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Background: The inverse care law states that availability of good medical care varies inversely with the need for it in the population served. In 2019, the main medical union and the Department of Health in the Republic of Ireland (RoI), agreed on funding a social deprivation practice grant for general practices in urban deprived areas. Aim: To examine the implementation and impact of the social deprivation practice grant in participating general practices. Design & setting: A mixed-methods study with sequential design based in Irish general practice. Method: Data were collected using a questionnaire and online semi-structured interviews with GPs and practice staff. Data were analysed separately, and the findings compared to examine the extent to which they converged or diverged. Results: There were 25 survey responses and nine interviews. All practices reported the grant was beneficial and most practices utilised the grant to fund additional doctor hours (17/25). Both surveys and interviews indicated that a small amount of additional funding allowed additional clinical need in areas of deprivation to be addressed, but there were some barriers identified in accessing the grant and implementing planned expenditure. Conclusion: Delivery of health care in areas of socioeconomic deprivation presents significant challenges. While there were some problems with implementation, the introduction of a small, targeted grant for general practices in areas of social deprivation allowed those practices to enhance their services, with tailored initiatives seeking to meet the needs of their patient populations.

Background: GPs aim to provide patient-centred care combining clinical evidence, clinical judgement, and patient priorities. Despite a recognition of the need to translate evidence to support patient care, barriers exist to the use of evidence in practice. Aim: To ascertain the needs and preferences of GPs regarding evidence-based guidance to support patient care. The study also aimed to prioritise content and optimise structure and dissemination of future evidence-based guidance. Design & setting: This was a convergent parallel mixed-methods study in collaboration with the national GP professional body in the Republic of Ireland (Irish College of General Practitioners [ICGP]). Quantitative and qualitative findings were integrated at the interpretive level. Method: A national GP survey was administered via the ICGP (December 2020) and seven GP focus groups were undertaken (April–May 2021). Results: Of 3496 GPs, a total of 509 responders (14.6%) completed the survey and 40 GP participants took part in focus groups. Prescribing updates, interpretation of test results, chronic disease management, and older person care were the preferred topics for future evidence-based guidance. GPs reported that they required rapid access to up-to-date and relevant evidence summaries online for use in clinical practice. Access to more comprehensive reviews for the purposes of continuing education and teaching was also a priority. Multimodal forms of dissemination were preferred to increase uptake of evidence in practice. Conclusion: GPs indicated that rapid access to up-to-date, summarised evidence-based resources, available from their professional organisation, is preferred. Evidence should reflect the disease burden of the population and involve multifaceted dissemination approaches.

Background: Atrial fibrillation (AF), the most common cardiac arrhythmia, is a major risk factor for stroke. AF is often asymptomatic, making it difficult to diagnose. Globally, stroke is a leading cause of morbidity and mortality. Opportunistic AF screening has been recommended in clinical practice within the Republic of Ireland (RoI) and internationally, though the optimal mode and location remains under investigation. Currently, there is no formal AF screening programme. Primary care has been proposed as a suitable setting. Aim: To identify the facilitators and barriers to AF screening in primary care from the perspective of GPs. Design & setting: A qualitative descriptive study design was adopted. Fifty-four GPs were invited from 25 practices in the RoI to participate in individual interviews at their practices. Participants were from both rural and urban locations. Method: A topic guide was developed to guide the interview content towards identification of facilitators and barriers to AF screening. The interviews were conducted in person, audio-recorded, transcribed verbatim, and analysed using framework analysis. Results: Eight GPs from five practices participated in an interview. Three GPs, two male and one female, were recruited from two rural practices and five GPs, two male and three female, were recruited from three urban practices. All eight GPs expressed a willingness to engage in AF screening. Time pressures and the need for additional staff to support were identified as barriers. Programme structure and patient awareness campaigns and education were identified as facilitators. Conclusion: The findings will help to anticipate barriers to AF screening and aid the development of clinical pathways for people with or at risk of AF. The results have been integrated into a pilot primary care-based screening programme for AF.

