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IntroductionProfessional identity formation (PIF) is an ongoing, self-reflective process involving habits of thinking, feeling and acting like a physician and is an integral component of medical education. While qualitative work has suggested that PIF is informed by professionalism, resilience, and leadership, there is a dearth of quantitative work in this area. Multiple methods build rigor and the present study aimed to quantitatively assess the relative psychometric contributions of professionalism, resilience, and leadership constructs to informing PIF, using a latent factor analysis approach.MethodsWe analyzed data from the PILLAR study, which is an online cross-sectional assessment of a pre-clinical cohort of medical students in the RCSI University of Medicine and Health Sciences, Dublin, using established and validated quantitative measures in each area of interest: PIF, professionalism, leadership and resilience. A total of 76 items, combining four validated scales, along with a selection of demographic questions, were used. The hypothesis that PIF is informed by, and correlates with, professionalism, resilience and leadership was examined by conducting a confirmatory factor analysis of a proposed three-factor higher-order model. Model estimation used Maximum Likelihood Method (MLM) with geomin rotation. The hypothesized (measurement) model was examined against an alternative (saturated) model, as well as a three-factor model.ResultsLatent variable analysis from 1,311 students demonstrated that a three-factor higher-order model best fit the data; suggesting PIF is informed by professionalism, resilience, and leadership, and that these constructs are statistically distinct and account for differential aspects of PIF. This higher-order model of PIF outperformed both the saturated model and the three-factor model. The analysis of which component may be the most or least influential was inconclusive, and the overall model was not influenced by year of training.DiscussionBuilding upon existing conceptual contentions, our study is the first to quantitatively support the contribution of professionalism, resilience, and leadership to the development of professional identity, and to delineate the inter-relationships between PIF and these constructs. This information can be used by medical educators when designing curricula and educational strategies intended to enhance PIF. Future work should seek to assess the influence of these constructs longitudinally.

Abstract UBTF tandem duplications are recurrent in adult and paediatric acute myeloid leukaemia and have been reported to be associated with a poor prognosis. Co‐mutations in WT1 and FLT3 are common while morphological dysplasia is frequent. The role of UBTF‐TDs in leukemogenesis is yet to be elucidated; however they have been proposed as early initiating events, making them attractive for assessment of MRD and a potential therapeutic target. We present two cases where the UBTF‐TD was observed in remission and discuss the implications of these findings in the clinicobiological understanding of this emerging entity.

Abstract Background Right dorsal colitis (RDC) is a nonsteroidal anti‐inflammatory drug (NSAID) induced, protein losing enteropathy in horses associated with a high case fatality rate. Objectives To describe signalment, NSAID usage, clinical presentations, clinical pathology, ultrasonographic findings, treatments, outcomes, and factors associated with survival in horses diagnosed with RDC. Animals Thirty‐five horses from 7 Australian equine hospitals diagnosed with RDC. Methods Retrospective case series. Clinical records of cases were accepted if definitively or presumptively diagnosed by an internist with RDC and had ≥3 of: hypoproteinemia or hypoalbuminemia; diarrhea with negative test results for infectious diseases; colic for which other diseases were excluded or right dorsal colon thickening on ultrasound. Descriptive data analysis was performed for categorical and continuous variables. Univariate binominal logistic regressions were used to assess factors associated with survival. Results An overdose of NSAIDs occurred in 84% (21/25) cases where dose was known. Common clinical presentations included diarrhea (69%; 22/32), colic (61%; 20/33), and tachycardia (53%, 17/32). Common clinicopathological findings included hypoalbuminemia (83%; 26/31), hypocalcaemia (79%, 23/29), and hyperlactatemia (77%, 14/18). The right dorsal colon wall appeared subjectively thickened in 77% (24/31) cases using ultrasonography. Case fatality rate was 43% (15/35). Odds of survival significantly decreased with increasing heart rate (odds 0.84, 95% CI = 0.71‐0.92, P = .01), packed cell volume (odds 0.91, 95% CI 0.82‐0.98, P = .05) and abnormal appearance of mucous membranes (odds 0.05, 95% CI 0.005‐0.28, P = .001) on hospital presentation. Conclusions and Clinical Importance An overdose of NSAIDs is common in horses diagnosed with RDC. Serum albumin concentrations should be monitored in horses receiving a prolonged course of NSAIDs. Overall prognosis for RDC remains fair.

Abstract A significant proportion of the infant gut microbiome is considered to be acquired from the mother during and after birth. Thus begins a lifelong and dynamic relationship with microbes that has an enduring impact on host health. Based on a cohort of 135 mother-infant (F = 72, M = 63) dyads (MicrobeMom: ISRCTN53023014), we investigated the phenomenon of microbial strain transfer, with a particular emphasis on the use of a combined metagenomic-culture-based approach to determine the frequency of strain transfer involving members of the genus Bifidobacterium, including species/strains present at low relative abundance. From the isolation and genome sequencing of over 449 bifidobacterial strains, we validate and augment metagenomics-based evidence to reveal strain transfer in almost 50% of dyads. Factors important in strain transfer include vaginal birth, spontaneous rupture of amniotic membranes, and avoidance of intrapartum antibiotics. Importantly, we reveal that several transfer events are uniquely detected employing either cultivation or metagenomic sequencing, highlighting the requirement for a dual approach to obtain an in-depth insight into this transfer process.

