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This article is the second in the two-part series comprising The Don Spring Memorial Oration delivered by Dr Patrick Turley at the Hamilton Island meeting of the Australian Foundation for Research and Education, in September 1992. The article has been reprinted with the permission of the Editor of the Pacific Coast Society of Orthodontists’ Bulletin. Both articles in the series have been smnmarized by Andrea L. Feature D.D.S., M.S..

In September 1992, the Australian Foundation for Orthodontic Research and Education held its biennial meeting at Hamilton Island, Queensland. The guest lecturer was Dr Patrick Turley. The first of Dr Turley’s presentations was the The Don Spring Memorial Oration, the content of which is included in the following article. The article has been reprinted with the permission of the Editor of the Pacific Coast Society of Orthodontists’ Bulletin. The second article will appear in the October 1993 edition of this Journal.

Abstract TGFβ signaling is associated with non-response to immune checkpoint blockade in patients with advanced cancers, particularly in the immune-excluded phenotype. While previous work demonstrates that converting tumors from excluded to inflamed phenotypes requires attenuation of PD-L1 and TGFβ signaling, the underlying cellular mechanisms remain unclear. Here, we show that TGFβ and PD-L1 restrain intratumoral stem cell-like CD8 T cell (TSCL) expansion and replacement of progenitor-exhausted and dysfunctional CD8 T cells with non-exhausted T effector cells in the EMT6 tumor model in female mice. Upon combined TGFβ/PD-L1 blockade IFNγhi CD8 T effector cells show enhanced motility and accumulate in the tumor. Ensuing IFNγ signaling transforms myeloid, stromal, and tumor niches to yield an immune-supportive ecosystem. Blocking IFNγ abolishes the anti-PD-L1/anti-TGFβ therapy efficacy. Our data suggest that TGFβ works with PD-L1 to prevent TSCL expansion and replacement of exhausted CD8 T cells, thereby maintaining the T cell compartment in a dysfunctional state.

Abstract Background RHAMM is a multifunctional protein that is upregulated in breast tumors, and the presence of strongly RHAMM+ve cancer cell subsets associates with elevated risk of peripheral metastasis. Experimentally, RHAMM impacts cell cycle progression and cell migration. However, the RHAMM functions that contribute to breast cancer metastasis are poorly understood. Methods We interrogated the metastatic functions of RHAMM using a loss-of-function approach by crossing the MMTV-PyMT mouse model of breast cancer susceptibility with Rhamm −/− mice. In vitro analyses of known RHAMM functions were performed using primary tumor cell cultures and MMTV-PyMT cell lines. Somatic mutations were identified using a mouse genotyping array. RNA-seq was performed to identify transcriptome changes resulting from Rhamm-loss, and SiRNA and CRISPR/Cas9 gene editing was used to establish cause and effect of survival mechanisms in vitro. Results Rhamm-loss does not alter initiation or growth of MMTV-PyMT-induced primary tumors but unexpectedly increases lung metastasis. Increased metastatic propensity with Rhamm-loss is not associated with obvious alterations in proliferation, epithelial plasticity, migration, invasion or genomic stability. SNV analyses identify positive selection of Rhamm −/− primary tumor clones that are enriched in lung metastases. Rhamm −/− tumor clones are characterized by an increased ability to survive with ROS-mediated DNA damage, which associates with blunted expression of interferon pathway and target genes, particularly those implicated in DNA damage-resistance. Mechanistic analyses show that ablating RHAMM expression in breast tumor cells by siRNA knockdown or CRISPR-Cas9 gene editing blunts interferon signaling activation by STING agonists and reduces STING agonist-induced apoptosis. The metastasis-specific effect of RHAMM expression-loss is linked to microenvironmental factors unique to tumor-bearing lung tissue, notably high ROS and TGFB levels. These factors promote STING-induced apoptosis of RHAMM+ve tumor cells to a significantly greater extent than RHAMM−ve comparators. As predicted by these results, colony size of Wildtype lung metastases is inversely related to RHAMM expression. Conclusion RHAMM expression-loss blunts STING-IFN signaling, which offers growth advantages under specific microenvironmental conditions of lung tissue. These results provide mechanistic insight into factors controlling clonal survival/expansion of metastatic colonies and has translational potential for RHAMM expression as a marker of sensitivity to interferon therapy.

Attention-deficit/hyperactivity disorder (ADHD) is a complex behavioral disorder characterized by hyperactivity, impulsivity, inattention, and deficits in working memory and time perception. While animal models have advanced our neurobiological understanding of this condition, there are limited and inconsistent data on working and elapsed time memory function. Inflammatory signaling has been identified as a key factor in memory and cognitive impairments, but its role in ADHD remains unclear. Additionally, the disproportionate investigation of male subjects in ADHD research has contributed to a poor understanding of the disorder in females. This study sought to investigate the potential connections between memory, neuroimmunology, and ADHD in both male and female animals. Specifically, we utilized the spontaneously hypertensive rat (SHR), one of the most extensively studied animal models of ADHD. Compared to their control, the Wistar-Kyoto (WKY) rat, male SHR are reported to exhibit several behavioral phenotypes associated with ADHD, including hyperactivity, impulsivity, and poor sustained attention, along with impairments in learning and memory. As the hippocampus is a key brain region for learning and memory, we examined the behavior of male and female SHR and WKY rats in two hippocampal-dependent memory tasks. Our findings revealed that SHR have delay-dependent working memory deficits that were similar to, albeit less severe than, those seen in hippocampal-lesioned rats. We also observed impairments in elapsed time processing in female SHR, particularly in the discrimination of longer time durations. To investigate the impact of inflammatory signaling on memory in these rats, we analyzed the levels of several cytokines in the dorsal and ventral hippocampus of SHR and WKY. Although we found some sex and genotype differences, concentrations were generally similar between groups. Taken together, our results indicate that SHR exhibit deficits in spatial working memory and memory for elapsed time, as well as some differences in hippocampal cytokine concentrations. These findings contribute to a better understanding of the neurobiological basis of ADHD in both sexes and may inform future research aimed at developing effective treatments for the disorder. Nonetheless, the potential mediating role of neuroinflammation in the memory symptomatology of SHR requires further investigation.

Abstract Honey bee colony management is critical to mitigating the negative effects of biotic and abiotic stressors. However, there is significant variation in the practices implemented by beekeepers, which results in varying management systems. This longitudinal study incorporated a systems approach to experimentally test the role of three representative beekeeping management systems (conventional, organic, and chemical-free) on the health and productivity of stationary honey-producing colonies over 3 years. We found that the survival rates for colonies in the conventional and organic management systems were equivalent, but around 2.8 times greater than the survival under chemical-free management. Honey production was also similar, with 102% and 119% more honey produced in conventional and organic management systems, respectively, than in the chemical-free management system. We also report significant differences in biomarkers of health including pathogen levels (DWV, IAPV, Vairimorpha apis, Vairimorpha ceranae) and gene expression (def-1, hym, nkd, vg). Our results experimentally demonstrate that beekeeping management practices are key drivers of survival and productivity of managed honey bee colonies. More importantly, we found that the organic management system—which uses organic-approved chemicals for mite control—supports healthy and productive colonies, and can be incorporated as a sustainable approach for stationary honey-producing beekeeping operations.

