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Background Cystic Fibrosis (CF) is a genetic life limiting disease that impacts upon quality of life. An aim of CF care is to preserve lung function, with physical activity (PA) being an important part of daily airway clearance. Ensuring children have opportunities to engage in PA at school should be an important part of their daily routine. It is important to gain parental perspectives on this, as they manage the daily care for their children. This study aims to explore parents’ perceptions of school-based PA for their children with CF. Methods Parents of children with CF (n = 10), from three regions of the UK (England, Wales and Northern Ireland) took part in online semi-structured interviews. Data were analysed using Interpretative Phenomenological Analysis (IPA). Results Although parents recognized the benefits of school-based PA for their children, systemic barriers in the school setting often inhibit daily PA for children with CF, including teachers’ misconceptions, emotional and physical barriers, and PA not being a priority. Conclusion Recommendations for practice have been developed to help engage children with CF in daily school-based PA in an inclusive way, with the hope of maintaining health outcomes for children with CF.

Introduction: During cloacal reconstruction, vaginal replacement with an intestinal graft is considered when native vagina does not reach the perineum. Risks include need for revision surgery, mucus production, colitis, and rarely dysplasia. Given these concerns, alternative vaginal reconstructive procedures are being considered. We present a novel case using AlloDerm for vaginal replacement in a female infant undergoing cloacal reconstruction. Case presentation: A 17-month-old female with a complex medical history including Stage 5 chronic kidney disease (CKD) underwent repair of a 4.5 cm cloaca via a posterior sagittal approach. Although the rectum was adequately mobilized off tension, the vagina remained 4 cm from the perineum when off tension. Because vaginal replacement using sigmoid colon would have required exploratory laparotomy in this medically complex child, decision was made to proceed with vaginoplasty using an AlloDerm graft. Two 2 × 4 cm pieces of AlloDermwere placed longitudinally to create the anterior and posterior vaginal walls. The lateral walls and surrounding fat were then secured and the introitus was created. Vaginoscopy was performed three months post-operatively and confirmed an intact graft approximately 2–3 cm long with a patent anastomosis to the native vagina. Conclusion: AlloDerm is an acellular tissue matrix that supports tissue regeneration. This is a promising vaginal replacement option for patients with cloaca who are not good candidates for a colonic vaginoplasty. Future studies are needed to assess long-term outcomes of this graft for prepubertal vaginoplasties.

Despite increasing access to higher education (HE) over the past two decades, students from disadvantaged backgrounds remain less likely to enter the most selective institutions, and less likely to achieve good outcomes. In England, providers that charge more than £6,000 a year tuition fees must have an Access and Participation Plan (APP) approved by the Office for Students (OfS). Plans aim to improve equality in student access, success, and progression. APPs typically focus on snapshots of equality gaps, inputs over outcomes, and individual institutions over collaborative efforts. These limitations encourage a “whack-a-mole” approach, reducing effectiveness of interventions. A more nuanced approach to evaluation is needed, together with increased and organized sector-wide collaboration, and acknowledgment of the dynamic operating context.

Oceanic islands are particularly vulnerable to the global decline of biological diversity, suffering disproportionally large losses of endemic species. A primary tool for mitigating species loss is the establishment of protected area networks. The 2030 Global Biodiversity Framework target calls for the protection of 30% of Earth’s land surface by 2030. This study identifies areas within the Tropical Important Plant Areas network of the British Virgin Islands (BVI), to better inform the expansion of the current protected area network with the objective of conserving the BVI’s unique flora. We identified and applied conservation targets for five threatened habitats and 34 species of conservation concern, including four endemic to the BVI. A total of 5,248 georeferenced plant records for the 34 species collected through decades of collaborative work between the National Parks Trust of the Virgin Islands and the Royal Botanical Gardens, Kew, along with the distribution of five threatened habitats were used within the decision support system MARXAN to identify four spatial portfolios to guide the expansion of the BVI’s current protected area network. Highlighting the need to expand the current (2007–2017) Protected Areas System Plan in the BVI, we found that the current Plan only covers 15% of terrestrial land and does not meet the conservation targets for plants and habitats. The portfolios identified in our analysis efficiently expand the current Protected Areas System Plan to strategically expand coverage for all conservation features, with two main portfolios reaching all defined conservation targets for protection. Notably, to evaluate options not requiring land purchase, we extracted areas within state-owned Crown land from two main identified portfolios and found that the two Crown land-portfolios could protect 28% and 23% of the BVI, respectively, while meeting the targets for most plants of conservation concern. However, to reach 30% land protection and meet the conservation targets for all plant species, including endemics, private land would need to be considered for this inclusion within the protected area network. Our results provide science-based guidance for the selection of candidate protected area expansion sites that include threatened plants and habitats for reaching the 2030 Biodiversity Framework targets. While systematic conservation planning can provide guidance on protected area expansion, it is important to evaluate and prioritise conservation actions, based on multiple solutions and available resources. We recommend similar approaches are applied more broadly throughout the Caribbean and other archipelagos across the world.

