Recent Submissions

  • Enhanced Objective Detection of Retinal Nerve Fiber Bundle Defects in Glaucoma With a Novel Method for En Face OCT Slab Image Construction and Analysis

    Cheloni, R.; Dewsbery, S.D.; Denniss, Jonathan (2021-10-04)
    To introduce and evaluate the performance in detecting glaucomatous abnormalities of a novel method for extracting en face slab images (SMAS), which considers varying individual anatomy and configuration of retinal nerve fiber bundles. Dense central retinal spectral domain optical coherence tomography scans were acquired in 16 participants with glaucoma and 19 age-similar controls. Slab images were generated by averaging reflectivity over different depths below the inner limiting membrane according to several methods. SMAS considered multiple 16 µm thick slabs from 8 to 116 µm below the inner limiting membrane, whereas 5 alternative methods considered single summary slabs of various thicknesses and depths. Superpixels in eyes with glaucoma were considered abnormal if below the first percentile of distributions fitted to control data for each method. The ability to detect glaucoma defects was measured by the proportion of abnormal superpixels. Proportion of superpixels below the fitted first percentile in controls was used as a surrogate false-positive rate. The effects of slab methods on performance measures were evaluated with linear mixed models. The ability to detect glaucoma defects varied between slab methods, χ2(5) = 120.9, P
  • Fundus-controlled perimetry (microperimetry): Application as outcome measure in clinical trials

    Pfau, M.; Jolly, J.K.; Wu, Z.; Denniss, Jonathan; Lad, E.M.; Guymer, R.H.; Fleckenstein, M.; Holz, F.G.; Schmitz-Valckenberg, S. (2021-05)
    Fundus-controlled perimetry (FCP, also called 'microperimetry') allows for spatially-resolved mapping of visual sensitivity and measurement of fixation stability, both in clinical practice as well as research. The accurate spatial characterization of visual function enabled by FCP can provide insightful information about disease severity and progression not reflected by best-corrected visual acuity in a large range of disorders. This is especially important for monitoring of retinal diseases that initially spare the central retina in earlier disease stages. Improved intra- and inter-session retest-variability through fundus-tracking and precise point-wise follow-up examinations even in patients with unstable fixation represent key advantages of these technique. The design of disease-specific test patterns and protocols reduces the burden of extensive and time-consuming FCP testing, permitting a more meaningful and focused application. Recent developments also allow for photoreceptor-specific testing through implementation of dark-adapted chromatic and photopic testing. A detailed understanding of the variety of available devices and test settings is a key prerequisite for the design and optimization of FCP protocols in future natural history studies and clinical trials. Accordingly, this review describes the theoretical and technical background of FCP, its prior application in clinical and research settings, data that qualify the application of FCP as an outcome measure in clinical trials as well as ongoing and future developments.
  • What Are the Barriers and Enablers to the Implementation of Pharmacogenetic Testing in Mental Health Care Settings?

    Jameson, Adam; Fylan, Beth; Bristow, Greg C.; Sagoo, G.S.; Dalton, C.; Cardno, A.; Sohal, J.; McLean, Samantha L. (2021-09-22)
    In psychiatry, the selection of antipsychotics and antidepressants is generally led by a trial-and-error approach. The prescribing of these medications is complicated by sub-optimal efficacy and high rates of adverse drug reactions (ADRs). These both contribute to poor levels of adherence. Pharmacogenetics (PGx) considers how genetic variation can influence an individual’s response to a drug. Pharmacogenetic testing is a tool that could aid clinicians when selecting psychotropic medications, as part of a more personalized approach to prescribing. This may improve the use of and adherence to these medications. Yet to date, the implementation of PGx in mental health environments in the United Kingdom has been slow. This review aims to identify the current barriers and enablers to the implementation of PGx in psychiatry and determine how this can be applied to the uptake of PGx by NHS mental health providers. A systematic searching strategy was developed, and searches were carried out on the PsychInfo, EmBase, and PubMed databases, yielding 11 appropriate papers. Common barriers to the implementation of PGx included cost, concerns over incorporation into current workflow and a lack of knowledge about PGx; whilst frequent enablers included optimism that PGx could lead to precision medicine, reduce ADRs and become a more routine part of psychiatric clinical care. The uptake of PGx in psychiatric care settings in the NHS should consider and overcome these barriers, while looking to capitalize on the enablers identified in this review.
  • USP11 controls R-loops by regulating senataxin proteostasis

    Jurga, Mateusz; Abugable, A.A.; Goldman, Alastair S.H.; El-Khamisy, Sherif F. (2021)
    R-loops are by-products of transcription that must be tightly regulated to maintain genomic stability and gene expression. Here, we describe a mechanism for the regulation of the Rloop- specific helicase, senataxin (SETX), and identify the ubiquitin specific peptidase 11 (USP11) as an R-loop regulator. USP11 de-ubiquitinates SETX and its depletion increases SETX K48-ubiquitination and protein turnover. Loss of USP11 decreases SETX steady-state levels and reduces R-loop dissolution. Ageing of USP11 knockout cells restores SETX levels via compensatory transcriptional downregulation of the E3 ubiquitin ligase, KEAP1. Loss of USP11 reduces SETX enrichment at KEAP1 promoter, leading to R-loop accumulation, enrichment of the endonuclease XPF and formation of double-strand breaks. Overexpression of KEAP1 increases SETX K48-ubiquitination, promotes its degradation and R-loop accumulation. These data define a ubiquitination-dependent mechanism for SETX regulation, which is controlled by the opposing activities of USP11 and KEAP1 with broad applications for cancer and neurological disease.
  • Scales of relevance and the importance of ambiguity

