Sensitive bispecific chimeric T cell receptors for cancer therapy.

The expression of a synthetic chimeric antigen receptor (CAR) to redirect antigen specificity of T cells is transforming the treatment of hematological malignancies and autoimmune diseases [1-7]. In cancer, durable efficacy is frequently limited by the escape of tumors that express low levels or lack the target antigen [8-12]. These clinical results emphasize the need for immune receptors that combine high sensitivity and multispecificity to improve outcomes. Current mono- and bispecific CARs do not faithfully recapitulate T cell receptor (TCR) function and require high antigen levels on tumor cells for recognition [13-17]. Here, we describe a novel synthetic chimeric TCR (ChTCR) that exhibits superior antigen sensitivity and is readily adapted for bispecific targeting. Bispecific ChTCRs mimic TCR structure, form classical immune synapses, and exhibit TCR-like proximal signaling. T cells expressing Bi-ChTCRs more effectively eliminated tumors with heterogeneous antigen expression in vivo compared to T cells expressing optimized bispecific CARs. The Bi-ChTCR architecture is resilient and can be designed to target multiple B cell lineage and multiple myeloma antigens. Our findings identify a broadly applicable approach for engineering T cells to target hematologic malignancies with heterogeneous antigen expression, thereby overcoming the most frequent mechanism of relapse after current CAR T therapies.

Lateral Femoral Condyle Allograft in the Treatment of Elbow Capitellar Avascular Necrosis: A Case Report.

CASE: A 27-year-old woman developed capitellar osteonecrosis after long-term corticosteroid use to treat non-Hodgkin lymphoma. She underwent an osteochondral reconstruction using a lateral femoral condyle (LFC) allograft. This graft was selected because it has a similar radius of curvature to the capitellum. The patient had osseous integration, painless, near full range of motion of her elbow 6 months postoperatively and good shoulder function 1.0 year postoperatively. CONCLUSION: The LFC allograft should be considered a viable option in treating capitellar osteonecrosis.

Signaling via a CD27-TRAF2-SHP-1 axis during naive T cell activation promotes memory-associated gene regulatory networks.

The interaction of the tumor necrosis factor receptor (TNFR) family member CD27 on naive CD8+ T (Tn) cells with homotrimeric CD70 on antigen-presenting cells (APCs) is necessary for T cell memory fate determination. Here, we examined CD27 signaling during Tn cell activation and differentiation. In conjunction with T cell receptor (TCR) stimulation, ligation of CD27 by a synthetic trimeric CD70 ligand triggered CD27 internalization and degradation, suggesting active regulation of this signaling axis. Internalized CD27 recruited the signaling adaptor TRAF2 and the phosphatase SHP-1, thereby modulating TCR and CD28 signals. CD27-mediated modulation of TCR signals promoted transcription factor circuits that induced memory rather than effector associated gene programs, which are induced by CD28 costimulation. CD27-costimulated chimeric antigen receptor (CAR)-engineered T cells exhibited improved tumor control compared with CD28-costimulated CAR-T cells. Thus, CD27 signaling during Tn cell activation promotes memory properties with relevance to T cell immunotherapy.

The role of body mass index on survivorship and clinical outcomes in total shoulder arthroplasty.