Introduction: Atrial fibrillation (AF), the most common cardiac arrhythmia, is a major risk factor for stroke. AF is often asymptomatic and, if identified, treatment can be offered that can reduce stroke risk by up to two thirds. AF screening meets many of the Wilson Jungner criteria for screening. While AF screening is recommended in clinical practice and internationally, the optimal mode and location for AF screening remains under investigation. Primary care has been identified as a potential setting. This study aimed to identify facilitators and barriers to AF screening from the perspective of GPs.Methods: The study adopted a qualitative descriptive design conducted in the south of Ireland. 58 GPs were invited from the north Cork region to participate in individual interviews at their practices, rural and urban, with a view to recruiting a purposive sample of up to 12 GPs. The interviews were audio-recorded, transcribed verbatim and analysed using a framework analysis.Results: Eight GPs (four male, four female) from five practices participated. Five GPs were from urban practices and three were from rural practices. Facilitators and barriers were sub-categorised into patient facilitators, practice facilitators, GP facilitators, patient barriers, practice barriers, GP barriers, attitudes to AF screening, willingness to facilitate and priority ranking. All eight participants expressed a willingness to engage in AF screening. Time was the barrier discussed most frequently by all participants along with the need for additional staff. Programme structure was the most discussed facilitator by all participants and patient awareness campaigns.Discussion: Despite barriers to AF screening identified by GPs, there was a significant willingness to engage and identify potential facilitators to support such screening.

Lung development is precisely controlled by underlying gene regulatory networks (GRN). Disruption of genes in the network can interrupt normal development and cause diseases such as bronchopulmonary dysplasia (BPD) – a chronic lung disease in preterm infants with morbid and sometimes lethal consequences characterized by lung immaturity and reduced alveolarization. Here, we generated a transgenic mouse exhibiting a moderate severity BPD phenotype by blocking IGF1 signaling in secondary crest myofibroblasts (SCMF) at the onset of alveologenesis. Using approaches mirroring the construction of the model GRN in sea urchin’s development, we constructed the IGF1 signaling network underlying alveologenesis using this mouse model that phenocopies BPD. The constructed GRN, consisting of 43 genes, provides a bird’s eye view of how the genes downstream of IGF1 are regulatorily connected. The GRN also reveals a mechanistic interpretation of how the effects of IGF1 signaling are transduced within SCMF from its specification genes to its effector genes and then from SCMF to its neighboring alveolar epithelial cells with WNT5A and FGF10 signaling as the bridge. Consistently, blocking WNT5A signaling in mice phenocopies BPD as inferred by the network. A comparative study on human samples suggests that a GRN of similar components and wiring underlies human BPD. Our network view of alveologenesis is transforming our perspective to understand and treat BPD. This new perspective calls for the construction of the full signaling GRN underlying alveologenesis, upon which targeted therapies for this neonatal chronic lung disease can be viably developed.

Objectives To establish the evidence base for the effects on health outcomes and costs of social prescribing link workers (non-health or social care professionals who connect people to community resources) for people in community settings focusing on people experiencing multimorbidity and social deprivation.Design Systematic review and narrative synthesis using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach.Data sources Cochrane Database, Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, EU Clinical Trials Register, CINAHL, Embase, Global Health, PubMed/MEDLINE, PsycInfo, LILACS, Web of Science and grey literature were searched up to 31 July 2021. A forward citation search was completed on 9 June 2022.Eligibility criteria Controlled trials meeting the Cochrane Effectiveness of Practice and Organisation of Care (EPOC) guidance on eligible study designs assessing the effect of social prescribing link workers for adults in community settings on any outcomes. No language restrictions were applied.Data extraction and synthesis Two independent reviewers extracted data, evaluated study quality using the Cochrane EPOC risk of bias tool and judged certainty of the evidence. Results were synthesised narratively.Results Eight studies (n=6500 participants), with five randomised controlled trials at low risk of bias and three controlled before–after studies at high risk of bias, were included. Four included participants experiencing multimorbidity and social deprivation. Four (n=2186) reported no impact on health-related quality of life (HRQoL). Four (n=1924) reported mental health outcomes with three reporting no impact. Two US studies found improved ratings of high-quality care and reduced hospitalisations for people with multimorbidity experiencing deprivation. No cost-effectiveness analyses were identified. The certainty of the evidence was low or very low.Conclusions There is an absence of evidence for social prescribing link workers. Policymakers should note this and support evaluation of current programmes before mainstreaming.PROSPERO registration number CRD42019134737.

