies (eg, progressive supranuclear palsy and corticobasal degeneration), and the MAPT H2 haplotype is protective for these disorders. The primary aim of this study was to evaluate the association of MAPT H2 with Pick's disease risk, age at onset, and disease duration. METHODS: In this genetic association study, we used data from the Pick's disease International Consortium, which we established to enable collection of data from individuals with pathologically confirmed Pick's disease worldwide. For this analysis, we collected brain samples from individuals with pathologically confirmed Pick's disease from 35 sites (brainbanks and hospitals) in North America, Europe, and Australia between Jan 1, 2020, and Jan 31, 2023. Neurologically healthy controls were recruited from the Mayo Clinic (FL, USA, or MN, USA between March 1, 1998, and Sept 1, 2019). For the primary analysis, individuals were directly genotyped for the MAPT H1-H2 haplotype-defining variant rs8070723. In a secondary analysis, we genotyped and constructed the six-variant-defined (rs1467967-rs242557-rs3785883-rs2471738-rs8070723-rs7521) MAPT H1 subhaplotypes. Associations of MAPT variants and MAPT haplotypes with Pick's disease risk, age at onset, and disease duration were examined using logistic and linear regression models; odds ratios (ORs) and ß coefficients were estimated and correspond to each additional minor allele or each additional copy of the given haplotype. FINDINGS: We obtained brain samples from 338 people with pathologically confirmed Pick's disease (205 [61%] male and 133 [39%] female; 338 [100%] White) and 1312 neurologically healthy controls (611 [47%] male and 701 [53%] female; 1312 [100%] White). The MAPT H2 haplotype was associated with increased risk of Pick's disease compared with the H1 haplotype (OR 1·35 [95% CI 1·12 to 1·64], p=0·0021). MAPT H2 was not associated with age at onset (ß -0·54 [95% CI -1·94 to 0·87], p=0·45) or disease duration (ß 0·05 [-0·06 to 0·16], p=0·35). Although not significant after correcting for multiple testing, associations were observed at p less than 0·05: with risk of Pick's disease for the H1f subhaplotype (OR 0·11 [0·01 to 0·99], p=0·049); with age at onset for H1b (ß 2·66 [0·63 to 4·70], p=0·011), H1i (ß -3·66 [-6·83 to -0·48], p=0·025), and H1u (ß -5·25 [-10·42 to -0·07], p=0·048); and with disease duration for H1x (ß -0·57 [-1·07 to -0·07], p=0·026). INTERPRETATION: The Pick's disease International Consortium provides an opportunity to do large studies to enhance our understanding of the pathobiology of Pick's disease. This study shows that, in contrast to the decreased risk of four-repeat tauopathies, the MAPT H2 haplotype is associated with an increased risk of Pick's disease in people of European ancestry. This finding could inform development of isoform-related therapeutics for tauopathies. FUNDING: Wellcome Trust, Rotha Abraham Trust, Brain Research UK, the Dolby Fund, Dementia Research Institute (Medical Research Council), US National Institutes of Health, and the Mayo Clinic Foundation.

Designing a muon scattering scanner for nuclear debris measurement.

Removal of fuel debris is planned to start at Unit 2 of the Fukushima Daiichi Nuclear Power Plant. During the removal, it is desirable to distinguish fuel debris from radioactive wastes and to sort the fuel debris accordingly to the amounts of nuclear material contained. Muon scattering tomography invented at Los Alamos in the early 2000s is highly sensitivity to high-atomic-number materials such as uranium. A muon scanner to sort the debris is designed and currently in production. One of the challenges is to operate the muon scanner in the presence of high γ-ray radiations from the debris: muon-event-identification electronics and a muon-tracking algorithm in the presence of high γ-ray radiations were developed.

Interventions to improve continence for children and young people with neurodisability: a national survey of practitioner and family perspectives and experiences.