BACKGROUND: Increased body mass index (BMI) is a potential risk factor for poorer outcomes and complications. However, the influence of BMI on the long-term outcomes of anatomic and reverse total shoulder arthroplasty (aTSA and rTSA) remains to be fully elucidated. METHODS: Institutional records were queried to identify patients who underwent primary TSA between 2009-2020 with a minimum of 2 years of clinical follow-up. Retrospective review was performed to collect demographics, comorbidity status, and range of motion and strength measurements in forward elevation, external rotation, and internal rotation. Patients were called to obtain patient reported outcomes. Patients were stratified into 3 cohorts, by BMI: underweight or normal weight (U/NW, BMI≤25), overweight (OW, 2530). RESULTS: Among 466 TSA patients, 245 underwent aTSA while 221 underwent rTSA. In the aTSA cohort, 40 were classified as U/NW, 72 as OW, and 133 as obese. Comparatively, the rTSA cohort was composed of 33 U/NW, 79 OW, and 209 obese patients. aTSA and rTSA patients had an average follow-up of 5.8±3.2 years and 4.5±2.3 years, respectively. No differences were found in age at surgery for the aTSA group (U/NW: 65.2±7.9 vs obese: 61.9±8.9 years; p=0.133), however, in the rTSA cohort, BMI was found to be inversely related to age at surgery (U/NW: 72.4±8.8 vs obese: 65.7±8.3 years; p<0.001). Across all BMI cohorts, patients saw great improvement in range of motion and strength. Postoperative patient reported outcomes for TSA did not vary by BMI in SANE, SST, VAS pain, and ASES scores. There was no significant difference in survival rates at 10-year follow-up in aTSA (U/NW: 95.8% vs obese: 93.2%; p=0.753) or rTSA (U/NW: 94.7% vs obese: 94.5%; p=0.791). CONCLUSION: With dramatic improvements in range of motion, minimal differences in patient reported outcomes, and high rates of implant survival, TSA is a safe and effective treatment option for all patients, including for overweight and obese patients.

Hip, knee, and shoulder arthroplasty in patients with a history of solid organ transplant: A review.

Solid organ transplants (SOT) have evolved into life-saving interventions for end-stage diseases affecting vital organs. Advances in transplantation techniques, donor selection, and immunosuppressive therapies have enhanced outcomes, leading to a growing demand for SOT. Patients with a solid organ transplant are living long enough to develop the same pathologies which are indicated for joint replacement surgery in the general population. SOT patients who undergo a total hip, knee, or shoulder arthroplasty do similarly in the context of clinical outcomes and implant survival when compared to the general population. These immunosuppressed patients tend to have higher complication rates in the short-term following surgery. Prudent management of these patients in the short-term may be necessary, but patients can expect to do well otherwise.

Systemically administered low-affinity HER2 CAR T cells mediate antitumor efficacy without toxicity.

BACKGROUND: The paucity of tumor-specific targets for chimeric antigen receptor (CAR) T-cell therapy of solid tumors necessitates careful preclinical evaluation of the therapeutic window for candidate antigens. Human epidermal growth factor receptor 2 (HER2) is an attractive candidate for CAR T-cell therapy in humans but has the potential for eliciting on-target off-tumor toxicity. We developed an immunocompetent tumor model of CAR T-cell therapy targeting murine HER2 (mHER2) and examined the effect of CAR affinity, T-cell dose, and lymphodepletion on safety and efficacy. METHODS: Antibodies specific for mHER2 were generated, screened for affinity and specificity, tested for immunohistochemical staining of HER2 on normal tissues, and used for HER2-targeted CAR design. CAR candidates were evaluated for T-cell surface expression and the ability to induce T-cell proliferation, cytokine production, and cytotoxicity when transduced T cells were co-cultured with mHER2+ tumor cells in vitro. Safety and efficacy of various HER2 CARs was evaluated in two tumor models and normal non-tumor-bearing mice. RESULTS: Mice express HER2 in the same epithelial tissues as humans, rendering these tissues vulnerable to recognition by systemically administered HER2 CAR T cells. CAR T cells designed with single-chain variable fragment (scFvs) that have high-affinity for HER2 infiltrated and caused toxicity to normal HER2-positive tissues but exhibited poor infiltration into tumors and antitumor activity. In contrast, CAR T cells designed with an scFv with low-affinity for HER2 infiltrated HER2-positive tumors and controlled tumor growth without toxicity. Toxicity mediated by high-affinity CAR T cells was independent of tumor burden and correlated with proliferation of CAR T cells post infusion. CONCLUSIONS: Our findings illustrate the disadvantage of high-affinity CARs for targets such as HER2 that are expressed on normal tissues. The use of low-affinity HER2 CARs can safely regress tumors identifying a potential path for therapy of solid tumors that exhibit high levels of HER2.

