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Abstract Background Social prescribing link workers are non-health or social care professionals who connect people with psychosocial needs to non-clinical community supports. They are being implemented widely, but there is limited evidence for appropriate target populations or cost effectiveness. This study aimed to explore the feasibility, potential impact on health outcomes and cost effectiveness of practice-based link workers for people with multimorbidity living in deprived urban communities. Methods A pragmatic exploratory randomised trial with wait-list usual care control and blinding at analysis was conducted during the COVID 19 pandemic (July 2020 to January 2021). Participants had two or more ongoing health conditions, attended a general practitioner (GP) serving a deprived urban community who felt they may benefit from a one-month practice-based social prescribing link worker intervention.. Feasibility measures were recruitment and retention of participants, practices and link workers, and completion of outcome data. Primary outcomes at one month were health-related quality of life (EQ-5D-5L) and mental health (HADS). Potential cost effectiveness from the health service perspective was evaluated using quality adjusted life years (QALYs), based on conversion of the EQ-5D-5L and ICECAP-A capability index to utility scoring. Results From a target of 600, 251 patients were recruited across 13 general practices. Randomisation to intervention (n = 123) and control (n = 117) was after baseline data collection. Participant retention at one month was 80%. All practices and link workers (n = 10) were retained for the trial period. Data completion for primary outcomes was 75%. There were no significant differences identified using mixed effects regression analysis in EQ-5D-5L (MD 0.01, 95% CI -0.07 to 0.09) or HADS (MD 0.05, 95% CI -0.63 to 0.73), and no cost effectiveness advantages. A sensitivity analysis that considered link workers operating at full capacity in a non-pandemic setting, indicated the probability of effectiveness at the €45,000 ICER threshold value for Ireland was 0.787 using the ICECAP-A capability index. Conclusions While the trial under-recruited participants mainly due to COVID-19 restrictions, it demonstrates that robust evaluations and cost utility analyses are possible. Further evaluations are required to establish cost effectiveness and should consider using the ICE-CAP-A wellbeing measure for cost utility analysis. Registration This trial is registered on ISRCTN. Title: Use of link workers to provide social prescribing and health and social care coordination for people with complex multimorbidity in socially deprived areas. Trial ID: ISRCTN10287737. Date registered 10/12/2019. Link: https://www.isrctn.com/ISRCTN10287737

Abstract Background Evidence synthesis is used by decision-makers in various ways, such as developing evidence-based recommendations for clinical guidelines. Clinical guideline development groups (GDGs) typically discuss evidence synthesis findings in a multidisciplinary group, including patients, healthcare providers, policymakers, etc. A recent mixed methods systematic review (MMSR) identified no gold standard format for optimally presenting evidence synthesis findings to these groups. However, it provided 94 recommendations to help produce more effective summary formats for general evidence syntheses (e.g., systematic reviews). To refine the MMSR recommendations to create more actionable guidance for summary producers, we aimed to explore these 94 recommendations with participants involved in evidence synthesis and guideline development. Methods We conducted a descriptive qualitative study using online focus group workshops in February and March 2023. These groups used a participatory co-design approach with interactive voting activities to identify preferences for a summary format's essential content and style. We created a topic guide focused on recommendations from the MMSR with mixed methods support, ≥ 3 supporting studies, and those prioritized by an expert advisory group via a pragmatic prioritization exercise using the MoSCoW method (Must, Should, Could, and Will not haves). Eligible participants must be/have been involved in GDGs and/or evidence synthesis. Groups were recorded and transcribed. Two independent researchers analyzed transcripts using directed content analysis with 94 pre-defined codes from the MMSR. Results Thirty individuals participated in six focus groups. We coded 79 of the 94 pre-defined codes. Participants suggested a “less is more” structured approach that minimizes methodological steps and statistical data, promoting accessibility to all audiences by judicious use of links to further information in the full report. They emphasized concise, consistently presented formats that highlight key messages, flag readers to indicators of trust in the producers (i.e., logos, websites, and conflict of interest statements), and highlight the certainty of evidence (without extenuating details). Conclusions This study identified guidance based on the preferences of guideline developers and evidence synthesis producers about the format of evidence synthesis summaries to support decision-making. The next steps involve developing and user-testing prototype formats through one-on-one semi-structured interviews to optimize evidence synthesis summaries and support decision-making.

Abstract Background Incorporating Public and Patient Involvement (PPI) into doctoral research is valued by PhD funders and scholars. Providing early career researchers with appropriate training to develop skills to conduct meaningful PPI involvement is important. The Health Research Board (HRB) Collaborative Doctoral Award in MultiMorbidity programme (CDA-MM) embedded formal PPI training in its structured education. The four participating PhD scholars established a PPI panel comprising people living with two or more chronic conditions, presenting an opportunity for experiential PPI training. This study aimed to evaluate the process and impact of embedding PPI training in a structured PhD programme. Methods This study was a longitudinal mixed-methods evaluation, conducted over 24 months (June 2020 to June 2022). A process evaluation provided an understanding of how PPI was embedded and explored the experiences of key stakeholders involved. An impact evaluation assessed the impact of embedding PPI training in the programme. Participants included PhD scholars, PPI contributors and PhD supervisors. The data collection and analysis was led by an independent researcher not aligned with the CDA-MM. Data collection methods included five focus groups, individual interviews (n = 6), an impact log, activity logs and group reflections. Qualitative data were analysed using thematic and content analysis and quantitative data analysed using descriptive statistics. Results Embedding formal and experiential PPI training in a structured PhD programme is feasible. Both approaches to training are fundamental to building PPI capacity. Involvement of an experienced and knowledgeable PPI lead throughout is perceived as critical. The PPI panel approach offered a good example of embedded consultation and worked well in a structured PhD programme, providing PhD scholars with ample opportunities for learning about PPI and its implementation. For PPI contributors, culture was the most important indicator of quality and was positively evaluated. Key roles for PhD supervisors were identified. Embedding formal and experiential PPI training impacted positively on many different aspects of individual PhD research projects and on PhD scholars as researchers. There were positive impacts for PPI contributors and PhD supervisors. Conclusions Embedding formal and experiential PPI training in a structured PhD programme is a novel approach. The evaluation has identified a number of lessons that can inform future doctoral programmes seeking to embed formal and experiential PPI training.

Current evidence suggests that iron deficiency (ID) plays a key role in the pathogenesis of conditions presenting with restlessness such as attention deficit hyperactivity disorder (ADHD) and restless legs syndrome (RLS). In clinical practice, ID and iron supplementation are not routinely considered in the diagnostic work-up and/or as a treatment option in such conditions. Therefore, we conducted a scoping literature review of ID guidelines. Of the 58 guidelines included, only 9 included RLS, and 3 included ADHD. Ferritin was the most frequently cited biomarker, though cutoff values varied between guidelines and depending on additional factors such as age, sex, and comorbidities. Recommendations surrounding measurable iron biomarkers and cutoff values varied between guidelines; moreover, despite capturing the role of inflammation as a concept, most guidelines often did not include recommendations for how to assess this. This lack of harmonization on the interpretation of iron and inflammation biomarkers raises questions about the applicability of current guidelines in clinical practice. Further, the majority of ID guidelines in this review did not include the ID-associated disorders, ADHD and RLS. As ID can be associated with altered movement patterns, a novel consensus is needed for investigating and interpreting iron status in the context of different clinical phenotypes.

Abstract Background Patients with multimorbidity are frequent users of healthcare, but fragmented care may lead to suboptimal treatment. Yet, this has never been examined across healthcare sectors on a national scale. We aimed to quantify care fragmentation using various measures and to analyze the associations with patient outcomes. Methods We conducted a register-based nationwide cohort study with 4.7 million Danish adult citizens. All healthcare contacts to primary care and hospitals during 2018 were recorded. Clinical fragmentation indicators included number of healthcare contacts, involved providers, provider transitions, and hospital trajectories. Formal fragmentation indices assessed care concentration, dispersion, and contact sequence. The patient outcomes were potentially inappropriate medication and all-cause mortality adjusted for demographics, socioeconomic factors, and morbidity level. Results The number of involved healthcare providers, provider transitions, and hospital trajectories rose with increasing morbidity levels. Patients with 3 versus 6 conditions had a mean of 4.0 versus 6.9 involved providers and 6.6 versus 13.7 provider transitions. The proportion of contacts to the patient’s own general practice remained stable across morbidity levels. High levels of care fragmentation were associated with higher rates of potentially inappropriate medication and increased mortality on all fragmentation measures after adjusting for demographic characteristics, socioeconomic factors, and morbidity. The strongest associations with potentially inappropriate medication and mortality were found for ≥ 20 contacts versus none (incidence rate ratio 2.83, 95% CI 2.77–2.90) and ≥ 20 hospital trajectories versus none (hazard ratio 10.8, 95% CI 9.48–12.4), respectively. Having less than 25% of contacts with your usual provider was associated with an incidence rate ratio of potentially inappropriate medication of 1.49 (95% CI 1.40–1.58) and a mortality hazard ratio of 2.59 (95% CI 2.36–2.84) compared with full continuity. For the associations between fragmentation measures and patient outcomes, there were no clear interactions with number of conditions. Conclusions Several clinical indicators of care fragmentation were associated with morbidity level. Care fragmentation was associated with higher rates of potentially inappropriate medication and increased mortality even when adjusting for the most important confounders. Frequent contact to the usual provider, fewer transitions, and better coordination were associated with better patient outcomes regardless of morbidity level.