Introduction The COVID-19 pandemic significantly disrupted primary healthcare globally, with particular impacts on diabetes and hypertension care. This review will examine the impact of pandemic disruptions of diabetes and hypertension care services and the evidence for interventions to mitigate or reverse pandemic disruptions in the Latin America and Caribbean (LAC) region.Methods and analyses This scoping review will examine care delivery disruption and approaches for recovery of primary healthcare in the LAC region during the COVID-19 pandemic, focusing on diabetes and hypertension awareness, detection, treatment and control. Guided by Arksey and O’Malley’s scoping review methodology framework, this protocol adheres to the Joanna Briggs Institute guidelines for scoping review protocols and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidance for protocol development and scoping reviews. We searched MEDLINE, CINAHL, Global Health, Embase, Cochrane, Scopus, Web of Science and LILACS for peer-reviewed literature published from 2020 to 12 December 2022 in English, Spanish or Portuguese. Studies will be considered eligible if reporting data on pandemic disruptions to primary care services within LAC, or interventions implemented to mitigate or reverse pandemic disruptions globally. Studies on COVID-19 or acute care will be excluded. Two reviewers will independently screen each title/abstract for eligibility, screen full texts of titles/abstracts deemed relevant and extract data from eligible full-text publications. Conflicts will be resolved through discussion and with the help of a third reviewer. Appropriate analytical techniques will be employed to synthesise the data, for example, frequency counts and descriptive statistics. Quality will be assessed using the Newcastle Ottawa Quality Assessment Scale.Ethics and dissemination No ethics approval was needed as this is a scoping review of published literature. Results will be disseminated in a report to the World Bank and the Pan American Health Organization, in peer-reviewed scientific journals, and at national and international conferences.

Abstract Background Establishing an effective continuum of care is a pivotal part of providing support for older populations. In contemporary practice; however, a subset of older adults experience delayed entry and/or are denied access to appropriate care. While previously incarcerated older adults often face barriers to accessing health care services to support community reintegration, there has been limited research on their transitions into long-term care. Exploring these transitions, we aim to highlight the challenges of securing long-term care services for previously incarcerated older adults and shed light on the contextual landscape that reinforces the inequitable care of marginalized older populations across the care continuum. Methods We performed a case study of a Community Residential Facility (CRF) for previously incarcerated older adults which leverages best practices in transitional care interventions. Semi-structured interviews were conducted with CRF staff and community stakeholders to determine the challenges and barriers of this population when reintegrating back into the community. A secondary thematic analysis was conducted to specifically examine the challenges of accessing long-term care. A code manual representing the project themes (e.g., access to care, long-term care, inequitable experiences) was tested and revised, following an iterative collaborative qualitative analysis (ICQA) process. Results The findings indicate that previously incarcerated older adults experience delayed access and/or are denied entry into long-term care due to stigma and a culture of risk that overshadow the admissions process. These circumstances combined with few available long-term care options and the prominence of complex populations already in long-term care contribute to the inequitable access barriers of previously incarcerated older adults seeking entry into long-term care. Conclusions We emphasize the many strengths of utilizing transitional care interventions to support previously incarcerated older adults as they transition into long-term care including: 1) education & training, 2) advocacy, and 3) a shared responsibility of care. On the other hand, we underscore that more work is needed to redress the layered bureaucracy of long-term care admissions processes, the lack of long-term care options and the barriers imposed by restrictive long-term care eligibility criteria that sustain the inequitable care of marginalized older populations.

Background Modern psychometric methods make it possible to eliminate nonperforming items and reduce measurement error. Application of these methods to existing outcome measures can reduce variability in scores, and may increase treatment effect sizes in depression treatment trials. Aims We aim to determine whether using confirmatory factor analysis techniques can provide better estimates of the true effects of treatments, by conducting secondary analyses of individual patient data from randomised trials of antidepressant therapies. Method We will access individual patient data from antidepressant treatment trials through Clinicalstudydatarequest.com and Vivli.org, specifically targeting studies that used the Hamilton Rating Scale for Depression (HRSD) as the outcome measure. Exploratory and confirmatory factor analytic approaches will be used to determine pre-treatment (baseline) and post-treatment models of depression, in terms of the number of factors and weighted scores of each item. Differences in the derived factor scores between baseline and outcome measurements will yield an effect size for factor-informed depression change. The difference between the factor-informed effect size and each original trial effect size, calculated with total HRSD-17 scores, will be determined, and the differences modelled with meta-analytic approaches. Risk differences for proportions of patients who achieved remission will also be evaluated. Furthermore, measurement invariance methods will be used to assess potential gender differences. Conclusions Our approach will determine whether adopting advanced psychometric analyses can improve precision and better estimate effect sizes in antidepressant treatment trials. The proposed methods could have implications for future trials and other types of studies that use patient-reported outcome measures.