Validated medication deprescribing instruments for patients with palliative care needs: a systematic review.

OBJECTIVES: Patients with life-limiting illnesses are prone to unnecessary polypharmacy. Deprescribing tools may contribute to minimizing negative outcomes. Thus, the aims of the study were to identify validated instruments for deprescribing inappropriate medications for patients with palliative care needs and to assess the impact on clinical, humanistic, and economic outcomes. METHODS: A systematic review was conducted in LILACS, PUBMED, EMBASE, COCHRANE, and WEB OF SCIENCE databases (until May 2021). A manual search was performed in the references of enrolled articles. The screening, eligibility, extraction, and bias risk assessment were carried out by 2 independent researchers. Experimental and observational studies were eligible for inclusion. RESULTS: Out of the 5791 studies retrieved, after excluding duplicates (n = 1050), conducting title/abstract screening (n = 4741), and full reading (n = 41), only 1 study met the inclusion criteria. In this included study, a randomized controlled trial was conducted, which showed a high level of bias risk overall. Adults 75 years or older (n = 130) with limited life expectancy and polypharmacy were allocated to 2 groups [intervention arm (deprescribing); and control arm (usual care)]. Deprescribing was performed with the aid of the STOPPFrail tool. The mean number of inappropriate medications and monthly medication costs were significantly lower in the intervention arm. No statistically significant differences were found in terms of unscheduled hospital presentations, falls, fractures, mortality, and quality of life. CONCLUSIONS: Despite the availability of several instruments to support deprescribing in patients with palliative care needs, only 1 of them has undergone validation and robust assessment for effectiveness in clinical practice. The STOPPFrail tool appears to reduce the number of inappropriate medications for older people with limited life expectancy (and probably palliative care needs) and decrease the monthly costs of pharmacotherapy. Nevertheless, the impact on patient safety and humanistic outcomes remain unclear.

Validated medication deprescribing instruments for patients with palliative care needs palliative care: A systematic review. / [Artículo traducido] Instrumentos validados de desprescripción de medicamentos para los pacientes con necesidades de cuidados paliativos: una revisión sistemática.

OBJECTIVES: Patients with life-limiting illnesses are prone to unnecessary polypharmacy. Deprescribing tools may contribute to minimizing negative outcomes. Thus, the aims of the study were to identify validated instruments for deprescribing inappropriate medications for patients with palliative care needs and to assess the impact on clinical, humanistic, and economic outcomes. METHODS: A systematic review was conducted in LILACS, PUBMED, EMBASE, COCHRANE, and WEB OF SCIENCE databases (until May 2021). A manual search was performed in the references of enrolled articles. The screening, eligibility, extraction, and bias risk assessment were carried out by two independent researchers. Experimental and observational studies were eligible for inclusion. RESULTS: Out of the 5,791 studies retrieved, after excluding duplicates (n = 1,050), conducting title/abstract screening (n = 4,741), and full reading (n = 41), only one study met the inclusion criteria. In this included study, a randomized controlled trial was conducted, which showed a high level of bias risk overall. Adults 75 years or older (n = 130) with limited life expectancy and polypharmacy were allocated to two groups [intervention arm (deprescribing); and control arm (usual care)]. Deprescribing was performed with the aid of the STOPPFrail tool. The mean number of inappropriate medications and monthly medication costs were significantly lower in the intervention arm. No statistically significant differences were found in terms of unscheduled hospital presentations, falls, fractures, mortality, and quality of life. CONCLUSIONS: Despite the availability of several instruments to support deprescribing in patients with palliative care needs, only one of them has undergone validation and robust assessment for effectiveness in clinical practice. The STOPPFrail tool appears to reduce the number of inappropriate medications for older people with limited life expectancy (and probably palliative care needs) and decrease the monthly costs of pharmacotherapy. Nevertheless, the impact on patient safety and humanistic outcomes remain unclear.