OBJECTIVE: Describe families' experiences of interventions to improve continence in children and young people with neurodisability, and health professionals' and school and social care staff's perspectives regarding factors affecting intervention use. DESIGN: Four online surveys were developed and advertised to parent carers, young people with neurodisability, health professionals and school and social care staff, via societies, charities, professional contacts, schools, local authorities, and national parent carer and family forums, who shared invitations with their networks. Survey questions explored: difficulties helping children and young people use interventions; acceptability of interventions and waiting times; ease of use and availability of interventions, and facilitators and barriers to improving continence. RESULTS: 1028 parent carers, 26 young people, 352 health professionals and 202 school and social care staff registered to participate. Completed surveys were received from 579 (56.3%) parent carers, 20 (77%) young people, 193 (54.8%) health professionals, and 119 (58.9%) school and social care staff. Common parent carer-reported difficulties in using interventions to help their children and young people to learn to use the toilet included their child's lack of understanding about what was required (reported by 337 of 556 (60.6%) parent carers who completed question) and their child's lack of willingness (343 of 556, 61.7%). Almost all (142 of 156, 91%) health professionals reported lack of funding and resources as barriers to provision of continence services. Many young people (14 of 19, 74%) were unhappy using toilet facilities while out and about. CONCLUSIONS: Perceptions that children lack understanding and willingness, and inadequate facilities impact the implementation of toileting interventions for children and young people with neurodisability. Greater understanding is needed for children to learn developmentally appropriate toileting skills. Further research is recommended around availability and acceptability of interventions to ensure quality of life is unaffected.

Outcomes following proton therapy for pediatric esthesioneuroblastoma.

BACKGROUND: Pediatric esthesioneuroblastoma (EN) can infiltrate skull base anatomy, presenting challenges due to high radiation doses and pediatric tissue sensitivity. This study reports outcomes of pediatric EN treated with proton radiotherapy (PT). PROCEDURE: Using an IRB-approved prospective outcomes registry, we evaluated patient, tumor, and treatment-related variables impacting disease control and toxicity in pediatric nonmetastatic EN treated with modern multimodality therapy, including PT. RESULTS: Fifteen consecutive patients (median age 16) comprising Kadish stage B (n = 2), C (n = 9), and D (n = 4) tumors were assessed, including six with intracranial involvement, four with cranial nerve deficits, and four with cervical lymphadenopathy. Before radiation, two had subtotal and 13 had gross total resections (endoscopic or craniofacial). Two underwent neck dissection. Eleven received chemotherapy before radiation (n = 5), concurrent with radiation (n = 4), or both (n = 2). Median total radiation dose (primary site) was 66 Gy/CGE for gross disease and 54 Gy/CGE (cobalt Gray equivalent) for microscopic disease. Median follow-up was 4.8 years. No patients were lost to follow-up. Five-year disease-free and overall survival rates were 86% (no local or regional recurrences). Two patients developed vertebral metastases and died. Two required a temporary feeding tube for oral mucositis/dysphagia. Late toxicities included symptomatic retinopathy, major reconstructive surgery, cataracts, chronic otitis media, chronic keratoconjunctivitis, hypothyroidism, and in-field basal cell skin cancer. CONCLUSIONS: A multimodality approach for pediatric EN results in excellent local control. Despite the moderate-dose PT, serious radiation toxicity was observed; further dose and target volume reductions may benefit select patients. Longer follow-up and comparative data from modern photon series are necessary to fully characterize any relative PT advantage.

Stereotactic Radiosurgery for Vestibular Schwannoma With Radiographic Brainstem Compression.

OBJECTIVE: The safety of single-treatment stereotactic radiosurgery (SRS) for vestibular schwannoma (VS) with radiographic evidence of brainstem compression but without motor deficit is controversial. Data on linear accelerator (linac)-based SRS in this setting are scarce. We address this with an outcomes report from an unselected series of patients with VS with radiographic brainstem compression treated with linac SRS. METHODS: We included 139 patients with unilateral VS (any size) with radiographic brainstem compression (all without serious brainstem neurological deficits). The SRS prescription dose was 12.5 Gy (single fraction) using 6MV linac-produced photon beams, delivered with a multiple arc technique. Inclusion criteria required at least 1 year of radiographic follow-up with magnetic resonance imaging. The primary endpoint was freedom from serious brainstem toxicity (≥grade 3 Common Terminology Criteria for Adverse Events v5); the secondary was freedom from enlargement (tumor progression or any requiring intervention). We assessed serious cranial nerve complications, excluding hearing loss, defined as Common Terminology Criteria for Adverse Events v5 grade 3 toxicity. RESULTS: Median magnetic resonance imaging follow-up time was 5 years, and median tumor size was 2.5 cm in greatest axial dimension and 5 ml in volume. The median brainstem D0.03 ml=12.6 Gy and median brainstem V10 Gy=0.4 ml. At 5 years, the actuarial freedom from serious brainstem toxicity was 100%, and freedom from tumor enlargement (requiring surgery and/or due to progression) was 90%. Severe facial nerve damage in patients without tumor enlargement was 0.9%. CONCLUSION: Linac-based SRS, as delivered in our series for VS with radiographic brainstem compression, is safe and effective.