Roses (Rosa spp. L.) are valuable horticultural crops with global production, markets, and utilization. Cytogenetics of roses can be complicated with variation in ploidy among species and hybrids and occurrence of unreduced gametes, unbalanced (canina) meiosis, and aneuploidy. Most modern rose cultivars are complex, interspecific hybrids with unknown ploidy. Despite most breeding efforts being focused on crossing cultivated varieties, the genome size information is often only available at the generalized species level. The goal of this study was to survey cultivars and breeding lines to determine relative genome sizes and ploidy levels. Flow cytometry was used to determine relative genome size and ploidy levels of 174 accessions of shrub, hybrid tea, grandiflora, floribunda, polyantha, R. chinensis, and R. rugosa cultivars and breeding lines. Chromosome counts were performed to calibrate relative genome size to ploidy level and confirm previously published ploidy reports. 1Cx relative genome size ranged from 0.46 to 0.64 pg and the 2C relative genome size ranged from 0.96 pg to 1.28 pg for diploids, 1.38 to 1.86 pg for triploids, and 1.87 to 2.50 pg for tetraploids when using DAPI fluorochrome and Pisum sativum 'Ctirad' as the internal standard. Chromosome counts further substantiated these ranges and confirmed ploidy of cultivars that were in disagreement with earlier reports for three cultivars. These results provide an extensive database of genome sizes and ploidy for diverse cultivars and breeding lines of rose and establish/validate flow cytometry methods for future applications.

Abstract Understanding prostate cancer onset and progression in order to rationally treat this disease has been critically limited by a dire lack of relevant pre-clinical animal models. We have generated a set of genetically engineered mice that mimic human prostate cancer, initiated from the gland epithelia. We chose driver gene mutations that are specifically relevant to cancers of young men, where aggressive disease poses accentuated survival risks. An outstanding advantage of our models are their intact repertoires of immune cells. These mice provide invaluable insight into the importance of immune responses in prostate cancer and offer scope for studying treatments, including immunotherapies. Our prostate cancer models strongly support the role of tumour suppressor p53 in functioning to critically restrain the emergence of cancer pathways that drive cell cycle progression; alter metabolism and vasculature to fuel tumour growth; and mediate epithelial to mesenchymal-transition, as vital to invasion. Importantly, we also discovered that the type of p53 alteration dictates the specific immune cell profiles most significantly disrupted, in a temporal manner, with ramifications for disease progression. These new orthotopic mouse models demonstrate that each of the isogenic hotspot p53 amino acid mutations studied (R172H and R245W, the mouse equivalents of human R175H and R248W respectively), drive unique cellular changes affecting pathways of proliferation and immunity. Our findings support the hypothesis that individual p53 mutations confer their own particular oncogenic gain of function in prostate cancer.

Objectives To describe the characteristics of clinical study report (CSR) documents published by the European Medicines Agency (EMA), and for included pivotal trials, to quantify the timeliness of access to trial results from CSRs compared with conventional published sources.Design Cross-sectional analysis of CSR documents published by the EMA from 2016 to 2018.Methods CSR files and medication summary information were downloaded from the EMA. Individual trials in each submission were identified using document filenames. Number and length of documents and trials were determined. For pivotal trials, trial phase, dates of EMA document publication and matched journal and registry publications were obtained.Results The EMA published documents on 142 medications that were submitted for regulatory drug approval. Submissions were for initial marketing authorisations in 64.1%. There was a median of 15 (IQR 5–46) documents, 5 (IQR 2–14) trials and 9629 (IQR 2711–26,673) pages per submission, and a median of 1 (IQR 1–4) document and 336 (IQR 21–1192) pages per trial. Of all identified pivotal trials, 60.9% were phase 3 and 18.5% were phase 1. Of 119 unique submissions to the EMA, 46.2% were supported by a single pivotal trial, with 13.4% based on a single pivotal phase 1 trial. No trial registry results were identified for 26.1% trials, no journal publications for 16.7% and 13.5% of trials had neither. EMA publication was the earliest information source for 5.8% of pivotal trials, available a median 523 days (IQR 363–882 days) before the earliest publication.Conclusions The EMA Clinical Data website contains lengthy clinical trial documents. Almost half of submissions to the EMA were based on single pivotal trials, many of which were phase 1 trials. CSRs were the only source and a timelier source of information for many trials. Access to unpublished trial information should be open and timely to support decision-making for patients.

