A note on versions:The version presented here may differ from the published version or, version of record, if you wish to cite this item you are advised to consult the publisher's version. Please see the 'permanent WRAP url' above for details on accessing the published version and note that access may require a subscription.

A note on versions:The version presented here may differ from the published version or, version of record, if you wish to cite this item you are advised to consult the publisher's version. Please see the 'permanent WRAP url' above for details on accessing the published version and note that access may require a subscription.For more information, please contact the WRAP Team at: wrap@warwick.ac.uk ACCEPTED MANUSCRIPT A C C E P T E D M A N U S C R I P TResearch Highlights: Experience-based analysis of opportunities and challenges for using HRA in health  Considers reliability, performance variability, regulator, and patient role  HRA should have clinical engagement and patient participation  HRA cost-effectiveness should be rigorously evaluated  HRA can provide requisite imagination and build social safety infrastructure Abstract: Safety in healthcare is a relatively recent field, but has received considerable attention over the past 15 years. Healthcare organisations have been encouraged to learn from safety management practices in other industries. In this paper we analyse opportunities and challenges for the application of Human Reliability Analysis (HRA) in healthcare. We consider the poor levels of reliability of many healthcare processes, performance variability, the absence of regulatory frameworks that incentivise proactive risk management, and the unique role of the patient. We conclude that HRA could provide a useful framework for the analysis and reduction of risk in healthcare, but techniques might have to be adapted and applied with due consideration of the specifics of the cultural and regulatory context of this domain. This includes clinical engagement with and ownership of the HRA process, greater focus on rigorous evaluation of costeffectiveness of HRA techniques, and active involvement of patients.

BackgroundIntensive care treatment can be life-saving, but it is invasive and distressing for patients receiving it and it is not always successful. Deciding whether or not a patient will benefit from intensive care is a difficult clinical and ethical challenge.ObjectivesTo explore the decision-making process for referral and admission to the intensive care unit and to develop and test an intervention to improve it.MethodsA mixed-methods study comprising (1) two systematic reviews investigating the factors associated with decisions to admit patients to the intensive care unit and the experiences of clinicians, patients and families; (2) observation of decisions and interviews with intensive care unit doctors, referring doctors, and patients and families in six NHS trusts in the Midlands, UK; (3) a choice experiment survey distributed to UK intensive care unit consultants and critical care outreach nurses, eliciting their preferences for factors used in decision-making for intensive care unit admission; (4) development of a decision-support intervention informed by the previous work streams, including an ethical framework for decision-making and supporting referral and decision-support forms and patient and family information leaflets. Implementation feasibility was tested in three NHS trusts; (5) development and testing of a tool to evaluate the ethical quality of decision-making related to intensive care unit admission, based on the assessment of patient records. The tool was tested for inter-rater and intersite reliability in 120 patient records.ResultsInfluences on decision-making identified in the systematic review and ethnographic study included age, presence of chronic illness, functional status, presence of a do not attempt cardiopulmonary resuscitation order, referring specialty, referrer seniority and intensive care unit bed availability. Intensive care unit doctors used a gestalt assessment of the patient when making decisions. The choice experiment showed that age was the most important factor in consultants’ and critical care outreach nurses’ preferences for admission. The ethnographic study illuminated the complexity of the decision-making process, and the importance of interprofessional relationships and good communication between teams and with patients and families. Doctors found it difficult to articulate and balance the benefits and burdens of intensive care unit treatment for a patient. There was low uptake of the decision-support intervention, although doctors who used it noted that it improved articulation of reasons for decisions and communication with patients.LimitationsLimitations existed in each of the component studies; for example, we had difficulty recruiting patients and families in our qualitative work. However, the project benefited from a mixed-method approach that mitigated the potential limitations of the component studies.ConclusionsDecision-making surrounding referral and admission to the intensive care unit is complex. This study has provided evidence and resources to help clinicians and organisations aiming to improve the decision-making for and, ultimately, the care of critically ill patients.Future workFurther research is needed into decision-making practices, particularly in how best to engage with patients and families during the decision process. The development and evaluation of training for clinicians involved in these decisions should be a priority for future work.Study registrationThe systematic reviews of this study are registered as PROSPERO CRD42016039054, CRD42015019711 and CRD42015019714.FundingThe National Institute for Health Research Health Services and Delivery Research programme. The University of Aberdeen and the Chief Scientist Office of the Scottish Government Health and Social Care Directorates fund the Health Economics Research Unit.

Inflammatory myofibroblastic tumor (IMT) can occur rarely in the soft tissue or joint of the limb. We retrospectively collected IMT cases of these rare sites and analyzed their clinical and imaging appearance. Thirteen cases of IMT were clinically diagnosed and underwent surgical procedures, pathological analyses, and postsurgical follow-up in our two hospitals. Other than one case of IMT of the bladder wall that presented with gross hematuria, none presented with local swelling, fever, or weakness. All the cases of IMT occurring at the bone showed destruction and parosteal soft tissue masses. The boundaries between the mass and normal bone were vague, without calcifications or any periosteal reaction. Five cases of IMF showed continuous enhancement on CT; seven cases demonstrated iso- or hyposignal intensity on T1WI; one case showed hypersignal intensity on T1WI, and eight cases demonstrated a hypersignal intensity signal on T2WI. All the masses located in soft tissues showed clear and sharp boundaries with different sizes of the swelling regions surrounding muscle interspaces. Three cases showed homogeneous enhancement, one case demonstrated heterogeneous enhancement, and two cases showed edge enhancement on enhanced MRI scans. On pathology, all the lesions showed an absence of a pseudocapsule, and four cases of ALK were positive. The radiological manifestations of IMT located at the soft tissue and bones were similar to benign tumors in shape; however, peritumoral edema, parosteal soft tissue, and the invasive rim of IMT are similar to the features of malignant tumors. Different radiological methods should be used to obtain an accurate diagnosis.

