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Aim: Although the US FDA encourages manufacturers of medical devices to submit real-world evidence (RWE) to support regulatory decisions, the ability of real-world data (RWD) to generate evidence suitable for decision making remains unclear. The 2017 Medical Device User Fee Amendments (MDUFA IV), authorized the National Evaluation System for health Technology Coordinating Center (NESTcc) to conduct pilot projects, or ‘Test-Cases’, to assess whether current RWD captures the information needed to answer research questions proposed by industry stakeholders. We synthesized key lessons about the challenges conducting research with RWD and the strategies used by research teams to enhance their ability to generate evidence from RWD based on 18 Test-Cases conducted between 2020 and 2022. Materials & methods: We reviewed study protocols and reports from each Test-Case team and conducted 49 semi-structured interviews with representatives of participating organizations. Interview transcripts were coded and thematically analyzed. Results: Challenges that stakeholders encountered in workingwith RWD included the lack of unique device identifiers, capturing key data elements and their appropriate meaning in structured data, limited reliability of diagnosis and procedure codes in structured data, extracting information from unstructured electronic health record (EHR) data, limited capture of long-term study end points, missing data and data sharing. Successful strategies included using manufacturer and supply chain data, leveraging clinical registries and registry reporting processes to collect and aggregate data, querying standardized EHR data, implementing natural language processing algorithms and using multidisciplinary research teams. Conclusion: The Test-Cases identified numerous challenges working with RWD but also opportunities to address these challenges and improve researchers’ ability to use RWD to generate evidence on medical devices.

The pancreas is a heavily innervated organ, but pancreatic innervation can be challenging to comprehensively assess using conventional histological methods. However, recent advances in whole-mount tissue clearing and 3D rendering techniques have allowed detailed reconstructions of pancreatic innervation. Optical clearing is used to enhance tissue transparency and reduce light scattering, thus eliminating the need to section the tissue. Here, we describe a modified version of the optical tissue clearing protocol iDISCO+ (immunolabeling-enabled three-dimensional imaging of solvent-cleared organs) optimized for pancreatic innervation and endocrine markers. The protocol takes 13-19 days, depending on tissue size. In addition, we include protocols for imaging using light sheet and confocal microscopes and for 3D segmentation of pancreatic innervation and endocrine cells using Imaris.

Hypoglycemia is a frequent complication of diabetes, limiting therapy and increasing morbidity and mortality. With recurrent hypoglycemia, the counterregulatory response (CRR) to decreased blood glucose is blunted, resulting in hypoglycemia-associated autonomic failure (HAAF). The mechanisms leading to these blunted effects are only poorly understood. Here, we report, with ISH, IHC, and the tissue-clearing capability of iDISCO+, that growth hormone releasing hormone (GHRH) neurons represent a unique population of arcuate nucleus neurons activated by glucose deprivation in vivo. Repeated glucose deprivation reduces GHRH neuron activation and remodels excitatory and inhibitory inputs to GHRH neurons. We show that low glucose sensing is coupled to GHRH neuron depolarization, decreased ATP production, and mitochondrial fusion. Repeated hypoglycemia attenuates these responses during low glucose. By maintaining mitochondrial length with the small molecule mitochondrial division inhibitor-1, we preserved hypoglycemia sensitivity in vitro and in vivo. Our findings present possible mechanisms for the blunting of the CRR, significantly broaden our understanding of the structure of GHRH neurons, and reveal that mitochondrial dynamics play an important role in HAAF. We conclude that interventions targeting mitochondrial fission in GHRH neurons may offer a new pathway to prevent HAAF in patients with diabetes.