Objectives Individuals with multimorbidity use more health services and take more medicines. This can lead to high out-of-pocket (OOP) healthcare expenditure. This study, therefore, aimed to assess the association between multimorbidity (two or more chronic conditions) and OOP healthcare expenditure in a nationally representative sample of adults aged 50 years or over.Design Cross-sectional analysis of data collected in 2016 from wave 4 of The Irish Longitudinal Study on Ageing.SettingIreland.ParticipantsCommunity-dwelling adults aged 50 years and over.MethodA generalised linear model with log-link and gamma distributed errors was fitted to assess the association between multimorbidity and OOP healthcare expenditure (including general practitioner, emergency department, outpatients, specialist consultations, hospital admissions, home care and prescription drugs).Results Overall, 3453 (58.5%) participants had multimorbidity. Among those with any OOP healthcare expenditure, individuals with multimorbidity spent more on average per annum (€806.8 for two conditions, €885.8 for three or more conditions), than individuals with no conditions (€580.3). Pharmacy-dispensed medicine expenditure was the largest component of expenditure. People with multimorbidity on average spent more of their equivalised household income on healthcare (7.1% for two conditions, 9.7% for three or more conditions), than people with no conditions (5.0%). A strong positive association was found between number of conditions and OOP healthcare expenditure (p

BackgroundThere is a rising prevalence of multimorbidity, particularly in older patients, and a need for evidence-based medicines management interventions for this population. The Supporting Prescribing in Older Adults with Multimorbidity in Irish Primary Care (SPPiRE) trial aimed to investigate the effect of a general practitioner (GP)-delivered, individualised medication review in reducing polypharmacy and potentially inappropriate prescriptions (PIPs) in community-dwelling older patients with multimorbidity in primary care.Methods and findingsWe conducted a cluster randomised controlled trial (RCT) set in 51 GP practices throughout the Republic of Ireland. A total of 404 patients, aged ≥65 years with complex multimorbidity, defined as being prescribed ≥15 regular medicines, were recruited from April 2017 and followed up until October 2020. Furthermore, 26 intervention GP practices received access to the SPPiRE website where they completed an educational module and used a template for an individualised patient medication review that identified PIP, opportunities for deprescribing, and patient priorities for care. A total of 25 control GP practices delivered usual care. An independent blinded pharmacist assessed primary outcome measures that were the number of medicines and the proportion of patients with any PIP (from a predefined list of 34 indicators based predominantly on the STOPP/START version 2 criteria). We performed an intention-to-treat analysis using multilevel modelling. Recruited participants had substantial disease and treatment burden at baseline with a mean of 17.37 (standard deviation [SD] 3.50) medicines. At 6-month follow-up, both intervention and control groups had reductions in the numbers of medicines with a small but significantly greater reduction in the intervention group (incidence rate ratio [IRR] 0.95, 95% confidence interval [CI]: 0.899 to 0.999, p = 0.045). There was no significant effect on the odds of having at least 1 PIP in the intervention versus control group (odds ratio [OR] 0.39, 95% CI: 0.140 to 1.064, p = 0.066). Adverse events recorded included mortality, emergency department (ED) presentations, and adverse drug withdrawal events (ADWEs), and there was no evidence of harm. Less than 2% of drug withdrawals in the intervention group led to a reported ADWE. Due to the inability to electronically extract data, primary outcomes were measured at just 2 time points, and this is the main limitation of this work.ConclusionsThe SPPiRE intervention resulted in a small but significant reduction in the number of medicines but no evidence of a clear effect on PIP. This reduction in significant polypharmacy may have more of an impact at a population rather than individual patient level.Trial registrationISRCTN Registry ISRCTN12752680.