Analysis of applying a patient safety taxonomy to patient and clinician-reported incident reports during the COVID-19 pandemic: a mixed methods study.

BACKGROUND: The COVID-19 pandemic resulted in major disruption to healthcare delivery worldwide causing medical services to adapt their standard practices. Learning how these adaptations result in unintended patient harm is essential to mitigate against future incidents. Incident reporting and learning system data can be used to identify areas to improve patient safety. A classification system is required to make sense of such data to identify learning and priorities for further in-depth investigation. The Patient Safety (PISA) classification system was created for this purpose, but it is not known if classification systems are sufficient to capture novel safety concepts arising from crises like the pandemic. We aimed to review the application of the PISA classification system during the COVID-19 pandemic to appraise whether modifications were required to maintain its meaningful use for the pandemic context. METHODS: We conducted a mixed-methods study integrating two phases in an exploratory, sequential design. This included a comparative secondary analysis of patient safety incident reports from two studies conducted during the first wave of the pandemic, where we coded patient-reported incidents from the UK and clinician-reported incidents from France. The findings were presented to a focus group of experts in classification systems and patient safety, and a thematic analysis was conducted on the resultant transcript. RESULTS: We identified five key themes derived from the data analysis and expert group discussion. These included capitalising on the unique perspective of safety concerns from different groups, that existing frameworks do identify priority areas to investigate further, the objectives of a study shape the data interpretation, the pandemic spotlighted long-standing patient concerns, and the time period in which data are collected offers valuable context to aid explanation. The group consensus was that no COVID-19-specific codes were warranted, and the PISA classification system was fit for purpose. CONCLUSIONS: We have scrutinised the meaningful use of the PISA classification system's application during a period of systemic healthcare constraint, the COVID-19 pandemic. Despite these constraints, we found the framework can be successfully applied to incident reports to enable deductive analysis, identify areas for further enquiry and thus support organisational learning. No new or amended codes were warranted. Organisations and investigators can use our findings when reviewing their own classification systems.

Rationale for the shielding policy for clinically vulnerable people in the UK during the COVID-19 pandemic: a qualitative study.

INTRODUCTION: Shielding aimed to protect those predicted to be at highest risk from COVID-19 and was uniquely implemented in the UK during the first year of the pandemic from March 2020. As the first stage in the EVITE Immunity evaluation (Effects of shielding for vulnerable people during COVID-19 pandemic on health outcomes, costs and immunity, including those with cancer:quasi-experimental evaluation), we generated a logic model to describe the programme theory underlying the shielding intervention. DESIGN AND PARTICIPANTS: We reviewed published documentation on shielding to develop an initial draft of the logic model. We then discussed this draft during interviews with 13 key stakeholders involved in putting shielding into effect in Wales and England. Interviews were recorded, transcribed and analysed thematically to inform a final draft of the logic model. RESULTS: The shielding intervention was a complex one, introduced at pace by multiple agencies working together. We identified three core components: agreement on clinical criteria; development of the list of people appropriate for shielding; and communication of shielding advice. In addition, there was a support programme, available as required to shielding people, including food parcels, financial support and social support. The predicted mechanism of change was that people would isolate themselves and so avoid infection, with the primary intended outcome being reduction in mortality in the shielding group. Unintended impacts included negative impact on mental and physical health and well-being. Details of the intervention varied slightly across the home nations of the UK and were subject to minor revisions during the time the intervention was in place. CONCLUSIONS: Shielding was a largely untested strategy, aiming to mitigate risk by placing a responsibility on individuals to protect themselves. The model of its rationale, components and outcomes (intended and unintended) will inform evaluation of the impact of shielding and help us to understand its effect and limitations.

Modern Applications of Machine Learning in Shoulder Arthroplasty: A Review.