Genotype-by-environment interaction (G × E) is a common phenomenon influencing genetic improvement in plants, and a good understanding of this phenomenon is important for breeding and cultivar deployment strategies. However, there is little information on G × E in horticultural tree crops, mostly due to evaluation costs, leading to a focus on the development and deployment of locally adapted germplasm. Using sweetness (measured as soluble solids content, SSC) in peach/nectarine assessed at four trials from three US peach-breeding programs as a case study, we evaluated the hypotheses that (i) complex data from multiple breeding programs can be connected using GBLUP models to improve the knowledge of G × E for breeding and deployment and (ii) accounting for a known large-effect quantitative trait locus (QTL) improves the prediction accuracy. Following a structured strategy using univariate and multivariate models containing additive and dominance genomic effects on SSC, a model that included a previously detected QTL and background genomic effects was a significantly better fit than a genome-wide model with completely anonymous markers. Estimates of an individual’s narrow-sense and broad-sense heritability for SSC were high (0.57–0.73 and 0.66–0.80, respectively), with 19–32% of total genomic variance explained by the QTL. Genome-wide dominance effects and QTL effects were stable across environments. Significant G × E was detected for background genome effects, mostly due to the low correlation of these effects across seasons within a particular trial. The expected prediction accuracy, estimated from the linear model, was higher than the realised prediction accuracy estimated by cross-validation, suggesting that these two parameters measure different qualities of the prediction models. While prediction accuracy was improved in some cases by combining data across trials, particularly when phenotypic data for untested individuals were available from other trials, this improvement was not consistent. This study confirms that complex data can be combined into a single analysis using GBLUP methods to improve understanding of G × E and also incorporate known QTL effects. In addition, the study generated baseline information to account for population structure in genomic prediction models in horticultural crop improvement.

Clostridioides difficile poses an ongoing threat as a cause of gastrointestinal disease in humans and animals. Traditionally considered a human healthcare-related disease, increases in community-associated C. difficile infection (CDI) and growing evidence of inter-species transmission suggest a wider perspective is required for CDI control. In horses, C. difficile is a major cause of diarrhoea and life-threatening colitis. This study aimed to better understand the epidemiology of CDI in Australian horses and provide insights into the relationships between horse, human and environmental strains. A total of 752 faecal samples from 387 Western Australian horses were collected. C. difficile was isolated from 104 (30.9%) horses without gastrointestinal signs and 19 (37.8%) with gastrointestinal signs. Of these, 68 (55.3%) harboured one or more toxigenic strains, including C. difficile PCR ribotypes (RTs) 012 (n = 14), 014/020 (n = 10) and 087 (n = 7), all prominent in human infection. Whole-genome analysis of 45 strains identified a phylogenetic cluster of 10 closely related C. difficile RT 012 strains of equine, human and environmental origin (0–62 SNP differences; average 23), indicating recent shared ancestry. Evidence of possible clonal inter-species transmission or common-source exposure was identified for a subgroup of three horse and one human isolates, highlighting the need for a One Health approach to C. difficile surveillance.

A well designed observing network is vital to improve our understanding of the oceans and to obtain better predictions of the future. As autonomous marine technology develops, the potential for deploying large autonomous observing systems becomes feasible. Though there are many design considerations to take into account (according to the target data use cases), a fundamental requirement is to take observations that capture the variability at the appropriate length scales. In doing so, a balance must be struck between the limited observation resources available and how well they are able to represent different areas of the ocean. In this paper we present and evaluate a new method to aid decision makers in designing near-optimal observing networks. The method uses ideas from set theory to recommend an irregular network of observations which provides a guaranteed level of representation (correlation) across a domain. We show that our method places more observations in areas with smaller characteristic length scales and vice versa, as desired. We compare the method to two other grid types: regular and randomly allocated observation locations. Our new method is able to provide comparable average representation of data across the domain, whilst efficiently targeting resource to regions with shorter length scale and thereby elevating the minimum skill baseline, compared to the other two grid types. The method is also able to provide a network that represents up to 15% more of the domain area. Assessing error metrics such as Root Mean Square Error and correlation shows that our method is able to reconstruct data more consistently across all length scales, especially at smaller scales where we see RMSE 2-3 times lower and correlations of over 0.2 higher. We provide an additional discussion on the variability inherent in such methods as well as practical advice for the user. We show that considerations must be made based on time filtering, seasonality, depth and horizontal resolution.