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: Incorporating Public and Patient Involvement (PPI) into doctoral research is valued by PhD scholars. The importance of providing early career researchers with appropriate education and training to develop skills to conduct meaningful involvement has been articulated. The Collaborative Doctoral Award in MultiMorbidity (CDA-MM) PhD programme embedded formal PPI training as a postgraduate education component. Four PhD scholars taking part in the CDA-MM established a PPI panel comprising people, and carers of people, living with multimorbidity (≥2 chronic conditions), presenting an opportuning for experiential PPI training. The proposed study aims to evaluate the process and impact of formal and experiential PPI training during a PhD programme. Design: Embedding PPI training in a PhD programme is a novel approach. This evaluation will include a process evaluation to provide an understanding of the workings of the PPI panel and explore the experiences of key stakeholders involved, and an impact evaluation to assess the impact of embedding PPI training in a PhD programme. This study is a longitudinal mixed-methods evaluation, conducted over 24 months. Participants include PhD scholars, PPI contributors and PhD supervisors. An independent researcher not aligned with the CDA-MM will lead the evaluation. Data collection methods include focus groups, individual interviews, an impact log and group reflections. Qualitative data will be analysed using thematic and content analysis and quantitative data will be analysed using descriptive statistics. Discussion: This evaluation will report the learnings from embedding formal and experiential PPI training and education across a PhD programme.

Objectives To explore primary care clinician perceptions of barriers and facilitators in delivering care for common mental disorders (CMD) before and after implementation of a consultation-liaison psychiatry service (Psychiatry in Primary Care (PIPC)) in government-operated primary care clinics and to explore the clinicians’ experience of the PIPC service itself.Design This longitudinal qualitative study was informed by the Normalisation Process Model and involved audiotaped semi-structured individual interviews with front-line clinicians before (Time 1) and after (Time 2) the PIPC intervention. The Framework Method was used in the thematic analysis of pre/post interview transcripts.Setting Two government-operated primary care clinics in Penang, Malaysia.Participants 17 primary care medical, nursing and allied health staff recruited purposely to achieve a range of disciplines and a balanced representation from both clinics.Intervention Psychiatrists, accompanied by medical students in small numbers, provided one half-day consultation visit per week, to front-line clinicians in each clinic over an 8-month period. The service involved psychiatric assessment of patients with suspected CMDs, with face-to-face discussion with the referring clinician before and after the patient assessment.Results At Time 1 interviewees tended to equate CMDs with stress and embraced a holistic model of care while also reporting considerable autonomy in mental healthcare and positively appraising their current practices. At Time 2, post-intervention, participants demonstrated a shift towards greater understanding of CMDs as treatable conditions. They reported time pressures and the demands of key performance indicators in other areas as barriers to participation in PIPC. Yet they showed increased awareness of current service deficits and of their potential in delivering improved mental healthcare.Conclusions Despite resource-related and structural barriers to implementation of national mental health policy in Malaysian primary care settings, our findings suggest that front-line clinicians are receptive to future interventions designed to improve the mental healthcare capacity.

Introduction: Individuals with multimorbidity in deprived areas experience worse health outcomes and fragmented care. Research suggests that primary care-based link workers providing social prescribing have potential to improve health and well-being. This paper reports the results of a pilot study conducted in preparation for a randomised controlled trial (RCT) that aims to test the effectiveness of primary care-based link workers providing social prescribing in improving health outcomes for people with multimorbidity who attend general practices in deprived areas in Ireland. Methods: An uncontrolled pilot study of an intervention based on the Glasgow Deep End links worker programme, in a single general practice, tested the feasibility and acceptability of planned processes for a RCT. Outcomes were recruitment and retention rates and acceptability of the trial processes and intervention to patients, general practitioners (GPs) and the link worker. Structured interviews were conducted with six patients, the link worker and two GPs within the practice and analysed using descriptive qualitative analysis. Feedback from a Public Patient Involvement group and an Implementation Advisory Group of key stakeholders was incorporated into the evaluation process. Results: Twelve out of 14 patients completed the intervention. Selection and recruitment processes were lengthier than expected. GPs recommended including psychosocial need in the selection process. Interviewed patients, the GPs and the link worker were positive about the intervention. Conclusion: A range of adaptations were identified for the main trial, mainly considering psychosocial need in the selection process to reflect normal referral pathways. This has resulted in a pragmatic RCT design.