Background & aimsHepatoblastoma (HB) and hepatocellular carcinoma (HCC) are the predominant liver cancers in children, though their respective treatment options and associated outcomes differ dramatically. Risk stratification using a combination of clinical, histological, and molecular parameters can improve treatment selection, but it is particularly challenging for tumors with mixed histological features, including those in the recently created hepatocellular neoplasm not otherwise specified (HCN NOS) provisional category. We aimed to perform the first molecular characterization of clinically annotated cases of HCN NOS.MethodsWe tested whether these histological features are associated with genetic alterations, cancer gene dysregulation, and outcomes. Namely, we compared the molecular features of HCN NOS, including copy number alterations, mutations, and gene expression profiles, with those in other pediatric hepatocellular neoplasms, including HBs and HCCs, as well as HBs demonstrating focal atypia or pleomorphism (HB FPAs), and HBs diagnosed in older children (>8).ResultsMolecular profiles of HCN NOS and HB FPAs revealed common underlying biological features that were previously observed in HCCs. Consequently, we designated these tumor types collectively as HBs with HCC features (HBCs). These tumors were associated with high mutation rates (∼3 somatic mutations/Mb) and were enriched with mutations and alterations in key cancer genes and pathways. In addition, recurrent large-scale chromosomal gains, including gains of chromosomal arms 2q (80%), 6p (70%), and 20p (70%), were observed. Overall, HBCs were associated with poor clinical outcomes.ConclusionsOur study indicates that histological features seen in HBCs are associated with combined molecular features of HB and HCC, that HBCs are associated with poor outcomes irrespective of patient age, and that transplanted patients are more likely to have good outcomes than those treated with chemotherapy and surgery alone. These findings highlight the importance of molecular testing and early therapeutic intervention for aggressive childhood hepatocellular neoplasms.Lay summaryWe molecularly characterized a class of histologically aggressive childhood liver cancers and showed that these tumors are clinically aggressive and that their observed histological features are associated with underlying recurrent molecular features. We proposed a diagnostic algorithm to identify these cancers using a combination of histological and molecular features, and our analysis suggested that these cancers may benefit from specialized treatment strategies that may differ from treatment guidelines for other childhood liver cancers.

Abstract Clinical translation of AAV-mediated gene therapy requires preclinical development across different experimental models, often confounded by variable transduction efficiency. Here, we describe a human liver chimeric transgene-free Il2rg −/− /Rag2 −/− /Fah −/− /Aavr −/− (TIRFA) mouse model overcoming this translational roadblock, by combining liver humanization with AAV receptor (AAVR) ablation, rendering murine cells impermissive to AAV transduction. Using human liver chimeric TIRFA mice, we demonstrate increased transduction of clinically used AAV serotypes in primary human hepatocytes compared to humanized mice with wild-type AAVR. Further, we demonstrate AAV transduction in human teratoma-derived primary cells and liver cancer tissue, displaying the versatility of the humanized TIRFA mouse. From a mechanistic perspective, our results support the notion that AAVR functions as both an entry receptor and an intracellular receptor essential for transduction. The TIRFA mouse should allow prediction of AAV gene transfer efficiency and the study of AAV vector biology in a preclinical human setting.

Objective To estimate the cost-effectiveness of craniotomy, compared with decompressive craniectomy (DC) in UK patients undergoing evacuation of acute subdural haematoma (ASDH).Design Economic evaluation undertaken using health resource use and outcome data from the 12-month multicentre, pragmatic, parallel-group, randomised, Randomised Evaluation of Surgery with Craniectomy for Patients Undergoing Evacuation-ASDH trial.Setting UK secondary care.Participants 248 UK patients undergoing surgery for traumatic ASDH were randomised to craniotomy (N=126) or DC (N=122).Interventions Surgical evacuation via craniotomy (bone flap replaced) or DC (bone flap left out with a view to replace later: cranioplasty surgery).Main outcome measures In the base-case analysis, costs were estimated from a National Health Service and Personal Social Services perspective. Outcomes were assessed via the quality-adjusted life-years (QALY) derived from the EuroQoL 5-Dimension 5-Level questionnaire (cost-utility analysis) and the Extended Glasgow Outcome Scale (GOSE) (cost-effectiveness analysis). Multiple imputation and regression analyses were conducted to estimate the mean incremental cost and effect of craniotomy compared with DC. The most cost-effective option was selected, irrespective of the level of statistical significance as is argued by economists.Results In the cost-utility analysis, the mean incremental cost of craniotomy compared with DC was estimated to be −£5520 (95% CI −£18 060 to £7020) with a mean QALY gain of 0.093 (95% CI 0.029 to 0.156). In the cost-effectiveness analysis, the mean incremental cost was estimated to be −£4536 (95% CI −£17 374 to £8301) with an OR of 1.682 (95% CI 0.995 to 2.842) for a favourable outcome on the GOSE.Conclusions In a UK population with traumatic ASDH, craniotomy was estimated to be cost-effective compared with DC: craniotomy was estimated to have a lower mean cost, higher mean QALY gain and higher probability of a more favourable outcome on the GOSE (though not all estimated differences between the two approaches were statistically significant).Ethics Ethical approval for the trial was obtained from the North West—Haydock Research Ethics Committee in the UK on 17 July 2014 (14/NW/1076).Trial registration number ISRCTN87370545.