Equine respiratory physiology might be influenced by the presence of an endotracheal tube (ETT). This experimental, randomized cross-over study aimed to compare breathing pattern (BrP) and ventilation distribution in anesthetized horses spontaneously breathing room air via ETT or facemask (MASK). Six healthy adult horses were anesthetized with total intravenous anesthesia (TIVA; xylazine, ketamine, guaiphenesin), breathing spontaneously in right lateral recumbency, and randomly assigned to ETT or MASK for 30 min, followed by the other treatment for an additional 30 min. During a second anesthesia 1 month later, the treatment order was inversed. Electrical impedance tomography (EIT) using a thoracic electrode belt, spirometry, volumetric capnography, esophageal pressure difference (ΔPoes), venous admixture, and laryngoscopy data were recorded over 2 min every 15 min. Breaths were classified as normal or alternate (sigh or crown-like) according to the EIT impedance curve. A mixed linear model was used to test the effect of treatment on continuous outcomes. Cochran-Mantel-Haenszel analysis was used to test for associations between global BrP and treatment. Global BrP was associated with treatment (p = 0.012) with more alternate breaths during ETT. The center of ventilation right-to-left (CoVRL) showed more ventilation in the non-dependent lung during ETT (p = 0.025). The I:E ratio (p = 0.017) and ΔPoes (p < 0.001) were smaller, and peak expiratory flow (p = 0.009) and physiologic dead space (p = 0.034) were larger with ETT. The presence of an ETT alters BrP and shifts ventilation toward the non-dependent lung in spontaneously breathing horses anesthetized with TIVA.

Ten phenological and fruit quality traits were evaluated in seedlings from nine F1 low to medium chill full-sib peach (Prunus persica) families and their parents over 2 years at two locations (Fowler, CA, and College Station, TX) to estimate variance components, genotype by environment interaction (G×E), and phenotypic correlations using restricted maximum likelihood mixed and multivariate models. The removal of nectarine [P. persica var. nucipersica (fruit without fuzz)] and pantao (flat shape fruit) seedlings from the analysis decreased the heritability for the fruit size, blush, tip, and soluble solids concentration (SSC), indicating the importance of taking the effects of the major gene of nectarine/pantao into account when assessing the heritability of traits. A strong correlation coefficient (r = 0.92) found between ripe date (RD) and fruit development period (FDP) and between fruit weight (FW) and fruit diameter (FD), indicates that either measure is equally effective, although the negative correlation between bloom date (BD) and FDP (r = −0.46) implies earlier blooming during cool temperatures tends to extend FDP. FW, FD, blush, and SSC had moderately weak correlations with RD (r = 0.56, 0.53, −0.41, and 0.48) and FDP (r = 0.57, 0.56, −0.50, and 0.39, respectively), which could be explained either by the presence of a strong link between quantitative trait loci of these traits and the ripening date locus or the pleiotropic effect of ripening date on many quantitative fruit characters. The traits RD, FDP, and titratable acidity (TA) had the highest broad-sense heritability (H2) and lowest G×E. FW, tip, and shape showed the lowest H2, the highest of G×E variance to the genetic F (G×E variance/total genotypic variance), and high G×E, whereas the other traits showed moderate G×E. For the traits that had a higher G×E interaction, selection for or against these traits should be done at the production location. A moderate narrow-sense heritability (h2) was estimated for BD, blush, fruit tip, and shape. FW and FD showed low to moderate h2 while H2 was high, whereas RD, FDP, SSC, and TA showed low h2 and high H2 estimates, indicating important nonadditive effects for these traits.

The sharp decline in levels of state-funded legal support has highlighted the importance of publicly available sources of legal information for facilitating access to justice. Mobile apps present an opportunity to provide legal information that can be targeted at particular audiences. University law schools, sometimes in partnership with civil society organisations, are beginning to engage their students in cross-disciplinary projects to create mobile apps, which can provide free legal information and guidance to the public.The aim of this case study was to evaluate one such project which involved the co-design of a mobile app for the purpose of disseminating information on employment law. Law, education and computing academics worked with undergraduate law students over a period of 3 months and the prototype app was reviewed by legal advice charities. The findings have implications for how universities can work across disciplines and in partnership with civil society to provide opportunities for their students to use technology to apply their disciplinary knowledge to enhance the public good.

Educators' attitudes toward Social and Emotional Learning (SEL) and health and wellbeing promotion can significantly influence the success (or otherwise) of such policies and practices. While numerous studies exist, from which a broad understanding of such attitudes can be garnered, there is currently no attendant measurement which quantifies educators attitudes regarding the promotion of student wellbeing. The aim of this study was to address this gap in knowledge by quantifying the degree to which educators are positively or negatively disposed to the promotion of student wellbeing. The Attitudes Toward Wellbeing Promotion (ATWP) scale was administered to a diverse participant sample (n = 324), which was opportunistically recruited from the population of post-primary educators in Ireland. Analyses using General Linear Modelling (GLM) identified several statistically significant differences in attitude. Main effects included position held in school and the presence/absence of practices such as streaming and vertical education, while Interactions included educator gender*age and educator gender*single-sex/co-educational school status. The results of this study suggest that, overall, educators appear to be positively disposed toward the promotion of student wellbeing. The highest levels of positivity were observed among female educators, particularly those working in all-girls schools. The lowest levels of positivity were observed among older male educators and educators working in schools that adopt streaming and vertical education practices. This study provides the first baseline data pertaining to the degree to which post-primary educators may be positively or negatively disposed to the promotion of students' social and emotional wellbeing.