Abstract Background Clinical guidelines should be based on a thorough evaluation of the evidence and generally include a rating of the quality of evidence and assign a strength to recommendations. Grading of Recommendations Assessment, Development and Evaluation (GRADE) guidance warns against making strong recommendations when the certainty of the evidence is low or very low, but has identified five paradigmatic situations (e.g. life-threatening situations) where this may be justified. Aims and objectives We aimed to characterize the strength of recommendations and certainty of the evidence in Irish National Clinical Guidelines using the GRADE approach. Methods All National Clinical Guidelines from the National Clinical Effectiveness Committee (NCEC) website using the GRADE approach (fully or partially) were included. All recommendations and their corresponding certainty of the evidence, strength of recommendations and justifications were extracted. Authors classified instances of strong recommendations with low certainty evidence (referred to as discordant recommendations) into one of the five paradigmatic situations. Descriptive statistics were calculated. Results From the 29 NCEC Clinical Guidelines available at the time of analysis, we identified 8 guidelines using GRADE with a total of 240 recommendations; 38 recommendations did not use the GRADE approach and were excluded. Half of the included guidelines focused on emergency situations. In the final dataset of 202 recommendations, 151 (74.7%) were classified as strong and 51 (25.3%) as conditional. Of the 151 strong recommendations, 55 (36.4%) were supported by high or moderate certainty evidence and 96 (63.6%) by low or very low certainty evidence and were considered discordant. Of these 96 discordant recommendations, 55 (73.7%) were consistent with one of the five paradigmatic situations. However, none were specifically described as such within the guidelines. Conclusions The proportion of discordant recommendations identified in this analysis was higher than some previous international studies (range of all strong recommendations being discordant 30–50%), but similar to other guidelines focused on emergency situations. The majority of discordant recommendations could be mapped to one of the five situations, but no National Clinical Guideline explicitly referenced this. Guideline developers require further guidance to enable greater transparency in the reporting of the reasons for discordant recommendations.

Prenatal alcohol exposure (PAE) is a leading cause of neurodevelopmental disability through its induction of neuronal growth dysfunction through incompletely understood mechanisms. Ribosome biogenesis regulates cell cycle progression through p53 and the nucleolar cell stress response. Whether those processes are targeted by alcohol is unknown. Pregnant C57BL/6J mice received 3 g alcohol/kg daily at E8.5–E17.5. Transcriptome sequencing was performed on the E17.5 fetal cortex. Additionally, primary neural stem cells (NSCs) were isolated from the E14.5 cerebral cortex and exposed to alcohol to evaluate nucleolar stress and p53/MDM2 signaling. Alcohol suppressed KEGG pathways involving ribosome biogenesis (rRNA synthesis/processing and ribosomal proteins) and genes that are mechanistic in ribosomopathies (Polr1d, Rpl11; Rpl35; Nhp2); this was accompanied by nucleolar dissolution and p53 stabilization. In primary NSCs, alcohol reduced rRNA synthesis, caused nucleolar loss, suppressed proliferation, stabilized nuclear p53, and caused apoptosis that was prevented by dominant-negative p53 and MDM2 overexpression. Alcohol’s actions were dose-dependent and rapid, and rRNA synthesis was suppressed between 30 and 60 min following alcohol exposure. The alcohol-mediated deficits in ribosomal protein expression were correlated with fetal brain weight reductions. This is the first report describing that pharmacologically relevant alcohol levels suppress ribosome biogenesis, induce nucleolar stress in neuronal populations, and involve the ribosomal/MDM2/p53 pathway to cause growth arrest and apoptosis. This represents a novel mechanism of alcohol-mediated neuronal damage.

Background: Correct staging and risk stratification is essential in ensuring prostate cancer patients are offered the most appropriate treatment. Interest has been growing in the use of radiotracers targeting prostate specific membrane antigen (PSMA), including the use of 18F-PSMA PET-CT, as part of the primary staging or restaging of prostate cancer. Preliminary scoping identified a number of relevant systematic reviews and meta-analyses; however, individually, these each appear to look at only part of the picture. An overview of reviews aims to systematically identify, appraise and synthesise multiple systematic reviews, related to a relevant research question or questions. We present a protocol for an overview of reviews, which aims to collate existing evidence syntheses exploring the diagnostic accuracy of 18F-PSMA in staging and restaging of prostate cancer. It also aims to highlight evidence gaps in prostate cancer staging or restaging. Methods: This protocol is reported in line with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for systematic review protocols (PRISMA-P). The search strategy will be designed in consultation with a librarian. Searches will be performed in Medline (EBSCO), Embase (Ovid), Google Scholar and the Cochrane Database for Systematic Reviews, supplemented by a targeted grey literature search, forward citation searching and searching reference lists of included reviews. No language or date restrictions will be applied to the eligibility criteria or the search strategy. Title & abstract and full text screening will be performed independently by two reviewers. Data will be extracted by one reviewer and checked in full by a second reviewer. Quality appraisal will be performed using the Risk of Bias in Systematic Reviews (ROBIS) tool independently by two reviewers, and results will be narratively synthesised. Conclusions: This overview of reviews may be of interest to healthcare professionals, academics and health policy decision-makers. Registration: OSF (September 7, 2023).

Abstract Background Polypharmacy and associated potentially inappropriate prescribing (PIP) place a considerable burden on patients and represent a challenge for general practitioners (GPs). Integration of pharmacists within general practice (herein ‘pharmacist integration’) may improve medications management and patient outcomes. This systematic review assessed the effectiveness and costs of pharmacist integration. Methods A systematic search of ten databases from inception to January 2021 was conducted. Studies that evaluated the effectiveness or cost of pharmacist integration were included. Eligible interventions were those that targeted medications optimization compared to usual GP care without pharmacist integration (herein ‘usual care’). Primary outcomes were PIP (as measured by PIP screening tools) and number of prescribed medications. Secondary outcomes included health-related quality of life, health service utilization, clinical outcomes, and costs. Randomised controlled trials (RCTs), non-RCTs, interrupted-time-series, controlled before-after trials and health-economic studies were included. Screening and risk of bias using Cochrane EPOC criteria were conducted by two reviewers independently. A narrative synthesis and meta-analysis of outcomes where possible, were conducted; the certainty of evidence was assessed using the Grading of Recommendations, Assessment, Development and Evaluation approach. Results In total, 23 studies (28 full text articles) met the inclusion criteria. In ten of 11 studies, pharmacist integration probably reduced PIP in comparison to usual care (moderate certainty evidence). A meta-analysis of number of medications in seven studies reported a mean difference of -0.80 [-1.17, -0.43], which indicated pharmacist integration probably reduced number of medicines (moderate certainty evidence). It was uncertain whether pharmacist integration improved health-related quality of life because the certainty of evidence was very low. Twelve health-economic studies were included; three investigated cost effectiveness. The outcome measured differed across studies limiting comparisons and making it difficult to make conclusions on cost effectiveness. Conclusions Pharmacist integration probably reduced PIP and number of medications however, there was no clear effect on other patient outcomes; and while interventions in a small number of studies appeared to be cost-effective, further robust, well-designed cluster RCTs with economic evaluations are required to determine cost-effectiveness of pharmacist integration. Trial registration CRD42019139679.

Abstract Introduction The SPPiRE cluster randomized controlled trial found that a general practitioner (GP)‐delivered medication review that incorporated screening for potentially inappropriate prescriptions (PIP), a brown bag review and a patient priority assessment, resulted in a significant but small reduction in the number of medicines and no significant reduction in PIP. This process evaluation aims to explore the experiences of GPs and patients and the potential for system‐wide implementation. Methods The trial included 51 general practices and 404 participants with multimorbidity aged ≥65 years, prescribed ≥15 medicines. The process evaluation used mixed methods and ran parallel to the trial. Quantitative data was collected from the SPPiRE intervention website and analysed descriptively. Qualitative data on medication changes were collected from intervention GPs (18/26) and a purposive sample of intervention patients (27/208) via semi‐structured telephone interviews. All interviews were transcribed verbatim and analysed using a thematic analysis. Qualitative and quantitative data were integrated using a triangulation protocol. Results The analysis generated two themes, intervention implementation and mechanisms of action, and both were underpinned by the theme of context. Intervention delivery varied among practices and 45 patients (28%) had no review, primarily due to insufficient GP time. 80% of reviewed patients had ≥1 PIP identified, 59% had ≥1 problem identified during the brown bag review and 79% had ≥1 priority recorded. The brown bag review resulted in the most deprescription of medications. GPs and patients responded positively to the intervention but most GPs did not engage with the patient priority‐setting process. GPs identified a lack of integration into practice software and resources as barriers to future implementation. Conclusion The SPPiRE intervention had a small effect in reducing the number of medicines and this was primarily mediated through the brown bag review. The context of resource shortages and deep‐seated views around medical decision‐making influenced intervention implementation. Patient or Public Contribution Qualitative data on the implementation of the medication review and their wider views on their medicines was collected from older people with multimorbidity through semi‐structured telephone interviews. Clinical Trial Registration The SPPiRE trial was registered prospectively on the ISRCTN registry (ISRCTN12752680).

Background How research findings are presented through domestic news can influence behaviour and risk perceptions, particularly during emergencies such as the coronavirus disease 2019 (COVID-19) pandemic. Monitoring media communications to track misinformation and find information gaps is an important component of emergency risk communication. Therefore, this study investigated the traditional media coverage of nine selected COVID-19 evidencebased research reports and associated press releases (PRs) published during the initial phases of the pandemic (April to July 2020) by one national agency.Methods NVivo was used for summative content analysis. ‘Key messages’ from each research report were proposed and 488 broadcast, print, and online media sources were coded at the phrase level. Manifest content was coded and counted to locate patterns in the data (what and how many) while latent content was analysed to further investigate these patterns (why and how). This included the coding of the presence of political and public health actors in coverage.Results Coverage largely did not misrepresent the results of the reports, however, selective reporting and the variability in the use of quotes from governmental and public health stakeholders changed and contextualised results in different manners than perhaps originally intended in the PR. Reports received varying levels of media attention. Coverage focused on more ‘human-interest’ stories (eg, spread of COVID-19 by children and excess mortality) as opposed to more technical reports (eg, focusing on viral load, antibodies, testing, etc).Conclusion Our findings provide a case-study of European media coverage of evidence reports produced by a national agency. Results highlighted several strengths and weaknesses of current communication efforts.

