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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.

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.

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

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.

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.

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.

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.

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.

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.

[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.

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.

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.

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.

Background: Marine ω-3 polyunsaturated fatty acids (PUFAs), primarily found in dark fish, may prevent colorectal cancer progression, in part through inhibition of prostaglandin-endoperoxide synthase 2 (PTGS2). However, data in humans are limited.Methods: We examined marine ω-3 PUFAs and fish intake and survival among 1,011 colon cancer patients enrolled in Cancer and Leukemia Group B 89803 between 1999 and 2001 and followed through 2009. Diet was assessed during and 6 months after chemotherapy. We used Cox proportional hazards regression to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for disease-free (DFS), recurrence-free (RFS), and overall survival (OS).Results: We observed 343 recurrences and 305 deaths (median follow-up: 7 years). Patients in the highest vs. lowest quartile of marine ω-3 PUFA intake had an HR for DFS of 0.72 (95% CI, 0.54-0.97; Ptrend = 0.03). Individuals who consumed dark fish ≥1/week versus never had longer DFS (HR 0.65; 95% CI, 0.48-0.87; P-value = 0.007), RFS (HR 0.61; 95% CI, 0.46-0.86; Ptrend = 0.007), and OS (HR 0.68; 95% CI, 0.48-0.96; Ptrend = 0.04). In a subset of 510 patients, the association between marine ω-3 PUFA intake and DFS appeared stronger in patients with high PTGS2 expression (HR 0.32; 95% CI, 0.11-0.95; Ptrend = 0.01) compared with patients with absent/low PTGS2 expression (HR 0.78; 95% CI, 0.48-1.27; Ptrend = 0.35; Pinteraction = 0.19).Conclusions: Patients with high intake of marine ω-3 PUFAs and dark fish after colon cancer diagnosis may have longer DFS.Impact: Randomized controlled trials examining dark fish and/or marine ω-3 PUFA supplements and colon cancer recurrence/survival are needed. Cancer Epidemiol Biomarkers Prev; 27(4); 438-45. ©2018 AACR.

BACKGROUND:The majority of patients with pancreatic cancer who undergo curative resection experience rapid disease recurrence. In previous small studies, high expression of the mismatch-repair protein mutL protein homolog 1 (MLH1) in pancreatic cancers was associated with better outcomes. The objective of this study was to validate the association between MLH1 expression and survival in patients who underwent resection of pancreatic cancer and received adjuvant chemoradiation. METHODS:Samples were obtained from the NRG Oncology Radiation Therapy Oncology Group 9704 prospective, randomized trial (clinicaltrials.gov identifier NCT00003216), which compared 2 adjuvant protocols in patients with pancreatic cancer who underwent resection. Tissue microarrays were prepared from formalin-fixed, paraffin-embedded, resected tumor tissues. MLH1 expression was quantified using fluorescence immunohistochemistry and automated quantitative analysis, and expression was dichotomized above and below the median value. RESULTS:Immunohistochemical staining was successfully performed on 117 patients for MLH1 (60 and 57 patients from the 2 arms). The characteristics of the participants who had tissue samples available were similar to those of the trial population as a whole. At the time of analysis, 84% of participants had died, with a median survival of 17 months. Elevated MLH1 expression levels in tumor nuclei were significantly correlated with longer disease-free and overall survival in each arm individually and in both arms combined. Two-year overall survival was 16% in patients who had low MLH1 expression levels and 53% in those who had high MLH1 expression levels (P

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.

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.

BackgroundObservational studies suggest that higher levels of 25-hydroxyvitamin D3 (25(OH)D) are associated with a reduced risk of colorectal cancer and improved survival of colorectal cancer patients. However, the influence of vitamin D status on cancer recurrence and survival of patients with stage III colon cancer is unknown.Patients and methodsWe prospectively examined the influence of post-diagnosis predicted plasma 25(OH)D on outcome among 1016 patients with stage III colon cancer who were enrolled in a National Cancer Institute-sponsored adjuvant therapy trial (CALGB 89803). Predicted 25(OH)D scores were computed using validated regression models. We examined the influence of predicted 25(OH)D scores on cancer recurrence and mortality (disease-free survival; DFS) using Cox proportional hazards.ResultsPatients in the highest quintile of predicted 25(OH)D score had an adjusted hazard ratio (HR) for colon cancer recurrence or mortality (DFS) of 0.62 (95% confidence interval [CI], 0.44-0.86), compared with those in the lowest quintile (Ptrend = 0.005). Higher predicted 25(OH)D score was also associated with a significant improvement in recurrence-free survival and overall survival (Ptrend = 0.01 and 0.0004, respectively). The benefit associated with higher predicted 25(OH)D score appeared consistent across predictors of cancer outcome and strata of molecular tumor characteristics, including microsatellite instability and KRAS, BRAF, PIK3CA, and TP53 mutation status.ConclusionHigher predicted 25(OH)D levels after a diagnosis of stage III colon cancer may be associated with decreased recurrence and improved survival. Clinical trials assessing the benefit of vitamin D supplementation in the adjuvant setting are warranted.Clinicaltrials.gov identifierNCT00003835.