Finding ways to stimulate the regeneration of endogenous pancreatic beta cells is an important goal in the treatment of diabetes. Parathyroid hormone-related protein (PTHrP), the full-length (1-139) and amino-terminal (1-36) peptides, enhance beta cell function, proliferation, and survival. Therefore, we hypothesize that PTHrP(1-36) has the potential to regenerate endogenous beta cells.The partial pancreatectomy (PPx) mouse model of beta cell injury was used to test this hypothesis. Male Balb/c mice underwent either sham-operation or PPx, and were subsequently injected with PTHrP(1-36) (160μg/kg) or vehicle (veh), for 7, 30, or 90 days. The four groups of mice, sham-veh, sham-PTHrP, PPx-veh, and PPx-PTHrP were assessed for PTHrP and receptor expression, and glucose and beta cell homeostasis.PTHrP-receptor, but not the ligand, was significantly up-regulated in islets from mice that underwent PPx compared to sham-operated mice. This suggests that exogenous PTHrP could further enhance beta cell regeneration after PPx. PTHrP did not significantly affect body weight, blood glucose, plasma insulin, or insulin sensitivity, in either sham or PPx mice. Glucose tolerance improved in the PPx-PTHrP versus PPx-veh mice only in the early stages of treatment. As hypothesized, there was a significant increase in beta cell proliferation in PPx-PTHrP mice at days 7 and 30; however, this was normalized by day 90, compared to PPx-veh mice. Enhanced beta cell proliferation translated to a marked increase in beta cell mass at day 90, in PPx-PTHrP versus PPx-veh mice.PTHrP(1-36) significantly enhances beta cell regeneration through increased beta cell proliferation and beta cell mass after PPx. Future studies will determine the potential of PTHrP to enhance functional beta cell mass in the setting of diabetes.

BackgroundAchalasia is a rare motility disorder affecting the oesophagus, leading to difficulties with eating and drinking. Participants in previous studies reported that they needed more social, clinical and behavioural support in the long-term management of achalasia. This study, therefore aimed to 1) identify the most challenging eating behaviour for people living with achalasia and 2) co-design a behaviour change intervention to help address the challenges they experience.MethodsThis study used a qualitative approach involving online focus groups. The COM-B model was the theoretical framework, with behaviour change techniques (BCTs) as the active ingredients that target a mixture of capability, opportunity and/or motivation. Three focus groups were undertaken to obtain a range of input from different people living with achalasia. Participants in this study identified the target behaviour, prioritised the different BCTs which most resonated with them to design an intervention and decided on the mode of delivery. The research team analysed the techniques that helped participants with their eating behaviour using the COM-B model as a framework to create the intervention.ResultsThe 24 participants in this study identified “eating in a social setting” as the target behaviour for the intervention. A workbook that can be personalised by the individual was the most suitable intervention. The workbook structure aligns with the constructs of the COM-B model. It includes reflection, activities and goal-setting sections based on what was indicated to be useful for the majority of the participants. Key techniques to overcome the challenges with eating in a social setting included social support, regulation to reduce negative emotions, goals and planning.ConclusionUsing a focus group approach with the COM-B model as the theoretical framework, the participants in this study developed an intervention to support people living with achalasia. In order to achieve long-term behaviour change, engagement with a personalised workbook could facilitate eating in a social setting. Future work will need to pilot the workbook to ensure it can support people to improve their quality of life and complement the ongoing care they receive from health services.

Abstract Background The use of variable rate intravenous insulin infusion (VRIII) is a complex process that has consistently been implicated in reports of error and consequent harm. Investment in patient safety has focused mainly on learning from errors, though this has yet to be proved to reduce error rates. The Resilient Health Care approach advocates learning from everyday practices. Video reflexive ethnography (VRE) is an innovative methodology used to capture everyday practices, reflect on and thereby improve these. This study set out to explore the use of VRIIIs by utilising the VRE methodology. Methods This study was conducted in a Vascular Surgery Unit. VRE methodology was used to collect qualitative data that involved videoing healthcare practitioners caring for patients treated with VRIII and discussing the resulting clips with participants in reflexive meetings. Transcripts of these were subjected to thematic analysis. Quantitative data (e.g. blood glucose measurements) were collected from electronic patient records in order to contextualise the outcomes of the video-observed tasks. Results The use of VRE in conjunction with quantitative data revealed that context-dependent adaptations (seeking verbal orders to treat hypoglycaemia) and standardised practices (using VRIII guidelines) were strategies used in everyday work. Reflexive meetings highlighted the challenges faced while using VRIII, which were mainly related to lack of clinical knowledge, e.g. prescribing/continuing long-acting insulin analogues alongside the VRIII, and problems with organisational infrastructure, i.e. the wireless blood glucose meter results sometimes not updating on the electronic system. Reflexive meetings also enabled participants to share the meanings of the reality surrounding them and encouraged them to suggest solutions tailored to their work, for example face-to-face, VRIII-focused training. Conclusions VRE deepened understanding of VRIII by shedding light on its essential tasks and the challenges and adaptations entailed by its use. Future research might focus on collecting data across various units and hospitals to develop a full picture of the use of VRIIIs.