Abstract Background While international guidelines recommend medication reviews as part of the management of multimorbidity, evidence on how to implement reviews in practice in primary care is lacking. The MyComrade (MultimorbiditY Collaborative Medication Review And Decision Making) intervention is an evidence-based, theoretically informed novel intervention which aims to support the conduct of medication reviews for patients with multimorbidity in primary care. Aim The pilot study aimed to assess the feasibility of a definitive trial of the MyComrade intervention across two healthcare systems (Republic of Ireland (ROI) and Northern Ireland (NI)). Design A pilot cluster-randomised controlled trial was conducted (clustered at general practice level), using specific progression criteria and a process evaluation framework. Setting General practices in the ROI and NI. Participants Eligible practices were those in defined geographical areas who had GP’s and Practice Based Pharmacists (PBP’s) (in NI) willing to conduct medication reviews. Eligible patients were those aged 18 years and over, with multi morbidity and on ten or more medications. Intervention The MyComrade intervention is an evidence-based, theoretically informed novel intervention which aims to support the conduct of medication reviews for patients with multimorbidity in primary care, using a planned collaborative approach guided by an agreed checklist, within a specified timeframe. Outcome measures Feasibility outcomes, using pre-determined progression criteria, assessed practice and patient recruitment and retention and intervention acceptability and fidelity. Anonymised patient-related quantitative data, from practice medical records and patient questionnaires were collected at baseline, 4 and 8 months, to inform potential outcome measures for a definitive trial. These included (i) practice outcomes—completion of medication reviews; (ii) patient outcomes—treatment burden and quality of life; (iii) prescribing outcomes—number and changes of prescribed medications and incidents of potentially inappropriate prescribing; and (iv) economic cost analysis. The framework Decision-making after Pilot and feasibility Trials (ADePT) in conjunction with a priori progression criteria and process evaluation was used to guide the collection and analysis of quantitative and qualitative data. Results The recruitment of practices (n = 15) and patients (n = 121, mean age 73 years and 51% female), representing 94% and 38% of a priori targets respectively, was more complex and took longer than anticipated; impacted by the global COVID-19 pandemic. Retention rates of 100% of practices and 85% of patients were achieved. Both practice staff and patients found the intervention acceptable and reported strong fidelity to the My Comrade intervention components. Some practice staff highlighted concerns such as poor communication of the reviews to patients, dissatisfaction regarding incentivisation and in ROI the sustainability of two GPs collaboratively conducting the medication reviews. Assessing outcomes from the collected data was found feasible and appropriate for a definitive trial. Two progression criteria met the ‘Go’ criterion (practice and patient retention), two met the ‘Amend’ criterion (practice recruitment and intervention implementation) and one indicated a ‘Stop – unless changes possible’ (patient recruitment). Conclusion The MyComrade intervention was found to be feasible to conduct within two different healthcare systems. Recruitment of participants requires significant time and effort given the nature of this population and the pairing of GP and pharmacist may be more sustainable to implement in routine practice. Trial registration Registry: ISRCTN, ISRCTN80017020 ; date of confirmation 4/11/2019; retrospectively registered.

Abstract Introduction Clinical guideline development often involves a rigorous synthesis of evidence involving multidisciplinary stakeholders with different priorities and knowledge of evidence synthesis; this makes communicating findings complex. Summary formats are typically used to communicate the results of evidence syntheses; however, there is little consensus on which formats are most effective and acceptable for different stakeholders. Methods This mixed-methods systematic review (MMSR) aimed to evaluate the effectiveness and acceptability (e.g. preferences and attitudes and preferences towards) of evidence synthesis summary formats for GDG members. We followed the PRISMA 2020 guideline and Joanna Briggs Institute Manual for Evidence Synthesis for MMSRs. We searched six databases (inception to April 20, 2021) for randomised controlled trials (RCTs), RCTs with a qualitative component, and qualitative studies. Screening, data extraction, and quality appraisal were performed in duplicate. Qualitative findings were synthesised using meta-aggregation, and quantitative findings are described narratively. Results We identified 17,240 citations and screened 54 full-text articles, resulting in 22 eligible articles (20 unique studies): 4 articles reported the results of 5 RCTs, one of which also had a qualitative component. The other 18 articles discussed the results of 16 qualitative studies. Therefore, we had 5 trials and 17 qualitative studies to extract data from. Studies were geographically heterogeneous and included a variety of stakeholders and summary formats. All 5 RCTs assessed knowledge or understanding with 3 reporting improvement with newer formats. The qualitative analysis identified 6 categories of recommendations: ‘presenting information’, ‘tailoring information’ for end users, ‘trust in producers and summary’, ‘knowledge required’ to understand findings, ‘quality of evidence’, and properly ‘contextualising information’. Across these categories, the synthesis resulted in 126 recommendations for practice. Nine recommendations were supported by both quantitative and qualitative evidence and 116 by only qualitative. A majority focused on how to present information (n = 64) and tailor content for different end users (n = 24). Conclusions This MMSR provides guidance on how to improve evidence summary structure and layout. This can be used by synthesis producers to better communicate to GDGs. Study findings will inform the co-creation of evidence summary format prototypes based on GDG member’s needs. Trial registration The protocol for this project was previously published, and the project was preregistered on Open Science Framework (Clyne and Sharp, Evidence synthesis and translation of findings for national clinical guideline development: addressing the needs and preferences of guideline development groups, 2021; Sharp and Clyne, Evidence synthesis summary formats for decision-makers and Clinical Guideline Development Groups: A mixed-methods systematic review protocol, 2021).

BackgroundIreland’s Model of Care for the Management of Overweight and Obesity outlines a plan for treating adolescent and child obesity (CO). However, engagement with key stakeholders is required to support its implementation and improve health services.AimThis study aims to map the perceived barriers and facilitators related to CO management across healthcare settings, professional disciplines, and regions in the Republic of Ireland (ROI).Materials and methodsAn online cross-sectional survey of registered healthcare professionals (HPs), designed to adhere to the Consolidated Framework for Implementation Research (CFIR), was co-developed by a project team consisting of researchers, healthcare professionals, and patient advocates. The survey was pilot tested with project stakeholders and distributed online to professional groups and via a social media campaign, between September 2021 and May 2022, using “SurveyMonkey.” Data were summarised using descriptive statistics and thematic analyses. Themes were mapped to the CFIR framework to identify the type of implementation gaps that exist for treating obesity within the current health and social care system.ResultsA total of 184 HPs completed the survey including nurses (18%), physicians (14%), health and social care professionals (60%), and other HPs (8%). The majority were female (91%), among which 54% reported conducting growth monitoring with a third (32.6%) giving a diagnosis of paediatric/adolescent obesity as part of their clinical practice. Nearly half (49%) of the HPs reported having the resources needed for clinical assessment. However, 31.5% of the HPs reported having enough “time,” and almost 10% of the HPs reported having no/limited access to suitable anthropometric measurement tools. Most HPs did not conduct obesity-related clinical assessments beyond growth assessment, and 61% reported having no paediatric obesity training. CFIR mapping identified several facilitators and barriers including time for clinical encounters, suitable materials and equipment, adequate training, perceived professional competency and self-efficacy, human equality and child-centredness, relative priorities, local attitudes, referral protocols, and long waiting times.ConclusionsThe findings provide actionable information to guide the implementation of the Model of Care for the Management of Overweight and Obesity in Ireland. Survey findings will now inform a qualitative study to explore implementation barriers and facilitators and prioritise actions to improve child and adolescent obesity management.

IntroductionPrenatal alcohol exposure (PAE) causes neuroinflammation that may contribute to the pathophysiology underlying Fetal Alcohol Spectrum Disorder. Supplementation with omega-3 polyunsaturated fatty acids (PUFAs) has shown success in mitigating effects of PAE in animal models, however, the underlying mechanisms are unknown. Some PUFA metabolites, specialized pro-resolving mediators (SPMs), play a role in the resolution phase of inflammation, and receptors for these are in the brain.MethodsTo test the hypothesis that the SPM receptors FPR2 and ChemR23 play a role in PAE-induced behavioral deficits, we exposed pregnant wild-type (WT) and knockout (KO) mice to alcohol in late gestation and behaviorally tested male and female offspring as adolescents and young adults.ResultsMaternal and fetal outcomes were not different among genotypes, however, growth and behavioral phenotypes in the offspring did differ and the effects of PAE were unique to each line. In the absence of PAE, ChemR23 KO animals showed decreased anxiety-like behavior on the elevated plus maze and FPR2 KO had poor grip strength and low activity compared to age-matched WT mice. WT mice showed improved performance on fear conditioning between adolescence and young adulthood, this was not seen in either KO.DiscussionThis PAE model has subtle effects on WT behavior with lower activity levels in young adults, decreased grip strength in males between test ages, and decreased response to the fear cue indicating an effect of alcohol exposure on learning. The PAE-mediated decreased response to the fear cue was also seen in ChemR23 KO but not FPR2 KO mice, and PAE worsened performance of adolescent FPR2 KO mice on grip strength and activity. Collectively, these findings provide mechanistic insight into how PUFAs could act to attenuate cognitive impairments caused by PAE.

Abstract Background While international guidelines recommend medication reviews as part of the management of multimorbidity, evidence on how to implement reviews in practice in primary care is lacking. The MultimorbiditY Collaborative Medication Review And Decision Making (MyComrade) intervention is an evidence-based, theoretically informed novel intervention which aims to support the conduct of medication reviews for patients with multimorbidity in primary care. Our aim in this pilot study is to evaluate the feasibility of a trial of the intervention with unique modifications accounting for contextual variations in two neighbouring health systems (Republic of Ireland (ROI) and Northern Ireland (NI)). Methods A pilot cluster randomised controlled trial will be conducted, using a mixed-methods process evaluation to investigate the feasibility of a trial of the MyComrade intervention based on pre-defined progression criteria. A total of 16 practices will be recruited (eight in ROI; eight in NI), and four practices in each jurisdiction will be randomly allocated to intervention or control. Twenty people living with multimorbidity and prescribed ≥ 10 repeat medications will be recruited from each practice prior to practice randomisation. In intervention practices, the MyComrade intervention will be delivered by pairs of general practitioners (GPs) in ROI, and a GP and practice-based pharmacist (PBP) in NI. The GPs/GP and PBP will schedule the time to review the medications together using a checklist. Usual care will proceed in practices in the control arm. Data will be collected via electronic health records and postal questionnaires at recruitment and 4 and 8 months after randomisation. Qualitative interviews to assess the feasibility and acceptability of the intervention and explore experiences related to multimorbidity management will be conducted with a purposive sample of GPs, PBPs, practice administration staff and patients in intervention and control practices. The feasibility of conducting a health economic evaluation as part of a future definitive trial will be assessed. Discussion The findings of this pilot study will assess the feasibility of a trial of the MyComrade intervention in two different health systems. Evaluation of the progression criteria will guide the decision to progress to a definitive trial and inform trial design. The findings will also contribute to the growing evidence-base related to intervention development and feasibility studies. Trial registration ISRCTN Registry, ISRCTN80017020 . Date of confirmation is 4/11/2019.

