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Abstract Objective For treatment of medication-related osteonecrosis of the jaw, one proposed approach is the use of a topical agent to block entry of these medications in oral soft tissues. We tested the ability of phosphonoformic acid (PFA), an inhibitor of bisphosphonate entry through certain sodium-dependent phosphate contransporters (SLC20A1, 20A2, 34A1-3) as well as Dynasore, a macropinocytosis inhibitor, for their abilities to prevent zoledronate-induced (ZOL) death in human gingival fibroblasts (HGFs). Methodology MTT assay dose-response curves were performed to determine non-cytotoxic levels of both PFA and Dynasore. In the presence of 50 μM ZOL, optimized PFA and Dynasore doses were tested for their ability to restore HGF viability. To determine SLC expression in HGFs, total HGF RNA was subjected to quantitative real-time RT-PCR. Confocal fluorescence microscopy was employed to see if Dynasore inhibited macropinocytotic HGF entry of AF647-ZOL. Endosomal acidification in the presence of Dynasore was measured by live cell imaging utilizing LysoSensor Green DND-189. As a further test of Dynasore’s ability to interfere with ZOL-containing endosomal maturation, perinuclear localization of mature endosomes containing AF647-ZOL or TRITC-dextran as a control were assessed via confocal fluorescence microscopy with CellProfiler™ software analysis of the resulting photomicrographs. Results 0.5 mM PFA did not rescue HGFs from ZOL-induced viability loss at 72 hours while 10 and 30 μM geranylgeraniol did partially rescue. HGFs did not express the SLC transporters as compared to the expression in positive control tissues. 10 μM Dynasore completely prevented ZOL-induced viability loss. In the presence of Dynasore, AF647-ZOL and FITC-dextran co-localized in endosomes. Endosomal acidification was inhibited by Dynasore and perinuclear localization of both TRITC-dextran- and AF647-ZOL-containing endosomes was inhibited by 30 μM Dynasore. Conclusion Dynasore prevents ZOL-induced viability loss in HGFs by partially interfering with macropinocytosis and by inhibiting the endosomal maturation pathway thought to be needed for ZOL delivery to the cytoplasm.

Abstract High individual detection success enables precise estimates of density and the ability to monitor trends in abundance for wolverine and other low‐density species, information that is critical for the implementation and assessment of conservation measures. We evaluated a dataset that included six different wolverine capture–recapture studies over a large gradient in wolverine (Gulo gulo) density to provide recommendations for increasing detection. We examined factors related to bait station components, habitat, and seasonal timing. Accounting for variation in wolverine density and trap duration, our results suggest that bait stations setups having a run pole, frame, and camera to photograph unique ventral color patterns, in addition to hair snag devices, identify more individual wolverine than those without. The presence of snow is a habitat feature that also increases individual detection. Female detection rates were lower than male detection rates at the onset of the reproductive denning season in late February and early March compared with January and early February. We found latency to detection was independent of wolverine density, but greater in areas with human influence. Relatively high rates of genotyping success (55%) were predicted by even a single guard hair left at bait stations, while underfur required ~15 hairs for similar success. Longer sampling intervals reduced genotyping success in spring, more so for underfur than guard hair. Hair samples acquired from barbwire were of higher quality than those from either alligator clips or gun brushes. To improve individual detection for wolverine inventory and monitoring, we recommend deploying run pole setups in areas with low human disturbance that will retain snow into late spring. Extending the winter trapping effort into April and May could increase the chances of detecting denning females. Latency to detection suggests that traps should be active for more than a month, especially in human‐influenced areas, but genotyping success suggests that traps should also be cleared of hair samples at smaller intervals of a month or less, during late winter/spring.

Aims: The rate of day-case total knee arthroplasty (TKA) in the UK is currently approximately 0.5%. Reducing length of stay allows orthopaedic providers to improve efficiency, increase operative throughput, and tackle the rising demand for joint arthroplasty surgery and the COVID-19-related backlog. Here, we report safe delivery of day-case TKA in an NHS trust via inpatient wards with no additional resources. Methods: Day-case TKAs, defined as patients discharged on the same calendar day as surgery, were retrospectively reviewed with a minimum follow-up of six months. Analysis of hospital and primary care records was performed to determine readmission and reattendance rates. Telephone interviews were conducted to determine patient satisfaction. Results: Since 2016, 301/7350 TKAs (4.1%) in 290 patients at our institution were discharged on the day of surgery. Mean follow-up was 31.4 months (6.2 to 70.0). In all, 28 patients (9.3%) attended the emergency department or other acute care settings within 90 days of surgery, most often with wound concerns or leg swelling; six patients (2.0%) were readmitted. No patients underwent a subsequent revision procedure, and there were no periprosthetic infections. Two patients (0.7%) underwent secondary patella resurfacing, and one patient underwent arthroscopic arthrolysis after previous manipulation under anaesthetic (MUA). Three patients (1.0%) underwent MUA alone. Primary care consultation records, available for 206 patients, showed 16 patients (7.8%) contacted their general practitioner within two weeks postoperatively; two (1.0%) were referred to secondary care. Overall, 115/121 patients (95%) telephoned stated they would have day-case TKA again. Conclusion: Day-case TKA can be safely delivered in the NHS with no additional resources. We found low incidence of contact with primary and secondary care in the postoperative period, and high patient satisfaction. Cite this article: Bone Jt Open 2023;4(8):621–627.

