Background Inappropriate use of antimicrobial agents in healthcare settings is one area that has received attention as a possible route to mitigate the threat of antimicrobial resistance. Globally, the highest consumption of antimicrobials in human healthcare originates from prescriptions in Primary Care. Strategies to increase appropriate antibiotic prescribing, which can mean not prescribing an antibiotic e.g. cases of viral infection, have been developed and evaluated. This systematic review aims to review the literature of studies of group based in person educational interventions designed to increase appropriate antibiotic prescribing behaviours in General Practice settings. Methods EMBASE, CINAHL, Cochrane Central Register of Controlled Trials, MEDLINE and PsycINFO will be systematically searched from inception until February 2024 for primary studies of group based educational interventions designed to improve the antimicrobial prescribing behaviours in General Practice. Qualitative, quantitative and mixed methods studies that report on the phenomenon of interest will be included. All identified articles will be double screened at title and abstract level. One reviewer will then screen all included studies at full text level, extract the data, code the intervention and perform risk of bias assessment with a second reviewer performing verification of a randomly selected 20% of the articles. We will use an integrated approach to mixed method systematic reviews and will perform a narrative, or if possible quantitative, synthesis. Discussion The review will identify and assess the efficacy and / or effectiveness of small group based educational interventions designed to improve the antibiotic prescribing behaviours of General Practitioners. By using a mixed methods approach we aim to identify the salient content of the included interventions and the perspectives of participants on the content and delivery of the included interventions. We will use the findings to inform the design and content of a small group educational intervention for GP registrars.

BACKGROUND:The World Health Organization declared the COVID-19 pandemic on 11 March 2020. Vaccine development and deployment were swiftly prioritised as a method to manage and control disease spread. The development of an effective vaccine relies on people's participation in randomised trials. Recruitment to vaccine trials is particularly challenging as it involves healthy volunteers who may have concerns around the potential risks and benefits associated with rapidly developed vaccines.OBJECTIVES:To explore the factors that influence a person's decision to participate in a vaccine trial in the context of a pandemic or epidemic.SEARCH METHODS:We used standard, extensive Cochrane search methods. The latest search date was June 2021.SELECTION CRITERIA:We included qualitative studies and mixed-methods studies with an identifiable qualitative component. We included studies that explored the perspectives of adults aged 18 years or older who were invited to take part in vaccine trials in the context of a pandemic or epidemic.DATA COLLECTION AND ANALYSIS:We assessed the title, abstracts and full texts identified by the search. We used a sampling frame to identify data-rich studies that represented a range of diseases and geographical spread. We used QSR NVivo to manage extracted data. We assessed methodological limitations using an adapted version of the Critical Skills Appraisal Programme (CASP) tool for qualitative studies. We used the 'best-fit framework approach' to analyse and synthesise the evidence from our included studies. We then used the Confidence in the Evidence from Reviews of Qualitative research (GRADE-CERQual) assessment to assess our confidence in each finding and develop implications for practice.MAIN RESULTS:We included 34 studies in our review. Most studies related to HIV vaccine trials. The other studies related to Ebola virus, tuberculosis, Zika virus and COVID-19. We developed 20 key findings, under three broad themes (with seven subthemes), that described the factors that people consider when deciding whether to take part in a vaccine trial for a pandemic or epidemic disease. Our GRADE-CERQual confidence was high in nine of the key findings, moderate in 10 key findings and low in one key finding. The main reason for downgrading review findings were concerns regarding the relevance and adequacy of the underlying data. As a result of the over-representation of HIV studies, our GRADE-CERQual assessment of some findings was downgraded in terms of relevance because the views described may not reflect those of people regarding vaccine trials for other pandemic or epidemic diseases. Adequacy relates to the degree of richness and quantity of data supporting a review finding. Moderate concerns about adequacy resulted in a downgrading of some review findings. Some factors were considered to be under the control of the trial team. These included how trial information was communicated and the inclusion of people in the community to help with trial information dissemination. Aspects of trial design were also considered under control of the trial team and included convenience of participation, provision of financial incentives and access to additional support services for those taking part in the trial. Other factors influencing people's decision to take part could be personal, from family, friends or wider society. From a personal perceptive, people had concerns about vaccine side effects, vaccine efficacy and possible impact on their daily lives (carer responsibilities, work, etc.). People were also influenced by their families, and the impact participation may have on relationships. The fear of stigma from society influenced the decision to take part. Also, from a societal perspective, the level of trust in governments' involvement in research and trial may influence a person's decision. Finally, the perceived rewards, both personal and societal, were influencing factors on the decision to participate. Personal rewards included access to a vaccine, improved health and improved disease knowledge, and a return to normality in the context of a pandemic or epidemic. Potential societal rewards included helping the community and contributing to science, often motivated by the memories of family and friends who had died from the disease.AUTHORS' CONCLUSIONS:This review identifies many of the factors that influence a person's decision to take part in a vaccine trial, and these reflect findings from reviews that examine trials more broadly. However, we also recognise some factors that become more important in connection with a vaccine trial in the context of a pandemic or epidemic. These factors include the potential stigma of taking part, the possible adverse effects of a vaccine, the added motivation for helping society, the role of community leaders in trial dissemination, and the level of trust placed in governments and companies developing vaccines. These specific influences need to be considered by trial teams when designing, and communicating about, vaccine trials in the context of a pandemic or epidemic.

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.