¼ There is increased integration of machine learning (ML) to aid clinical decision-making in orthopaedic surgery.¼ ML has the ability to predict both clinical outcomes such as range of motion and complications in total shoulder arthroplasty patients.¼ An increased area of focus is the ability for ML to identify implants to aid in revision surgery planning.¼ In this article, we review the current applications of ML in shoulder arthroplasty and discuss future areas where it may enhance orthopaedic practice.

Shoulder arthroplasty following solid organ transplant: A systematic review and meta-analysis.

Introduction: The purpose of this study is to report a systematic review and meta-analysis of solid organ transplant (SOT) patients undergoing shoulder arthroplasty to compare functional and radiographic outcomes, demographics, and complications with non-transplant patients. Methods: Studies were included if they examined patients undergoing shoulder arthroplasty in the setting of prior solid organ transplantation and included post operative range of motion, patient-reported outcomes, complications, or revisions. Studies were excluded if they were national database analyses or lacked clinical data. Pubmed, MEDLine, Scopus, and Web of Science were queried using relevant search terms in July 2022. Data was pooled, weighted, and a paired t-test and chi-square analysis was performed. Results: There were 71 SOT and 159 non-SOT shoulders included in the study. The most common indication for surgery was avascular necrosis (n = 26) in the solid organ transplant group and osteoarthritis (n = 60) in the non-SOT group. Forward elevation, external rotation, ASES, and VAS pain scores improved significantly in both cohorts following surgery. There was no significant difference in age at surgery (p-value = 0.20), postoperative forward elevation (p-value = 0.08), postoperative external rotation (0.84), and postoperative ASES scores (p-value = 0.11) between the two cohorts. VAS pain scores were significantly lower in the SOT cohort (p-value<0.01). The risk of death was significantly higher in the SOT group (p-value<0.01). but the rate of overall complications (p = 0.47), surgical complication (p-value = 0.79), or revision surgery (p-value = 1.00) was not significantly different between the two cohorts. Conclusion: Shoulder arthroplasty is a safe, effective option in patients following solid organ transplant. There is not an increased risk of adverse outcomes, and SOT patients had comparable range of motion and patient-reported outcomes when compared to their non-SOT peers. Level of evidence: III.

Photobiomodulation in Acute Traumatic Brain Injury: A Systematic Review and Meta-Analysis.

Photobiomodulation (PBM) is a therapeutic modality that has gained increasing interest in neuroscience applications, including acute traumatic brain injury (TBI). Its proposed mechanisms for therapeutic effect when delivered to the injured brain include antiapoptotic and anti-inflammatory effects. This systematic review summarizes the available evidence for the value of PBM in improving outcomes in acute TBI and presents a meta-analysis of the pre-clinical evidence for neurological severity score (NSS) and lesion size in animal models of TBI. A systematic review of the literature was performed, with searches and data extraction performed independently in duplicate by two authors. Eighteen published articles were identified for inclusion: seventeen pre-clinical studies of in vivo animal models and one clinical study in human patients. The available human study supports safety and feasibility of PBM in acute moderate TBI. For pre-clinical studies, meta-analysis for NSS and lesion size were found to favor intervention versus control. Subgroup analysis based on PBM parameter variables for these outcomes was performed. Favorable parameters were identified as: wavelengths in the region of 665 nm and 810 nm; time to first administration of PBM ≤4 h; total number of daily treatments ≤3. No differences were identified between pulsed and continuous wave modes or energy delivery. Mechanistic substudies within included in vivo studies are presented and were found to support hypotheses of antiapoptotic, anti-inflammatory, and pro-proliferative effects, and a modulation of cellular metabolism. This systematic review provides substantial meta-analysis evidence of the benefits of PBM on functional and histological outcomes of TBI in in vivo mammalian models. Study design and PBM parameters should be closely considered for future human clinical studies.

A mixed-methods characterisation of patient safety incidents by primary eye care practitioners.