Abstract Background Sudden acquired retinal degeneration syndrome (SARDS) is a common cause of irreversible blindness in dogs. It bears clinical resemblance to hypercortisolism, which can be associated with hypercoagulability. The role of hypercoagulability in dogs with SARDS is unknown. Objective Determine hemostatic profiles in dogs with SARDS. Animals Prospective pilot study: Dogs with a history of SARDS (n = 12). Prospective case‐control study: Dogs with recent onset of SARDS (n = 7) and age‐, breed‐, and sex‐matched controls (n = 7). Methods Prospective pilot study: We performed thromboelastography (TEG). Prospective case‐control study: Dogs had CBC, serum biochemistry, urinalysis, TEG, fibrinogen concentration, antithrombin activity, D‐dimers, thrombin‐antithrombin complexes, and optical platelet aggregometry performed. Results Prospective pilot study: 9/12 dogs with a history of SARDS were hypercoagulable with increased TEG G value and 2/3 had hyperfibrinogenemia. Case‐control study: All dogs with SARDS and 5/7 controls were hypercoagulable based on TEG G value. Dogs with SARDS had significantly higher G values (median, 12.7 kdynes/s; range, 11.2‐25.4; P = .04) and plasma fibrinogen concentration (median, 463 mg/dL; range, 391‐680; P

Purpose: The Australian Genomics Cardiovascular Disorders Flagship was a national multidisciplinary collaboration. It aimed to investigate the feasibility of genome sequencing (GS) and functional genomics to resolve variants of uncertain significance (VUS) in the clinical management of patients and families with cardiomyopathies, primary arrhythmias, and congenital heart disease (CHD). Methods: Between April 2019 and December 2021, 600 probands meeting cardiovascular disorder criteria from 17 cardiology and genetics clinics across Australia were enrolled in the Flagship and underwent GS. The Flagship adopted a tiered approach to GS analysis. Tier 1 analysis assessed genes with established clinical validity for each cardiovascular condition. Tier 2 analysis assessed lesser-evidenced research-based genes. Tier 3 analysis assessed the functional impact of VUS that remained after tier 1 and tier 2 analysis. Results: Overall, a pathogenic or likely pathogenic variant was identified in 41% of participants with a cardiomyopathy, 40% with an arrhythmia syndrome, and 15% with a familial CHD/CHD+Extra Cardiac Anomalies. A VUS outcome ranged from 13% for arrhythmias to 34% for CHD/CHD+Extra Cardiac Anomalies participants. Tier 2 research analysis identified a likely pathogenic/pathogenic variant for a further 15 participants and a VUS for an additional 15 participants. Conclusion: The Flagship successfully facilitated a model of care that harnesses clinical GS and functional genomics for the resolution of VUS in the clinical setting. This valuable data set can be used to inform clinical practice and facilitate research into the future.

Background & Aims: DNA methylation alterations may provide important insights into gene-environment interaction in cancer, aging, and complex diseases, such as inflammatory bowel disease (IBD). We aim first to determine whether the circulating DNA methylome in patients requiring surgery may predict Crohn’s disease (CD) recurrence following intestinal resection; and second to compare the circulating methylome seen in patients with established CD with that we had reported in a series of inception cohorts. Methods: TOPPIC was a placebo-controlled, randomized controlled trial of 6-mercaptopurine at 29 UK centers in patients with CD undergoing ileocolic resection between 2008 and 2012. Genomic DNA was extracted from whole blood samples from 229 of the 240 patients taken before intestinal surgery and analyzed using 450KHumanMethylation and Infinium Omni Express Exome arrays (Illumina, San Diego, CA). Coprimary objectives were to determine whether methylation alterations may predict clinical disease recurrence; and to assess whether the epigenetic alterations previously reported in newly diagnosed IBD were present in the patients with CD recruited into the TOPPIC study. Differential methylation and variance analysis was performed comparing patients with and without clinical evidence of recurrence. Secondary analyses included investigation of methylation associations with smoking, genotype (MeQTLs), and chronologic age. Validation of our previously published case-control observation of the methylome was performed using historical control data (CD, n = 123; Control, n = 198). Results: CD recurrence in patients following surgery is associated with 5 differentially methylated positions (Holm P < .05), including probes mapping to WHSC1 (P = 4.1 × 10-9, Holm P = .002) and EFNA3 (P = 4.9 × 10-8, Holm P = .02). Five differentially variable positions are demonstrated in the group of patients with evidence of disease recurrence including a probe mapping to MAD1L1 (P = 6.4 × 10-5). DNA methylation clock analyses demonstrated significant age acceleration in CD compared with control subjects (GrimAge + 2 years; 95% confidence interval, 1.2–2.7 years), with some evidence for accelerated aging in patients with CD with disease recurrence following surgery (GrimAge +1.04 years; 95% confidence interval, -0.04 to 2.22). Significant methylation differences between CD cases and control subjects were seen by comparing this cohort in conjunction with previously published control data, including validation of our previously described differentially methylated positions (RPS6KA2 P = 1.2 × 10-19, SBNO2 = 1.2 × 10-11) and regions (TXK [false discovery rate, P = 3.6 × 10-14], WRAP73 [false discovery rate, P = 1.9 × 10-9], VMP1 [false discovery rate, P = 1.7 × 10-7], and ITGB2 [false discovery rate, P = 1.4 × 10-7]). Conclusions: We demonstrate differential methylation and differentially variable methylation in patients developing clinical recurrence within 3 years of surgery. Moreover, we report replication of the CD-associated methylome, previously characterized only in adult and pediatric inception cohorts, in patients with medically refractory disease needing surgery.