Impact of Maximum Point Dose Within the Planning Target Volume on Local Control of Nonsmall Cell Lung Cancer Treated With Stereotactic Body Radiotherapy.

BACKGROUND: No consensus exists on the maximum dose delivered to the planning target volume (PTV) in the delivery of stereotactic body radiotherapy (SBRT) for primary lung cancer. We investigated whether higher biologically effective doses (BED) within the PTV were associated with improved tumor control. METHODS: We reviewed patients with early-stage, node-negative nonsmall cell lung cancer who received curative-intent SBRT between 2005 and 2018. We calculated the maximum BED (maxBED) within the PTV for all patients, analyzing outcomes using the cumulative incidence method and Fine-Gray test statistics to assess prognostic impact. RESULTS: We analyzed 171 patients (median age, 70.2; range, 43 to 90 y) with 181 lung nodules. Median follow-up was 2.7 years (range, 0.1 to 12 y) for all patients and 4.2 years (range, 0.2 to 8.4 y) for living patients. Median maximum tumor diameter was 1.9 cm (range, 0.7 to 5.6 cm). Patients received a prescription of 48 or 50 Gy in 4 or 5 fractions, respectively, except for one who received 60 Gy in 5 fractions. Median maxBED was 120 Gy (range, 101 to 171 Gy). There was no difference in the 3-year local control (LC) rate among patients treated with a maxBED<120 Gy versus ≥120 Gy ( P =0.83). CONCLUSIONS: No significant differences in LC were observed between patients with early-stage nonsmall cell lung cancer treated with SBRT in 4 or 5 fractions with a maxBED≥120 Gy. However, a higher maxBED trended toward improved LC rates, suggesting a maxBED threshold greater than 120 Gy may be needed to improve LC rates.

A cross-sectional survey of healthcare professionals supporting children and young people with epilepsy and their parents/carers: which topics are raised in clinical consultations and can healthcare professionals provide the support needed?

BACKGROUND AND PURPOSE: Children and young people (CYP) with epilepsy see healthcare professionals (HCPs) for management of their seizures but may require information, advice and support with a range of broader topics. The purpose of the survey was to identify from HCPs, which topics CYP with epilepsy and their parents/carers ask about other than seizure management, and how adequately HCPs feel able to support them with these topics. METHOD: A cross-sectional online survey was used to collect data. Adverts which included a link to the survey were shared via social media channels, professional networks and United Kingdom (UK)-based epilepsy networks. Eighty-eight HCPs in the UK (who worked with CYP with epilepsy and their parents/carers) completed the survey. Quantitative data are presented descriptively. Qualitative data (free-text responses) were reflexively thematically analysed. RESULTS: CYP with epilepsy and their parents/carers were reported to ask HCPs for information, advice and support about a range of topics, most commonly, cognition and mental health. CYP were reported as also frequently asking about aspects of their social life while parents/carers commonly asked about sleep. HCPs varied in how able they felt to adequately support families about these topics, as well as in their views about which resources could be most useful. Having insufficient time and a lack of suitable services and resources to refer to, or draw upon, were key barriers to HCPs being able to support CYP and their families. DISCUSSION: Findings highlight the broad array of topics CYP with epilepsy and their families are reported as seeking support for. HCPs identified gaps in services and their abilities to meet those needs. There appeared to be a mismatch between the support that families were seeking and the ability of HCPs to meet these needs. Findings have implications for how HCPs could best be supported to deal with topics raised by CYP and families in clinic, highlighting the potential usefulness of informational resources on key topics for HCPs, parents/carers and CYP.