Summary: Introduction: We assessed change in substance use from before to during the COVID-19 pandemic in young adults and identified factors associated with initiation/increase in use. Methods: The sample comprised young adults from a longitudinal investigation of 1294 youth recruited at ages 12-13 (1999-2000) in 10 Montréal-area high schools. Pre-pandemic data on use of cannabis, alcohol, combustible cigarette, e-cigarette and binge drinking were collected at ages 20.4, 24.0 and 30.6. During COVID-19, data were collected from December 2020 to June 2021 (age 33.6). We studied the prevalence of any and weekly/daily use from age 20.4 to 33.6. Individual-level change in substance use during the pandemic was estimated as differences in the frequency of use from age 30.6 to 33.6 versus from age 24.0 to 30.6. Heterogeneity in the risk of initiated/increased substance use during COVID-19 across sociodemographic subgroups was assessed using modified Poisson regression. Results: The prevalence of cannabis use increased from 17.5% to 23.1% from before to during the pandemic; e-cigarette use increased from 3.8% to 5.4%. In individual change analyses, the proportion of participants whose substance use did not change ranged from 48.9% (alcohol) to 84.0% (e-cigarettes). The incidence of initiated/increased cannabis use (22.4%), and quit/decreased alcohol (35.2%) and binge drinking (53.5%) were higher during the pandemic than between ages 24.0 to 30.6. Low education and living alone were associated with higher risks of initiated/increased use of most substances. Discussion: Most participants reported stable patterns in substance use from before to during the COVID-19 pandemic. Funding: The NDIT study was supported by the Canadian Cancer Society (grant numbers 010271, 017435, 704031) and the Canadian Institutes of Health Research (grant number 451832).

BackgroundCarboplatin (C) and paclitaxel (P) are standard treatments for carcinoma of unknown primary (CUP). Everolimus, an mTOR inhibitor, exhibits activity in diverse cancer types. We did a phase II trial combining everolimus with CP for CUP. We also evaluated whether a gene expression profiling (GEP) test that predicts tissue of origin (TOO) could identify responsive patients.Patients and methodsA tumor biopsy was required for central confirmation of CUP and GEP. Patients with metastatic, untreated CUP received everolimus (30 mg weekly) with P (200 mg/m(2)) and C (area under the curve 6) every 3 weeks. The primary end point was response rate (RR), with 22% needed for success. The GEP test categorized patients into two groups: those having a TOO where CP is versus is not considered standard therapy.ResultsOf 45 assessable patients, the RR was 36% (95% confidence interval 22% to 51%), which met criteria for success. Grade ≥3 toxicities were predominantly hematologic (80%). Adequate tissue for GEP was available in 38 patients and predicted 10 different TOOs. Patients with a TOO where platinum/taxane is a standard (n = 19) tended to have higher RR (53% versus 26%) and significantly longer PFS (6.4 versus 3.5 months) and OS (17.8 versus 8.3 months, P = 0.005), compared with patients (n = 19) with a TOO where platinum/taxane is not standard.ConclusionsEverolimus combined with CP demonstrated promising antitumor activity and an acceptable side-effect profile. A tumor biomarker identifying TOO may be useful to select CUP patients for specific antitumor regimens.ClinicaltrialsgovNCT00936702.

PurposeObservational studies have demonstrated increased colon cancer recurrence in states of relative hyperinsulinemia, including sedentary lifestyle, obesity, and increased dietary glycemic load. Greater coffee consumption has been associated with decreased risk of type 2 diabetes and increased insulin sensitivity. The effect of coffee on colon cancer recurrence and survival is unknown.Patients and methodsDuring and 6 months after adjuvant chemotherapy, 953 patients with stage III colon cancer prospectively reported dietary intake of caffeinated coffee, decaffeinated coffee, and nonherbal tea, as well as 128 other items. We examined the influence of coffee, nonherbal tea, and caffeine on cancer recurrence and mortality using Cox proportional hazards regression.ResultsPatients consuming 4 cups/d or more of total coffee experienced an adjusted hazard ratio (HR) for colon cancer recurrence or mortality of 0.58 (95% CI, 0.34 to 0.99), compared with never drinkers (Ptrend = .002). Patients consuming 4 cups/d or more of caffeinated coffee experienced significantly reduced cancer recurrence or mortality risk compared with abstainers (HR, 0.48; 95% CI, 0.25 to 0.91; Ptrend = .002), and increasing caffeine intake also conferred a significant reduction in cancer recurrence or mortality (HR, 0.66 across extreme quintiles; 95% CI, 0.47 to 0.93; Ptrend = .006). Nonherbal tea and decaffeinated coffee were not associated with patient outcome. The association of total coffee intake with improved outcomes seemed consistent across other predictors of cancer recurrence and mortality.ConclusionHigher coffee intake may be associated with significantly reduced cancer recurrence and death in patients with stage III colon cancer.