Extracellular matrix (ECM) stiffening is a common occurrence during the progression of many diseases, such as breast cancer. To accurately mimic the pathophysiological context of disease within 3D in vitro models, there is high demand for smart biomaterials which replicate the dynamic and temporal mechanical cues of diseased states. This study describes a preclinical disease model, using breast cancer as an example, which replicates the dynamic plasticity of the tumour microenvironment by incorporating temporal (3-week progression) biomechanical cues within a tissue-specific hydrogel microenvironment. The composite hydrogel formulation, integrating adipose-derived decellularised ECM (AdECM) and silk fibroin, was initially crosslinked using a visible light-mediated system, and then progressively stiffened through spontaneous secondary structure interactions inherent between the polymer chains (∼10–15 kPa increase, with a final stiffness of 25 kPa). When encapsulated and cultured in vitro, MCF-7 breast cancer cells initially formed numerous, large spheroids (>1000 μm2 in area), however, with progressive temporal stiffening, cells demonstrated growth arrest and underwent phenotypic changes resulting in intratumoral heterogeneity. Unlike widely-investigated static mechanical models, this stiffening hydrogel allowed for progressive phenotypic changes to be observed, and fostered the development of mature organoid-like spheroids, which mimicked both the organisation and acinar-structures of mature breast epithelium. The spheroids contained a central population of cells which expressed aggressive cellular programs, evidenced by increased fibronectin expression and reduction of E-cadherin. The phenotypic heterogeneity observed using this model is more reflective of physiological tumours, demonstrating the importance of establishing temporal cues within preclinical models in future work. Overall, the developed model demonstrated a novel strategy to uncouple ECM biomechanical properties from the cellular complexities of the disease microenvironment and offers the potential for wide applicability in other 3D in vitro disease models through addition of tissue-specific dECM materials.

Abstract Objective Hepatoblastoma (HB) is the most common primary hepatic malignancy in childhood. Relapse occurs in more than 50% of high‐risk patients with a high mortality due to ineffective salvage therapies. The purpose of this study is to identify risk factors for relapsed HB and predictors of survival in a single tertiary referral center. Methods A retrospective chart review showed 129 surgically treated HB patients from October 2004 to July 2020. Of the cohort, 22 patients presented with relapsed HB. Relapse was defined as re‐appearance of malignancy after 4 weeks of normalized AFP and disappearance of all tumors on imaging. Results Patients with relapsed HB had a 5‐year overall survival (OS) of 45.4% compared to 93.1% in those without relapse (p = 0.001). When comparing PRETEXT IV, microvascular invasion, metastatic disease, and age on multivariate logistic regression, only PRETEXT IV was an independent risk factor for relapsed HB with an OR of 2.39 (95% CI: 1.16–4.96; p = 0.019). Mixed epithelial and mesenchymal HB (12/19, 63.2%) was the most common histology of primary tumors while pure epithelial HB (13/15, 86.6%) was the most common relapsed histology. Combination of surgical and medical therapy for relapsed disease was predictive of survival with an HR of 16.3 (95% CI: 1.783–149.091; p = 0.013) compared to only chemotherapy. Conclusions This study demonstrates that PRETEXT IV staging is an independent predictor of relapsed disease. The most common relapsed histology was epithelial, suggesting a potential selection or resistance of this component. Surgical resection is a critical component of multimodal therapy for relapsed HB.

Plasmaspheric hiss waves at the Earth are well known for causing losses of electrons from the radiation belts through wave particle interactions. At Saturn, however, we show that the different plasma density environment leads to acceleration of the electrons rather than loss. The ratio of plasma frequency to electron gyrofrequency frequently falls below one creating conditions for hiss to accelerate electrons. The location of hiss at high latitudes (>25°) coincides very well with this region of very low density. The interaction between electrons and hiss only occurs at these higher latitudes, therefore the acceleration is limited to mid to low pitch angles leading to butterfly pitch angle distributions. The hiss is typically an order of magnitude stronger than chorus at Saturn and the resulting acceleration is rapid, approaching steady state in one day at 0.4 MeV at L = 7 and the effect is stronger with increasing L-shell.