Abstract The intestinal lamina propria contains a diverse network of fibroblasts that provide key support functions to cells within their local environment. Despite this, our understanding of the diversity, location and ontogeny of fibroblasts within and along the length of the intestine remains incomplete. Here we show that the small and large intestinal lamina propria contain similar fibroblast subsets that locate in specific anatomical niches. Nevertheless, we find that the transcriptional profile of similar fibroblast subsets differs markedly between the small intestine and colon suggesting region specific functions. We perform in vivo transplantation and lineage-tracing experiments to demonstrate that adult intestinal fibroblast subsets, smooth muscle cells and pericytes derive from Gli1-expressing precursors present in embryonic day 12.5 intestine. Trajectory analysis of single cell RNA-seq datasets of E12.5 and adult mesenchymal cells suggest that adult smooth muscle cells and fibroblasts derive from distinct embryonic intermediates and that adult fibroblast subsets develop in a linear trajectory from CD81+ fibroblasts. Finally, we provide evidence that colonic subepithelial PDGFRαhi fibroblasts comprise several functionally distinct populations that originate from an Fgfr2-expressing fibroblast intermediate. Our results provide insights into intestinal stromal cell diversity, location, function, and ontogeny, with implications for intestinal development and homeostasis.

Open educational resources (OER), including open textbooks, are free, adaptable learning resources. The integration of these materials in place of commercial textbooks allows for considerable financial savings for students and creates opportunities for more active and engaged learning. The growing interest in the use of OER at a Western Canadian university led to the chance to survey students for their feedback on using OER instead of traditional commercial textbooks. This paper focuses on the views of students in an introductory sociology course for which an instructor adopted an open textbook and otherwise left the course unchanged from when it was taught with a traditional textbook. In addition, completion rates for the offerings with the open textbook are compared to previous offerings with a commercial textbook.

Abstract Historical persecution of grizzly bears in North America reduced the species range by 55%. Today, dedicated recovery efforts and shifting societal perceptions have supported the recovery and expansion of grizzly bear populations in many areas. With increasing overlap between people and bears, conservation actions and scientific inquiry are now shifting efforts toward supporting coexistence with bears. Here, we assessed the demography and behavior of grizzly bears in a coexistence landscape in southeast British Columbia, Canada, where abundant grizzly bear populations occur among busy, human‐settled valleys. Between 2016 and 2022, we captured 76 individual grizzly bears and monitored their conflict behavior, survival, and reproduction for 160 animal‐years. The cause of death for 14 animals with a functioning collar was human–wildlife conflict (n = 6), road or rail collision (n = 6), unknown but human suspected (n = 1), and natural (n = 1). Subadult survival was the lowest recorded in North America, while adult survival was similar to other studies, suggesting an intense demographic filter for young animals. We estimate that human‐caused mortality is underreported in government databases by 65%, or for every recorded mortality, there are ~2 that go unreported. Reporting was especially low for road and rail mortalities. Grizzly bear mortality in the Elk Valley due to collisions and conflicts with people is an order of magnitude greater than elsewhere in British Columbia. Combining DNA‐ and collar‐based estimates of population growth, we show that grizzly bear abundance is stable due to source‐sink dynamics, whereby ~7 immigrant bears per year offset the high mortality rates in the area. Grizzly bears dispersing into the valley are often young and more conflict‐naïve, creating a conflict spiral that can be interrupted by reducing mortality of young animals. Creating a self‐sustaining population of bears in the Elk Valley that is not reliant on immigration will require targeted efforts to reduce or secure attractants on private property and strategies to minimize collisions with trains and vehicles.

Stable isotopes of animal tissue have been used to estimate diet for many consumer species and places, but the ability to assign contributions to all food items is limited by the number of tracers used, and the separation of the tracer data among the dietary sources. We tested whether we could detect caribou (Rangifer tarandus) in the diet of individual predators in southwest Canada, where caribou are endangered. The separation between caribou tissue and that of other common prey was minimal using C13 and N15 isotope ratios and our confidence in assigning the caribou diet fraction correctly was low despite testing several fractionation values and priors. We measured the concentration of a suite of elements in the tissue of lichen, large prey and predators to investigate whether we could use an elemental concentration as a diet tracer and better assign the caribou diet fraction, because several of these elements were known to be more abundant in lichen, a major food for caribou in winter. Strontium and cesium had higher concentrations, when normalized by a common salt (we chose calcium), in caribou tissue than the other prey species we measured; this was also true for strontium isotope ratios. The elemental tracers appeared to overestimate caribou in the diet however, we suggest that the addition of either cation could yield finer and more accurate estimates of diet for large terrestrial predators after further investigation. The addition of a strontium isotope ratio tracer to a diet investigation may be equally informative and require less pre-work, because one ratio (Sr87/Sr86) has already been well studied.

IntroductionDim light vision as assessed by proxy and clinical tools is commonly impaired in older humans and impacts quality of life. Although proxy visual assessment tools have been developed for dogs, it is unclear if they are sensitive enough to detect subtle visual dysfunction in older dogs. We sought to determine if a newly designed proxy visual function questionnaire could detect age-associated differences in visual behaviors in varying lighting conditions in dogs.MethodsA 27-item questionnaire (the dog variable lighting questionnaire, dogVLQ) was designed to assess visual behavior in dogs in different lighting settings. We conducted the dogVLQ, a previously validated visual function questionnaire the dog vision impairment score and performed light- and dark-adapted electroretinography (ERG) on a subset of dogs. Questionnaire scores were analyzed for dog age associations using correlation analysis.ResultsQuestionnaire responses from 235 dog owners were obtained (122 female, 112 male dogs), 79 of which underwent ERG (43 female, 36 male dogs). Bright light visual behavior was significantly associated with light-adapted bright flash ERG amplitudes, visual behavior in near darkness was associated with dark-adapted ERG amplitudes. The dogVLQ identified worse vision in older dogs in bright light, dim light, and darkness; predicted onset was younger for vision in near darkness. Older dogs had more difficulty navigating transitions between lighting conditions.DiscussionSubjective dog owner assessment of visual function associates with objective measurement of retinal function in dogs and supports reduced vision-mediated behaviors in older dogs.

