Qualitative evaluation of the Safety and Improvement in Primary Care (SIPC) pilot collaborative in Scotland: perceptions and experiences of participating care teams

Objectives: To explore general practitioner (GP) team perceptions and experiences of participating in a large-scale safety and improvement pilot programme to develop and test a range of interventions that were largely new to this setting. Design: Qualitative study using semistructured interviews. Data were analysed thematically. Subjects and setting: Purposive sample of multiprofessional study participants from 11 GP teams based in 3 Scottish National Health Service (NHS) Boards. Results: 27 participants were interviewed. 3 themes were generated: (1) programme experiences and benefits, for example, a majority of participants referred to gaining new theoretical and experiential safety knowledge (such as how unreliable evidence-based care can be) and skills (such as how to search electronic records for undetected risks) related to the programme interventions; (2) improvements to patient care systems, for example, improvements in care systems reliability using care bundles were reported by many, but this was an evolving process strongly dependent on closer working arrangements between clinical and administrative staff; (3) the utility of the programme improvement interventions, for example, mixed views and experiences of participating in the safety climate survey and meeting to reflect on the feedback report provided were apparent. Initial theories on the utilisation and potential impact of some interventions were refined based on evidence. Conclusions: The pilot was positively received with many practices reporting improvements in safety systems, team working and communications with colleagues and patients. Barriers and facilitators were identified related to how interventions were used as the programme evolved, while other challenges around spreading implementation beyond this pilot were highlighted

What Postgraduates Appreciate in Online Tutor Feedback on Academic Writing

Improving postgraduate student writing in English is an ongoing concern in the increasingly internationalised UK Higher Education context. Although the importance of feedback for developing academic writing skills is well-established (Hyland and Hyland 2006), there is still much debate about the components of effective feedback. In response to the call for research investigating teachers’ real-world practices in giving feedback in specific contexts (Lee 2014 and 2012), this article presents an initiative to develop students’ abilities to tackle written postgraduate writing (essays and dissertations) through collaborative on-line academic writing courses. The Grounded Theory-inspired study explores student perceptions of the effectiveness of online formative feedback on postgraduate academic writing in order to identify best practices which can contribute to developing skills in providing feedback. The study analyses tutor feedback on student texts and student responses to feedback. We applied categories which emerged from this data and concluded that the students we investigated had responded most positively when a combination of confidence-developing feedback practices were employed. These included both principled corrective language feedback and positive, personalised feedback on academic conventions and practices. This collaboration between academic writing and content specialists continues to provide further opportunities for embedding practices that encourage the development of academic writing skills on one year postgraduate programmes at the University of Edinburgh.

How can behavioural science help us design better trials?

Peer reviewedPublisher PD

Systematic Techniques to Enhance rEtention in Randomised controlled trials: the STEER study protocol

Background Non-retention of participants seriously affects the credibility of clinical trial results and significantly reduces the potential of a trial to influence clinical practice. Non-retention can be defined as instances where participants leave the study prematurely. Examples include withdrawal of consent and loss to follow-up and thus outcome data cannot be obtained. The majority of existing interventions targeting retention fail to describe any theoretical basis for the observed improvement, or lack of improvement. Moreover, most of these interventions lack involvement of participants in their conception and/or design, raising questions about their relevance and acceptability. Many of the causes of non-retention involve people performing a behaviour (e.g. not returning a questionnaire). Behaviour change is difficult, and the importance of a strong theoretical basis for interventions that aim to change behaviour is increasingly recognised. This research aims to develop and pilot theoretically informed, participant-centred, evidence-based behaviour change interventions to improve retention in trials. Methods This research will generate data through semi-structured interviews on stakeholders’ perspectives of the reasons for trial non-retention. It will identify perceived barriers and enablers to trial retention using the Theoretical Domains Framework. The intervention development work will involve identification of behaviour change techniques, using recognised methodology, and co-production of retention interventions through discussion groups with end-users. An evaluation of intervention acceptability and feasibility will be conducted in focus groups. Finally, a ready-to-use evaluation framework to deploy in Studies Within A Trial as well as an explanatory retention framework will be developed for identifying and tackling modifiable issues to improve trial retention. Discussion We believe this to be one of the first studies to apply a theoretical lens to the development of interventions to improve trial retention that have been informed by, and are embedded within, participants’ experiential accounts. By developing and identifying priority interventions this study will support efforts to reduce research waste

COVID-19 trajectories among 57 million adults in England: a cohort study using electronic health records