Abstract Background Achalasia is a rare motility disorder affecting the oesophagus, which is associated with a range of symptoms and different treatment strategies. Currently, little is known about people's experiences with achalasia and its management. This study aimed to understand the experiences of people living with achalasia, from the initial onset of symptoms to long‐term management. Method This qualitative study explored the journey of people living with achalasia and outlined the care pathway using a process map. Ten female and five male participants living with achalasia (age range: 40‐73) took part, and all aspects of their diagnosis, treatment and management were discussed. A process map showing people's experiences by separating the management of their condition into a series of steps was developed to present the pathway in the participants’ journey. The analysis involved discussing the process map within the research team. Results The process map comprised of 10 steps, which occurred before and after diagnosis. The developed map indicates that most participants managed their on‐going symptoms through stress management techniques and dietary changes. Key issues that participants highlighted about their journey managing achalasia were misdiagnosis, delay in diagnosis and lack of support in the long‐term management of achalasia. Conclusions This research was a novel study exploring patients’ experiences and management of achalasia and mapping their journey. Two distinct phases to their journeys were identified: before and after diagnosis. Areas highlighted by this study can provide a basis for future research, in particular behaviour change to support the long‐term management of achalasia.

Objective Variable rate intravenous insulin infusions (VRIII) is a high-risk medication that has a potential to cause significant patient harm if used in error. Complex preparation of VRIII in clinical areas and the need for frequent monitoring and adjustment increase the complexity of using VRIII. An emerging approach, called Resilient Healthcare, proposes understanding complexity of work by exploring how work is assumed to be done and compare it with everyday work. This study aimed to explore how VRIII is perceived to be used by healthcare practitioners, focusing on one aspect of Resilient Healthcare: understanding how work is assumed to be done, using a method called hierarchical task analysis (HTA).Design A qualitative study using document analysis and focus groups.Setting A vascular surgery unit in an acute National Health Service teaching hospital in the UK.Participants Stakeholders/users in different professional roles involved in the process of using VRIII.Results The HTA showed the complexity of using VRIII and highlighted more than 115 steps required to treat elevated blood glucose. The process of producing hospital-specific guidelines was iterative. Careful consideration was taken to coordinate the development and implementation of guidelines. Documents provided detailed clinical instructions related to the use of VRIII but practitioners selectively used them, often in deference to senior colleagues. Intentional adaptations, for example, proactively asking for a VRIII prescription occurred and were acknowledged as part of providing individualised patient care.Conclusion Using VRIII to treat elevated blood glucose is a complex but necessary process mediated by a range of factors such as organisational influences. Adaptive strategies to mitigate errors were common and future research can build on insights from this study to develop a broader understanding of how VRIII is used and to understand how adaptations are made in relation to the use of VRIII.

Antimicrobial stewardship (AMS) programmes in human health and livestock production are vital to tackling antimicrobial resistance (AMR). Data on antimicrobial use (AMU), resistance, and drivers for AMU in livestock are needed to inform AMS efforts. However, such data are limited in Fiji. Therefore, this study aimed to evaluate the association between farmer (socio-economic, demographic) and livestock production and management factors with AMU. Information was collected using purposive and snowball sampling from 236 livestock farmers and managers located in Central and Western divisions, Viti Levu, Fiji. Multinomial logistic regression was used to determine the factors associated with AMU in farms using an aggregated livestock farm model. Farms that raised cattle only for dairy (farm factor) were more likely to use antibiotics and anthelmintics (p = 0.018, OR = 22.97, CI 1.713, 308.075) compared to mixed cattle and poultry farms. Farms that maintained AMU records were more likely to use antibiotics (p = 0.045, OR = 2.65, CI 1.024, 6.877) compared to farms that did not. Other livestock production and management factors had no influence on AMU on the livestock farms. AMU in livestock farms was not influenced by the socio-economic and demographic characteristics of the farmer. There were differences between livestock enterprises regarding their management. The lack of association between management system and AMU could be because there was so much variation in management system, levels of farmer knowledge and awareness of AMU, and in management of farm biosecurity. Future studies exploring farmers’ knowledge and awareness of AMU and livestock management are required to design AMS programmes promoting prudent AMU in all livestock farms locally.