Abstract Background Children’s interstitial and diffuse lung disease (chILD) is a complex heterogeneous group of lung disorders. Gene panel approaches have a reported diagnostic yield of ~ 12%. No data currently exist using trio exome sequencing as the standard diagnostic modality. We assessed the diagnostic utility of using trio exome sequencing in chILD. We prospectively enrolled children meeting specified clinical criteria between 2016 and 2020 from 16 Australian hospitals. Exome sequencing was performed with analysis of an initial gene panel followed by trio exome analysis. A subset of critically ill infants underwent ultra-rapid trio exome sequencing as first-line test. Results 36 patients [median (range) age 0.34 years (0.02–11.46); 11F] were recruited from multiple States and Territories. Five patients had clinically significant likely pathogenic/pathogenic variants (RARB, RPL15, CTCF, RFXANK, TBX4) and one patient had a variant of uncertain significance (VIP) suspected to contribute to their clinical phenotype, with VIP being a novel gene candidate. Conclusions Trio exomes (6/36; 16.7%) had a better diagnostic rate than gene panel (1/36; 2.8%), due to the ability to consider a broader range of underlying conditions. However, the aetiology of chILD in most cases remained undetermined, likely reflecting the interplay between low penetrant genetic and environmental factors.

Abstract Helicobacter (H.) pylori-induced gastritis is a risk factor for gastric cancer (GC). Deleted-in-liver-cancer-1 (DLC1/ARHGAP7) inhibits RHOA, a downstream mediator of virulence factor cytotoxin-A (CagA) signalling and driver of consensus-molecular-subtype-2 diffuse GC. DLC1 located to enterochromaffin-like and MIST1+ stem/chief cells in the stomach. DLC1+ cells were reduced in H. pylori gastritis and GC, and in mice infected with H. pylori. DLC1 positivity inversely correlated with tumour progression in patients. GC cells retained an N-terminal truncation variant DLC1v4 in contrast to full-length DLC1v1 in non-neoplastic tissues. H. pylori and CagA downregulated DLC1v1/4 promoter activities. DLC1v1/4 inhibited cell migration and counteracted CagA-driven stress phenotypes enforcing focal adhesion. CagA and DLC1 interacted via their N- and C-terminal domains, proposing that DLC1 protects against H. pylori by neutralising CagA. H. pylori-induced DLC1 loss is an early molecular event, which makes it a potential marker or target for subtype-aware cancer prevention or therapy.

IntroductionColorectal cancer (CRC) is a leading cause of death worldwide and its growth can either be promoted or inhibited by the metabolic activities of intestinal microbiota. Short chain fatty acids (SCFAs) are microbial metabolites with potent immunoregulatory properties yet there is a poor understanding of how they directly regulate immune modulating pathways within the CRC cells.MethodsWe used engineered CRC cell lines, primary organoid cultures, orthotopic in vivo models, and patient CRC samples to investigate how SCFA treatment of CRC cells regulates their ability to activate CD8+ T cells.ResultsCRC cells treated with SCFAs induced much greater activation of CD8+ T cells than untreated CRC cells. CRCs exhibiting microsatellite instability (MSI) due to inactivation of DNA mismatch repair were much more sensitive to SCFAs and induced much greater CD8+ T cell activation than chromosomally instable (CIN) CRCs with intact DNA repair, indicating a subtype-dependent response to SCFAs. This was due to SCFA-induced DNA damage that triggered upregulation of chemokine, MHCI, and antigen processing or presenting genes. This response was further potentiated by a positive feedback loop between the stimulated CRC cells and activated CD8+ T cells in the tumor microenvironment. The initiating mechanism in the CRCs was inhibition of histone deacetylation by the SCFAs that triggered genetic instability and led to an overall upregulation of genes associated with SCFA signaling and chromatin regulation. Similar gene expression patterns were found in human MSI CRC samples and in orthotopically grown MSI CRCs independent of the amount of SCFA producing bacteria in the intestine.DiscussionMSI CRCs are widely known to be more immunogenic than CIN CRCs and have a much better prognosis. Our findings indicate that a greater sensitivity to microbially produced SCFAs contributes to the successful activation of CD8+ T cells by MSI CRCs, thereby identifying a mechanism that could be therapeutically targeted to improve antitumor immunity in CIN CRCs.

BackgroundUp to 6 years after the 2011 Christchurch earthquakes, approximately one-third of parents in the Christchurch region reported difficulties managing the continuously high levels of distress their children were experiencing. In response, an app named Kākano was co-designed with parents to help them better support their children’s mental health. ObjectiveThe objective of this study was to evaluate the acceptability, feasibility, and effectiveness of Kākano, a mobile parenting app to increase parental confidence in supporting children struggling with their mental health. MethodsA cluster-randomized delayed access controlled trial was carried out in the Christchurch region between July 2019 and January 2020. Parents were recruited through schools and block randomized to receive immediate or delayed access to Kākano. Participants were given access to the Kākano app for 4 weeks and encouraged to use it weekly. Web-based pre- and postintervention measurements were undertaken. ResultsA total of 231 participants enrolled in the Kākano trial, with 205 (88.7%) participants completing baseline measures and being randomized (101 in the intervention group and 104 in the delayed access control group). Of these, 41 (20%) provided full outcome data, of which 19 (18.2%) were for delayed access and 21 (20.8%) were for the immediate Kākano intervention. Among those retained in the trial, there was a significant difference in the mean change between groups favoring Kākano in the brief parenting assessment (F1,39=7, P=.012) but not in the Short Warwick-Edinburgh Mental Well-being Scale (F1,39=2.9, P=.099), parenting self-efficacy (F1,39=0.1, P=.805), family cohesion (F1,39=0.4, P=.538), or parenting sense of confidence (F1,40=0.6, P=.457). Waitlisted participants who completed the app after the waitlist period showed similar trends for the outcome measures with significant changes in the brief assessment of parenting and the Short Warwick-Edinburgh Mental Well-being Scale. No relationship between the level of app usage and outcome was found. Although the app was designed with parents, the low rate of completion of the trial was disappointing. ConclusionsKākano is an app co-designed with parents to help manage their children’s mental health. There was a high rate of attrition, as is often seen in digital health interventions. However, for those who did complete the intervention, there was some indication of improved parental well-being and self-assessed parenting. Preliminary indications from this trial show that Kākano has promising acceptability, feasibility, and effectiveness, but further investigation is warranted. Trial RegistrationAustralia New Zealand Clinical Trials Registry ACTRN12619001040156; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=377824&isReview=true