Background: The pharmaceutical industry invests heavily in promoting medications to physicians. This promotion may influence physicians’ prescribing behaviour and lead to inappropriately increased prescribing rates. Aim: To understand GPs’ experience of interacting with the pharmaceutical industry, and explore their views and perceptions of the impact of this interaction in general practice in Ireland. Design & setting: A qualitative design was used, and GPs practicing in Ireland were eligible. Method: A combination of purposive and snowball sampling techniques was applied and semi-structured interviews were conducted. Thematic analysis was used to develop themes from the data. Results: Twenty-one GPs and one GP trainee participated. Five themes were developed: 1) GP and pharmaceutical industry interface; 2) the industry’s methods of influence; 3) the uncomfortable relationship between GPs and industry; 4) GPs’ perceptions of being unconsciously influenced; and 5) GPs’ lack of knowledge of relevant regulations. Participants interacted with pharmaceutical representatives in their surgery and through continuing professional development (CPD). Reported methods of influence included biased information and the offer of gifts. Most participants felt their prescribing was unconsciously influenced. A minority felt that they were only influenced in a way that improved their prescribing. Conclusion: The study shows that there can be a lack of clarity among GPs about relevant regulations and about the potential impact on prescribing of interactions with the pharmaceutical industry. Education of trainees and GPs has the potential to address this. Restrictions on interactions with the pharmaceutical industry may also play a role, although alternative CPD funding sources would need to be established.

Background: Potentially inappropriate care can result from overuse or underuse of treatments, tests, or procedures. Overuse is defined as the use of health services with no clear benefit to the recipient or where harms outweigh benefits and/or costs of care. Underuse is defined as failure to deliver an effective and cost-effective healthcare intervention. Cardiovascular procedures such as coronary artery bypass grafting, carotid endarterectomy, coronary angiography, and coronary angioplasty (with/without stenting) are potentially both underused and overused. This systematic review aims to identify rates of potential overuse and underuse of these cardiovascular procedures and explore any associated patient or healthcare system factors. Methods: A systematic review and meta-analysis will be conducted in accordance with the PRISMA guidelines. A systematic search of MEDLINE (via Ovid), Embase, Cumulative Index to Nursing and Allied Health Literature and the Cochrane library will be conducted using a predefined search strategy. Eligible studies for inclusion will examine rates of overuse and underuse of cardiovascular procedures, measured against national/international guidelines, for adults aged ≥18 years. Primary observational studies including cross-sectional and cohort studies will be included. Titles, abstracts, and full texts will be screened for inclusion by two reviewers. Data will be extracted using a standardised form. Risk of bias for all included studies will be assessed using a modified version of the Hoy risk of bias tool. Where adequate data exists, and if statistically appropriate, meta-analyses will be conducted. If statistical pooling of the data is not possible, the findings will be narratively summarised focusing on the review’s objectives. Conclusion: This systematic review will examine overuse and underuse of cardiovascular procedures for adults. The results will help inform policy makers, researchers, patients, and clinicians in the appropriate use of these procedures, in line with international guidelines. Registration: This protocol has been submitted for registration on PROSPERO (CRD42021239041).

Background: Sacubitril/valsartan is a first-in-class angiotensin-receptor neprilysin inhibitor used to treat heart failure. The evidence for this novel medication is largely based on one pivotal phase III trial which was stopped early due to significant clinical benefits being shown. However potential limitations in trial design have been highlighted in recent literature, necessitating a thorough review of all evidence for sacubitril/valsartan. Methods: This review will be conducted using the PRISMA reporting guidelines. Relevant randomised controlled trials (RCTs) for sacubitril/valsartan will be systematically searched for in Medline (PubMed), Embase, Cochrane library, Google Scholar, Web of Science, Toxline and Scopus. Clinical trials registries will be searched, as will eight grey literature databases. In addition, unpublished clinical study reports (CSRs) of relevant trials will be requested from the European Medicines Agency (EMA) and the Clinical Study Data Request database. Studies will be included if they involve randomising adult patients with heart failure to either sacubitril/valsartan or usual care, with either an active comparator or placebo as a control. Heart failure of any subtype or NYHA class will be included. All relevant clinical and safety outcomes will be reviewed, particularly hospitalisation due to heart failure and cardiovascular mortality. Two reviewers will assess eligibility of selected studies for inclusion. Data extraction will be performed separately for trial publications, clinical trial registries and for CSRs using a piloted form. Methodological quality of included trials from published sources will be assessed separately using the Cochrane Risk of Bias tool (RoB 2). Narrative synthesis of included studies will be conducted and, if appropriate, meta-analysis for clinical efficacy and safety outcomes. Discussion: This review will collate all available RCT data on sacubitril/valsartan including published and unpublished sources in order to obtain a more complete picture of the evidence base for sacubitril/valsartan. Registration: This protocol is registered on PROSPERO (reference CRD42020162031).