Summary: Polygenic risk scores (PRSs) developed from multi-ancestry genome-wide association studies (GWASs), PRSmulti, hold promise for improving PRS accuracy and generalizability across populations. To establish best practices for leveraging the increasing diversity of genomic studies, we investigated how various factors affect the performance of PRSmulti compared with PRSs constructed from single-ancestry GWASs (PRSsingle). Through extensive simulations and empirical analyses, we showed that PRSmulti overall outperformed PRSsingle in understudied populations, except when the understudied population represented a small proportion of the multi-ancestry GWAS. Furthermore, integrating PRSs based on local ancestry-informed GWASs and large-scale, European-based PRSs improved predictive performance in understudied African populations, especially for less polygenic traits with large-effect ancestry-enriched variants. Our work highlights the importance of diversifying genomic studies to achieve equitable PRS performance across ancestral populations and provides guidance for developing PRSs from multiple studies.

Summary: Background: While vaccines have established utility against COVID-19, phase 3 efficacy studies have generally not comprehensively evaluated protection provided by previous infection or hybrid immunity (previous infection plus vaccination). Individual patient data from US government-supported harmonized vaccine trials provide an unprecedented sample population to address this issue. We characterized the protective efficacy of previous SARS-CoV-2 infection and hybrid immunity against COVID-19 early in the pandemic over three-to six-month follow-up and compared with vaccine-associated protection. Methods: In this post-hoc cross-protocol analysis of the Moderna, AstraZeneca, Janssen, and Novavax COVID-19 vaccine clinical trials, we allocated participants into four groups based on previous-infection status at enrolment and treatment: no previous infection/placebo; previous infection/placebo; no previous infection/vaccine; and previous infection/vaccine. The main outcome was RT-PCR-confirmed COVID-19 >7–15 days (per original protocols) after final study injection. We calculated crude and adjusted efficacy measures. Findings: Previous infection/placebo participants had a 92% decreased risk of future COVID-19 compared to no previous infection/placebo participants (overall hazard ratio [HR] ratio: 0.08; 95% CI: 0.05–0.13). Among single-dose Janssen participants, hybrid immunity conferred greater protection than vaccine alone (HR: 0.03; 95% CI: 0.01–0.10). Too few infections were observed to draw statistical inferences comparing hybrid immunity to vaccine alone for other trials. Vaccination, previous infection, and hybrid immunity all provided near-complete protection against severe disease. Interpretation: Previous infection, any hybrid immunity, and two-dose vaccination all provided substantial protection against symptomatic and severe COVID-19 through the early Delta period. Thus, as a surrogate for natural infection, vaccination remains the safest approach to protection. Funding: National Institutes of Health.

Background: Open tibial shaft fractures comprise almost 45% of all open fractures and are frequently the result of high-energy trauma. Due to contamination, limited soft tissue coverage of the tibial shaft and poor tibial blood supply, open tibial shaft fractures are associated with high rates of complication including malunion, non-union and infection. Intramedullary nailing (IMN) is a mainstay of treatment. This study aims to determine the frequency of the various complications in this cohort. Methods: A systematic review of papers published on Embase, PubMed and Cochrane databases pertaining to the use of IMN to fix open tibial shaft fractures were included. The available evidence was collated in regard to the incidence of union, malunion, non-union and infection seen in this cohort. Results: A total of 2767 citations were reviewed, and 17 studies comprising 1850 patients were included in the analysis. There was a delayed union rate of 22.4%, malunion rate of 8.3%, non-union rate of 9.7% and infection rate of 8.1% (95% CI: 5.7%–10.8%) in this patient cohort. Subgroup analysis showed a 3-fold increase in non-union and a 2-fold increase in deep infection among Gustilo III injuries compared to Gustilo I and II. Conclusions: IMN for open tibial shaft fractures results in high rates of union and low rates of infection, comparable to figures seen in closed injuries and superior to those seen with alternative methods of fixation. There is a substantially increased risk of complication associated with Gustilo III injuries, reinforcing the significance of the soft tissue injury in these patients.

Property taxes are common in countries around the world. Until recently, Ireland was an exception as there was no annual tax on residential property. This paper is a review of the Local Property Tax (LPT) system that was introduced in 2013 and had its first property revaluations in 2021. Using the lens of municipal finance and tax assignment, the rationale, history, features and administration of this new residential property tax are outlined. While recognising country-specific circumstances, lessons, opportunities and challenges are explored with a view to future improvements in the design and implementation of the LPT. Lessons from the LPT experience are the importance of tax administration and the role of the central tax collection agency, and, in terms of design, the need for a tailored approach to suit local circumstances. Challenges include the rates/LPT mix and the relative tax burdens on non-residential and residential properties, the long-term sustainability of the LPT arising from design issues, the current low tax rate and future revaluations, and, finally, the need for regular property tax reform because of political and taxpayers’ opposition to a highly visible, unpopular but good local tax.

AimsThe use of fluoroscopy in orthopaedic surgery creates risk of radiation exposure to surgeons. Appropriate personal protective equipment (PPE) can help mitigate this. The primary aim of this study was to assess if current radiation protection in orthopaedic trauma is safe. The secondary aims were to describe normative data of radiation exposure during common orthopaedic procedures, evaluate ways to improve any deficits in protection, and validate the use of electronic personal dosimeters (EPDs) in assessing radiation dose in orthopaedic surgery.MethodsRadiation exposure to surgeons during common orthopaedic trauma operations was prospectively assessed using EPDs and thermoluminescent dosimeters (TLDs). Normative data for each operation type were calculated and compared to recommended guidelines.ResultsCurrent PPE appears to mitigate more than 90% of ionizing radiation in orthopaedic fluoroscopic procedures. There is a higher exposure to the inner thigh during seated procedures. EPDs provided results for individual procedures.ConclusionPPE currently used by surgeons in orthopaedic trauma theatre adequately reduces radiation exposure to below recommended levels. Normative data per trauma case show specific anatomical areas of higher exposure, which may benefit from enhanced radiation protection. EPDs can be used to assess real-time radiation exposure in orthopaedic surgery. There may be a role in future medical wearables for orthopaedic surgeons.Cite this article: Bone Jt Open 2022;3(11):907–912.

Abstract High-energy tau neutrinos are rarely produced in atmospheric cosmic-ray showers or at cosmic particle accelerators, but are expected to emerge during neutrino propagation over cosmic distances due to flavor mixing. When high energy tau neutrinos interact inside the IceCube detector, two spatially separated energy depositions may be resolved, the first from the charged current interaction and the second from the tau lepton decay. We report a novel analysis of 7.5 years of IceCube data that identifies two candidate tau neutrinos among the 60 “High-Energy Starting Events” (HESE) collected during that period. The HESE sample offers high purity, all-sky sensitivity, and distinct observational signatures for each neutrino flavor, enabling a new measurement of the flavor composition. The measured astrophysical neutrino flavor composition is consistent with expectations, and an astrophysical tau neutrino flux is indicated at 2.8 $$\sigma $$ σ significance.