Introduction: Active Breathing Control (ABC) is a motion management strategy that facilitates reproducible breath-hold for thoracic radiotherapy (RT), which may reduce radiation dose to organs at risk (OARs). Reduction of radiation-induced toxicity is of high importance in younger patients. However, there is little published literature on the feasibility of ABC in this group. The purpose of this study was to report our experience of using ABC for paediatric and teenage patients. Methods: Patients ≤18 years referred for thoracic RT using ABC at our centre from 2013–2021 were identified. Electronic records were retrospectively reviewed to obtain information on diagnosis, RT dose and technique, OAR dosimetry, tolerability of ABC, post-treatment imaging and early toxicity rates. Results: 12 patients completed RT and were able to comply with ABC during planning and for the duration of RT. Median age was 15.5 years (10–18 years). Diagnoses were: Hodgkin lymphoma (n = 5), mediastinal B-cell lymphoma (n = 1), Ewing sarcoma (n = 5) and rhabdomyosarcoma (n = 1). For mediastinal RT cases (n = 6), median dose delivered was 30.6Gy(19.8–40Gy), median mean heart dose was 11.4Gy(4.8–19.4Gy), median mean lung dose was 9.9Gy(5.7–14.5Gy) and mean lung V20 was 10.9%. For ipsilateral RT cases, (n = 6), median hemithorax and total doses to primary tumour were 18Gy(15–20Gy) and 52.2Gy(36–60Gy) respectively. Median mean heart dose was 19.5Gy(10.6–33.2Gy) and median mean lung dose was 17.7Gy(16.3–30.5Gy). Mean bilateral lung V20 was 39.6%. Median mean contralateral lung dose was 5.2Gy(3.5–11.6Gy) and mean contralateral lung V20 was 1.5%. At a median follow-up of 36 months, only 1 patient had symptomatic radiation pneumonitis having received further thoracic RT following relapse. Conclusions: ABC is feasible and well tolerated in younger patients receiving RT. Children as young as 10 years are able to comply. Use of ABC results in OAR dosimetry which is comparable to similar data in adults and can facilitate RT for extensive thoracic sarcoma

Abstract Addressing threats to biodiversity from pest species is a global challenge. One such challenge is to mitigate the impact of an overabundant Australian songbird, the noisy miner Manorina melanocephala, on woodland birds. The overabundance of noisy miners is listed as a key threatening process under federal biodiversity legislation, but current understanding of where and how noisy miner populations can be managed to yield conservation benefits is unclear. We evaluated the effectiveness of noisy miner removal across 12 treatment areas totaling 3913 ha and nine control areas totaling 1487 ha important for the critically endangered regent honeyeater Anthochaera phrygia. Removal of noisy miners significantly reduced their densities in all but one of the treatment areas. In 10 of the 12 treatment areas, noisy miner densities remained below an impact threshold of 0.65–0.83 birds ha−1 for at least 3 to more than 12 months. The percentage of suitable noisy miner habitat in the surrounding landscape was not a strong predictor of noisy miner management success. Regent honeyeaters occupied six treatment areas, nesting successfully in four. The abundance of other songbirds increased post‐miner removal in seven areas, decreased in three, and was mixed in two. Data from the control areas showed some variation in songbird numbers was independent of noisy miner management. We conclude that noisy miners can be managed in areas of high conservation value for a minimum cost of AUD $10 ha−1. Larger treatment areas may be more important than the broader landscape context in maintaining long‐term noisy miner suppression. Standardized, long‐term monitoring is crucial to identify not only the drivers of pest species recolonization but also locations where threats from pests on endangered species can be addressed effectively while minimizing animal welfare and financial costs.

The expected outcome after a scaffold augmented hernia repair is the regeneration of a tissue composition strong enough to sustain biomechanical function over long periods. It is hypothesised that melt electrowriting (MEW) medical-grade polycaprolactone (mPCL) scaffolds loaded with platelet-rich plasma (PRP) will enhance soft tissue regeneration in fascial defects in abdominal and vaginal sheep models. A pre-clinical evaluation of vaginal and abdominal hernia reconstruction using mPCL mesh scaffolds and polypropylene (PP) meshes was undertaken using an ovine model. Each sheep was implanted with both a PP mesh (control group), and a mPCL mesh loaded with PRP (experimental group) in both abdominal and vaginal sites. Mechanical properties of the tissue-mesh complexes were assessed with plunger tests. Tissue responses to the implanted meshes were evaluated via histology, immunohistochemistry and histomorphometry. At 6 months post-surgery, the mPCL mesh was less stiff than the PP mesh, but stiffer than the native tissue, while showing equitable collagen and vascular ingrowth when compared to PP mesh. The results of this pilot study were supportive of mPCL as a safe and effective biodegradable scaffold for hernia and vaginal prolapse repair, hence a full-scale long-term study (over 24–36 months) with an adequate sample size is recommended.