PURPOSE: Patient safety in eye health care is an underdeveloped field of research. A patient safety incident occurs when an unintended incident happens that could have (or did) lead to harm. To enable learning from patient safety incidents in optometry, a characterisation of commonly experienced safety incidents is needed to identify options to improve the quality of care. This study aimed to characterise eye health-related patient safety incidents from the perspective of eye care practitioners. METHODS: At a national conference in Wales, 56 eye care practitioners participated in a stakeholder workshop on eye care-related patient safety incidents. Participants were asked to suggest patient safety incidents that have occurred, or based on their experience, could occur in optometric practice. Using the nominal group technique, participants voted on the incident they perceived could cause the most harm and the incident observed most frequently in practice. Framework analysis supported identification of themes about the nature and outcomes of incidents in eye care. RESULTS: Diagnostic incidents were perceived to be the most severe (highest number of 'severity votes', n = 38), whilst administration-related incidents were most frequent (highest number of 'frequency votes' n = 39). Four themes were identified which are as follows: inappropriate clinical decision-making; delayed or missed referral of patients to general medical practitioners or ophthalmologists; compromised communication with other practitioners or patients and delays in receiving eye care. The results suggest that incidents relating to inappropriate clinical decision-making could result in the most severe harm to patients but may not occur frequently. CONCLUSIONS: Diagnostic- and administrative-related incidents pose clear challenges for improvement in quality and safety of care. The breadth of themes reflecting the nature and outcomes from unsafe eye care highlights the complexity underpinning incidents and the burden to patients. This work has informed the content of an all-Wales incident report form for primary eye care practitioners.

Radiotherapy in Oligometastatic, Oligorecurrent and Oligoprogressive Prostate Cancer: A Mini-Review.

Globally, prostate cancer is one of the most common malignancies affecting men. With the advent of advanced molecular imaging, an increasing number of men are found to have oligometastatic disease (OD) either at primary diagnosis or at the time of biochemical failure. No strict definition exists for OD, with historical and ongoing studies utilizing diverse criteria. There is mounting evidence from many different malignancies that patients with OD have improved outcomes compared to their widely metastatic counterparts. As such, treatment intensification of those with OD or oligoprogressive disease has become an area of intense interest and study. This article will review the biology, evidence and controversy behind the treatment of de novo oligometastatic, oligorecurrent and oligoprogressive prostate cancer.

Which human factors design issues are influencing system performance in out-of-hours community palliative care? Integration of realist approaches with an established systems analysis framework to develop mid-range programme theory.

OBJECTIVE: To develop mid-range programme theory from perceptions and experiences of out-of-hours community palliative care, accounting for human factors design issues that might be influencing system performance for achieving desirable outcomes through quality improvement. SETTING: Community providers and users of out-of-hours palliative care. PARTICIPANTS: 17 stakeholders participated in a workshop event. DESIGN: In the UK, around 30% of people receiving palliative care have contact with out-of-hours services. Interactions between emotions, cognition, tasks, technology and behaviours must be considered to improve safety. After sharing experiences, participants were presented with analyses of 1072 National Reporting and Learning System incident reports. Discussion was orientated to consider priorities for change. Discussions were audio-recorded and transcribed verbatim by the study team. Event artefacts, for example, sticky notes, flip chart lists and participant notes, were retained for analysis. Two researchers independently identified context-mechanism-outcome configurations using realist approaches before studying the inter-relation of configurations to build a mid-range theory. This was critically appraised using an established human factors framework called Systems Engineering Initiative for Patient Safety (SEIPS). RESULTS: Complex interacting configurations explain relational human-mediated outcomes where cycles of thought and behaviour are refined and replicated according to prior experiences. Five such configurations were identified: (1) prioritisation; (2) emotional labour; (3) complicated/complex systems; (4a) system inadequacies and (4b) differential attention and weighing of risks by organisations; (5) learning. Underpinning all these configurations was a sixth: (6a) trust and access to expertise; and (6b) isolation at night. By developing a mid-range programme theory, we have created a framework with international relevance for guiding quality improvement work in similar modern health systems. CONCLUSIONS: Meta-cognition, emotional intelligence, and informal learning will either overcome system limitations or overwhelm system safeguards. Integration of human-centred co-design principles and informal learning theory into quality improvement may improve results.