Background: Primary care transformation in Scotland aims to improve population health, reduce health inequalities and reduce GP workload. Two key strategies (formalised in April 2018 in the new Scottish GP contract though started in early 2016) are the expansion of the multidisciplinary team (MDT) and GP cluster working. Aim: To explore progress in the implementation of the GP contract in Scotland in terms of MDT and cluster working. Design and Setting: Qualitative study with key national primary care stakeholders (PCSs) (n=6) and Cluster Quality Leads (CQLs) in clusters serving urban high deprivation areas (n=4), urban mixed areas (n=4), and remote and rural areas (n=4). Methods: Semi-structured interviews with thematic analysis. Results: There was general support for the initial aims of the new GP contract but all interviewees felt that progress on both MDT expansion and cluster working was slow, even prior to the pandemic. None of the CQLs (and few PCSs) felt that GP workload had reduced significantly, nor that the care of patients with complex needs had improved. Lack of time and poorly developed relationships were key barriers, as was a lack of relevant primary care data, and additional support (including guidance, administration, training, and protected time). Conclusion: Key PCSs and CQLs in different areas of Scotland report limited progress in primary care transformation, only partly related to the pandemic. There is a need for better workforce planning and support if the new GP contract is to succeed in transforming primary care in Scotland.

Elderly patients may be heterogeneous in their abilities to tolerate immunochemotherapy-associated toxicities. We describe the morbidity of rituximab-chemotherapy combinations among 205 newly-diagnosed diffuse large B-cell lymphoma (DLBCL) patients aged ≥60 years from 3 tertiary hospitals between 2009 and 2016, and explore the utility of retrospectivelyassigned baseline Comprehensive Geriatric Assessment (CGA) in predicting these toxicities. Seventy-three percent (146/201) experienced grade ≥3 toxicities, 81% (163/201) needed admission, 52% (107/205) had ≥2 unplanned admissions, 82/201 (41%) required dose reductions (DR) subsequent to Cycle 1, 39/166 (23%) had chemotherapy delays and 26/198 (13%) ceased therapy early. CGA was associated with pre-emptive baseline DR and perhaps because of this, did not predict grade ≥3 toxicities, ≥2 unplanned admissions or subsequent DR. Three-year overall survival (OS) of CGA-fit, CGA-unfit and CGA-frail patients was 82%, 60% and 53%, respectively. Three-year progression-free survival (PFS) of CGA-fit, CGA-unfit and CGA-frail patients was 66%, 58% and 46%, respectively. OS of CGA-fit patients was not statistically different from CGA-unfit patients, but was superior to CGA-frail patients (hazard ratio 2Á892, 95% confidence interval 1Á275-6Á559, P = 0Á011). PFS differences were not statistically significant. Baseline DR and early therapy cessation were associated with inferior OS and PFS independent of CGA. Prospective studies are needed to confirm if CGA-adapted treatment strategies minimize morbidity and improves survival.

Background: Scotland abolished the Quality and Outcomes Framework (QOF) in April 2016, prior to implementing a new Scottish GP contract in April 2018. Since 2016, groups of practices (GP clusters) have been incentivised to meet regularly, to plan and organise quality improvement (QI) as part of this new direction in primary care policy. Aim: To understand the organisation and perceived impact of GP clusters, including how they use quantitative data for improvement. Design/Setting/Methods: Thematic analysis, of semi-structured interviews with key stakeholders (n=17) and observations of GP cluster meetings (n=6) in two clusters. Results: There was uncertainty whether GP clusters should focus on activities generated internally or externally by the wider healthcare system (e.g. from Scottish Health Boards), although the two clusters we observed generally generated their own ideas and issues. Clusters operated with variable administrative/managerial and data support, and variable baseline leadership experience and QI skills. Qualitative approaches formed the focus of collaborative learning in cluster meetings, through sharing and discussion of member practices’ own understandings and experiences. We observed less evidence of data analytics being championed in these meetings, partly because of barriers accessing the analytics data and existing data quality. Conclusion: Cluster development would benefit from more consistent training and support for cluster leads in small group facilitation, leadership and QI expertise, and data analytics access and capacity. Whilst GP clusters are up and running, their impact is likely to be limited without further investment in developing capacity in these areas.

EGFR-T790M and BRAF V600E are the common resistance mechanisms to EGFRtyrosine kinase inhibitors (TKIs). Standard treatment for the triple mutations of EGFR-19del, T790M, and BRAF V600E is still under debate. Herein, we present a case of therapeutic efficacy of osimertinib and dabrafenib plus trametinib on a 63-year-old man with advanced lung adenocarcinoma. This patient reached a remarkable progression-free survival of 9 months without any serious adverse reaction. At the progression of the disease, C797S mutation in cis was detected by liquid biopsy. Subsequently, brigatinib with cetuximab was administered but no curative effect was observed. Then, therapy was changed to apatinib combined with osimertinib. The subsequent CT scan showed that the lesions reached stable disease (SD), and the survival benefit has been evaluated. This case showed that the combination treatment of osimertinib and dabrafenib plus trametinib might be a great treatment option for NSCLC patients with triple mutations (EGFR-19del/T790M/BRAFV600E).