The poverty-related attainment gap is an internationally recognised problem. It resides within a culture of performativity in which international comparators, underpinned by neo-liberal ideology, drive national policy. This conceptual paper interrogates the relationship between poverty, attainment and children's mental health and wellbeing to inform public policy and practice in Scotland and beyond. A key theme identified from the analysis of the literature is the nature, quality and strength of social and support networks around schools, families and children. This is contextualised within a discussion of the nature of childhood poverty and mental health in children in Scotland and the response of the Scottish Government. A focus on educational policy and schools alone will not in itself address the poverty-related attainment gap. What is required is a holistic focus on public policy, informed by interdisciplinary research, and a focus on building a strong infrastructure of support around schools, families and communities.

This article discusses how we are living through unprecedented times and times which will test leadership capacities at all levels of the system to the full. This crisis needs to be understood from a global perspective and within broader social parameters--the quest for social justice, amongst other imperatives. This article discusses why it is important to recognise that COVID-19 restrictions were experienced differentially by children and young people (CYP) and that it presents not only as a time of challenge but also as a time of opportunity and for learning. Leadership programmes, and headship programmes in particular, have always stressed the need for emotionally intelligent leaders. The pandemic has provided an opportunity to stand back, take stock, to identify what is really important to the school community, and to consider what can be learned and built upon in the future.

Introduction Pacific people have an increased risk of hospitalisation if barriers to immunisation against vaccine-preventable diseases are not reduced. This research sought to determine what is known about the barriers to immunisations in Pacific people living in New Zealand and identify ways to reduce these barriers and inform health care. Aim To identify the barriers to immunisation for Pasifika and to identify ways to reduce these barriers and inform health care. Methods An integrative review was undertaken with databases searched for articles published between February 2021 and May 2021. The review follows the five-stage process of problem formulation; literature search; evaluation of data; data analysis and interpretation; and presentation of the results through discussion. Results Twelve studies were included. Three themes were identified: Deprivation, Health Literacy (which covered understanding the importance of immunisation programmes, attitudes and beliefs and communication), and access to health care (including communication accessibility to health professionals and physical access). Discussion This review has identified that barriers such as level of deprivation strongly influences immunisation uptake in Pacific people. The significance of government-led initiatives was shown to improve the rates of immunisation of Pacific children. Pacific people’s awareness of immunisation programmes and government campaigns are encouraged to incorporate ethnic-specific strategies in addressing barriers, such as bringing vaccinations to where Pacific people frequent, including churches, community hubs, and venues that parents can easily access.

Background: Posterior bleeds account for 5% of epistaxis. The patient cohort is often elderly and has significant co-morbidities. Such cases have been managed historically with urinary catheters, held in place with umbilical clips. Recently bespoke, double balloon, posterior packs have been utilised. The treatments remain in clinical equipoise with no gold standard or clear national guideline. Methodology: A ten question survey was sent out through www.surveymonkey.com. Attempts were made to contact all Trusts in the United Kingdom via the ENT on call service. A comparison of treatment costs was made. Results: 112 responses have been received. 54% of respondents reported a preference for bespoke posterior pack insertion, only 12% preferred catheters. Twice as many respondents have seen complications from urinary catheters: 14% vs 29%. The availability of posterior packs is inconsistent: 30% of respondents were not aware of the packs or reported them unavailable in their hospital. Conclusions: This survey provides the first comparison of the techniques in the United Kingdom. Bespoke packs have a lower complication rate and are preferred by ENT clinicians on the front line of patient care. We recommend that all UK trusts should stock posterior packs which should be used as first line treatment for cases of posterior epistaxis.

[This corrects the article DOI: 10.1371/journal.pone.0015730.].

The ball valve effect occurs when an obstructing lesion allows inspiration of air, but opposes the egression of exhaled air, causing gas trapping. The phenomenon is commonly described secondary to bronchial foreign body inhalation. However, it is less well reported in other disease processes. We report a unique case of a carcinoid tumour causing ball valving following diagnostic bronchoscopy in a young patient. The procedure caused swelling and oedema around an isolated carcinoid tumour in the left main bronchus. An inspiratory chest X-ray was normal, complicating the diagnosis. At repeat bronchoscopy the tumour was cored with LASER.

Limited information exists on mercury concentrations and environmental drivers of mercury bioaccumulation in high latitude terrestrial carnivores. Spatial patterns of mercury concentrations in wolverine (Gulo gulo, n = 419) were assessed across a 1,600,000 km2 study area in relation to landscape, climate, diet and biological factors in Arctic and boreal biomes of western Canada. Hydrogen stable isotope ratios were measured in wolverine hair from a subset of 80 animals to assess the spatial scale for characterizing environmental conditions of their habitat. Habitat characteristics were determined using GIS methods and raster datasets at two scales, the collection location point and a 150 km radius buffer, which was selected based on results of a correlation analysis between hydrogen stable isotopes in precipitation and wolverine hair. Total mercury concentrations in wolverine muscle ranged >2 orders of magnitude from 0.01 to 5.72 μg/g dry weight and varied geographically, with the highest concentrations in the Northwest Territories followed by Nunavut and Yukon. Regression models at both spatial scales indicated diet (based on nitrogen stable isotope ratios) was the strongest explanatory variable of mercury concentrations in wolverine, with smaller though statistically significant contributions from landscape variables (soil organic carbon, percent cover of wet area, percent cover of perennial snow-ice) and distance to the Arctic Ocean coast. The carbon and nitrogen stable isotope ratios of wolverine muscle suggested greater mercury bioaccumulation could be associated with feeding on marine biota in coastal habitats. Landscape variables identified in the modelling may reflect habitat conditions which support enhanced methylmercury transfer to terrestrial biota. Spatially-explicit estimates of wet atmospheric deposition were positively correlated with wolverine mercury concentrations but this variable was not selected in the final regression models. These landscape patterns provide a basis for further research on underlying processes enhancing methylmercury uptake in high latitude terrestrial food webs.