Abstract Background Multimorbidity, defined as the co-existence of two or more chronic conditions, presents significant challenges to patients, healthcare providers and health systems. Despite this, there is ongoing uncertainty about the most effective ways to manage patients with multimorbidity. This review updated and narrowed the focus of a previous Cochrane review and aimed to determine the effectiveness of interventions designed to improve outcomes in people with multimorbidity in primary care and community settings, compared to usual care. Methods We searched eight databases and two trials registers up to 9 September 2019. Two review authors independently screened potentially eligible titles and selected studies, extracted data, evaluated study quality and judged the certainty of the evidence (GRADE). Interventions were grouped by their predominant focus into care-coordination/self-management support, self-management support and medicines management. Main outcomes were health-related quality of life (HRQoL) and mental health. Meta-analyses were conducted, where possible, but the synthesis was predominantly narrative. Results We included 16 RCTs with 4753 participants, the majority being older adults with at least three conditions. There were eight care-coordination/self-management support studies, four self-management support studies and four medicines management studies. There was little or no evidence of an effect on primary outcomes of HRQoL (MD 0.03, 95% CI −0.01 to 0.07, I 2 = 39%) and mental health or on secondary outcomes with a small number of studies reporting that care coordination may improve patient experience of care and self-management support may improve patient health behaviours. Overall, the certainty of the evidence was graded as low due to significant variation in study participants and interventions. Conclusions There are remaining uncertainties about the effectiveness of interventions for people with multimorbidity, despite the growing number of RCTs conducted in this area. Our findings suggest that future research should consider patient experience of care, optimising medicines management and targeted patient health behaviours such as exercise.

Obesity is a chronic disease that compromises the physical and mental health of an increasing proportion of children globally. In high-income countries, prevalence of paediatric obesity is increasing faster in those from marginalised populations such as low-income households, suggesting the disease as one that is largely systemic. Appropriate treatment should be prioritised in these settings to prevent the development of complications and co-morbidities and manage those that already exist. An array of clinical practice guidelines are available for managing overweight and obesity in children and adolescents, but no systematic review has yet compared their quality or synthesised their recommendations. We aimed to narratively review clinical practice guidelines published in English for treating child and adolescent obesity, to identify the highest quality guidelines, and assess similarities, conflicts, and gaps in recommendations. We systematically searched academic databases and grey literature for guidelines published. We used the AGREE II tool to assess the quality, and identified nine high quality guidelines for inclusion in a narrative review of recommendations. Guidelines predominantly recommended the delivery of multi-component behaviour-change interventions aimed at improving nutrition and physical activity. Treatment outcomes were generally focussed on weight, with less emphasis on managing complications or improving quality-of-life. There was no evidence-based consensus on the best mode of delivery, setting, or treatment format. The guidelines rarely included recommendations for addressing the practical or social barriers to behaviour change, such as cooking skills or supervised physical activity. There is insufficient evidence to evaluate pharmaceutical and surgical interventions in children, and these were generally not recommended. It should be noted that this review addressed documents published in English only, and therefore the included guidelines were applicable predominantly to high-resource settings.

Abstract Background Multimorbidity prevalence is increasing globally. People with multimorbidity have higher health care costs, which can create a financial burden. Objective To synthesize qualitative research exploring experience of financial burden for people with multimorbidity. Search strategy Six databases were searched in May 2019. A grey literature search and backward and forward citation checking were also conducted. Inclusion criteria Studies were included if they used a qualitative design, conducted primary data collection, included references to financial burden and had at least one community‐dwelling adult participant with two or more chronic conditions. Data extraction and synthesis Screening and critical appraisal were conducted by two reviewers independently. One reviewer extracted data from the results section; this was checked by a second reviewer. GRADE‐CERQual was used to summarize the certainty of the evidence. Data were analysed using thematic synthesis. Main results Forty‐six studies from six continents were included. Four themes were generated: the high costs people with multimorbidity experience, the coping strategies they use to manage these costs, and the negative effect of both these on their well‐being. Health insurance and government supports determine the manageability and level of costs experienced. Discussion Financial burden has a negative effect on people with multimorbidity. Continuity of care and an awareness of the impact of financial burden of multimorbidity amongst policymakers and health care providers may partially address the issue. Patient or public contribution Results were presented to a panel of people with multimorbidity to check whether the language and themes ‘resonated’ with their experiences.

Abstract Background The application of economic analysis within implementation science is still developing and the cost of intervention development, which differs markedly from the costs of initial implementation and maintenance, is often overlooked. Our aim was to retrospectively cost the development of a multifaceted intervention in primary care to improve attendance at diabetic retinopathy screening. Methods A retrospective micro costing of developing the intervention from the research funder perspective was conducted. It was based on a systematic intervention development process involving analysis of existing audit data and interviews with patients and healthcare professionals (HCPs), conducting consensus meetings with patients and HCPs, and using these data together with a rapid review of the effectiveness of interventions, to inform the final intervention. Both direct (non-personnel, e.g. travel, stationary, room hire) and indirect (personnel) costs were included. Data sources included researcher time logs, payroll data, salary scales, an online financial management system, invoices and purchase orders. Personnel involved in the intervention development were consulted to determine the activities they conducted and the duration of their involvement. Sensitivity and scenario analyses were conducted to estimate uncertainty around parameters and scope. Results The total cost of intervention development (July 2014–January 2019) was €40,485 of which 78% were indirect (personnel) costs (€31,451). In total, personnel contributed 1368 h to intervention development. Highest cost activities were the patient interviews, and consensus process, contributing 23% and 34% of the total cost. Varying estimated time spent on intervention development activities by + 10% increased total intervention development cost by 6% to €42,982. Conclusions Our results highlight that intervention development requires a significant amount of human capital input, combining research experience, patient and public experience, and expert knowledge in relevant fields. The time committed to intervention development is critical but has a significant opportunity cost. With limited resources for research on developing and implementing interventions, capturing intervention development costs and incorporating them as part of assessment of cost-effective interventions, could inform research priority and resource allocation decisions.

Abstract Prenatal alcohol exposure (PAE) causes permanent cognitive disability. The enteric microbiome generates microbial-dependent products (MDPs) that may contribute to disorders including autism, depression, and anxiety; it is unknown whether similar alterations occur in PAE. Using a mouse PAE model, we performed untargeted metabolome analyses upon the maternal–fetal dyad at gestational day 17.5. Hierarchical clustering by principal component analysis and Pearson’s correlation of maternal plasma (813 metabolites) both identified MDPs as significant predictors for PAE. The majority were phenolic acids enriched in PAE. Correlational network analyses revealed that alcohol altered plasma MDP-metabolite relationships, and alcohol-exposed maternal plasma was characterized by a subnetwork dominated by phenolic acids. Twenty-nine MDPs were detected in fetal liver and sixteen in fetal brain, where their impact is unknown. Several of these, including 4-ethylphenylsulfate, oxindole, indolepropionate, p-cresol sulfate, catechol sulfate, and salicylate, are implicated in other neurological disorders. We conclude that MDPs constitute a characteristic biosignature that distinguishes PAE. These MDPs are abundant in human plasma, where they influence physiology and disease. Their altered abundance here may reflect alcohol’s known effects on microbiota composition and gut permeability. We propose that the maternal microbiome and its MDPs are a previously unrecognized influence upon the pathologies that typify PAE.

ABSTRACT: Genetic selection for rapid growth in broilers has inadvertently resulted in increased susceptibility to heat stress, particularly in male birds. Increased oxidative stress associated with hyperthermia may be reduced by avian uncoupling protein (avUCP), which has been proposed to modulate free radical production. However, the relationship between avUCP expression and current heat stress management strategies is unclear. Embryonic acclimation or thermal manipulation (TM) and dietary fat source are 2 heat stress interventions that may alter avUCP expression and oxidative stress, but the literature is inconclusive. The objective of this trial was to investigate the effect of TM and dietary fat source on avUCP gene expression and oxidative damage in the breast meat of market age broilers before and after acute heat challenge. The influence of bird sex was also evaluated as broilers exhibit a high degree of sexual dimorphism in growth and stress susceptibility. Concentration of thiobarbituric acid reactive substances (TBARS) was measured as a marker of oxidative damage. Embryonic TM occurred from incubation d 7 to 16 for 12 h daily at 39.5°C. Dietary treatments were applied during the finisher period using either poultry fat, soya oil, or olive oil supplemented at 4.5% in the diet. Acute heat stress (AHS) occurred on d 43 at 32°C for 4 h. Bird performance was decreased by TM, but no significant differences were noted between dietary fat source treatments. Neither avUCP nor TBARS concentrations were significantly influenced by TM or dietary fat source. Downregulation of avUCP was observed following AHS, concurrent with an increase in TBARS concentration. Male birds exhibited higher levels of both avUCP expression and TBARS compared to females and a significant interaction was noted for heat stress by sex, with avUCP expression being greatest in males prior to AHS. The increase in avUCP expression and TBARS concentrations in male birds may be associated with an increased susceptibility to stress arising from the increased growth rate noted for male broilers.