Purpose: The success of measures aimed at promoting student health and wellbeing is greatly informed by the attitudes and perceptions of the educators assigned to implement these measures. The aim of this study was to examine the attitudes of post-primary educators in Ireland regarding the promotion of student wellbeing. Method: Semi-structured interviews (n = 11) were conducted with post-primary educators located across the Republic of Ireland. Data was analysed using reflexive thematic analysis. Results: Analysis resulted in the interpretation of five themes related to best practice, the value of wellbeing promotion, work-related time constraints, an atheoretical approach to wellbeing promotion and educators’ accounts of their own wellbeing. Participants shared numerous concerns regarding their ability to attend to student wellbeing, principal among which were a lack of appropriate training, work-related time constraints and a potential systematic de-valuing of the wellbeing curriculum relative to the core curriculum. Conclusion: It is recommended that appropriate accreditation be necessary in order to register to teach any aspect of the wellbeing curriculum, and that a requisite wellbeing-orientated knowledge and skillset be mandatory for all educators in order to register as a post-primary teacher with the teaching council in Ireland.

Background: There has been a policy shift towards public and patient involvement (PPI) in population health and health services research in Ireland and internationally. Despite growing evidence that PPI can have positive impacts on the quality and appropriateness of health research, little is known about the involvement and impact of older adults as research partners. The aim of this study is to 1) describe the process of establishing a PPI panel of older adults, family carers and ageing research academics and 2) to evaluate the impact of this research partnership on all research partners. Methods: A partnership-focused framework will guide the recruitment and establishment of a PPI panel of older adults, family carers and academic researchers. Eight to ten older adults and four to six family carers with experience of using health services will be recruited through gatekeepers in a range of non-governmental, voluntary, and community organisations in the Mid-West region of Ireland. Academic researchers will be recruited through the Ageing Research Centre at the University of Limerick. To evaluating the impact of the research partnership on all members of the PPI panel we propose to record an activity log, maintain a record of all meeting, panel discussions and conduct individual interviews with all members of the research team at key time points. The final plan for evaluation will be negotiated and agreed with all members of the PPI panel. Data will be transcribed, managed in NVivo and analysed using an inductive approach to thematic analysis. Dissemination of research findings will be facilitated by the research partnership team of academics and older adults. Discussion: This study will identify learning about the process of establishing a PPI panel guided by a partnership-focused framework and will evaluate the impact of participation in a PPI panel for all members of the research team.

Background: Sacubitril/valsartan is a first-in-class angiotensin-receptor neprilysin inhibitor used to treat heart failure with reduced ejection fraction. The evidence base for this novel medication is largely based on one pivotal phase III trial which was stopped early due to significant clinical benefits being shown. However potential limitations in the trial design have been highlighted in recent medical literature, necessitating a thorough review of the evidence base for sacubitril/valsartan. Methods: This review will be conducted using the PRISMA reporting guidelines. Relevant randomised controlled trials (RCTs) for sacubitril/valsartan will be systematically searched for in Medline (PubMed), Embase, Cochrane library, Google Scholar, Web of Science, Toxline and Scopus. Clinical trials registries will be searched, as will eight grey literature databases. In addition, unpublished clinical study reports (CSRs) of relevant trials will be requested from the European Medicines Agency (EMA) and the Clinical Study Data Request database. Studies will be included if they involve randomising adult patients with heart failure to either sacubitril/valsartan or usual care with either an active comparator or placebo as a control. All relevant clinical and safety outcomes will be reviewed, particularly hospitalisation due to heart failure and cardiovascular mortality. Two reviewers will assess eligibility of selected trials for inclusion. Data extraction will be performed separately for trial publications, clinical trial registries and for CSRs using a piloted form. Methodological quality of included trials from published sources will be assessed separately using the recently updated Cochrane Risk of Bias tool version 2. Narrative synthesis of included studies will be conducted and, if appropriate, meta-analysis for clinical efficacy and safety outcomes. Discussion: This review will collate all available RCT data on sacubitril/valsartan including published and unpublished sources in order to obtain a more complete picture of the evidence base for sacubitril/valsartan. Registration: This protocol has been submitted for registration on PROSPERO.

Abstract Objectives Tumor‐infiltrating lymphocytes (TIL), particularly CD8+ TILs in patients with colorectal cancer (CRC), are highly prognostic in the early‐disease stages (I‐II). In metastatic disease (stage IV; mCRC), their influence is less well defined. It has presumably failed to contain tumor cells to the primary site; however, is this evident? We explored the prognostic impact of TILs at the primary site in patients who presented de novo with mCRC. Methods Treatment‐naïve patients (109) with mCRC were assessed for CD8+ TILs and PD‐L1 expression. Microsatellite instability (MSI) was evaluated by IHC for PMS2 and MSH6 proteins and/or by PCR using the Bethesda panel. Results Microsatellite instability‐high tumors had significantly more CD8+ TILs, with no significant survival advantage observed between MSI‐H and microsatellite stable (MSS) tumors (12 vs 19 months, P = 0.304). TIL density for all cases had no impact on OS (low: 20 vs high: 13 months, P = 0.426), while PD‐L1 of 1% or higher was associated with reduced mean survival (9.6 vs 18.9 months; P = 0.038). MSI‐H tumors and associated immune cells had higher PD‐L1 expression than in MSS cases. A positive correlation between PD‐L1 on immune cells and CD8+ve TILs was found. A subset of MSS tumors had relatively high TILs approximating that of MSI‐H tumors. Conclusion In contrast to early‐stage CRC, the immune response in primary tumors of patients with de novo mCRC does not appear to influence survival. A subgroup of MSS tumors was identified with increased TILs/PD‐L1 comparable to MSI‐H tumors, traditionally not be considered for immune checkpoint blockade and perhaps should be.