The poverty-related attainment gap is an internationally recognised problem. There is growing recognition that it cannot either be understood or addressed without taking cognisance of children's mental health and wellbeing. The focus of this conceptual article is to examine the impact of social inequality and poverty on the mental health and wellbeing and attainment of children and young people in Scotland through the lens of resilience. While not a 'state of the art' literature review, a systematic approach was adopted in the selection of the literature and in the identification of themes to emerge from it. A range of risk and protective factors at the individual, social, societal and political levels emerged as impacting on the mental health and wellbeing and attainment of children living in poverty, and three important mediating variables are the negative impact of social stratification and adverse childhood experiences and the positive impact of a supportive adult. Schools alone cannot solve the problem. The findings revealed that there is a need to build a strong infrastructure around families and schools and to examine how economic, social, health and educational policy interact with each other as a starting point in addressing the problem, supported by inter-disciplinary research.

عنى هذا البحثُ بوصف نماذج مختارة من البُرد والبديعيَّات وتحليلها ومقارنتها, إذ حدَّد الباحثان مشكلة البحث بالسؤالين الرئيسين: هل تجلت الصورة البصرية في البُرد والبديعيَّات؟ وما هو الفرق الدلالي بينهما ؟ والاجابة عن هذين السؤالين هي اجراءات البحث. وجاءت أهمية البحث والحاجة اليه في النقاط التالية : أنْ يكون لبنة إضافية إلى المكتبة النقدية في معالجة ظاهرة بلاغية مائزة وردت في النصوص الشعرية المتعلقة بالبُرد والبديعيَّات. تتبع تلك المظاهر الدلالية في البُرد والبديعيَّات . البحث عن تمايز دلالة البُرد والبديعيَّات. تزويد المكتبة العربية أو الساحة الثقافية العربية بتطلعات وصفية تحليلية في البُرد والبديعيَّات. أهداف البحث: 1- الوقوف على دلالة الصور البصرية الَّتي تجلت في البُرد والبديعيَّات. 2- الكشف عن الإزاحة الابداعية لكلِّ من البُرد والبديعيَّات. حدود البحث : (الزمانية) العصر القديم والحديث. ( المكانية) نصوص البُرد والبديعيَّات ودراساتهما. منهجية البحث: اتبع الباحثان منهجين هما الوصف التحليلي والمنهج الموازن للوصول الى نتائج البحث في هذا الاتجاه. وبعدها حدَّد الباحثان بعض المصطلحات الَّتي استعملت في متن البحث للوقوف على مدلولها الاجرائي. امَّا المبحث الثاني: فقد حدد الباحثان المادة الأولية للتكوين الصوري للبُرد والبديعيَّات, وتحدث عن ماهية الصورة واشتراطاتها المجازية والاستعارية . امَّا المبحث الثالث : هي اجراءات البحث اذ تناول الباحثان بالوصف والتحليل المقارنة بين البُرد والبديعيَّات. وبعدها وصل الباحثان إلى أهم النتائج.

Abstract To understand the contribution of mononuclear phagocytes (MNP), which include monocyte-derived intestinal macrophages, to the pathogenesis of inflammatory bowel disease (IBD), it is necessary to identify functionally-different MNP populations. We aimed to characterise intestinal macrophage populations in patients with IBD. We developed 12-parameter flow cytometry protocols to identify and human intestinal MNPs. We used these protocols to purify and characterize colonic macrophages from colonic tissue from patients with Crohn’s disease (CD), ulcerative colitis (UC), or non-inflamed controls, in a cross-sectional study. We identify macrophage populations (CD45+CD64+ HLA-DR+) and describe two distinct subsets, differentiated by their expression of the mannose receptor, CD206. CD206+ macrophages expressed markers consistent with a mature phenotype: high levels of CD68 and CD163, higher transcription of IL-10 and lower expression of TREM1. CD206− macrophages appear to be less mature, with features more similar to their monocytic precursors. We identified and purified macrophage populations from human colon. These appear to be derived from a monocytic precursor with high CCR2 and low CD206 expression. As these cells mature, they acquire expression of IL-10, CD206, CD63, and CD168. Targeting the newly recruited monocyte-derived cells may represent a fruitful avenue to ameliorate chronic inflammation in IBD.

Background: Current carrier screening methods do not identify a proportion of carriers that may have children affected by spinal muscular atrophy (SMA). Additional genetic data is essential to inform accurate risk assessment and genetic counselling of SMA carriers. This study aims to quantify the various genotypes among parents of children with SMA. Method: A retrospective cohort study was undertaken at Sydney Children’s Hospital Network, the major SMA referral centre for New South Wales, Australia. Participants included children with genetically confirmed SMA born between 2005 and 2021. Data was collected on parent genotype inclusive of copy number of SMN1 exons 7 and 8. The number of SMN2 exon 7 copies were recorded for the affected children. Descriptive statistics were used to determine the proportion of carriers of 2+0 genotype classified as silent carriers. Chi-square test was used to correlate the association between parents with a heterozygous SMN1 exon 7 deletion and two copies of exon 8 and ≥3 SMN2 copy number in the proband. Results: SMA carrier testing was performed in 118/154 (76.6%) parents, incorporating 59 probands with homozygous SMN1 deletions and one proband with compound heterozygote pathogenic variants. Among parents with a child with SMA, 7.6% had two copies of SMN1 exon 7. When only probands with a homozygous SMN1 exon 7 deletion were included, 6.9% of parents had two copies of SMN1 exon 7. An association was observed between heterozygous deletion of SMN1 exon 7 with two copies of exon 8 in a parent and ≥3 SMN2 copy number in the affected proband (p = 0.07). Conclusions: This study confirmed a small but substantial proportion of silent carriers not identified by conventional screening within an Australian context. Accordingly, the effectiveness of carrier screening for SMA is linked with genetic counselling to enable health literacy regarding high and low risk results and is complemented by new-born screening and maintaining clinical awareness for SMA. Gene conversion events may underpin the associations between parent carrier status and proband SMN2 copy number.