Introduction: Evidence syntheses, often in the form of systematic reviews, are essential for clinical guideline development and informing changes to health policies. However, clinical guideline development groups (CGDG) are multidisciplinary, and participants such as policymakers, healthcare professionals and patient representatives can face obstacles when trying to understand and use evidence synthesis findings. Summary formats to communicate the results of evidence syntheses have become increasingly common, but it is currently unclear which format is most effective for different stakeholders. This mixed-methods systematic review (MMSR) evaluates the effectiveness and acceptability of different evidence synthesis summary formats for CGDG members. Methods: This protocol follows guidance from the Joanna Briggs Institute on MMSRs and is reported according to the Preferred Reporting Items for Systematic Reviews (PRISMA)-P guideline. A comprehensive search of six databases will be performed with no language restrictions. Primary outcomes are those relating to the effectiveness and preferences for and attitudes towards the different summary formats. We will include qualitative research and randomised controlled trials. Two reviewers will perform title, abstract, and full-text screening. Independent double-extraction of study characteristics and critical appraisal items will be undertaken using a standardised form. We will use a convergent segregated approach to analyse quantitative and qualitative data separately; results will then be integrated. Discussion: The results of this systematic review will provide an overview of the effectiveness and acceptability of different summary formats for evidence synthesis findings. These findings can be helpful for those in or communicating to guideline development groups. The results can also inform the development and pilot-testing of summary formats for evidence summaries.

Abstract Background Individuals exposed to gestational stressors such as alcohol exhibit a spectrum of growth patterns, suggesting individualized responses to the stressors. We hypothesized that intrauterine growth responses to gestational alcohol are modified not only by the stressor’s severity but by fetal sex and the placenta’s adaptive capacity. Methods Pregnant C57BL/6J mice were assigned to one of three groups. Group 1 consumed a normal protein diet (18% protein by weight) and received 4.5 g alcohol/kg body weight (NP-Alc-8) or isocaloric maltodextrin (NP-MD-8) daily from embryonic day (E) 8.5–E17.5. Group 2 consumed the same diet but received alcohol (NP-Alc-13) or maltodextrin (NP-MD-13) daily from E13.5–E17.5. Group 3 consumed the same diet but containing a lower protein content (12% protein by weight) from E0.5 and also received alcohol (LP-Alc-8) or maltodextrin (LP-MD-8) daily from E8.5–E17.5. Maternal, placental, and fetal outcomes were assessed on E17.5 using 2-way ANOVA or mixed linear model. Results We found that intrauterine growth differed in the alcohol-exposed fetuses depending on sex and insult severity. Both NP-Alc-8 (vs. NP-MD-8) males and females had lower body weight and asymmetrical growth, but only NP-Alc-8 females had lower placental weight (P < 0.05). NP-Alc-13 (vs. NP-MD-13) females, but not their male littermates, had lower body weight (P = 0.019). Alcohol exposure beginning from E8.5 (vs. E13.5) decreased the ratio of fetal liver-to-body weight and increased the ratio of fetal brain-to-liver weight in both sexes (P < 0.05). LP-Alc-8 (vs. NP-MD-8) group had smaller litter size (P = 0.048), but the survivors had normal placental and body weight at E17.5. Nevertheless, LP-Alc-8 fetuses still showed asymmetrical growth. Correlation analyses reveal a relationship between litter size and placental outcomes, which were related to fetal outcomes in a sex-dependent manner, suggesting that the placenta may mediate the consequence of LP-Alc-altered litter size on fetal development. Conclusions Our data indicate that the placenta is strongly involved in the fetal stress response and adapts in a sex-dependent fashion to support fetal development under the alcohol stressor. These variables may further influence the spectrum of intrauterine growth outcomes observed in those diagnosed with fetal alcohol spectrum disorder.

Abstract Background Despite efforts to improve the accuracy and transparency of the design, conduct, and reporting of randomised controlled trials (RCTs), deficiencies remain. Such deficiencies contribute to significant, avoidable waste of health research investment and impede reproducibility. This study aimed to synthesise and critically analyse changes over time in the conduct and reporting of internationally published evidence on patient and/or population health-oriented RCTs conducted in one country. Methods This observational study drew on systematic review methods. We searched six databases for published RCTs (database inception to December 2018) where ≥ 80% of participants were recruited in the Republic of Ireland. RCTs of interventions targeted at patients, providers and/or policy makers intended to improve health, healthcare or health research were included. For each study, screening, data extraction and methodological quality appraisal were conducted by one member of the author team. Results From 17,560 titles and abstracts, 752 unique RCTs were published in 745 papers between 1968 and 2018, with a steady year-on-year increase since 1968. The number of participants was in the range of 2–8628. The majority were parallel design (86%) and classified as treatment evaluation. Of the 418 RCTs published since the introduction of mandatory clinical trial registration by the International Committee of Medical Journal Editors in 2005, 32% (n = 134) provided a trial registration number. This increased to 47% when taking studies published between 2013 and 2018 (n = 232). Since the 1996 publication of the CONSORT statement, 16% of included RCTs made specific reference to a standardised reporting guideline and this increased to 31% for more recent studies published between 2013 and 2018. Overall, 7% (n = 53) of studies referred to a published study protocol, increasing to 20% for studies published between 2013 and 2018. Conclusion Evidence from this single-country study of RCTs published in the international literature suggests that both the number overall, the number registered and the number referencing reporting guidelines have increased steadily over time. Despite widespread endorsement of reporting standards, reporting of RCTs remains suboptimal in domains such as compliance with the CONSORT statement and prospective trial registration. Researchers, funders and journal editors, nationally and internationally, should continue to focus on improving reporting and examining avoidable waste of health research investment.

Abstract Background Diabetic retinopathy screening (DRS) leads to the earlier detection of retinopathy and treatment that can prevent or delay the development of diabetes-related blindness. However, uptake continues to be sub-optimal in many countries, including Ireland. Routine management of type 2 diabetes largely takes place in primary care. As such, there may be an opportunity in primary care to introduce interventions to improve DRS uptake. However, few studies test the feasibility of interventions to enhance DRS uptake in this context. Our aim is to investigate the feasibility of an implementation intervention (IDEAs (Improving Diabetes Eye screening Attendance)) delivered in general practice to improve the uptake of the national DRS programme, RetinaScreen. Methods The IDEAs study is a cluster randomised pilot trial with an embedded process evaluation and economic evaluation. Following stratification by practice size, eight general practices (clusters) will be randomly allocated to intervention (n = 4) or wait-list control groups (n = 4). The intervention will be delivered for 6 months, after which, it will be administered to wait-list control practices. The intervention is multi-faceted and comprises provider-level components (training, audit and feedback, health care professional prompt, reimbursement) and patient-level components (GP-endorsed reminder with information leaflet delivered opportunistically face-to-face, and systematically by phone and letter). Patient inclusion criteria are type 1 or type 2 diabetes and DRS programme non-attendance. A multi-method approach will be used to determine screening uptake, evaluate the trial and study procedures and examine the acceptability and feasibility of the intervention from staff and patient perspectives. Quantitative and qualitative data will be collected on intervention uptake and delivery, research processes and outcomes. Data will be collected at the practice, health professional and patient level. A partial economic evaluation will be conducted to estimate the cost of delivering the implementation intervention in general practice. Formal continuation criteria will be used to determine whether IDEAs should progress to a definitive trial. Discussion Findings will determine whether IDEAsis feasible and acceptable and will be used to refine the intervention and study procedures. A definitive trial will determine whether IDEAs is a cost-effective intervention to improve DRS uptake and reduce diabetes-related blindness. Trial registration ClinicalTrials.gov NCT03901898 . Registered 3rd April 2019,

Abstract Background ‘Implementation interventions’ refer to methods used to enhance the adoption and implementation of clinical interventions such as diabetic retinopathy screening (DRS). DRS is effective, yet uptake is often suboptimal. Despite most routine management taking place in primary care and the central role of health care professionals (HCP) in referring to DRS, few interventions have been developed for primary care. We aimed to develop a multifaceted intervention targeting both professionals and patients to improve DRS uptake as an example of a systematic development process combining theory, stakeholder involvement, and evidence. Methods First, we identified target behaviours through an audit in primary care of screening attendance. Second, we interviewed patients (n = 47) and HCP (n = 30), to identify determinants of uptake using the Theoretical Domains Framework, mapping these to behaviour change techniques (BCTs) to develop intervention content. Thirdly, we conducted semi-structured consensus groups with stakeholders, specifically users of the intervention, i.e. patients (n = 15) and HCPs (n = 16), regarding the feasibility, acceptability, and local relevance of selected BCTs and potential delivery modes. We consulted representatives from the national DRS programme to check intervention ‘fit’ with existing processes. We applied the APEASE criteria (affordability, practicability, effectiveness, acceptability, side effects, and equity) to select the final intervention components, drawing on findings from the previous steps, and a rapid evidence review of operationalised BCT effectiveness. Results We identified potentially modifiable target behaviours at the patient (consent, attendance) and professional (registration) level. Patient barriers to consent/attendance included confusion between screening and routine eye checks, and fear of a negative result. Enablers included a recommendation from friends/family or professionals and recognising screening importance. Professional barriers to registration included the time to register patients and a lack of readily available information on uptake in their local area/practice. Most operationalised BCTs were acceptable to patients and HCPs while the response to feasibility varied. After considering APEASE, the core intervention, incorporating a range of BCTs, involved audit/feedback, electronic prompts targeting professionals, HCP-endorsed reminders (face-to-face, by phone and letter), and an information leaflet for patients. Conclusions Using the example of an intervention to improve DRS uptake, this study illustrates an approach to integrate theory with user involvement. This process highlighted tensions between theory-informed and stakeholder suggestions, and the need to apply the Theoretical Domains Framework (TDF)/BCT structure flexibly. The final intervention draws on the trusted professional-patient relationship, leveraging existing services to enhance implementation of the DRS programme. Intervention feasibility in primary care will be evaluated in a randomised cluster pilot trial.