This article reassesses the link between ICT prices, technology, and productivity. To understand how the ICT sector could come to the rescue of a whole economy, a multi-sector model developed by Oulton (2012) is extended to include ICT services and used to calibrate the steady-state contribution of the ICT sector to growth in aggregate U.S. labour productivity. The extended model also has implications for the relationship between prices for ICT services and prices for the ICT assets used to supply them, namely, that, ICT service prices may diverge from ICT asset prices and reflect productivity gains from ICT asset management by the sector. All told, because ICT technologies increasingly diffuse through the economy via purchased services (e.g. cloud services, data analytic services), they are not fully accounted for in the standard narrative of ICT’s contribution to economic growth. When this omission is corrected and the price indexes for ICT assets developed in Byrne and Corrado (2017a) are used to indicate the relative productivity of the ICT sector, its contribution to potential labour productivity growth is estimated to be substantially larger than generally thought — 1.4 percentage points per year.

Abstract Unlocking clinically translatable genomic information, including copy number alterations (CNA), from formalin-fixed paraffin-embedded (FFPE) tissue is challenging due to low yields and degraded DNA. We describe a robust, cost-effective low-coverage whole genome sequencing (LC WGS) method for CNA detection using 5 ng of FFPE-derived DNA. CN profiles using 100 ng or 5 ng input DNA were highly concordant and comparable with molecular inversion probe (MIP) array profiles. LC WGS improved CN profiles of samples that performed poorly using MIP arrays. Our technique enables identification of driver and prognostic CNAs in archival patient samples previously deemed unsuitable for genomic analysis due to DNA limitations.

Conventional approaches to causation in the social sciences draw on approaches in the Philosophy of Science in which a causal force acts on cases and generates change in the form of events. This relies on just one of the Aristotelian conceptions of cause - efficient cause - what brings the effect in to being. We should also pay attention to Final Cause - purpose and Formal cause, what makes something what it is and no other. The somethings are complex far from equilbric socio-ecological systems in which human agency has causal powers. This resonates with the understanding of the nature of effect in the complexity frame of reference as the state of the system both in relation to stability and transformation of kind. Effects are systems states. The argument draws on Hegel's and Dewey's understandings of cause / effect relationships as not separable but intimately interwoven. Effects have continuing reciprocal impacts on causes themselves as in positive feedback in systems. This way of thinking about causation allows us to engage with macro social change. The argument will be illustrated by a discussion of the transformation from industrial to post-industrial character across port city regions in high income countries.

BACKGROUND: Growing evidence shows the potential of nutritional interventions to treat obesity but most investigations have utilized non-digestible carbohydrates only. Peach and plum contain high amounts of polyphenols, compounds with demonstrated anti-obesity effects. The underlying process of successfully treating obesity using polyphenols may involve an alteration of the intestinal microbiota. However, this phenomenon is not well understood. METHODOLOGY/PRINCIPAL FINDINGS: Obese Zucker rats were assigned to three groups (peach, plum, and control, n = 10 each), wild-type group was named lean (n = 10). Carbohydrates in the fruit juices were eliminated using enzymatic hydrolysis. Fecal samples were obtained after 11 weeks of fruit or control juice administration. Real-time PCR and 454-pyrosequencing were used to evaluate changes in fecal microbiota. Over 1,500 different Operational Taxonomic Units at 97% similarity were detected in all rats. Several bacterial groups (e.g. Lactobacillus and members of Ruminococcacea) were found to be more abundant in the peach but especially in the plum group (plum juice contained 3 times more total polyphenolics compared to peach juice). Principal coordinate analysis based on Unifrac-based unweighted distance matrices revealed a distinct separation between the microbiota of control and treatment groups. These changes in fecal microbiota occurred simultaneously with differences in fecal short-chain acids concentrations between the control and treatment groups as well as a significant decrease in body weight in the plum group. CONCLUSIONS: This study suggests that consumption of carbohydrate-free peach and plum juice has the potential to modify fecal microbial ecology in an obese animal model. The separate contribution of polyphenols and non-polyphenols compounds (vitamins and minerals) to the observed changes is unknown.