Introduction: By the time an intervention is ready for evaluation in a definitive RCT the context of the evidence base may have evolved. To avoid research waste, it is imperative that intervention design and evaluation is an adaptive process incorporating emerging evidence and novel concepts. The aim of this study is to describe changes that were made to an evidence based intervention at the protocol stage of the definitive RCT to incorporate emerging evidence. Methods: The original evidence based intervention, a GP delivered web guided medication review, was modified in a five step process: Identification of core components of the original intervention. Literature review. Modification of the intervention. Pilot study. Final refinements. A framework, developed in public health research, was utilised to describe the modification process. Results: The population under investigation changed from older people with a potentially inappropriate prescription (PIP) to older people with significant polypharmacy, a proxy marker for complex multimorbidity. An assessment of treatment priorities and brown bag medication review, with a focus on deprescribing were incorporated into the original intervention. The number of repeat medicines was added as a primary outcome measure as were additional secondary patient reported outcome measures to assess treatment burden and attitudes towards deprescribing. Conclusions: A framework was used to systematically describe how and why the original intervention was modified, allowing the new intervention to build upon an effective and robustly developed intervention but also to be relevant in the context of the current evidence base.

Aim: The aim of this study is to investigate the benefits and harms of therapeutic exercise in people with multimorbidity defined as the combination of two or more of the following conditions: knee and hip osteoarthritis, hypertension, diabetes type 2, depression, heart failure, ischaemic heart disease and chronic obstructive pulmonary disease, by performing a systematic review of randomized controlled trials (RCTs). Methods: This study will be performed according to the recommendations from the Cochrane Collaboration and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). We will search for RCTs investigating the effect of therapeutic exercise in multimorbidity, as defined above, in MEDLINE, EMBASE, CENTRAL and CINAHL from 1990. Cochrane reviews on the effect of therapeutic exercise for each of the aforementioned conditions and references of the included studies will be checked for eligible studies and citation tracking will be performed in Web of Science. We will assess the risk of bias of the included studies using the Cochrane ‘Risk of Bias Tool’ 2.0 and the Grading of Recommendations Assessment, Development and Evaluation assessment for judging the overall quality of evidence. Meta-analyses will be performed, if possible, using a random-effects model as heterogeneity is expected due to differences in interventions and participant characteristics and outcome measures. Subgroup and meta-regression analyses will be performed to explore potential predictors of outcomes. Dissemination: The results of this systematic review will be published in a peer-review journal, presented at national and international conferences and made available to end users via infographics, podcasts, press releases and videos.

Abstract Background Poorly controlled type 2 diabetes mellitus (T2DM) is associated with significant morbidity, mortality and healthcare costs. Control of T2DM can be challenging for healthcare professionals for a number of reasons, including poor concordance with medications, difficulties modifying lifestyle behaviour and also clinical inertia, which is defined as a reluctance among health professionals to intensify medications. A complex intervention, called ComputeriseD dECisIonal support for poorly controlleD typE 2 Diabetes mellitus in Irish General Practice (DECIDE), was developed, identifying T2DM patients with poor glycaemic and blood pressure control and aiming to target clinical inertia, by supporting therapeutic action, including GP-led medication intensification where appropriate. A small-scale, uncontrolled, non-randomised feasibility study highlighted the acceptability of the DECIDE intervention within Irish General Practice. This paper presents a protocol for a pilot cluster randomised controlled trial (RCT) of the DECIDE intervention. Methods/Design The pilot cluster RCT will involve 14 practices and 140 patients in Irish General Practice. Intervention GPs will participate in the DECIDE intervention, comprising (a) a training programme for the practices and (b) a web-based clinical decision support system supporting treatment escalation, tailored to specific patient information. Only patients who have poorly controlled T2DM (defined as HbA1c > 70 mmol/mol and/or BP > 150/95) will be included. The primary outcomes will include measures of feasibility such as recruitment and retention of practices and acceptability of the intervention and also HbA1c. Secondary outcomes will include medication intensification, blood pressure and lipids. Control GPs will continue to provide usual care. A process evaluation will be performed to determine whether the intervention is delivered as intended and treatment fidelity assessed to monitor and enhance the reliability and validity of interventions. An exploratory health economic analysis will examine the potential costs and cost effectiveness of the intervention relative to the control. Discussion A pilot cluster RCT will establish the feasibility of a complex intervention which aims to support primary care for patients with poorly controlled T2DM in Irish General Practice. Trial registration The protocol for the pilot cluster RCT is registered on the ISRCTN Registry at: ISRCTN69498919.