Impact of mandated drug monitoring on opioid use during highly conformal radiotherapy for oropharynx cancer.

BACKGROUND: Prescription drug monitoring programs (PDMPs) have proliferated due to increasing opioid-related deaths. We evaluated acute opioid use changes for 64 patients treated with highly conformal radiotherapy (RT) following a state-mandated PDMP. METHODS: Patients receiving proton therapy (PT) (n=40), intensity-modulated RT (IMRT) (n=14), or both (n=10) were divided into preintervention (n=26) and postintervention cohorts (n=38); records were reviewed retrospectively under an institutional review board (IRB)-approved tracking protocol. Dosages prescribed during acute therapy (during RT-3 months post-RT) and patient-reported pain (Defense and Veterans Pain Rating Scale) were endpoints. Dosages were treated as responses in Chi-square tests (three-level ordinal response). RESULTS: Overall, 72% (n=46) received opioids; of which 22% (n=10) of all patients and 10% (n=2) of opioid-naive patients continued analgesic management 3 months post-RT. Median total doses were 975 and 1,025 morphine milligram equivalents (MME) in pre- and postintervention groups, with no significant differences in MME prescribed (P=0.8) or uncontrolled pain (P=0.3). Statistically significant factors were tonsil primaries (P<0.01) and alcohol use (P=0.02). Uncontrolled pain episodes during and post-RT did not vary per cohort (P=0.19). CONCLUSIONS: PDMP use was not associated with management changes in patient-reported acute pain during RT (IMRT or PT). Following highly conformal RT, few patients remained on narcotics 3 months post-RT.

Circadian misalignment increases 24-hour acylated ghrelin in chronic shift workers: a randomized crossover trial.

OBJECTIVE: Shift workers typically experience misalignment between their circadian system and behavioral/environmental cycles and have an increased risk for obesity. Experimental studies in non-shift workers have suggested that circadian misalignment can disrupt energy balance regulation. This study examined the impact of circadian misalignment in the most relevant population, i.e., chronic shift workers. METHODS: Seven healthy chronic night shift workers underwent a randomized crossover study with two 3-day laboratory protocols: a night work protocol including 12-hour inverted behavioral/environmental cycles (circadian misalignment) and a day work protocol (circadian alignment). RESULTS: Circadian misalignment led to a ~17% increase in 24-hour acylated ghrelin levels in the chronic shift workers (p = 0.009). Consistently, circadian misalignment resulted in ~14% higher hunger at breakfast in the night shift (p = 0.04). Circadian misalignment did not significantly change fasting and postprandial energy expenditure or respiratory exchange ratio (all p > 0.32). Unexpectedly, 24-hour behavioral activity levels were ~38% higher (p < 0.0001) during circadian misalignment, despite a concurrent increase in sleepiness (p = 0.03). CONCLUSIONS: These results reveal that circadian misalignment, while carefully controlling for dietary intake, increases acylated ghrelin in chronic shift workers. Further studies should test whether the observed acute effects of circadian misalignment in chronic shift workers contribute to their increased obesity risk in the long term.

Healthy Parent Carers: Acceptability and practicability of online delivery and learning through implementation by delivery partner organisations.

BACKGROUND: Parent carers of disabled children are at increased risk of physical and mental health problems. The Healthy Parent Carers (HPC) programme is a manualised peer-led group-based programme that aims to promote parent carer health and wellbeing. Previously, the programme had been delivered in person, with recruitment and delivery managed in a research context. This study explored implementation by two delivery partner organisations in the United Kingdom. Facilitator Training and Delivery Manuals were modified for online delivery using Zoom due to COVID-19. METHODS: The study methodology utilised the Replicating Effective Programs framework. A series of stakeholder workshops informed the development of the Implementation Logic Model and an Implementation Package. After delivering the programme, delivery partner organisations and facilitators participated in a workshop to discuss experiences of implementing the programme. A wider group of stakeholders, including commissioners, Parent Carer Forums and charity organisations representatives and researchers subsequently met to consider the sustainability and potential barriers to delivering the programme outside the research context. RESULTS: This study explored implementation by two delivery partner organisations in the United Kingdom that were able to recruit facilitators, who we trained, and they recruited participants and delivered the programme to parent carers in different localities using Zoom. The co-created Implementation Logic Model and Implementation Package were subsequently refined to enable the further roll-out of the programme with other delivery partner organisations. CONCLUSIONS: This study provides insight and understanding of how the HPC programme can be implemented sustainably outside of the research context. Further research will evaluate the effectiveness of the programme and refine the implementation processes. PATIENT AND PUBLIC CONTRIBUTION: Parent carers, delivery partner organisation staff and service commissioners were consulted on the design, delivery and reporting of the research.