Introduction: General practitioners (GPs) strive to use a patient centered approach to achieve shared decision making by integrating clinical evidence, clinical judgement, and patient priorities. In order to achieve this standard of care, GPs require relevant, up to date and high quality evidence. Currently there is a gap in the literature regarding the role of GP professional organisations internationally in producing and publishing evidence based guidance and clinical guidelines for GPs. This protocol outlines a scoping review to identify what evidence-based guidance is produced by general practitioner professional organisations internationally in terms of topic content, the structure and methods used to develop guidance and ways of disseminating this guidance, to support general practice clinical decision making. Methods: This scoping review will be conducted using the framework proposed by the Joanna Briggs Institute and the Preferred Reporting Items for Systematic Reviews and Meta-analysis extension for scoping reviews (PRISMA-ScR), will be used to guide the reporting. Two researchers will search electronic databases (Medline, Embase, Cochrane Library and Scopus), grey literature sources and contact international GP professional organisations directly to identify appropriate studies for inclusion. Key information will be categorised and classified to generate a summary of the methods used internationally to develop and implement evidence-based guides for general practitioners and a narrative synthesis will be conducted. Conclusions: This scoping review will examine current practice internationally regarding the role of General Practice professional organisations in producing and publishing clinical guidelines and evidence based guidance to support general practitioner’s clinical decision making to benefit patient care.

Background There 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 findings We 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. Conclusions The 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 registration ISRCTN Registry ISRCTN12752680. Caroline McCarthy and colleagues investigate the effect of a general practitioner-delivered, individualized medication review on polypharmacy and potentially inappropriate prescribing in community dwelling older patients with multimorbidity in Irish primary care. Author summary Why was this study done? Polypharmacy is frequently cited as a major concern by patients with multimorbidity. More evidence-based medicines management interventions are needed to improve care for this growing and vulnerable population. What did the researchers do and find? We conducted a pragmatic, 2-arm cluster randomised controlled trial (RCT) in Irish primary care to investigate whether a general practitioner (GP)-delivered individualised medication review with a deprescribing approach could reduce polypharmacy and improve prescribing in older people with multimorbidity and significant polypharmacy. There was a small but significant reduction in the number of medicines in the intervention compared to control group at follow-up but no significant effect on potentially inappropriate prescribing (PIP). Out of 826 medicines stopped in the intervention group, just 15 adverse drug withdrawal events (ADWEs) were reported. What do these findings mean? A primary care–based medication review intervention that aims to reduce significant polypharmacy is safe and could lead to the deprescription of unnecessary medicines. However, this may have a greater impact at a population rather than individual patient level. Improvements in the control group suggest that identification of patients with significant polypharmacy may in itself lead to reduction in the number of medicines. Recruitment and retention of patients with a high degree of disease and treatment burden into RCTs are possible but require significant resource and planning, and targeting those with less severe disease burden may be more appropriate and may lead to greater gains for individual patients.

Prenatal alcohol exposure can produce offspring growth deficits and is a leading cause of neurodevelopmental disability. We used untargeted metabolomics to generate mechanistic insight into how alcohol impairs fetal development. In the Western Cape Province of South Africa, 52 women between gestational weeks 5–36 (mean 18.5 ± 6.5) were recruited, and they provided a finger-prick fasting bloodspot that underwent mass spectrometry. Metabolomic data were analyzed using partial least squares-discriminant analyses (PLS-DA) to identify metabolites that correlated with alcohol exposure and infant birth outcomes. Women who consumed alcohol in the past seven days were distinguished by a metabolite profile that included reduced sphingomyelins, cholesterol, and pregnenolones, and elevated fatty acids, acyl and amino acyl carnitines, and androsterones. Using PLS-DA, 25 of the top 30 metabolites differentiating maternal groups were reduced by alcohol with medium-chain free fatty acids and oxidized sugar derivatives having the greatest influence. A separate ortho-PLS-DA analysis identified a common set of 13 metabolites that were associated with infant length, weight, and head circumference. These included monoacylglycerols, glycerol-3-phosphate, and unidentified metabolites, and most of their associations were negative, implying they represent processes having adverse consequences for fetal development.

Background: The burden of osteoarthritis (OA) to individuals and health systems is substantial and is expected to increase due to population ageing and rising prevalence of obesity and multimorbidity. Primary care-based models of care (MoCs) are being increasingly developed in response to this growing burden. However, these MoCs have yet to be formally reviewed. A MoC can be defined as an ‘evidence-informed strategy, framework or pathway that outlines the optimal manner in which condition-specific care should be delivered to consumers within a local health system’. Objective: To identify and describe the available research regarding the extent, nature and characteristics of MoCs for OA that have been developed or evaluated in primary care. Methods: A scoping review will be conducted in accordance with the Arksey and O’Malley scoping review framework and the PRISMA-ScR guidelines. Systematic literature searches of MEDLINE, EMBASE, CINAHL, PsychINFO, Web of Science and LILACs will be conducted from 2010 to present, aligning with publication dates of recent clinical guidelines. A structured iterative search of grey literature will be conducted. Full-text original quantitative or mixed method studies which describe the development or evaluation of MoCs for OA in primary care will be considered. Data will be charted and synthesised and a narrative synthesis will be conducted. Conclusions: This scoping review will provide a broad overview regarding the extent, nature and characteristics of the available literature on primary care based MoCs for OA. Findings will be used to identify gaps in the current evidence to identify areas for future research.

Introduction Understanding primary care practices’ ‘readiness’ to engage in trials and their experience is important to inform trial procedures and supports. Few studies report on the feasibility of study procedures though this is a central part of pilot trials. We explored the acceptability and feasibility of study procedures of a cluster randomised pilot trial of an intervention in primary care to improve uptake of Ireland’s national diabetic retinopathy programme. Methods As part of the embedded mixed-methods process evaluation, quantitative and qualitative data were gathered across four general practices participating in the intervention. Interviews were conducted with a purposive sample of staff. Research logs on time spent on intervention delivery, staff assignment, resources, problems/changes, and reasons for drop-outs, were maintained over the course of intervention rollout, and practice audit data were analysed. Quantitative outcomes included recruitment, retention, completion, and data quality and completeness. Qualitative data on perceptions and experience of the pilot trial procedures were analysed using the Framework Method. Findings Nine staff (3 GPs, 4 nurses, 2 administrators) were interviewed. An interest in the topic area or in research motivated practices to take part in the trial. Reimbursement meant they could ‘afford’ to participate. Staff valued the researcher briefing at the start of the trial, to avoid ‘going in slightly blind’. While staff varied in audit skills and confidence, and some found this aspect of data collection challenging, a ‘step-by-step’ audit manual and regular researcher contact, helped them stay on track and troubleshoot during data collection. Audit quality was acceptable overall, however there were some issues, incorrect assignment of patient status being most common. Conclusion The IDEAs trial procedures were acceptable and feasible for primary care staff, however, challenges with conducting the audit may reflect staff skills gaps and the need for greater guidance and support from researchers.

Abstract Background Community pharmacy represents an important setting to identify patients who may benefit from an adherence intervention, however it remains unclear whether it would be feasible to monitor antihypertensive adherence within the workflow of community pharmacy. The aim of this study was to identify facilitators and barriers to monitoring antihypertensive medication adherence of older adults at the point of repeat dispensing. Methods We undertook a factorial survey of Irish community pharmacists, guided by a conceptual model adapted from the Theory of Planned Behaviour (TPB). Respondents completed four sections, 1) five factorial vignettes (clinical scenario of repeat dispensing), 2) a medication monitoring attitude measure, 3) subjective norms and self-efficacy questions, and 4) demographic and workplace questions. Barriers and facilitators to adherence monitoring behaviour were identified in factorial vignette analysis using multivariate multilevel linear modelling, testing the effect of both contextual factors embedded within the vignettes (section 1), and respondent-level factors (sections 2–4) on likelihood to perform three adherence monitoring behaviours in response to the vignettes. Results Survey invites (n = 1543) were sent via email and 258 completed online survey responses were received; two-thirds of respondents were women, and one-third were qualified pharmacists for at least 15 years. In factorial vignette analysis, pharmacists were more inclined to monitor antihypertensive medication adherence by examining refill-patterns from pharmacy records than asking patients questions about their adherence or medication beliefs. Pharmacists with more positive attitudes towards medication monitoring and normative beliefs that other pharmacists monitored adherence, were more likely to monitor adherence. Contextual factors also influenced pharmacists’ likelihood to perform the three adherence monitoring behaviours, including time-pressures and the number of days late the patient collected their repeat prescription. Pharmacists’ normative beliefs and the number of days late the patient collected their repeat prescription had the largest quantitative influence on responses. Conclusions This survey identified that positive pharmacist attitudes and normative beliefs can facilitate adherence monitoring within the current workflow; however contextual time-barriers may prevent adherence monitoring. Future research should consider these findings when designing a pharmacist-led adherence intervention to be integrated within current pharmacy workflow.

Background: The burden of osteoarthritis (OA) to individuals and health systems is substantial and is expected to increase due to population ageing and rising prevalence of obesity and multimorbidity. Primary care-based models of care (MoCs) are being increasingly developed in response to this growing burden. However, these MoCs have yet to be formally reviewed. A MoC can be defined as an ‘evidence-informed strategy, framework or pathway that outlines the optimal manner in which condition-specific care should be delivered to consumers within a local health system’. Objective: To identify and describe the available research regarding the extent, nature and characteristics of MoCs for OA that have been developed or evaluated in primary care. Methods: A scoping review will be conducted in accordance with the Arksey and O’Malley scoping review framework and the PRISMA-ScR guidelines. Systematic literature searches of MEDLINE, EMBASE, CINAHL, PsychINFO, Web of Science and LILACs will be conducted from 2010 to present, aligning with publication dates of recent clinical guidelines. A structured iterative search of grey literature will be conducted. Full-text original quantitative or mixed method studies which describe the development or evaluation of MoCs for OA in primary care will be considered. Data will be charted and synthesised and a narrative synthesis will be conducted. Conclusions: This scoping review will provide a broad overview regarding the extent, nature and characteristics of the available literature on primary care based MoCs for OA. Findings will be used to identify gaps in the current evidence to identify areas for future research.