A cancer diagnosis is life-altering. Each patient situation is unique, including response to the news, approach to available treatment options, and insight into every aspect of life. As a pharmacist, the author shares personal insights into living with a cancer diagnosis, her new role as a patient, her perspective as a pharmacist, processing the reactions of those surrounding her, and what she’s learning about herself through all of this. Article Type: Commentary

Gestational alcohol exposure causes fetal alcohol spectrum disorder (FASD) and is a prominent cause of neurodevelopmental disability. Whole transcriptome sequencing (RNA-Seq) offer insights into mechanisms underlying FASD, but gene-level analysis provides limited information regarding complex transcriptional processes such as alternative splicing and non-coding RNAs. Moreover, traditional analytical approaches that use multiple hypothesis testing with a false discovery rate adjustment prioritize genes based on an adjusted p-value, which is not always biologically relevant. We address these limitations with a novel approach and implemented an unsupervised machine learning model, which we applied to an exon-level analysis to reduce data complexity to the most likely functionally relevant exons, without loss of novel information. This was performed on an RNA-Seq paired-end dataset derived from alcohol-exposed neural fold-stage chick crania, wherein alcohol causes facial deficits recapitulating those of FASD. A principal component analysis along with k-means clustering was utilized to extract exons that deviated from baseline expression. This identified 6857 differentially expressed exons representing 1251 geneIDs; 391 of these genes were identified in a prior gene-level analysis of this dataset. It also identified exons encoding 23 microRNAs (miRNAs) having significantly differential expression profiles in response to alcohol. We developed an RDAVID pipeline to identify KEGG pathways represented by these exons, and separately identified predicted KEGG pathways targeted by these miRNAs. Several of these (ribosome biogenesis, oxidative phosphorylation) were identified in our prior gene-level analysis. Other pathways are crucial to facial morphogenesis and represent both novel (focal adhesion, FoxO signaling, insulin signaling) and known (Wnt signaling) alcohol targets. Importantly, there was substantial overlap between the exomes themselves and the predicted miRNA targets, suggesting these miRNAs contribute to the gene-level expression changes. Our novel application of unsupervised machine learning in conjunction with statistical analyses facilitated the discovery of signaling pathways and miRNAs that inform mechanisms underlying FASD.

WNT5a is a mainly “non-canonical” WNT ligand whose dysregulation is observed in lung diseases such as idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD) and asthma. Germline deletion of Wnt5a disrupts embryonic lung development. However, the temporal-specific function of WNT5a remains unknown. In this study, we generated a conditional loss-of-function mouse model (Wnt5aCAG) and examined the specific role of Wnt5a during the saccular and alveolar phases of lung development. The lack of Wnt5a in the saccular phase blocked distal airway expansion and attenuated differentiation of endothelial and alveolar epithelial type I (AT1) cells and myofibroblasts. Postnatal Wnt5a inactivation disrupted alveologenesis, producing a phenotype resembling human bronchopulmonary dysplasia (BPD). Mutant lungs showed hypoalveolization, but endothelial and epithelial differentiation was unaffected. The major impact of Wnt5a inactivation on alveologenesis was on myofibroblast differentiation and migration, with reduced expression of key regulatory genes. These findings were validated in vitro using isolated lung fibroblasts. Conditional inactivation of the WNT5a receptors Ror1 and Ror2 in alveolar myofibroblasts recapitulated the Wnt5aCAG phenotype, demonstrating that myofibroblast defects are the major cause of arrested alveologenesis in Wnt5aCAG lungs. Finally, we show that WNT5a is reduced in human BPD lung samples, indicating the clinical relevance and potential role for WNT5a in pathogenesis of BPD.