Allied health professionals' views on important outcomes of children's elective lower limb orthopaedic surgery: a qualitative interview study to inform a core outcome set.

PURPOSE: A common methodological limitation of research that guides surgical procedure selection for children's elective lower limb orthopaedic surgeries is inconsistent outcome selection. Improving outcome consistency can be achieved through the development of a core outcome set (COS). The aim of this study is to identify which outcomes are considered important for children's elective lower limb orthopaedic surgeries by allied health professionals (AHPs) and explore why they select these outcomes, to inform a COS development project. METHODS: Online semi-structured interviews were conducted with relevant AHPs. Participants were selected using maximum variation purposive sampling; selection was based on profession and inpatient/outpatient role. The data set was analysed using an inductive and deductive approach to thematic analysis. RESULTS: Four physiotherapists, three orthotists, three prosthetists, and two occupational therapists were interviewed. Most identified outcomes of importance related to "activities and participation". From the data, we conceptualised that AHPs with effective multidisciplinary communication focused on child-centred outcomes, while clinicians with limited multidisciplinary teamwork focused on role-based outcomes. CONCLUSIONS: There is concurrence between outcomes identified as important in this study, and other qualitative studies in similar populations. These important outcomes were seldom measured in previous studies or in routine clinical practice.Implications for rehabilitationAllied health professionals (AHPs) prioritise activity and participation outcomes after children's elective lower limb orthopaedic surgery.It is important to the rehabilitation of children after elective lower limb orthopaedic surgery that all involved AHPs collaborate with the wider multidisciplinary team.Multidisciplinary team communication encourages collaborative outcome identification, and discourages role defined outcome focus.

Parent experience with ankle-foot orthoses for their young children with cerebral palsy: a qualitative study.

PURPOSE: This study explored the experiences of parents of young children with cerebral palsy who used Ankle-Foot Orthoses (AFOs). MATERIALS AND METHODS: Parents of children with cerebral palsy (n = 11; age range 2-6 years) who used solid or hinged AFOs participated. Interpretive Description, a qualitative methodological approach focused on the application of findings to clinical practice, was used. Semi-structured interviews were conducted, and themes were developed using thematic analysis. RESULTS: Four themes described parent experience with their children's AFOs: 1) "Hear what I am saying": Collaborative decision-making with families, 2) "Is my child going to be excluded because of AFOs?": Parent and child adjustment was a journey, 3) AFOs created financial and practical challenges, 4) The perceived benefits of AFO use. CONCLUSIONS: Adjusting to AFOs was a challenging and time-consuming process for parents and children, which may have resulted in lower frequency and duration of use than anticipated by clinicians. Clinicians must be aware of the physical and psychosocial adjustment process as children and families adapt over time and work with families to ensure AFO use is optimized and individualized.

IMPLICATIONS FOR REHABILITATIONClinical practice will be enhanced by understanding  parent experience with their children's receipt and use of Ankle-Foot Orthoses (AFOs).Clinicians should work with families to establish and monitor individualized wear-time schedules that align with family routines.Information about AFOs, including appearance and alternative clothing requirements, should be provided to families in advance of receiving AFOs.

Analysis of the Pediatric Radiotherapy Landscape in Mexico and a Subsequent Educational e-Contouring Intervention.