Abstract The reconstruction of event-level information, such as the direction or energy of a neutrino interacting in IceCube DeepCore, is a crucial ingredient to many physics analyses. Algorithms to extract this high level information from the detector’s raw data have been successfully developed and used for high energy events. In this work, we address unique challenges associated with the reconstruction of lower energy events in the range of a few to hundreds of GeV and present two separate, state-of-the-art algorithms. One algorithm focuses on the fast directional reconstruction of events based on unscattered light. The second algorithm is a likelihood-based multipurpose reconstruction offering superior resolutions, at the expense of larger computational cost.

Academic libraries use social media to build community and increase visibility and engagement among followers–students, faculty, and staff. Instagram, in particular, is a popular social media platform used by a college-aged demographic. Academic library Instagram administrators create and maintain Instagram accounts to post visual content to promote the physical library and library services. In March 2020, the COVID-19 pandemic closed the college campuses of the New York City-based City University of New York (CUNY) system to all but “essential staff” and compelled non-essential employees to work from home. During the first few months of 2020, college library Instagram administrators in the CUNY system considered how a once-in-a-century pandemic might affect the content of their Instagram posts and post frequency. The posts of Instagram accounts for eight CUNY libraries were this study’s subject. Data from each account’s Instagram posts were examined: images and captions, posting frequency, and the ways in which these accounts may have made a “pandemic pivot.”

Abstract Background Although socioeconomic status (SES) has been shown to modify associations between the neighborhood built environment and physical activity, contradictory results exist. Objectives of this cross-sectional and longitudinal analysis were to: 1) examine whether overall neighborhood walkability and specific built characteristics were associated with walking among adults at a single point in time and after they relocate neighborhoods, and 2) test for effect modification of these associations by SES. Methods We linked longitudinal data from 703 adults who relocated urban neighborhoods between two waves of Alberta’s Tomorrow Project (2008–2015) to neighborhood built environment data. We created a walkability index from measures of population counts, street connectivity, and destination diversity within 400 m of participants’ homes. In cross-sectional analyses, we used generalized linear models to estimate associations between built characteristics and minutes walked per week at baseline. For the longitudinal analyses, we used fixed-effects linear regression models to estimate associations between changes in built characteristics and minutes walked per week. We also assessed if indicators of SES (individual education or household income) modified both sets of associations. Results Most cross-sectional and longitudinal associations were small and statistically non-significant. Neighborhood population count (b = 0.03, 95% CI: 0.01, 0.07) and street connectivity (b = − 1.75, 95% CI: − 3.26, − 0.24) were cross-sectionally associated with walking duration among the overall sample. None of the longitudinal associations were statistically significant among the overall sample. There was limited evidence of effect modification by SES, however, we found negative cross-sectional associations between street connectivity and walking among adults with lower education and income, and a positive association between percent change in walkability and change in walking among lower educated adults. Conclusions Despite population count and street connectivity being associated with walking at baseline, changes in these built environment variables were not associated with changes in walking following residential relocation. Our findings also provide evidence, albeit weak, that changes in neighborhood walkability, resulting from residential relocation, might more strongly affect walking among low SES adults. Further longitudinal research is needed to examine built environment characteristics with walking for different purposes and to test for inequitable socioeconomic impacts.

Tumour volume is typically calculated using only length and width measurements, using width as a proxy for height in a 1:1 ratio. When tracking tumour growth over time, important morphological information and measurement accuracy is lost by ignoring height, which we show is a unique variable. Lengths, widths, and heights of 9522 subcutaneous tumours in mice were measured using 3D and thermal imaging. The average height:width ratio was found to be 1:3 proving that using width as a proxy for height overestimates tumour volume. Comparing volumes calculated with and without tumour height to the true volumes of excised tumours indeed showed that using the volume formula including height produced volumes 36X more accurate (based off of percentage difference). Monitoring the height:width relationship (prominence) across tumour growth curves indicated that prominence varied, and that height could change independent of width. Twelve cell lines were investigated individually; the scale of tumour prominence was cell line-dependent with relatively less prominent tumours (MC38, BL2, LL/2) and more prominent tumours (RENCA, HCT116) detected. Prominence trends across the growth cycle were also dependent on cell line; prominence was correlated with tumour growth in some cell lines (4T1, CT26, LNCaP), but not others (MC38, TC-1, LL/2). When pooled, invasive cell lines produced tumours that were significantly less prominent at volumes >1200 mm 3 compared to non-invasive cell lines ( P

Introduction People with severe mental illness have an increased vulnerability to cardiovascular disease due to multilple biopsychosocial factors and a potential adverse effects of longer term treatment with anti-psychotic medications. Treatment of severe and enduring mental illness with antipsychotic medications is likely to cause metabolic changes leading to weight gain and dyslipidaemia, thus increasing risk of cardiovascular disease. Cardiometabolic risk screening can be done using Lester Tool which also provides recommendations for interventions. Objectives To identify the compliance to Lester Tool in the monitoring of cardiometabolic risk factors and intervention provided on acute psychiatry inpatients. Methods We carried out a retrospective audit of 30 patients on regular antipsychotic medication on an adult inpatient ward in Macclesfield, United Kingdom. Electronic records were reviewed to establish whether the smoking status, lifestyle, BMI, blood pressure, blood glucose and blood lipid were documented with evidence of interventions being provided. Results Of all 30 patients, none had shown compliance to all the parameters within the Lester Tool. 100% of the smoking status was documented, amongst which 78% were provided with interventions. 7% has lifestyle and diet status documented, of which 50% were given dietary advice. 80% had BMI documented, amongst which none were provided with any intervention. 90% had blood pressure documented, of which 50% were given any intervention. 40% had blood glucose documented, of which all were provided with intervention. 57% had blood lipid documented, of which none were provided with any intervention. Conclusions Our results have shown the need of further awareness on the usefulness of the Lester Tool in an acute inpatient ward. Our recommendation would be to regularly train and educate inpatient staff to ensure that all the necessary parameters be monitored and provided with interventions. Disclosure of Interest None Declared

Introduction Previous studies demonstrated that the implementation of the Kidney Disease Improving Global Outcomes (KDIGO) guideline-based bundle, consisting of different supportive measures in patients at high risk for acute kidney injury (AKI), might reduce rate and severity of AKI after surgery. However, the effects of the care bundle in broader population of patients undergoing surgery require confirmation.Methods and analysis The BigpAK-2 trial is an international, randomised, controlled, multicentre trial. The trial aims to enrol 1302 patients undergoing major surgery who are subsequently admitted to the intensive care or high dependency unit and are at high-risk for postoperative AKI as identified by urinary biomarkers (tissue inhibitor of metalloproteinases 2*insulin like growth factor binding protein 7 (TIMP-2)*IGFBP7)). Eligible patients will be randomised to receive either standard of care (control) or a KDIGO-based AKI care bundle (intervention). The primary endpoint is the incidence of moderate or severe AKI (stage 2 or 3) within 72 hours after surgery, according to the KDIGO 2012 criteria. Secondary endpoints include adherence to the KDIGO care bundle, occurrence and severity of any stage of AKI, change in biomarker values during 12 hours after initial measurement of (TIMP-2)*(IGFBP7), number of free days of mechanical ventilation and vasopressors, need for renal replacement therapy (RRT), duration of RRT, renal recovery, 30-day and 60-day mortality, intensive care unit length-of-stay and hospital length-of-stay and major adverse kidney events. An add-on study will investigate blood and urine samples from recruited patients for immunological functions and kidney damage.Ethics and dissemination The BigpAK-2 trial was approved by the Ethics Committee of the Medical Faculty of the University of Münster and subsequently by the corresponding Ethics Committee of the participating sites. A study amendment was approved subsequently. In the UK, the trial was adopted as an NIHR portfolio study. Results will be disseminated widely and published in peer-reviewed journals, presented at conferences and will guide patient care and further research.Trial registration number NCT04647396.