INTRODUCTION:Self-reported measures of healthcare utilisation are often used in longitudinal cohort studies involving older community-dwelling people. The aim of this study is to compare healthcare utilisation rates using patient self-report and manual extraction from the general practice (GP) electronic medical record (EMR). METHODS:Study population: Two prospective cohort studies (n = 806 and n = 1,377, aged ≥70 years) conducted in the Republic of Ireland were compared. Study outcomes: GP, outpatient department (OPD) and emergency department (ED) visits over a one-year period. Statistical analysis: Descriptive statistics of the two cohorts are presented. A negative binomial regression was performed and results are presented as incidence rate ratios (IRR) with 95% confidence intervals (CI). For the outcome of any ED visit, linear regression was performed, yielding risk ratios (RR) with 95% CI. RESULTS:The annual rates of GP, OPD and ED visits were 6.30 (SD 4.63), 2.11 (SD 2.46) and 0.26 (SD 0.62) respectively in GP EMR cohort, compared to 5.65 (SD 8.06), 2.09 (SD 5.83) and 0.32 (SD 0.84) in the self-report cohort. In univariate regression analysis comparing healthcare utilisation, the self-report cohort reported a lower frequency of GP visits (unadjusted IRR 0.90 (95% CI 0.84, 0.96), p = 0.02)), a greater frequency of ED visits (1.20 (0.98, 1.49), p = 0.083)), and no difference in OPD visits (unadjusted IRR 0.99 (95% CI 0.86, 1.13), p = 0.845)). In multivariate analysis, adjusted for relevant confounders, there was no difference in GP visits (adjusted IRR 0.99 (95% CI 0.92, 1.06), p = 0.684)) or OPD visits (adjusted IRR 1.09 (0.95, 1.25), p = 0.23)) between the two cohorts. However, the self-report cohort reported 37% more ED visits (adjusted IRR 1.37 (1.10, 1.71), p = 0.005)) and were more likely to report any ED visit (adjusted RR 1.23 (95% CI 1.02, 1.48), p = 0.028)). CONCLUSIONS:This study demonstrates that reported rates of GP and OPD visits were similar but there were differences in reported ED visits, with significantly higher self-reported visits. This may be due to ED visits not being notified to the GP and contextual issues such as transfer of healthcare utilisation data between sectors may vary in different healthcare systems.

Although prenatal alcohol exposure (PAE) reduces offspring growth, it may increase obesity risk at adolescence. Animal models of PAE display glucose intolerance and increased adiposity, suggesting that PAE causes metabolic reprogramming. We tested this hypothesis in a mouse model of binge PAE, wherein pregnant C57Bl/6J females received 3 g/kg alcohol (ETOH) daily from gestational day 12.5 to 17.5; maltodextrin (MD) and medium chain triglycerides (MCT) served as isocaloric nutritional controls, and sham (H2O) treatment controlled for gavage stress. Our comprehensive assessment quantified body composition, energy expenditure, glucose tolerance, and cardiovascular function in offspring at age 17 weeks. Although ETOH pups were initially lighter than all other groups, they did not have a unique obesogenic phenotype. Instead, a similar obesogenic phenotype emerged in all three caloric groups (MCT, MD, ETOH), such that caloric groups had greater post-weaning weight gain (both sexes), reduced gonadal fat weight (males), and reduced glucose clearance (males) compared against H2O offspring. PAE did not affect body composition, respiratory exchange ratio, metabolic adaption to high-fat or low-fat diet, eating behavior, and blood pressure, and ETOH values did not differ from those obtained from isocaloric controls. Exposure to a higher alcohol dose (4.5 g/kg) or a high-fat (60%) diet did not exacerbate differences in body composition or glucose tolerance. "PAE-specific" effects on postnatal growth, glucose tolerance, adiposity, or hypertension only emerged when PAE offspring were compared just against H2O controls, or against MD controls. We conclude that prior reports of obesity and glucose intolerance in adult PAE offspring reflect the contribution of added gestational calories, and not alcohol's pharmacologic action. Results suggest that the increased adiposity risk in FASD is not caused by metabolic reprogramming, and instead originates from behavioral, medication, and/or dietary practices. This study highlights the importance of appropriate dietary controls in nutritional studies of PAE.