Objectives To assess the acceptability and feasibility of using a theory-based electronic learning intervention designed to support appropriate antibiotic prescribing by nurse and pharmacist independent prescribers for patients presenting with common, acute, uncomplicated self-limiting respiratory tract infections (RTIs).Design Experimental with mixed methods; preintervention and postintervention online surveys and semistructured interviews.Setting Primary care settings across the UK.Participants 11 nurse and 4 pharmacist prescribers.Intervention A theory-based brief interactive animation electronic learning activity comprised a consultation scenario by a prescriber with an adult presenting with a common, acute, uncomplicated self-limiting RTI to support a ‘no antibiotic prescribing strategy’.Outcome measures Recruitment, response and attrition rates were assessed. The overall usefulness of the intervention was assessed by analysing prescribers’ self-reported confidence and knowledge in treating patients with RTIs before and after undertaking the intervention, and views on the relevance of the intervention to their work. Acceptability of the intervention was assessed in semistructured interviews. The feasibility of data collection methods was assessed by recording the number of study components completed by prescribers.Results 15 prescribers (maximum sample size) consented and completed all four stages of the study. Prescribers reported high to very high levels of confidence and knowledge preintervention and postintervention, with slight postintervention increases in communicating with patients and a slight reduction in building rapport. Qualitative findings supported quantitative findings; prescribers were reassured of their own practice which in turn increased their confidence and knowledge in consultations. The information in the intervention was not new to prescribers but was applicable and useful to consolidate learning and enable self-reflection. Completing the e-learning intervention was acceptable to prescribers.Conclusions It was feasible to conduct the study. The intervention was acceptable and useful to prescribers. Future work will add complex clinical content in the intervention before conducting a full trial.

Antimicrobial resistance (AMR) is a major global threat to human and animal health. The use of antimicrobials in the livestock sector is considered to contribute to AMR. Therefore, a reduction in and prudent use of antimicrobials in livestock production systems have been advocated. This cross-sectional survey aimed to investigate the extent of imprudent antimicrobial use (AMU) and to determine whether the AMU practice was affected by either the farming system or species of farmed livestock in the largest island (Viti Levu) of Fiji. A total of 276 livestock enterprises were surveyed and antimicrobials were used on 309 occasions over 90 days. Overall, in 298 of 309 (96%) incidents, antimicrobials were used imprudently, comprising antibiotics, 160 of 170 (94%) and anthelmintics, 138 of 139 (99%). Prudent use of antibiotics was associated with commercial farming systems (X2 = 13, p = 0.001), but no association was observed with anthelmintic use (p > 0.05). Imprudent antibiotic use was associated with dairy (OR = 7.6, CI = 1.41, 41.57, p = 0.018) followed by layer and beef (p > 0.05) compared to broiler enterprises. Imprudent AMU was more common in the backyard and semi-commercial enterprises compared to commercial broiler enterprises. Policies promoting the prudent use of antimicrobials in Fiji should focus on smaller livestock production systems and enterprises.