Background Multimorbidity, defined as two or more chronic conditions is increasing in prevalence and is associated with increased health care use, fragmented care and poorer health outcomes. Link workers are non-health or social care professionals who support people to connect with resources in their community to improve their well-being, a process commonly referred to as social prescribing. The use of link workers in primary care may be an effective intervention in helping those with long‐term conditions manage their illness and improve health and well‐being, but the evidence base in limited. The LinkMM study is a randomised controlled trial of the effectiveness of link workers based in primary care, providing social prescribing and health and social care coordination for people with multimorbidity. The aim of the LinkMM process evaluation is to investigate the implementation of the link worker intervention, mechanisms of impact and influence of the specific context on these, as per the Medical Research Council framework, using quantitative and qualitative methods. Methods Quantitative data will be gathered from a number of sources including researcher logbooks, participant baseline questionnaires, client management database, and will be analysed using descriptive statistics. Semi structured interviews with participants will investigate their experiences of the intervention. Interviews with link workers, practices and community stakeholders will explore how the intervention was implemented and barriers and facilitators to this. Thematic analysis of interview transcripts will be conducted. Discussion The process evaluation of the LinkMM trial will provide important information allowing a more in-depth understanding of how the intervention worked and lessons for future wider scale implementation.

Background: The relationship between procedural volume and outcomes for percutaneous coronary interventions (PCI) is contentious, with previous reviews suggesting an inverse volume-outcome relationship. The aim of this study was to systematically review contemporary evidence to re-examine this relationship. Methods: A systematic review and meta-analysis was undertaken to examine the relationship between PCI procedural volume (both at hospital- and operator-levels) and outcomes in adults. The primary outcome was mortality. The secondary outcomes were complications, healthcare utilisation and process outcomes. Searches were conducted from 1 January 2008 to 28 May 2019. Certainty of the evidence was assessed using ‘Grading of Recommendations, Assessment, Development and Evaluations’ (GRADE). Screening, data extraction, quality appraisal and GRADE assessments were conducted independently by two reviewers. Results: Of 1,154 unique records retrieved, 22 observational studies with 6,432,265 patients were included. No significant association was found between total PCI hospital volume and mortality (odds ratio [OR]: 0.84, 95% confidence interval [CI]: 0.69-1.03, I2 = 86%). A temporal trend from significant to non-significant pooled effect estimates was observed. The pooled effect estimate for mortality was found to be significantly in favour of high-volume operators for total PCI procedures (OR: 0.77, 95% CI: 0.63-0.94, I2 = 93%), and for high-volume hospitals for primary PCI procedures (OR: 0.77, 95% CI: 0.62-0.94, I2 = 78%). Overall, GRADE certainty of evidence was ‘very low’. There were mixed findings for secondary outcomes. Conclusions: A volume-outcome relationship may exist in certain situations, although this relationship appears to be attenuating with time, and there is ‘very low’ certainty of evidence. While volume might be important, it should not be the only standard used to define an acceptable PCI service and a broader evaluation of quality metrics should be considered that encompass patient experience and clinical outcomes. Systematic review registration: PROSPERO, CRD42019125288

Prenatal alcohol exposure causes neurodevelopmental disability and is associated with a functional iron deficiency in the fetus and neonate, even when the mother consumes an apparently iron-adequate diet. Here, we test whether gestational administration of the clinically relevant iron supplement Fer-In-Sol mitigates alcohol’s adverse impacts upon the fetus. Pregnant Long-Evans rats consumed an iron-adequate diet and received 5 g/kg alcohol by gavage for 7 days in late pregnancy. Concurrently, some mothers received 6 mg/kg oral iron. We measured maternal and fetal weights, hematology, tissue iron content, and oxidative damage on gestational day 20.5. Alcohol caused fetal anemia, decreased fetal body and brain weight, increased hepatic iron content, and modestly elevated hepatic malondialdehyde (p’s < 0.05). Supplemental iron normalized this brain weight reduction in alcohol-exposed males (p = 0.154) but not female littermates (p = 0.031). Iron also reversed the alcohol-induced fetal anemia and normalized both red blood cell numbers and hematocrit (p’s < 0.05). Iron had minimal adverse effects on the mother or fetus. These data show that gestational iron supplementation improves select fetal outcomes in prenatal alcohol exposure (PAE) including brain weight and hematology, suggesting that this may be a clinically feasible approach to improve prenatal iron status and fetal outcomes in alcohol-exposed pregnancies.

Prenatal alcohol exposure (PAE) causes fetal growth restrictions. A major driver of fetal growth deficits is maternal metabolic disruption; this is under-investigated following PAE. Untargeted metabolomics on the dam and fetus exposed to alcohol (ALC) revealed that the hepatic metabolome of ALC and control (CON) dams were distinct, whereas that of ALC and CON fetuses were similar. Alcohol reduced maternal hepatic glucose content and enriched essential amino acid (AA) catabolites, N-acetylated AA products, urea content, and free fatty acids. These alterations suggest an attempt to minimize the glucose gap by increasing gluconeogenesis using AA and glycerol. In contrast, ALC fetuses had unchanged glucose and AA levels, suggesting an adequate draw of maternal nutrients, despite intensified stress on ALC dams. Maternal metabolites including glycolytic intermediates, AA catabolites, urea, and one-carbon-related metabolites correlated with fetal liver and brain weights, whereas lipid metabolites correlated with fetal body weight, indicating they may be drivers of fetal weight outcomes. Together, these data suggest that ALC alters maternal hepatic metabolic activity to limit glucose availability, thereby switching to alternate energy sources to meet the high-energy demands of pregnancy. Their correlation with fetal phenotypic outcomes indicates the influence of maternal metabolism on fetal growth and development.

People that experience prenatal alcohol exposure (PAE) may have behavioral and metabolic impairments, and it is unclear whether these remain stable or change with age. We assessed behavioral and metabolic endpoints across the lifespan in a mouse model of fetal alcohol spectrum disorder (FASD). Pregnant C57BL/6J mice received alcohol (ALC; 3 g/kg) or maltose-dextrin (control, CON) daily from embryonic day 8.5 to 17.5. Offspring were tested on accelerating rotarod, Y-maze, novel object recognition, and fear conditioning at 6 weeks and 10 and 17 months; females were also tested at 24 months. Body composition, fasting glucose, and glucose clearance were assessed at 18 months. Female but not male ALC mice had greater adiposity than age-matched CON from 7 months onward. At 18 months, male but not female ALC mice had reduced glucose clearance and ALC mice were more likely to have elevated fasting glucose. In the rotarod training session, ALC females performed worse than CON. In the Y-maze, significant exposure-age interactions affected ALC performance in both sexes versus age-match CON. For fear conditioning, all animals acquired the task and froze more at older ages. In both the context and cued tasks, there were exposure-age interactions and ALC animals frozen less than CON at 10 months. Correlation analysis revealed that fasting glucose and glucose clearance correlated with % of body fat in ALC but not in CON mice. Additionally, glucose intolerance and % body fat negatively correlated with performance in the rotarod, context learning, and novel object recognition tasks in ALC but not CON mice. All mice exhibit worsening of behavioral performance as they age, and PAE did not further exacerbate this. ALC but not CON mice displayed adiposity and glucose intolerance that correlate with their cognitive impairments, suggesting that these may be mechanistically related in PAE. Findings emphasize that FASD should be considered a whole-body disorder.

Introduction: The use of link workers for social prescribing and health and social care coordination is increasing, but there is insufficient data to demonstrate their effectiveness or for whom they work best. Multimorbidity is increasing in prevalence and affects those living in deprived areas ten years earlier than affluent areas. This systematic review aims to examine the evidence for the effectiveness and costs of link workers in improving health outcomes. We will also look for evidence for the use of link workers specifically for people living with multimorbidity and in deprived areas. Methods: Databases of published and grey literature will be searched for randomised and non-randomised controlled trials examining use of link workers based in primary care for community dwelling adults compared to usual care. Primary outcomes will be health related quality of life and mental health. Data on costs will be extracted. Studies will be selected for inclusion by title and abstract review by two reviewers. A Preferred Reporting Items for Systematic Reviews (PRISMA) flow diagram will document the selection process. A standardised form will be used to extract data. Data quality will be assessed using the Cochrane Risk of Bias tool for randomised controlled trials, a narrative synthesis will be completed and the GRADE assessment tool used to comment on evidence quality. A meta-analysis of effect size of primary outcomes and subgroup analysis for multimorbidity and social deprivation will be performed if there are sufficient comparable data. Conclusion: This systematic review will give an important overview of the evidence for the use of link workers providing social prescribing and health and social care coordination in primary care. This will help inform intervention development and guide policy makers on whether these interventions are cost effective and which groups stand to benefit most. Prospero registration: CRD42019134737 (04/07/2019)

Background: Diagnosis of chronic hepatitis C virus (HCV) infection typically involves collection of venous blood samples prior to serological investigation of an antibody response followed by a confirmatory viral load or antigen test to verify active HCV infection. This conventional pathway poses logistical challenges for the implementation of reflex testing, whereby the confirmatory test is performed on the same sample used for serological investigation. Dried blood spot (DBS) testing, in which capillary blood is deposited on filter paper, is a less invasive alternative that can enable reflex testing without the need for venepuncture, centrifugation and freezing of samples. Methods: This systematic review aims to assess the diagnostic accuracy of DBS compared with venous blood samples for diagnosis of chronic HCV infection. Observational studies which compare diagnostic tests using DBS with those using serum, plasma or whole blood in patients with chronic or resolved HCV infection will be included. Electronic searches will be conducted in PubMed, Embase, Scopus, Web of Science, Lilacs and the Cochrane library. Citation screening, data extraction and quality appraisal of included studies will be performed in duplicate using the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) tool. A meta-analysis will be conducted to derive pooled estimates of sensitivity, specificity, positive likelihood ratios, negative likelihood ratios, and diagnostic odds ratios. Sensitivity analyses and meta-regression will also be performed. Quality of the evidence will be evaluated using the GRADE criteria. Discussion: Identifying and linking people with currently undiagnosed chronic HCV infection to care is pivotal to attaining global viral hepatitis elimination targets. The use of DBS could simplify diagnostic testing strategies by integrating reflex testing into the care pathway and reducing drop-off along the cascade of care. Registration: PROSPERO, CRD42020205204. Registered 19th September 2020.