Fetal alcohol spectrum disorder (FASD) is a leading cause of neurodevelopmental disability. Individuals with FASD may exhibit a characteristic facial appearance that has diagnostic utility. The mechanism by which alcohol disrupts craniofacial development is incompletely understood, as are the genetic factors that can modify individual alcohol vulnerability. Using an established avian model, we characterized the cranial transcriptome in response to alcohol to inform the mechanism underlying these cells' vulnerability. Gallus gallus embryos having 3-6 somites were exposed to 52 mM alcohol and the cranial transcriptomes were sequenced thereafter. A total of 3422 genes had significantly differential expression. The KEGG pathways with the greatest enrichment of differentially expressed gene clusters were Ribosome (P = 1.2 x 10-17, 67 genes), Oxidative Phosphorylation (P = 4.8 x 10-12, 60 genes), RNA Polymerase (P = 2.2 x 10-3, 15 genes) and Spliceosome (P = 2.6 x 10-2, 39 genes). The preponderance of transcripts in these pathways were repressed in response to alcohol. These same gene clusters also had the greatest altered representation in our previous comparison of neural crest populations having differential vulnerability to alcohol-induced apoptosis. Comparison of differentially expressed genes in alcohol-exposed (3422) and untreated, alcohol-vulnerable (1201) transcriptomes identified 525 overlapping genes of which 257 have the same direction of transcriptional change. These included 36 ribosomal, 25 oxidative phosphorylation and 7 spliceosome genes. Using a functional approach in zebrafish, partial knockdown of ribosomal proteins zrpl11, zrpl5a, and zrps3a individually heightened vulnerability to alcohol-induced craniofacial deficits and increased apoptosis. In humans, haploinsufficiency of several of the identified ribosomal proteins are causative in craniofacial dysmorphologies such as Treacher Collins Syndrome and Diamond-Blackfan Anemia. This work suggests ribosome biogenesis may be a novel target mediating alcohol's damage to developing neural crest. Our findings are consistent with observations that gene-environment interactions contribute to vulnerability in FASD.

Epithelial-mesenchymal transition (EMT) is a normal cell differentiation event during development and contributes pathologically to carcinoma and fibrosis progression. EMT often associates with increased transforming growth factor-β (TGF-β) signaling, and TGF-β drives EMT, in part through Smad-mediated reprogramming of gene expression. TGF-β also activates the Erk MAPK pathway through recruitment and Tyr phosphorylation of the adaptor protein ShcA by the activated TGF-β type I receptor. We found that ShcA protects the epithelial integrity of nontransformed cells against EMT by repressing TGF-β-induced, Smad-mediated gene expression. p52ShcA competed with Smad3 for TGF-β receptor binding, and down-regulation of ShcA expression enhanced autocrine TGF-β/Smad signaling and target gene expression, whereas increased p52ShcA expression resulted in decreased Smad3 binding to the TGF-β receptor, decreased Smad3 activation, and increased Erk MAPK and Akt signaling. Furthermore, p52ShcA sequestered TGF-β receptor complexes to caveolin-associated membrane compartments, and reducing ShcA expression enhanced the receptor localization in clathrin-associated membrane compartments that enable Smad activation. Consequently, silencing ShcA expression induced EMT, with increased cell migration, invasion, and dissemination, and increased stem cell generation and mammosphere formation, dependent upon autocrine TGF-β signaling. These findings position ShcA as a determinant of the epithelial phenotype by repressing TGF-β-induced Smad activation through differential partitioning of receptor complexes at the cell surface.

Fetal alcohol spectrum disorders (FASD) are the leading non-genetic cause of neurodevelopmental disability in children. Although alcohol is clearly teratogenic, environmental factors such as gravidity and socioeconomic status significantly modify individual FASD risk despite equivalent alcohol intake. An explanation for this variability could inform FASD prevention. Here we show that the most common nutritional deficiency of pregnancy, iron deficiency without anemia (ID), is a potent and synergistic modifier of FASD risk. Using an established rat model of third trimester-equivalent binge drinking, we show that ID significantly interacts with alcohol to impair postnatal somatic growth, associative learning, and white matter formation, as compared with either insult separately. For the associative learning and myelination deficits, the ID-alcohol interaction was synergistic and the deficits persisted even after the offsprings' iron status had normalized. Importantly, the observed deficits in the ID-alcohol animals comprise key diagnostic criteria of FASD. Other neurobehaviors were normal, showing the ID-alcohol interaction was selective and did not reflect a generalized malnutrition. Importantly ID worsened FASD outcome even though the mothers lacked overt anemia; thus diagnostics that emphasize hematological markers will not identify pregnancies at-risk. This is the first direct demonstration that, as suggested by clinical studies, maternal iron status has a unique influence upon FASD outcome. While alcohol is unquestionably teratogenic, this ID-alcohol interaction likely represents a significant portion of FASD diagnoses because ID is more common in alcohol-abusing pregnancies than generally appreciated. Iron status may also underlie the associations between FASD and parity or socioeconomic status. We propose that increased attention to normalizing maternal iron status will substantially improve FASD outcome, even if maternal alcohol abuse continues. These findings offer novel insights into how alcohol damages the developing brain.