Patient Safety Incidents in Primary Care Dentistry in England and Wales: A Mixed-Methods Study.

BACKGROUND: In recent decades, there has been considerable international attention aimed at improving the safety of hospital care, and more recently, this attention has broadened to include primary medical care. In contrast, the safety profile of primary care dentistry remains poorly characterized. OBJECTIVES: We aimed to describe the types of primary care dental patient safety incidents reported within a national incident reporting database and understand their contributory factors and consequences. METHODS: We undertook a cross-sectional mixed-methods study, which involved analysis of a weighted randomized sample of the most severe incident reports from primary care dentistry submitted to England and Wales' National Reporting and Learning System. Drawing on a conceptual literature-derived model of patient safety threats that we previously developed, we developed coding frameworks to describe and conduct thematic analysis of free text incident reports and determine the relationship between incident types, contributory factors, and outcomes. RESULTS: Of 2000 reports sampled, 1456 were eligible for analysis. Sixty types of incidents were identified and organized across preoperative (40.3%, n = 587), intraoperative (56.1%, n = 817), and postoperative (3.6%, n = 52) stages. The main sources of unsafe care were delays in treatment (344/1456, 23.6%), procedural errors (excluding wrong-tooth extraction) (227/1456; 15.6%), medication-related adverse incidents (161/1456, 11.1%), equipment failure (90/1456, 6.2%) and x-ray related errors (87/1456, 6.0%). Of all incidents that resulted in a harmful outcome (n = 77, 5.3%), more than half were due to wrong tooth extractions (37/77, 48.1%) mainly resulting from distraction of the dentist. As a result of this type of incident, 34 of the 37 patients (91.9%) examined required further unnecessary procedures. CONCLUSIONS: Flaws in administrative processes need improvement because they are the main cause for patients experiencing delays in receiving treatment. Checklists and standardization of clinical procedures have the potential to reduce procedural errors and avoid overuse of services. Wrong-tooth extractions should be addressed through focused research initiatives and encouraging policy development to mandate learning from serious dental errors like never events.

Medication Safety in Mental Health Hospitals: A Mixed-Methods Analysis of Incidents Reported to the National Reporting and Learning System.

BACKGROUND: Medication safety incidents commonly occur in mental health hospitals. There is a need to improve the understanding of the circumstances that are thought to have played a part in the origin of these incidents to design safer systems to improve patient safety. AIM: This study aimed to undertake a mixed-methods analysis of medication safety incidents reported to the National Reporting and Learning System in England and Wales in 2010 to 2017. METHOD: Quantitative analyses of anonymized medication safety incidents occurring in mental health hospitals that were reported to the National Reporting and Learning System during an 8-year period were undertaken to characterize their type, severity, and the medication(s) involved. Second, a content analysis of the free-text reports associated with all incidents of at least moderate harm severity was undertaken to identify the underlying contributory factors. RESULTS: Overall, 94,134 medication incident reports were examined, of which 10.4% (n = 9811) were reported to have resulted in harm. The 3 most frequent types of reported medication incidents involved omission of medication (17,302; 18.3%), wrong frequency (11,882; 12.6%), and wrong/unclear dose of medication (10,272; 10.9%). Medicines from the central nervous system (42,609; 71.0%), cardiovascular (4537; 7.6%), and endocrine (3669; 6.1%) medication classes were the most frequently involved with incidents. Failure to follow protocols (n = 93), lack of continuity of care (n = 92), patient behaviors (n = 62), and lack of stock (n = 51) were frequently reported as contributory factors. CONCLUSIONS: Medication incidents pose an enduring threat to patient safety in mental health hospitals. This study has identified important targets that can guide the tailored development of remedial interventions.