Introduction Nurse and pharmacist independent prescribers manage patients with respiratory tract infections and are responsible for around 8% of all primary care antibiotic prescriptions. A range of factors influence the prescribing behaviour of these professionals, however, there are no interventions available specifically to support appropriate antibiotic prescribing behaviour by these groups. The aims of this paper are to describe (1) the development of an intervention to support appropriate antibiotic prescribing by nurse and pharmacist independent prescribers and (2) an acceptability and feasibility study designed to test its implementation with these prescribers.Method and analysis Development of intervention: a three-stage, eight-step method was used to identify relevant determinants of behaviour change and intervention components based on the Behaviour Change Wheel. The intervention is an online resource comprising underpinning knowledge and an interactive animation with a variety of open and closed questions to assess understanding. Acceptability and feasibility of intervention: nurse and pharmacist prescribers (n=12–15) will use the intervention. Evaluation includes semi-structured interviews to capture information about how the user reacts to the design, delivery and content of the intervention and influences on understanding and engagement, and a pre-post survey to assess participants’ perceptions of the impact of the intervention on knowledge, confidence and usefulness in terms of application to practice. Taking an initial inductive approach, data from interview transcripts will be coded and then analysed to derive themes. These themes will then be deductively mapped to the Capability, Opportunity, Motivation-Behaviour model. Descriptive statistics will be used to analyse the survey data, and trends identified.Ethics and dissemination Ethical approval for the study has been provided by the School of Healthcare Sciences Research Governance and Ethics Committee, Cardiff University. The findings will be disseminated via publication in peer-reviewed journals and through conference presentations.

Background Intravenous insulin infusions are considered the treatment of choice for critically ill patients and non-critically ill patients with persistent raised blood glucose who are unable to eat, to achieve optimal blood glucose levels. The benefits of using intravenous insulin infusions as well as the problems experienced are well described in the scientific literature. Traditional approaches for improving patient safety have focused on identifying errors, understanding their causes and designing solutions to prevent them. Such approaches do not take into account the complex nature of healthcare systems, which cannot be controlled solely by following standards. An emerging approach called Resilient Healthcare proposes that, to improve safety, it is necessary to focus on how work can be performed successfully as well as how work has failed.Methods and analysis The study will be conducted at Oxford University Hospitals NHS Foundation Trust and will involve three phases. Phase I: explore how work is imagined by analysing intravenous insulin infusion guidelines and conducting focus group discussions with guidelines developers, managers and healthcare practitioners. Phase II: explore the interplay between how work is imagined and how work is performed using mixed methods. Quantitative data will include blood glucose levels, insulin infusion rates, number of hypoglycaemic and hyperglycaemic events from patients’ electronic records. Qualitative data will include video reflexive ethnography: video recording healthcare practitioners using intravenous insulin infusions and then conducting reflexive meetings with them to discuss selected video footage. Phase III: compare findings from phase I and phase II to develop a model for using intravenous insulin infusions.Ethics and dissemination Ethical approvals have been granted by the South Central—Oxford C Research Ethics Committee, Oxford University Hospitals NHS Foundation Trust and University of Reading. The results will be disseminated through presentations at appropriate conferences and meetings, and publications in peer-reviewed journals.

Objectives Respiratory tract infections are frequently managed by nurse and pharmacist prescribers, and these prescribers are responsible for 8% of all primary care antibiotic prescriptions. Few studies have explored antibiotic prescribing among these prescribers, and interventions to target their antibiotic prescribing behaviour do not exist. Research objectives were to: (1) use the Theoretical Domains Framework to identify the factors that influence nurse and pharmacist prescriber management of respiratory tract infections and (2) identify the behaviour change techniques (BCTs) that can be used as the basis for the development of a theoretically informed intervention to support appropriate prescribing behaviour.Design Qualitative design comprising semistructured interviews, using the Theoretical Domains Framework and Capability, Opportunity and Motivation for Behaviour.Setting Primary care.Participants Twenty one prescribers (4 pharmacists and 17 nurses).Results A range of factors across 12 domains of the TDF were found to influence prescriber behaviour, and 40 BCTs were identified as supporting appropriate prescribing. For example, patient expectations (social influence) was identified as a factor influencing prescribing decisions, and a number of BCTs (problem solving, goal setting and information about health consequences) were identified as supporting prescribers in managing these expectations.Conclusion With increasing numbers of nurse and pharmacist prescribers managing infections in primary care, these findings will inform theoretically grounded interventions to support appropriate prescribing behaviour by these groups.