Rare familial spontaneous coronary artery dissection (SCAD) kindreds implicate genetic disease predisposition and provide a unique opportunity for candidate gene discovery. Whole-genome sequencing was performed in fifteen probands with non-syndromic SCAD who had a relative with SCAD, eight of whom had a second relative with extra-coronary arteriopathy. Co-segregating variants and associated genes were prioritized by quantitative variant, gene, and disease-level metrics. Curated public databases were queried for functional relationships among encoded proteins. Fifty-four heterozygous coding variants in thirteen families co-segregated with disease and fulfilled primary filters of rarity, gene variation constraint, and predicted-deleterious protein effect. Secondary filters yielded 11 prioritized candidate genes in 12 families, with high arterial tissue expression (n = 7), high-confidence protein-level interactions with genes associated with SCAD previously (n = 10), and/or previous associations with connective tissue disorders and aortopathies (n = 3) or other vascular phenotypes in mice or humans (n = 11). High-confidence associations were identified among 10 familial SCAD candidate-gene-encoded proteins. A collagen-encoding gene was identified in five families, two with distinct variants in COL4A2. Familial SCAD is genetically heterogeneous, yet perturbations of extracellular matrix, cytoskeletal, and cell–cell adhesion proteins implicate common disease-susceptibility pathways. Incomplete penetrance and variable expression suggest genetic or environmental modifiers.

Assigning recurrent taxes on immovable property to cities, municipalities, and rural districts is a common practice around the world. The Republic of Ireland is no different, with its annual taxes on real property assigned to local government. Following the 2008 financial crisis and the austerity era that ensued, Ireland’s property taxes underwent major reform, most notably the design and implementation of a new residential property tax 35 years after abolition of the previous system of ‘rates’ on residential properties. In this paper the new or different features of Ireland’s residential property tax are outlined, including the use of self-assessment and valuation bands, innovative payment methods and also the multiple compliance mechanisms for taxpayers. While recognising the importance of country-specific and local circumstances in property tax design, the paper concludes that elements of Ireland’s new residential property tax have potential lessons for other jurisdictions contemplating similar tax reform. These relate to the key tax principles of simplicity and public acceptability, and on specific design features of assessment and valuation, and collection and compliance.

Abstract Background Malaria and schistosomiasis present considerable disease burden in tropical and sub-tropical areas and severity is worsened by co-infections in areas where both diseases are endemic. Although pathogenesis of these infections separately is well studied, there is limited information on the pathogenic disease mechanisms and clinical disease outcomes in co-infections. In this study, we investigated the prevalence of malaria and schistosomiasis co-infections, and the hematologic and blood chemistry abnormalities in asymptomatic adults in a rural fishing community in western Kenya. Methods This sub-study used samples and data collected at enrollment from a prospective observational cohort study (RV393) conducted in Kisumu County, Kenya. The presence of malaria parasites was determined using microscopy and real-time-PCR, and schistosomiasis infection by urine antigen analysis (CCA). Hematological analysis and blood chemistries were performed using standard methods. Statistical analyses were performed to compare demographic and infection data distribution, and hematologic and blood chemistry parameters based on different groups of infection categories. Clinically relevant hematologic conditions were analyzed using general linear and multivariable Poisson regression models. Results From February 2017 to May 2018, we enrolled 671 participants. The prevalence of asymptomatic Plasmodium falciparum was 28.2% (157/556) and schistosomiasis 41.2% (229/562), with 18.0% (100/556) of participants co-infected. When we analyzed hematological parameters using Wilcoxon rank sum test to evaluate median (IQR) distribution based on malarial parasites and/or schistosomiasis infection status, there were significant differences in platelet counts (p = 0.0002), percent neutrophils, monocytes, eosinophils, and basophils (p

User measurement bias during subcutaneous tumor measurement is a source of variation in preclinical in vivo studies. We investigated whether this user variability could impact efficacy study outcomes, in the form of the false negative result rate when comparing treated and control groups. Two tumor measurement methods were compared; calipers which rely on manual measurement, and an automatic 3D and thermal imaging device. Tumor growth curve data were used to create an in silico efficacy study with control and treated groups. Before applying user variability, treatment group tumor volumes were statistically different to the control group. Utilizing data collected from 15 different users across 9 in vivo studies, user measurement variability was computed for both methods and simulation was used to investigate its impact on the in silico study outcome. User variability produced a false negative result in 0.7% to 18.5% of simulated studies when using calipers, depending on treatment efficacy. When using an imaging device with lower user variability this was reduced to 0.0% to 2.6%, demonstrating that user variability impacts study outcomes and the ability to detect treatment effect. Reducing variability in efficacy studies can increase confidence in efficacy study outcomes without altering group sizes. By using a measurement device with lower user variability, the chance of missing a therapeutic effect can be reduced and time and resources spent pursuing false results could be saved. This improvement in data quality is of particular interest in discovery and dosing studies, where being able to detect small differences between groups is crucial.

During the spring and summer of 2020, cities across the world responded to the global COVID-19 pandemic by converting roadway facilities into open pedestrian spaces. These conversions improved access to public open space, but measuring the variation in that improvement among different populations requires clear definitions of access and methods for measuring it. In this study, we evaluate the change in a utility-based park accessibility measure resulting from street conversions in Alameda County, California. Our utility-based accessibility measure is constructed from a park activity location choice model we estimate using mobile device data – supplied by StreetLight Data, Inc. – representing trips to parks in that county. The estimated model reveals heterogeneity in inferred affinity for park attributes among different sociodemographic groups. We find, for example, that neighborhoods with more lower-income residents and those with more residents of color show a greater preference for park proximty while neighborhods with higher incomes and those with more white residents show a greater preference for park size and amenities. We then apply this model to examine the accessibility benefits resulting from COVID-19 street conversions to create a set of small park-like open spaces; we find that this has been a pro-social policy in that Black, Hispanic, and low-income households receive a disproportionate share of the policy benefits, relative to the population distribution.

During the spring and summer of 2020, cities across the world responded to the global COVID-19 pandemic by converting roadway facilities into open pedestrian spaces. These conversions improved access to public open space, but measuring the variation in that improvement among different populations requires clear definitions of access and methods for measuring it. In this study, we evaluate the change in a utility-based park accessibility measure resulting from street conversions in Alameda County, California. Our utility-based accessibility measure is constructed from a park activity location choice model we estimate using mobile device data – supplied by StreetLight Data, Inc. – representing trips to parks in that county. The estimated model reveals heterogeneity in inferred affinity for park attributes among different sociodemographic groups. We find, for example, that neighborhoods with more lower-income residents and those with more residents of color show a greater preference for park proximty while neighborhods with higher incomes and those with more white residents show a greater preference for park size and amenities. We then apply this model to examine the accessibility benefits resulting from COVID-19 street conversions to create a set of small park-like open spaces; we find that this has been a pro-social policy in that Black, Hispanic, and low-income households receive a disproportionate share of the policy benefits, relative to the population distribution.