Introduction: Multimorbidity is increasingly important due to its high disease burden, prevalence and related high healthcare utilisation. For patients, there is also a high financial burden due to direct and indirect costs arising from their multimorbidity. It is unclear how this financial burden affects patients. This study aims to synthesise qualitative evidence exploring the experience of financial burden from the perspective of patients with multimorbidity. Methods: The review will be reported using the ENTREQ guidelines. A systematic search of Lilacs, PubMed, CINAHL, EMBASE, PsycINFO, and Applied Social Sciences Index and Abstracts will be conducted using a predefined search strategy. A search of fourteen pre-specified websites will be conducted for grey literature. Forward and backward citation checking of included studies will be conducted also. Studies will be included if they contain primary qualitative research and reference the experience of financial burden from the perspective of adult (≥ 18 years) community dwelling patients with multimorbidity. Studies from any country and in any language will be included. Titles and abstracts of search results will be screened; if a study appears relevant, then full-texts will be screened for eligibility. Study characteristics of included articles will be extracted. Study quality will be evaluated using the critical appraisal skills programme (CASP) checklist for qualitative research. These three processes will be carried out by two reviewers independently. Thematic-synthesis will be used to analyse data. This will be carried out by one reviewer and cross-checked by a second reviewer. The GRADE CERQual approach will be used to assess the overall confidence in the evidence. Discussion: This review will identify evidence on the experiences of financial burden for patients with multimorbidity and forms part of a project to support consideration of financial burden for patients in the development of clinical guidelines in Ireland. PROSPERO registration number: CRD42019135284

Introduction: Coordinating prescribing for patients with polypharmacy is a challenge for general practitioners. Pharmacists may improve management and outcomes for patients with polypharmacy. This systematic review aims to examine the clinical and cost-effectiveness of pharmacist interventions to optimise prescribing and improve health outcomes in patients with polypharmacy in primary care settings. Methods: The review will be reported using the PRISMA guidelines. A comprehensive search of 10 databases from inception to present, with no language restrictions will be conducted. Studies will be included where they evaluate the clinical or cost-effectiveness of a clinical pharmacist in primary care on potentially inappropriate prescriptions using validated indicators and number of medicines. Secondary outcomes will include health related quality of life measures, health service utilisation, clinical outcomes and data relating to cost effectiveness. Randomised controlled trials, non-randomised controlled trials, controlled before-after, interrupted-time-series and health economic studies will be eligible for inclusion. Titles, abstracts and full texts will be screened for inclusion by two reviewers. Data will be extracted using a standard form. Risk of bias in all included studies will be assessed using the Effective Practice and Organisation of Care (EPOC) criteria. Economic studies will be assessed using the Consensus Health Economic Criteria (CHEC) list as per the Cochrane Handbook for critical appraisal of methodological quality. A narrative synthesis will be performed, and the certainty of evidence will be assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) criteria. Where data support quantitative synthesis, a meta-analysis will be performed. Discussion: This systematic review will give an overview of the effectiveness of pharmacist interventions to improve prescribing and health outcomes in a vulnerable patient group. This will provide evidence to policy makers on strategies involving clinical pharmacists integrated within general practice, to address issues which arise in polypharmacy and multimorbidity. PROSPERO Registration: CRD42019139679 (28/08/19)

Background: Multimorbidity (the presence of two or more chronic conditions) is associated with poorer health outcomes, particularly for patients with significant polypharmacy (≥15 medications), due to the higher risk of adverse events and drug interactions. The SPPiRE study will assess the effectiveness of a complex intervention to support general practitioners (GPs) to reduce potentially inappropriate prescribing and consider deprescribing in older people with multimorbidity and significant polypharmacy. The aim of the SPPiRE process evaluation is to understand how and why the intervention is effective or ineffective and to explore the potential for system wide implementation of the intervention using the Medical Research Council general themes of context, implementation and mechanism of impact. Methods: The SPPiRE study is a clustered randomised controlled trial (RCT), aiming to recruit 55 general practices and 400 patients (≥65 years) on ≥15 medications throughout the Republic of Ireland. This mixed-methods process evaluation of the SPPiRE study will integrate both quantitative and qualitative data. Quantitative data will be collected on use of the intervention elements and from GP questionnaires. Qualitative data will be collected from semi-structured telephone interviews with all intervention GPs and a purposeful sample of patients from intervention practices. The topic guide will explore barriers and facilitators to participation and implementation of the intervention. Quantitative data will be analysed using descriptive statistics. Interviews will be transcribed and analysed using thematic analysis. Quantitative and qualitative data will be then be integrated. Discussion: The SPPiRE cluster RCT will provide evidence regarding the effectiveness and practicability of delivering a structured medication review in reducing polypharmacy and potentially inappropriate prescribing for patients with multimorbidity. This process evaluation will provide information on how the intervention was implemented, how it was or was not effective and the potential for a system wide implementation. Trial registration: ISRCTN 12752680, registration: 20/10/2016

Abstract Introduction Medication co-payments represent a financial barrier to antihypertensive medication adherence. The introduction of co-payments for Irish publically insured patients was associated with a 5% reduction in adherence. However there is socioeconomic variability within this population, and the impact may be greater for those on lower income. We evaluated medication-related financial burden of the co-payment in a cohort of Irish publically insured antihypertensive users and tested its association with adherence at 12 months. Methods This was a prospective cohort study of community dwelling older (> 65 yrs) adults (n = 1152) from 106 Irish community pharmacies. Participants completed a structured telephone interview at baseline, and a follow-up interview at 12-months, which we linked to pharmacy records. We assessed medication-related financial burden at baseline using a single questionnaire item, and adherence at 12 months via questionnaire and refill-adherence as Proportion of Days Covered (PDC). Results A third of participants (30.1%) reported financial burden due to medication costs. In adjusted linear regression models financially burdened participants had significantly lower self-reported adherence (β = − 0.29, 95% CI -0.48 to − 0.11), although this was not evident with PDC (β = − 2.76, 95% CI -5.65 to 0.14). Conclusion This co-payment represents a financial barrier to antihypertensive adherence for many older Irish publically insured patients. The negative impact to adherence will potentially increase the risk of adverse outcomes, such as stroke, and increase long-term healthcare costs.

Abstract Background Poorly controlled type 2 diabetes mellitus (T2DM) can be seen as failure to meet recommended targets for management of key risk factors including glycaemic control, blood pressure and lipids. Poor control of risk factors is associated with significant morbidity, mortality and healthcare costs. Failure to intensify medications for patients with poor control of T2DM when indicated is called clinical inertia and is one contributory factor to poor control of T2DM. We aimed to develop a theory and evidence-based complex intervention to improve appropriate prescribing and medication intensification in poorly controlled T2DM in Irish general practice. Methods The first stage of the Medical Research Council Framework for developing and evaluating complex interventions was utilised. To identify current evidence, we performed a systematic review to examine the effectiveness of interventions targeting patients with poorly controlled T2DM in community settings. The Behaviour Change Wheel theoretical approach was used to identify suitable intervention functions. Workshops, simulation, collaborations with academic partners and observation of physicians were utilised to operationalise the intervention functions and design the elements of the complex intervention. Results Our systematic review highlighted that professional-based interventions, potentially through clinical decision support systems, could address poorly controlled T2DM. Appropriate intensification of anti-glycaemic and cardiovascular medications, by general practitioners (GPs), for adults with poorly controlled T2DM was identified as the key behaviour to address clinical inertia. Psychological capability was the key driver of the behaviour, which needed to change, suggesting five key intervention functions (education, training, enablement, environmental restructuring and incentivisation) and nine key behaviour change techniques, which were operationalised into a complex intervention. The intervention has three components: (a) a training program/academic detailing of target GPs, (b) a remote finder tool to help GPs identify patients with poor control of T2DM in their practice and (c) A web-based clinical decision support system. Conclusions This paper describes a multifaceted process including an exploration of current evidence and a thorough theoretical understanding of the predictors of the behaviour resulting in the design of a complex intervention to promote the implementation of evidence-based guidelines, through appropriate prescribing and medication intensification in poorly controlled T2DM.

Abstract Background Multimorbidity, defined as the presence of at least two chronic conditions, becomes increasingly common in older people and is associated with poorer health outcomes and significant polypharmacy. The National Institute for Clinical Excellence (NICE) recently published a multimorbidity guideline that advises providing an individualised medication review for all people prescribed 15 or more repeat medicines. This study incorporates this guideline and aims to assess the effectiveness of a complex intervention designed to support general practitioners (GPs) to reduce potentially inappropriate prescribing and consider deprescribing in older people with multimorbidity and significant polypharmacy in Irish primary care. Methods This study is a cluster randomised controlled trial, involving 30 general practices and 450 patients throughout Ireland. Practices will be eligible to participate if they have at least 300 patients aged 65 years and over on their patient panel and if they use either one of the two predominant practice management software systems in use in Ireland. Using a software patient finder tool, practices will identify and recruit patients aged 65 years and over, who are prescribed at least 15 repeat medicines. Once baseline data collection is complete, practices will be randomised using minimisation by an independent third party to either intervention or control. Given the nature of the intervention, it is not possible to blind participants or study personnel. GPs in intervention practices will receive login details to a website where they will access training videos and a template for conducting an individualised structured medication review, which they will undertake with each of their included patients. Control practices will deliver usual care over the 6-month study period. Primary outcome measures pertain to the individual patient level and are the proportion of patients with any PIP and the number of repeat medicines. Discussion Disease-specific approaches in multimorbidity may be inappropriate and result in fragmented and poorly co-ordinated care. This pragmatic study is evaluating a complex intervention that is relevant across multiple conditions and addresses potential concerns around medicines safety in this vulnerable group of patients. The potential for system-wide implementation will be explored with a parallel mixed methods process evaluation. Trial registration ISRCTN: 12752680 , Registered 20 October 2016.

An amendment to this paper has been published and can be accessed via the original article.