BACKGROUND: Updatable estimates of COVID-19 onset, progression, and trajectories underpin pandemic mitigation efforts. To identify and characterise disease trajectories, we aimed to define and validate ten COVID-19 phenotypes from nationwide linked electronic health records (EHR) using an extensible framework. METHODS: In this cohort study, we used eight linked National Health Service (NHS) datasets for people in England alive on Jan 23, 2020. Data on COVID-19 testing, vaccination, primary and secondary care records, and death registrations were collected until Nov 30, 2021. We defined ten COVID-19 phenotypes reflecting clinically relevant stages of disease severity and encompassing five categories: positive SARS-CoV-2 test, primary care diagnosis, hospital admission, ventilation modality (four phenotypes), and death (three phenotypes). We constructed patient trajectories illustrating transition frequency and duration between phenotypes. Analyses were stratified by pandemic waves and vaccination status. FINDINGS: Among 57 032 174 individuals included in the cohort, 13 990 423 COVID-19 events were identified in 7 244 925 individuals, equating to an infection rate of 12·7% during the study period. Of 7 244 925 individuals, 460 737 (6·4%) were admitted to hospital and 158 020 (2·2%) died. Of 460 737 individuals who were admitted to hospital, 48 847 (10·6%) were admitted to the intensive care unit (ICU), 69 090 (15·0%) received non-invasive ventilation, and 25 928 (5·6%) received invasive ventilation. Among 384 135 patients who were admitted to hospital but did not require ventilation, mortality was higher in wave 1 (23 485 [30·4%] of 77 202 patients) than wave 2 (44 220 [23·1%] of 191 528 patients), but remained unchanged for patients admitted to the ICU. Mortality was highest among patients who received ventilatory support outside of the ICU in wave 1 (2569 [50·7%] of 5063 patients). 15 486 (9·8%) of 158 020 COVID-19-related deaths occurred within 28 days of the first COVID-19 event without a COVID-19 diagnoses on the death certificate. 10 884 (6·9%) of 158 020 deaths were identified exclusively from mortality data with no previous COVID-19 phenotype recorded. We observed longer patient trajectories in wave 2 than wave 1. INTERPRETATION: Our analyses illustrate the wide spectrum of disease trajectories as shown by differences in incidence, survival, and clinical pathways. We have provided a modular analytical framework that can be used to monitor the impact of the pandemic and generate evidence of clinical and policy relevance using multiple EHR sources. FUNDING: British Heart Foundation Data Science Centre, led by Health Data Research UK

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Multiple ligand-binding modes in bacterial R67 dihydrofolate reductase

R67 dihydrofolate reductase (DHFR), a bacterial plasmid-encoded enzyme associated with resistance to the drug trimethoprim, shows neither sequence nor structural homology with the chromosomal DHFR. It presents a highly symmetrical toroidal structure, where four identical monomers contribute to the unique central active-site pore. Two reactants (dihydrofolate, DHF), two cofactors (NADPH) or one of each (R67•DHF•NADPH) can be found simultaneously within the active site, the last one being the reactive ternary complex. As the positioning of the ligands has proven elusive to empirical determination, we addressed the problem from a theoretical perspective. Several potential structures of the ternary complex were generated using the docking programs AutoDock and FlexX. The variability among the final poses, many of which conformed to experimental data, prompted us to perform a comparative scoring analysis and molecular dynamics simulations to assess the stability of the complexes. Analysis of ligand-ligand and ligand-protein interactions along the 4 ns trajectories of eight different structures allowed us to identify important inter-ligand contacts and key protein residues. Our results, combined with published empirical data, clearly suggest that multipe binding modes of the ligands are possible within R67 DHFR. While the pterin ring of DHF and the nicotinamide ring of NADPH assume a stacked endo-conformation at the centre of the pore, probably assisted by V66, Q67 and I68, the tails of the molecules extend towards opposite ends of the cavity, adopting multiple configurations in a solvent rich-environment where hydrogen-bond interactions with K32 and Y69 may play important roles

User redesign, testing and evaluation of the Monitoring Risk and Improving System Safety (MoRISS) checklist for the general practice work environment

Background: Inadequate checking of safety-critical issues can compromise care quality in general practice (GP) work settings. Adopting a systemic, methodical approach may lead to improved standardisation of processes and reliability of task performance, strengthening the safety systems concerned. This study aimed to revise, modify and test the content and relevance of a previously validated safety checklist to the current GP context. Methods: A multimethod study was undertaken in Scottish GP involving: consensus building workshops with users and ‘experts’ to revise checklist content; regional testing of the modified checklist and follow-up usability evaluation survey of users. Quantitative data underwent descriptive statistical analyses and selected survey free-text comments are presented. Results: A redesigned checklist tool consisting of eight themes (eg, medication safety) and 61 items (eg, out-of-date stock is appropriately disposed) was agreed by 53 users/experts with items reclassified as: mandatory (n=25), essential (n=24) and advisory (n=12). Totally 42/55 GPs tested the tool and submitted checklist data (76.4%). The mean aggregated results demonstrated 92.0% compliance with all 61 checklist items (range: 83.0%–98.0%) and 25/42 GP managers responded to the survey (59.5%) and reported high mean levels of agreement on the usefulness of the checklist (77.0%), ease of use (89.0%), learnability (94.0%) and satisfaction (78.4%). Conclusions: The checklist was comprehensively redesigned as a practical safety monitoring and improvement tool for potential implementation in Scottish GP. Testing and evaluation demonstrated high levels of checklist content compliance and strong usability feedback, but some variation was evident indicating room for improvement in current safety-critical checking processes. The checklist should be of interest in similar GP settings internationally and to other areas of primary care practice