Abstract Wild bees form diverse communities that pollinate plants in both native and agricultural ecosystems making them both ecologically and economically important. The growing evidence of bee declines has sparked increased interest in monitoring bee community and population dynamics using standardized methods. Here, we studied the dynamics of bee biodiversity within and across years by monitoring wild bees adjacent to four apple orchard locations in Southern Pennsylvania, USA. We collected bees using passive Blue Vane traps continuously from April to October for 6 years (2014–2019) amassing over 26,000 bees representing 144 species. We quantified total abundance, richness, diversity, composition, and phylogenetic structure. There were large seasonal changes in all measures of biodiversity with month explaining an average of 72% of the variation in our models. Changes over time were less dramatic with years explaining an average of 44% of the variation in biodiversity metrics. We found declines in all measures of biodiversity especially in the last 3 years, though additional years of sampling are needed to say if changes over time are part of a larger trend. Analyses of population dynamics over time for the 40 most abundant species indicate that about one third of species showed at least some evidence for declines in abundance. Bee family explained variation in species‐level seasonal patterns but we found no consistent family‐level patterns in declines, though bumble bees and sweat bees were groups that declined the most. Overall, our results show that season‐wide standardized sampling across multiple years can reveal nuanced patterns in bee biodiversity, phenological patterns of bees, and population trends over time of many co‐occurring species. These datasets could be used to quantify the relative effects that different aspects of environmental change have on bee communities and to help identify species of conservation concern.

OBJECTIVES/GOALS: The aim of this study was to evaluate current and new anatomical approaches to treating obstructive sleep apnea (OSA) in patients who fail continuous positive airway pressure (CPAP). Understanding the breadth of devices and procedures increases clinical scope of practice and innovator opportunities. METHODS/STUDY POPULATION: A comprehensive review of literature, FDA approvals, patents, and commercially available technologies was undertaken with regards to anatomical approaches for treating OSA. These include experimental therapies, surgical approaches, and non-surgical ablative procedures. Oral appliances, positive airway pressure devices, and therapeutics were excluded. Key search terms included obstructive sleep apnea,’ anatomy,’ surgery,’ devices,’ experimental therapy,’ innovation,’ technology,’ and translational research.’ Publications were limited to the last five years. Innovations were evaluated for relevance to OSA treatment and then assessed in greater depth based on scientific literature. RESULTS/ANTICIPATED RESULTS: Numbers of preclinical and commercially available innovations pertinent to the anatomical treatment of OSA were reported along with clinically relevant outcome metrics. The greatest number of innovations was found in surgical approaches, including soft-tissue removal, orthognathic surgery, and electrical stimulation. Outcome parameters included safety, efficacy, patient compliance, and mean disease alleviation as a ratio of efficacy to compliance. Innovations were grouped by their intended anatomical targets including retrolingual, palatal, oropharyngeal, epiglottic, nasal, and complete concentric collapse, making special note of gaps in the treatment armamentarium. DISCUSSION/SIGNIFICANCE: In the last decade, sleep surgery has trended toward innovative CPAP alternatives. Nerve stimulation and ablative procedures have grown, but some anatomical presentations have been frequently excluded. These developments present opportunities for innovators to fill persistent gaps in treatment.

The exclusion of T cells from solid tumours is a potentially important mechanism that regulates whether or not cancer patients respond well to checkpoint blocking immunotherapies. Here the authors identify immune phenotypes and mediators of T cell exclusion among ovarian cancer patient samples from the ICON7 phase III trial.

Abstract Adopting the Standard Halo Model (SHM) of an isotropic Maxwellian velocity distribution for dark matter (DM) particles in the Galaxy, the most stringent current constraints on their spin-dependent scattering cross-section with nucleons come from the IceCube neutrino observatory and the PICO-60 $$\hbox {C}_3\hbox {F}_8$$ C 3 F 8 superheated bubble chamber experiments. The former is sensitive to high energy neutrinos from the self-annihilation of DM particles captured in the Sun, while the latter looks for nuclear recoil events from DM scattering off nucleons. Although slower DM particles are more likely to be captured by the Sun, the faster ones are more likely to be detected by PICO. Recent N-body simulations suggest significant deviations from the SHM for the smooth halo component of the DM, while observations hint at a dominant fraction of the local DM being in substructures. We use the method of Ferrer et al. (JCAP 1509: 052, 2015) to exploit the complementarity between the two approaches and derive conservative constraints on DM-nucleon scattering. Our results constrain $$\sigma _{\mathrm{SD}} \lesssim 3 \times 10^{-39} \mathrm {cm}^2$$ σ SD ≲ 3 × 10 - 39 cm 2 ( $$6 \times 10^{-38} \mathrm {cm}^2$$ 6 × 10 - 38 cm 2 ) at $$\gtrsim 90\%$$ ≳ 90 % C.L. for a DM particle of mass 1 TeV annihilating into $$\tau ^+ \tau ^-$$ τ + τ - ( $$b\bar{b}$$ b b ¯ ) with a local density of $$\rho _{\mathrm{DM}} = 0.3~\mathrm {GeV/cm}^3$$ ρ DM = 0.3 GeV / cm 3 . The constraints scale inversely with $$\rho _{\mathrm{DM}}$$ ρ DM and are independent of the DM velocity distribution.

Given the changes in the Irish economy since the economic crisis and, more specifically, reforms in the local government sector, this paper reassesses the financial position and fiscal sustainability of local authorities in Ireland. To do this we employ a local government financial performance framework that measures liquidity and solvency, but also operating performance and collection rates, for different sources of revenue income. Using financial data sourced from local council income and expenditure accounts and balance sheets, we report and analyse the financial position and performance during the 2007–17 period. The results indicate an improvement in the financial performance of local councils since the early 2010s. Cross-council differences persist, in particular, between large urban local authorities and smaller rural local authorities, albeit only for the liquidity and operating performance measures. Among the small rural councils, Sligo County Council’s financial position, although improving, remains a serious matter with ongoing consultation with and monitoring by central government. To help improve the measurement of local authority financial performance we recommend inclusion of this framework in the local authority Annual Financial Statement and also in the Performance Indicator Report with a view to making financial reports more accessible and transparent to citizens and taxpayers and, ultimately, to help improve performance and service delivery by the local authorities.

Adolescents who become pregnant during their secondary education experience a range of challenges that intersect and limit their opportunities to complete schooling and take up university places. One approach to addressing this issue at an Australian regional university is through the Tertiary Preparation Pathway (TPP) which has been delivered within the Supporting Teenagers with Education, Mothering, and Mentoring (STEMM) program, since 2008. The STEMM program offers teen mothers an opportunity to continue or re-engage with education during and beyond pregnancy. Adopting an intersectionality lens, interviews with adolescent mothers identified three key elements underpinning the success of the TPP/STEMM program: recognising the educational aspirations of teen mothers, developing agency and independence and promoting a strong sense of self. This article aims to provide practical implications for educators wishing to establish or develop programs based on this transformative teaching.