Concerns have been raised globally about the impact of the pandemic on the mental health and wellbeing of children and young people (CYP). How prospective headteachers rose to the challenge posed by the pandemic in supporting the wellbeing of their school communities and reaching out to the most vulnerable CYP and families during the recovery phase is the focus of this paper. It is a longitudinal, principally qualitative study conducted in two phases with 60 former students of the Into Headship programme in Scotland. Phase 2 of the study drew on the accounts of eight students drawn from the primary, secondary, and special education sectors using individual interviews and focus group discussions. This paper draws on the accounts of three secondary sector participants in interview. Data were analysed via thematic analysis using a modified framework of King and Horrocks. The respondents had encountered a wide range of challenges and had been highly proactive in their approach through adopting both targeted and universal approaches to meeting need and addressing inequalities. The findings of this paper should inform the development of headship preparation programmes globally and the responses of schools in the recovery phase, furthering our understanding as to what constitutes inclusion in education.

The primary-secondary transition presents both opportunities and challenges for children. For some, it may represent a 'critical period' which impacts their future mental health and well-being. This article focuses on identifying the affordances and constraints of a group-work approach to support children with social, emotional and behavioural needs (SEBN) across the transition with a specific focus on the socio-emotional aspects of transition. This evaluative, mixed-methods case study took place in six clusters of primary/secondary schools in Scotland involving 63 pupils who participated within support groups for around twenty 1-hour sessions. It focuses on the accounts of Support group Leaders, drawing from focus group discussions held within each cluster and a Likert-type scale questionnaire. A wide range of facilitators and barriers to implementation and to pupil progress were identified. Facilitators related principally to the quality of relationships and pedagogy which the support group afforded and the quality of support for the project. Barriers related principally to organisational and resource constraints and more general concerns around how behaviour support is perceived. The article argues that supporting the transition for pupils with SEBN is complex and there is no 'magic bullet'. Building a supportive infrastructure from the outset is key to success.

This conceptual paper provides a critical analysis of the current convergence of major policy initiatives in Scotland to improve learning and teaching, promote greater equity and close the attainment gap through systems level leadership and change. It is neither an empirical study nor a literature review but synthesises across a range of fields -- social justice, poverty, social mobility, school improvement, leadership and policy -- in order to cast light on the problem and to inform public policy and practice. However system level leadership is not unproblematic, with, as argued by Boylan, the terms system and leadership seen as malleable concepts, nor can it be seen as a panacea for all ills. The paper argues that educational policy needs to be seen as residing within wider social policy. Without recourse to addressing systemic inequalities in society and building the infrastructure and support structures around schools, schools, on their own, are unlikely to rise to the challenge. The paper argues for a melding of distributive leadership (with emancipatory intent and purpose) with systems leadership, characterised by meaningful collaboration and partnerships from 'within -- to between -- and beyond' schools (as suggested by Chapman), imbued with moral purpose.

Transitions represent an important milestone for children and are experienced differentially. For some children, transitions represent a critical period that can have a long-term impact on their lives. This paper examines the socio-emotional aspects of the transition through an exploration of the findings derived from an evaluative case study of a group-work intervention to support children with Social, Emotional and Behavioural Needs across the Primary-Secondary transition, seen through the eyes of an adolescent boy and related stakeholders. The study took place in two local authorities in Scotland. The intervention is informed by the 'Teaching for Understanding Framework' (Project Zero, Harvard University) and 'Multiple Intelligence Theory.' The study examines the impact of the intervention on participating pupils, in the process exploring the variables that impacted on pupil progress both internal and external to the intervention. The findings highlight the importance of: building trustful and respectful relationships between adults and children; creating a safe environment in which children will be listened to and cared for; high quality pedagogy and continuity and progression across the transition; and understanding the complexity of factors which may impact on the transition for individual children, particularly for those who may be at greater risk across it.

Metabolic changes are an important component of tumor cell progression. Tumor cells adapt to environmental stresses via changes to carbohydrate and lipid metabolism. Autophagy, a physiological process in mammalian cells that digests damaged organelles and misfolded proteins via lysosomal degradation, is closely associated with metabolism in mammalian cells, acting as a meter of cellular ATP levels. In this review, we discuss the changes in glycolytic and lipid biosynthetic pathways in mammalian cells and their impact on carcinogenesis via the autophagy pathway. In addition, we discuss the impact of these metabolic pathways on autophagy in lung cancer.

Virtual fencing technology uses on-animal devices to communicate boundaries via a warning audio tone and electrical pulse signals. There is currently limited validation work on sheep. This study used modified cattle eShepherd® virtual fencing neckbands on reduced-wool sheep with clipped necks to enable automated trials with small groups across both day and night. The first 5-day trial with six Dorper crossbred sheep was conducted in an experimental paddock setting, with a second 5-day trial conducted with 10 Ultra White sheep on a commercial farm. The animals across both trials were contained in the inclusion zone for 99.8% and 92.2% of the trial period, with a mean percentage (±SD) of total audio cues as audio only (i.e., not followed by an electrical pulse) being 74.9% ± 4.6 in the first trial, and 83.3% ± 20.6 for the second trial. In the second trial, sheep crossed over into the exclusion zone on the third night and remained there until they were walked out for their daily yard check in the morning. These preliminary trial results are promising for the use of automated technology on sheep, but suitable devices and algorithms still need to be designed specifically for sheep in the long term.