Oral anti-cancer medications (OAMs) are increasingly prescribed in oncology, and although administered at home, ongoing monitoring generally requires the patient to attend an acute hospital. With the requirement to provide safe yet convenient care and to increase hospital capacity, the potential exists to transition this cohort of patients to the community to be assessed by oncology health care professionals (HCPs). The onset of COVID-19 facilitated this planned transition. OBJECTIVE The primary objective was to understand stakeholders' perceptions of a community-based advanced nurse practitioner (ANP)-led integrated OAM care model for adults. METHODS Qualitative data from interviews and focus groups were obtained from 33 individuals; either service users who attended ANP-led OAM clinics or stakeholders involved in OAM care. Data were subsequently analysed using thematic analysis. RESULTS Four themes were identified and included reflection on pre-COVID-19 system, role of ANP in current OAM care, importance of robust communication and infrastructural requirements for transition to an integrated OAM care model. CONCLUSION This study demonstrated that patients and HCPs perceived the proposal positively. They identified the ANP as the appropriate HCP to care for this cohort and the importance of communication and strategic planning for transitioning this model of care to the community setting. CLINICAL TRIAL REGISTRATION ISRCTN10401455.

The numerous toxic responses of dioxin-like compounds are mediated by the intracellular Ah (aryl hydrocarbon) receptor. It has been suggested that the regulation of dioxins and similar substances could be placed on a molecular foundation by considering the proportion of Ah-receptor sites occupied by toxicant molecules. The present work has shown that the following formation not yet available would be needed in order to develop this approach: correlation between dioxin exposure and human tissue levels; accurate determination of the association constants for human Ah-receptor with toxicant, and for human receptor-ligand complex with DNA; and knowlegde of the intracellular concentrations of both receptor binding sites and DNA binding sites. Furthermore, since not all dioxin-like substances behave identically, this information would need to be gathered for a wide variety of substances.

Aims To identify all extant instruments used to measure diabetes distress in adults with Type 1 diabetes and to evaluate the evidence for the measurement properties of these instruments. Methods Medline, Embase, CINAHL plus and PsycINFO were systematically searched from inception up until 12 March 2020 for all publications which evaluated the psychometric properties of diabetes distress measurement instruments. The quality of the methodology and the measurement properties in the identified studies were evaluated using the COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) guidelines. Results Seven out of the 7656 articles retrieved in the search were included in the final review. Four diabetes distress measurement instruments were identified, none of which displayed evidence for all measurement properties specified in the COSMIN guidelines. The Problem Areas in Diabetes-11 (PAID-11) demonstrated the best psychometric properties, displaying strong evidence for structural validity, internal consistency, hypothesis testing, responsiveness and criterion validity. The Problem Areas in Diabetes scale (PAID) was the most frequently investigated instrument, demonstrating good relevance and hypothesis testing across four studies; however, concerns remain over its factor structure. Conclusion The PAID-11 appears to be the most psychometrically sound instrument for measuring diabetes distress in adults with Type 1 diabetes, displaying strong evidence for a range of measurement properties. However, as only one study evaluated this instrument and its content validity has yet to be assessed, further validation is warranted. Additional qualitative work is needed to assess the content validity of these instruments among individuals with Type 1 diabetes.

The monosaccharide, β-N-acetylglucosamine (GlcNAc), can be added to the hydroxyl group of either serines or threonines to generate an O-linked β-N-acetylglucosamine (O-GlcNAc) residue (Love, D. C., and Hanover, J. A. (2005) Sci. STKE 2005 312, 1–14; Hart, G. W., Housley, M. P., and Slawson, C. (2007) Nature 446, 1017–1022). This post-translational protein modification, termed O-GlcNAcylation, is reversible, analogous to phosphorylation, and has been implicated in many cellular processes. Here, we present evidence that in human cells all four core histones of the nucleosome are substrates for this glycosylation in the relative abundance H3, H4/H2B, and H2A. Increasing the intracellular level of UDP-GlcNAc, the nucleotide sugar donor substrate for O-GlcNAcylation enhanced histone O-GlcNAcylation and partially suppressed phosphorylation of histone H3 at serine 10 (H3S10ph). Expression of recombinant H3.3 harboring an S10A mutation abrogated histone H3 O-GlcNAcylation relative to its wild-type version, consistent with H3S10 being a site of histone O-GlcNAcylation (H3S10glc). Moreover, O-GlcNAcylated histones were lost from H3S10ph immunoprecipitates, whereas immunoprecipitation of either H3K4me3 or H3K9me3 (active or inactive histone marks, respectively) resulted in co-immunoprecipitation of O-GlcNAcylated histones. We also examined histone O-GlcNAcylation during cell cycle progression. Histone O-GlcNAcylation is high in G1 cells, declines throughout the S phase, increases again during late S/early G2, and persists through late G2 and mitosis. Thus, O-GlcNAcylation is a novel histone post-translational modification regulating chromatin conformation during transcription and cell cycle progression.

Loss of the control over cellular proliferation can lead to cell death or result in the abnormal proliferation characteristic of the cancerous state. Among the controls used to achieve normal cellular proliferation is the DNA damage checkpoint pathway that monitors genome integrity (Hartwell and Kastan 1994). 53BP1 was identified as a protein that interacts with the DNA-binding core domain of the tumor suppressor p53. The p53-binding region of 53BP1 maps to the C-terminal BRCT domains which are homologous to those found in the breast cancer protein BRCA1 and in other proteins involved in the DNA damage response, notably budding yeast Rad9. In addition to its recently reported role in sensing double strand breaks, 53BP1 is believed to have roles, currently ill understood, in many aspects of DNA metabolism ranging from transcription and class switch recombination to 'mediating' the DNA damage checkpoint response (Chai et al. 1999; Huyen et al. 2004; Sengupta et al. 2004; Ward et al. 2004). Here, we investigate 53BP1 complex formation. We investigate 53BP1 oligomerization and show that this is not dependent on the presence of disulfide bridges.