Abstract The Neutrino Mass Ordering (NMO) remains one of the outstanding questions in the field of neutrino physics. One strategy to measure the NMO is to observe matter effects in the oscillation pattern of atmospheric neutrinos above $$\sim 1\,\mathrm {GeV}$$ ∼1GeV , as proposed for several next-generation neutrino experiments. Moreover, the existing IceCube DeepCore detector can already explore this type of measurement. We present the development and application of two independent analyses to search for the signature of the NMO with three years of DeepCore data. These analyses include a full treatment of systematic uncertainties and a statistically-rigorous method to determine the significance for the NMO from a fit to the data. Both analyses show that the dataset is fully compatible with both mass orderings. For the more sensitive analysis, we observe a preference for normal ordering with a p-value of $$p_\mathrm {IO} = 15.3\%$$ pIO=15.3% and $$\mathrm {CL}_\mathrm {s}=53.3\%$$ CLs=53.3% for the inverted ordering hypothesis, while the experimental results from both analyses are consistent within their uncertainties. Since the result is independent of the value of $$\delta _\mathrm {CP}$$ δCP and obtained from energies $$E_\nu \gtrsim 5\,\mathrm {GeV}$$ Eν≳5GeV , it is complementary to recent results from long-baseline experiments. These analyses set the groundwork for the future of this measurement with more capable detectors, such as the IceCube Upgrade and the proposed PINGU detector.

Epithelial ovarian cancer (EOC) is a highly heterogeneous disease encompassing several distinct molecular subtypes and clinical entities. Despite the initial success of surgical debulking and adjuvant chemotherapy, recurrence with chemotherapy resistant tumors is common in patients with EOC and leads to poor overall survival. The extensive genetic and phenotypic heterogeneity associated with ovarian cancers has hindered the identification of effective prognostic and predictive biomarkers in EOC patients. In the current studies, we identify a tumor cell surface oncoantigen, chondroitin sulfate proteoglycan 4 (CSPG4), as an independent risk factor for decreased survival of patients with EOC. Our results show that CSPG4 promotes EOC cell invasion, cisplatin resistance and spheroid formation in vitro and tumor expansion in vivo. Mechanistically, spheroid formation and tumor cell invasion are due to CSPG4-stimulated expression of the mesenchymal transcription factor ZEB1. Furthermore, we have developed a novel monoclonal anti-CSGP4 antibody against the juxtamembrane domain of the core protein that limits CSPG4-stimulated ZEB1 expression, tumor cell invasion and promotes EOC apoptosis within spheroid cultures. We therefore propose that CSPG4 expression drives phenotypic heterogeneity and malignant progression in EOC tumors. These studies further demonstrate that CSPG4 expression levels are a potential diagnostic biomarker in EOC and indicate that targeting cells which express this oncoantigen could limit recurrence and improve outcomes in patients with EOC.

Many investigators have focused on the impact of fertilizers on crop yield and ignored fertilizers impact on the plants composition. The impact of seven types of soil treatments (sewage sludge, horse manure, chicken manure, vermicompost, elemental organic fertilizer, inorganic fertilizer, and native soil) and similar seven treatments amended with biochar on the concentrations of NH3 and NO3 in the roots and shoots of three commercial varieties of turnips, Brassica rapa was investigated. The three varieties (Purple Top White Globe PTWG, Scarlet Queen Red SQR, and Tokyo Cross TC) varied in concentrations of NH3 and NO3 levels. High levels of NO3 in edible plants is associated with harmful effects on human health, due to the risk of creation of carcinogenic N-nitroso compounds. NO3 in SQR roots and shoots (edible greens) was greater than varieties PTWG and TC. The concentration of NH3 averaged 20.2, 12.8, and 8.9 µg g−1 fresh turnip roots, whereas NO3 values averaged 107.6, 64.1, and 62.9 µg g−1 fresh turnip roots in varieties SQR, PTWG, and TC, respectively. Regardless of soil amendment type, the concentration of NH3 in the shoots (44.0 µg g−1) was greater than the roots (15 µg g−1). On the contrary, NO3 was higher in the roots (89.4 µg g−1) compared to the shoots (67.6 µg g−1 fresh tissue). Overall, biochar added to vermicompost amended soil increased NH3 by 73% compared to vermicompost not amended with biochar. Regarding acceptable daily intake (ADI) for NO3, none of the three varieties analyzed constitute any NO3 adverse effects on normal human intake. Similarly, consuming turnips grown in any of the animal manures tested do not represent any hazardous issues.

The years since the 2008 financial crisis and subsequent economic crash have witnessed significant changes to the funding of the local government system in Ireland. This paper outlines these developments, while, at the same time, exploring some of the most important future challenges relating to the financing of Irish local authorities. The dominant local government revenue issues of the last decade outlined here are fiscal autonomy and the balance between own-source income and central government grants, income differences between urban and rural councils, the Local Property Tax, changes in commercial rates and fiscal equalisation. In terms of fiscal dependency and equalisation, our findings show reductions in the vertical and horizontal fiscal imbalances in the Irish local government system. Likely future challenges include the need to re-examine the balance between business taxes and non-business taxes, funding the expected growth in metropolitan areas and the financing options for capital investment by local authorities, including consideration of municipal bond issuance for the Greater Dublin Area.

Objective:. To assess health care professionals’ attitudes on the Surgical Safety Checklist (“the Checklist”) in resource-rich health systems and provide insights on strategies for optimizing Checklist use. Background:. In use for over a decade, the Checklist is a safety instrument aimed at improving operating room communication, teamwork, and evidence-based safety practices. Methods:. An online survey was sent to surgeons, nurses, and anesthesiologists in 5 high-income countries (Canada, the United States, the United Kingdom, Australia, and New Zealand). Survey results were analyzed using SPSS. Results:. A total of 2032 health care professionals completed the survey. Of these respondents, 47.6% were nurses, 70.5% were women, 65.1% were from the United States, and 50.0% had 20 years of experience or more in their role. Most respondents felt the Checklist positively impacted patient safety (70.9%), team communication (73.1%), and teamwork (58.9%). Only 50.3% of respondents were satisfied their team’s use of the Checklist, and only 47.5% reported team members stopping to fully participate in the process. More nurses lacked confidence regarding their role in the Checklist process than surgeons and anesthesiologists combined (8.9% vs 4.3%). Fewer surgeons and anesthesiologists than nurses felt they received adequate training on the Checklist’s use (57.8% vs 76.7%). Conclusions:. While most respondents perceive the Checklist as enhancing patient safety, not all surgical team members are actively engaging with its use. To enhance buy-in and meaningful use of the Checklist, health systems should provide more training on the Checklist with respect to its purpose and strengthening teamwork.

Abstract Adenoviral‐vector based vaccines for coronavirus disease 2019 (COVID‐19) have been linked with a thrombotic syndrome, vaccine‐induced thrombotic thrombocytopenia (VITT). A key clinical question is whether VITT can be reliably ruled out by the absence of thrombocytopenia. We report on three patients who presented to our institute with this syndrome. Noteworthy in our presentations are two patients who presented for medical assessment of thrombotic symptoms with a normal platelet count, one preceding and one following a period of thrombocytopenia. Prompt diagnosis of VITT is critical to prevent rapid patient decline. We provide herein a new diagnostic algorithm that we believe will help optimally capture case presentations of VITT. These cases broaden and refine our understanding of the disease process and highlight to practitioners that VITT cannot be adequately ruled out by thrombocytopenia alone.