PURPOSE: Mexico and Central America have the highest childhood cancer incidence in the West. Pediatric-specific oncology knowledge contributes to the disparity. We sought to (1) determine the self-identified treatment patterns and needs of Mexican pediatric radiation oncologists and (2) pilot a workshop to improve contouring accuracy. MATERIALS AND METHODS: Partnering with local experts and the Sociedad Mexicana de Radioterapeutas (SOMERA), a 35-question survey was designed to ascertain pediatric radiotherapy capacity and distributed through the SOMERA listserv. The most challenging malignancies were selected for workshop. Participants received precontouring and postcontouring homework to assess improvement per the Dice metric. The Wilcoxon sign-rank test was used for comparative statistics. RESULTS: Ninety-four radiation oncologists attempted and 79 completed the survey. Forty-four (76%) felt comfortable treating a pediatric patient, and 36 (62%) were familiar with national protocols for pediatric treatment. Most had access to nutrition, rehabilitation, endocrinology, and anesthesia; 14% had access to fertility services and 27% to neurocognitive support; 11% noted no support, and only one respondent had child-life support. The postsurvey contouring workshop was conducted for high-grade glioma, medulloblastoma, and Hodgkin lymphoma. Significant improvements were seen in all target volumes. CONCLUSION: We present the first national survey of Mexico's pediatric radiotherapy capacity and Latin American e-contouring educational intervention with preworkshop and postworkshop Dice metrics, noting statistically significant improvement in all target volumes. Participation improved compared with prior experience through SOMERA partnership and Continuing Medical Education incentivization.

Efficacy and safety of vixotrigine in idiopathic or diabetes-associated painful small fibre neuropathy (CONVEY): a phase 2 placebo-controlled enriched-enrolment randomised withdrawal study.

Background: No pharmacological treatments are specifically indicated for painful small fibre neuropathy (SFN). CONVEY, a phase 2 enriched-enrolment study, evaluated the efficacy and safety of vixotrigine, a voltage- and use-dependent sodium channel blocker, in participants with idiopathic or diabetes-associated painful SFN. Methods: CONVEY was a phase 2, multicentre, placebo-controlled, double-blind (DB), enriched-enrolment, randomised withdrawal study. The study was conducted at 68 sites in 13 countries (Europe and Canada) between May 17, 2018, and April 12, 2021. Following a 4-week open-label period in which 265 adults with painful SFN (a mixture of large and small fibre neuropathy was not exclusionary) received oral vixotrigine 350 mg twice daily (BID), 123 participants (with a ≥30% reduction from baseline in average daily pain [ADP] score during the open-label period) were randomised 1:1:1 to receive 200 mg BID, 350 mg BID or placebo for a 12-week double-blind (DB) period. Primary endpoint was change from baseline in ADP at DB Week 12. Secondary endpoints included the proportion of participants with a ≥30% reduction from baseline in ADP and the proportion of Patient Global Impression of Pain (PGIC) responders at DB Week 12. Treatment-emergent adverse events (AEs) were monitored. Statistical significance was set at 0.10 (2-sided). The trial was registered on ClinicalTrials.gov (NCT03339336) and on ClinicalTrialsregister.eu (2017-000991-27). Findings: A statistically significant difference from placebo in least squares mean reduction in ADP score from baseline to DB Week 12 was observed with vixotrigine 200 mg BID (-0.85; SE, 0.43; 95% CI, -1.71 to 0.00; p = 0.050) but not 350 mg BID (-0.17; SE, 0.43; 95% CI, -1.01 to 0.68; p = 0.70). Numerically, but not statistically significantly, more participants who received vixotrigine vs placebo experienced a ≥30% ADP reduction from baseline (68.3-72.5% vs 52.5%), and only the 350 mg BID group had significantly more PGIC responders vs placebo (48.8% vs 30.0%; odds ratio = 2.60; 95% CI, 0.97-6.99; p = 0.058) at DB Week 12. AEs were mostly mild to moderate in the vixotrigine groups. The most common AEs (≥5% of vixotrigine-treated participants) in the DB 200 mg BID and 350 mg BID vixotrigine groups were falls, nasopharyngitis, muscle spasm, and urinary tract infection. Interpretation: In our study, vixotrigine 200 mg BID, but not 350 mg BID, met the primary endpoint; more vixotrigine-treated participants experienced a ≥30% reduction from baseline in ADP at DB Week 12. Vixotrigine (at both dosages) was well tolerated in participants with SFN. Funding: Biogen, Inc.