Protocol for a feasibility study incorporating a randomised pilot trial with an embedded process evaluation and feasibility economic analysis of ThinkCancer!: a primary care intervention to expedite cancer diagnosis in Wales.

BACKGROUND: Compared to the rest of Europe, the UK has relatively poor cancer outcomes, with late diagnosis and a slow referral process being major contributors. General practitioners (GPs) are often faced with patients presenting with a multitude of non-specific symptoms that could be cancer. Safety netting can be used to manage diagnostic uncertainty by ensuring patients with vague symptoms are appropriately monitored, which is now even more crucial due to the ongoing COVID-19 pandemic and its major impact on cancer referrals. The ThinkCancer! workshop is an educational behaviour change intervention aimed at the whole general practice team, designed to improve primary care approaches to ensure timely diagnosis of cancer. The workshop will consist of teaching and awareness sessions, the appointment of a Safety Netting Champion and the development of a bespoke Safety Netting Plan and has been adapted so it can be delivered remotely. This study aims to assess the feasibility of the ThinkCancer! intervention for a future definitive randomised controlled trial. METHODS: The ThinkCancer! study is a randomised, multisite feasibility trial, with an embedded process evaluation and feasibility economic analysis. Twenty-three to 30 general practices will be recruited across Wales, randomised in a ratio of 2:1 of intervention versus control who will follow usual care. The workshop will be delivered by a GP educator and will be adapted iteratively throughout the trial period. Baseline practice characteristics will be collected via questionnaire. We will also collect primary care intervals (PCI), 2-week wait (2WW) referral rates, conversion rates and detection rates at baseline and 6 months post-randomisation. Participant feedback, researcher reflections and economic costings will be collected following each workshop. A process evaluation will assess implementation using an adapted Normalisation Measure Development (NoMAD) questionnaire and qualitative interviews. An economic feasibility analysis will inform a future economic evaluation. DISCUSSION: This study will allow us to test and further develop a novel evidenced-based complex intervention aimed at general practice teams to expedite the diagnosis of cancer in primary care. The results from this study will inform the future design of a full-scale definitive phase III trial. TRIAL REGISTRATION: ClinicalTrials.gov NCT04823559 .

Nature and type of patient-reported safety incidents in primary care: cross-sectional survey of patients from Australia and England.

BACKGROUND: Patient engagement in safety has shown positive effects in preventing or reducing adverse events and potential safety risks. Capturing and utilising patient-reported safety incident data can be used for service learning and improvement. OBJECTIVE: The aim of this study was to characterise the nature of patient-reported safety incidents in primary care. DESIGN: Secondary analysis of two cross sectional studies. PARTICIPANTS: Adult patients from Australian and English primary care settings. MEASURES: Patients' self-reported experiences of safety incidents were captured using the validated Primary Care Patient Measure of Safety questionnaire. Qualitative responses to survey items were analysed and categorised using the Primary Care Patient Safety Classification System. The frequency and type of safety incidents, contributory factors, and patient and system level outcomes are presented. RESULTS: A total of 1329 patients (n=490, England; n=839, Australia) completed the questionnaire. Overall, 5.3% (n=69) of patients reported a safety incident over the preceding 12 months. The most common incident types were administration incidents (n=27, 31%) (mainly delays in accessing a physician) and incidents involving diagnosis and assessment (n=16, 18.4%). Organisation of care accounted for 27.6% (n=29) of the contributory factors identified in the safety incidents. Staff factors (n=13, 12.4%) was the second most commonly reported contributory factor. Where an outcome could be determined, patient inconvenience (n=24, 28.6%) and clinical harm (n=21, 25%) (psychological distress and unpleasant experience) were the most frequent. CONCLUSIONS: The nature and outcomes of patient-reported incidents differ markedly from those identified in studies of staff-reported incidents. The findings from this study emphasise the importance of capturing patient-reported safety incidents in the primary care setting. The patient perspective can complement existing sources of safety intelligence with the potential for service improvement.