Introduction: Research capacity building is a critical component of professional development for pediatrician scientists, yet this process has been elusive in the literature. The ECHO IDeA States Pediatric Clinical Trials Network (ISPCTN) seeks to implement pediatric trials across medically underserved and rural populations. A key component of achieving this objective is building pediatric research capacity, including enhancement of infrastructure and faculty development. This article presents findings from a site assessment inventory completed during the initial year of the ISPCTN.Methods: An assessment inventory was developed for surveying ISPCTN sites. The inventory captured site-level activities designed to increase clinical trial research capacity for pediatrician scientists and team members. The inventory findings were utilized by the ISPCTN Data Coordinating and Operations Center to construct training modules covering 3 broad domains: Faculty/coordinator development; Infrastructure; Trials/Research concept development.Results: Key lessons learned reveal substantial participation in the training modules, the importance of an inventory to guide the development of trainings, and recognizing local barriers to clinical trials research.Conclusions: Research networks that seek to implement successfully completed trials need to build capacity across and within the sites engaged. Our findings indicate that building research capacity is a multi-faceted endeavor, but likely necessary for sustainability of a unique network addressing high impact pediatric health problems. The ISPCTN emphasis on building and enhancing site capacity, including pediatrician scientists and team members, is critical to successful trial implementation/completion and the production of findings that enhance the lives of children and families.

Vasoplegic syndrome, a possible complication of cardiopulmonary bypass, is a critical state of unregulated systemic vasodilation with decreased vascular resistance and a pathological insensitivity to conventional inotropes and vasoconstrictors. This case demonstrates the use of methylene blue and hydroxocobalamin as medications in the treatment of refractory vasoplegic syndrome in the context of cardiac surgery due to their differences in mechanism of action. A 24-year-old female with history of intravenous drug abuse and hepatitis C infection underwent mitral valve repair for infective endocarditis. Preoperative transesophageal echocardiography showed normal right ventricular function, left ventricular ejection fraction of 65%–75%, and severe mitral regurgitation with vegetation. In order to maintain a mean arterial pressure over 60 mmHg during cardiopulmonary bypass, norepinephrine, epinephrine, and vasopressin infusions were required. Given the patient’s minimal response to these medications, a 1.5 mg/kg bolus of intravenous methylene blue was also given intraoperatively; vasoplegic syndrome remained refractory in the post-cardiopulmonary bypass period. A 5 g dose of intravenous hydroxocobalamin was administered in the intensive care unit postoperatively. Postoperative liver function tests were abnormal, and post-cardiopulmonary bypass transesophageal echocardiography revealed mildly decreased right ventricular function. While in the intensive care unit, the patient was placed on venoarterial extracorporeal membrane oxygenation and underwent therapeutic plasma exchange. Vasopressors were weaned over the course of the next 24 h. The patient was able to be transferred out of the intensive care unit on postoperative day 5. Traditional vasoconstrictors activate signal transduction pathways that lead to myosin phosphorylation. Vasodilatory molecules such as nitric oxide (NO) activate the enzyme soluble guanylyl cyclase (sGC), ultimately leading to the dephosphorylation of myosin. Nitric Oxide Synthase (NOS) can potentially increase NO levels 1000-fold when activated by inflammatory cytokines. Methylene blue is a direct inhibitor of NOS. It also binds and inhibits sGC. Hydroxocobalamin is a direct inhibitor of NO, likely inhibits NOS and may also act through additional mechanisms.

Abstract Background Patients are increasingly recognized as playing important roles in improving health services. Little is known about the mechanisms by which patients develop and diffuse local innovations in a complex health‐care system. Objective To ascertain how diffusion of an innovation, My Medication Passport, occurred and roles played by patients in it. Design Case study: quantitative mapping of innovation's diffusion and analysis of the routes and occupations of those through whom the innovation spread; documentary analysis; reflective assessment of patient's roles. Setting and participants NHS Trusts, third sector organizations, patients and health‐care professionals. Interventions studied Co‐produced action to raise awareness and influence use of the innovation; order database which enabled ease of access to the innovation. Main outcome measures Geographical spread of innovation; occupations of individuals; types of organizations using the innovation. Results The innovation spread from initial development and use in Northwest London across the UK and beyond. Key roles played by patients were as follows: co‐producer; advocate; relationship builder; relationship broker; planner; presenter; awareness raiser; trainer; networker. Patients identified and introduced potential audiences and users to MMP, using social, organizational, sectoral, lay and professional networks to do so. They organized a range of awareness‐raising and communication activities, monitored feedback, evaluated the impact and responded to new interest. Discussion and conclusions The roles of patients in diffusing innovations are under‐recognized. Collaborative working between patients, carers and health‐care professionals in planning and progressing the use and supporting diffusion of the innovation was important. Principles described in this study are relevant to progressing other patient‐led ideas for innovative changes relating to health service development.

Abstract The IceCube Collaboration has observed a high-energy astrophysical neutrino flux and recently found evidence for neutrino emission from the blazar TXS 0506$$+$$ + 056. These results open a new window into the high-energy universe. However, the source or sources of most of the observed flux of astrophysical neutrinos remains uncertain. Here, a search for steady point-like neutrino sources is performed using an unbinned likelihood analysis. The method searches for a spatial accumulation of muon-neutrino events using the very high-statistics sample of about 497,000 neutrinos recorded by IceCube between 2009 and 2017. The median angular resolution is $$\sim 1^\circ $$ ∼1∘ at 1 TeV and improves to $$\sim 0.3^\circ $$ ∼0.3∘ for neutrinos with an energy of 1 PeV. Compared to previous analyses, this search is optimized for point-like neutrino emission with the same flux-characteristics as the observed astrophysical muon-neutrino flux and introduces an improved event-reconstruction and parametrization of the background. The result is an improvement in sensitivity to the muon-neutrino flux compared to the previous analysis of $$\sim 35\%$$ ∼35% assuming an $$E^{-2}$$ E-2 spectrum. The sensitivity on the muon-neutrino flux is at a level of $$E^2 \mathrm {d} N /\mathrm {d} E = 3\cdot 10^{-13}\,\mathrm {TeV}\,\mathrm {cm}^{-2}\,\mathrm {s}^{-1}$$ E2dN/dE=3·10-13TeVcm-2s-1 . No new evidence for neutrino sources is found in a full sky scan and in an a priori candidate source list that is motivated by gamma-ray observations. Furthermore, no significant excesses above background are found from populations of sub-threshold sources. The implications of the non-observation for potential source classes are discussed.

Abstract Background Decision making in health and social care requires robust syntheses of both quantitative and qualitative evidence. Meta-ethnography is a seven-phase methodology for synthesising qualitative studies. Developed in 1988 by sociologists in education Noblit and Hare, meta-ethnography has evolved since its inception; it is now widely used in healthcare research and is gaining popularity in education research. The aim of this article is to provide up-to-date, in-depth guidance on conducting the complex analytic synthesis phases 4 to 6 of meta-ethnography through analysis of the latest methodological evidence. Methods We report findings from a methodological systematic review conducted from 2015 to 2016. Fourteen databases and five other online resources were searched. Expansive searches were also conducted resulting in inclusion of 57 publications on meta-ethnography conduct and reporting from a range of academic disciplines published from 1988 to 2016. Results Current guidance on applying meta-ethnography originates from a small group of researchers using the methodology in a health context. We identified that researchers have operationalised the analysis and synthesis methods of meta-ethnography – determining how studies are related (phase 4), translating studies into one another (phase 5), synthesising translations (phase 6) and line of argument synthesis - to suit their own syntheses resulting in variation in methods and their application. Empirical research is required to compare the impact of different methods of translation and synthesis. Some methods are potentially better at preserving links with the context and meaning of primary studies, a key principle of meta-ethnography. A meta-ethnography can and should include reciprocal and refutational translation and line of argument synthesis, rather than only one of these, to maximise the impact of its outputs. Conclusion The current work is the first to articulate and differentiate the methodological variations and their application for different purposes and represents a significant advance in the understanding of the methodological application of meta-ethnography.

Abstract Aims The aim of this study was to provide guidance to improve the completeness and clarity of meta-ethnography reporting. Background Evidence-based policy and practice require robust evidence syntheses which can further understanding of people’s experiences and associated social processes. Meta-ethnography is a rigorous seven-phase qualitative evidence synthesis methodology, developed by Noblit and Hare. Meta-ethnography is used widely in health research, but reporting is often poor quality and this discourages trust in and use of its findings. Meta-ethnography reporting guidance is needed to improve reporting quality. Design The eMERGe study used a rigorous mixed-methods design and evidence-based methods to develop the novel reporting guidance and explanatory notes. Methods The study, conducted from 2015 to 2017, comprised of: (1) a methodological systematic review of guidance for meta-ethnography conduct and reporting; (2) a review and audit of published meta-ethnographies to identify good practice principles; (3) international, multidisciplinary consensus-building processes to agree guidance content; (4) innovative development of the guidance and explanatory notes. Findings Recommendations and good practice for all seven phases of meta-ethnography conduct and reporting were newly identified leading to 19 reporting criteria and accompanying detailed guidance. Conclusion The bespoke eMERGe Reporting Guidance, which incorporates new methodological developments and advances the methodology, can help researchers to report the important aspects of meta-ethnography. Use of the guidance should raise reporting quality. Better reporting could make assessments of confidence in the findings more robust and increase use of meta-ethnography outputs to improve practice, policy, and service user outcomes in health and other fields. This is the first tailored reporting guideline for meta-ethnography. This article is being simultaneously published in the following journals: Journal of Advanced Nursing, Psycho-oncology, Review of Education, and BMC Medical Research Methodology.

Deep-sea corals are important benthic inhabitants that support the biodiversity and function of the wider faunal community; however, their taxonomy is underdeveloped and their accurate identification is often difficult. In our study, we investigated the utility of a superextended (>3000 bp) barcode and explored the effectiveness of various molecular species delimitation techniques with an aim to put upper and lower bounds on the estimated number of calcaxonian species in Irish waters. We collected 112 calcaxonians (70 Keratoisididae, 22 Primnoidae, 20 Chrysogorgiidae) and one chelidonisid from the Irish continental slope and sequenced a 3390 bp DNA barcode comprising four mitochondrial regions (mtMutS, COI + igr1, 16S rRNA-ND2, and igr4), recovering 38 haplotypes. Individuals that shared a haplotype were often morphologically distinct, and we thus undertook detailed morphological work, including SEM of sclerites, on one representative of each morphotype within each haplotype. GMYC, bGMYC, and mPTP returned incongruent estimates of species numbers. In total, there are between 25 and 40 species, although no definitive number could be assigned, primarily due to poorly defined keratoisidid species boundaries. As expected, the superextended barcode provided greater discrimination power than single markers; bGMYC appeared to be the most effective delimiter. Among the identified species were Chelidonisis aurantiaca, collected deeper than previously known at 1507 m, and Calyptrophora clinata, recorded for the second time from the Northeast Atlantic. A full understanding of the diversity and distribution of calcaxonians requires substantial taxonomic work, but we highlight the Irish continental slope as harbouring significant diversity.

This paper sets out to establish the extent of austerity in the Irish local government system during and after the Great Recession. Austerity is measured by the adjusted change in local government expenditure from peak to trough years, and is analysed by type of expenditure, service division and local authority. Stripping out the change in local government current spending that is due to expenditure reassignments reveals that the austerity-related reduction in local government operating expenditure is not as large as often portrayed. As for other findings, there are sizeable differences across the aforementioned classifications, with, most notably, capital expenditure cuts far exceeding cuts in current expenditure. The largest decreases in total spending were on roads and housing services, and small rural county councils endured the most austerity, as measured by the initial reductions in current expenditure. In terms of policy implications, the biggest concern is the large infrastructural deficit that needs to be tackled, arising from austerity cuts in capital expenditure imposed at both central and local government level. As the economy recovers from the Great Recession and the subsequent era of austerity, failure to address this problem will hinder Ireland’s international competitiveness, constrain the economy’s future growth rate and result in impoverishment of public services at local level.

The cancer-associated fibroblast (CAF) marker podoplanin (PDPN) is generally correlated with poor clinical outcomes in cancer patients and thus represents a promising therapeutic target. Despite its biomedical relevance, basic aspects of PDPN biology such as its cellular functions and cell surface ligands remain poorly uncharacterized, thus challenging drug development. Here, we utilize a high throughput platform to elucidate the PDPN cell surface interactome, and uncover the neutrophil protein CD177 as a new binding partner. Quantitative proteomics analysis of the CAF phosphoproteome reveals a role for PDPN in cell signaling, growth and actomyosin contractility, among other processes. Moreover, cellular assays demonstrate that CD177 is a functional antagonist, recapitulating the phenotype observed in PDPN-deficient CAFs. In sum, starting from the unbiased elucidation of the PDPN co-receptome, our work provides insights into PDPN functions and reveals the PDPN/CD177 axis as a possible modulator of fibroblast physiology in the tumor microenvironment.

The cancer-associated fibroblast (CAF) marker podoplanin (PDPN) is generally correlated with poor clinical outcomes in cancer patients and thus represents a promising therapeutic target. Despite its biomedical relevance, basic aspects of PDPN biology such as its cellular functions and cell surface ligands remain poorly uncharacterized, thus challenging drug development. Here, we utilize a high throughput platform to elucidate the PDPN cell surface interactome, and uncover the neutrophil protein CD177 as a new binding partner. Quantitative proteomics analysis of the CAF phosphoproteome reveals a role for PDPN in cell signaling, growth and actomyosin contractility, among other processes. Moreover, cellular assays demonstrate that CD177 is a functional antagonist, recapitulating the phenotype observed in PDPN-deficient CAFs. In sum, starting from the unbiased elucidation of the PDPN co-receptome, our work provides insights into PDPN functions and reveals the PDPN/CD177 axis as a possible modulator of fibroblast physiology in the tumor microenvironment.