    Croucher, Karina T.; AHRC, University of Bradford and the Higher Education Innovation Fund. (2021-08)
  • Probing the role of Val228 on the catalytic activity of Scytalidium catalase

    Goc, G.; Balci, B.A.; Yorke, Briony A.; Pearson, Y.; Yuzugullu Karakus, Y. (2021-08)
    Scytalidium catalase is a homotetramer including heme d in each subunit. Its primary function is the dismutation of H2O2 to water and oxygen, but it is also able to oxidase various small organic compounds including catechol and phenol. The crystal structure of Scytalidium catalase reveals the presence of three linked channels providing access to the exterior like other catalases reported so far. The function of these channels has been extensively studied, revealing the possible routes for substrate flow and product release. In this report, we have focussed on the semi-conserved residue Val228, located near to the vinyl groups of the heme at the opening of the lateral channel. Its replacement with Ala, Ser, Gly, Cys, Phe and Ile were tested. We observed a significant decrease in catalytic efficiency in all mutants with the exception of a remarkable increase in oxidase activity when Val228 was mutated to either Ala, Gly or Ser. The reduced catalytic efficiencies are characterized in terms of the restriction of hydrogen peroxide as electron acceptor in the active centre resulting from the opening of lateral channel inlet by introducing the smaller side chain residues. On the other hand, the increased oxidase activity is explained by allowing the suitable electron donor to approach more closely to the heme. The crystal structures of V228C and V228I were determined at 1.41 and 1.47 Å resolution, respectively. The lateral channels of the V228C and V228I presented a broadly identical chain of arranged waters to that observed for wild-type enzyme.
  • Social status and diet. Reconstruction of diet of individuals buried in some early medieval chamber graves from Poland by carbon and nitrogen stable isotopes analysis

    Blaszczyck, D.; Beaumont, Julia; Krzyszowski, A.; Poliński, D.; Drozd-Lipińska, A. (Science Direct, 2021-08)
    The study presents results of the investigations of diet based on carbon and nitrogen stable isotope ratios (δ13C and δ15N) of the bone collagen of individuals buried in medieval elite chamber graves from the territory of the state of the first Piasts, Poland (the second half of the 10th and the first half of the 11th century). The aim of the research was to determine the diet of individuals buried in such funerary structures, to compare this with commoners buried in ordinary graves, and investigate any sex-related patterns. Rib bone samples were taken from individuals buried in chamber graves at Bodzia, Dziekanowice, Pień and Sowinki. Results indicate that the elite male diet was based on C3 plants with possible contribution of some C4 plants (millet) and substantial consumption of animal proteins including fish. The bone collagen δ13C and δ15N of male chamber burials suggested consumption of higher trophic level foodstuffs (meat and fish) whilst the female diet, and that of the juveniles, was similar to the commoners in the rest of the population.
  • A Pharmacist view of the impact/management of medicines shortages (MedS) in the pharmaceutical supply chain (Spain)

    Sai Reddy Jetty, V.; Breen, Liz; Acosta Gomez, J. (Pharmacy Education, 2020-09)
  • Stressors and coping mechanisms of family care-givers of older relatives living with long-term conditions in mainland China: A scoping review of the evidence

    Bífárìn, Oládayò, O.; Quinn, Catherine; Breen, Liz; Wu, C.; Ke, M.; Yu, L.; Oyebode, Jan R. (Cambridge University Press, 2021)
    As the ageing population in China continues to grow, more people will be living with long-term health conditions and require support from family care-givers. This scoping review therefore aims to explore sources of stress and coping mechanisms adopted by care-givers of older relatives living with long-term conditions in mainland China. Literature searches were conducted in English (CINAHL, EMBASE, MEDLINE, PsycINFO and SCOPUS) and Chinese (CNKI, WANFANG DATA, CQVIP and CBM) databases between October and November 2019. The searches focused on the stressors and coping mechanisms utilised by family care-givers residing in the community. Narrative synthesis was used to identify themes within the data. Forty-six papers were included: 20 papers from English and 26 from Chinese databases. Six themes captured stressors: care-giving time (N = 22), financial resources (N = 17), role and personal strains (N = 42), preparedness (N = 4), social roles (N = 10) and lack of adequate formal support (N = 22); and one theme captured coping (N = 14). Unmet needs of care-givers of older relatives in mainland China were found to be extensive. Only a few studies had attempted to explore the causal link between stressors, coping and the influence of culture. Findings underscore the significance of adequately capturing intricacies around care-givers’ unmet needs, rather than generalising on the basis of culture. Qualitative studies are critical to providing a better understanding of the relationship between stressors, coping and resources afforded to care-givers by their cultural environment. Having such understanding is crucial to inform the development of competent care, which promotes self-efficacy and self-actualisation in care-givers in mainland China.
  • An exploration of the impact of SARS-CoV-2 (COVID-19) restrictions on marginalised groups in the UK

    Eshareturi, Cyril; Wareham, C.; Rattray, Marcus; Haith-Cooper, Melanie; McCarthy, R. (2021-08)
    Background: To contain the spread of COVID-19 within the UK over the past year, there have been a series of local and national lockdowns. These restrictions are likely to have impacted upon the health and well-being of marginalised groups who rely on now closed social and community support services to stay healthy. An understanding of the experiences of marginalised people is important; therefore, this study aimed to explore the impact of the COVID-19 restrictions on the health and well-being of marginalised groups in the UK. Methods: In summer 2020, a rapid telephone survey was conducted by trained, trusted volunteers with 76 participants who were from marginalised groups. As part of this survey, 64 participants consented to describe their experience of lockdown. These case studies were thematically analysed to identify patterns of meaning. Results: Findings indicate that lockdown led to the deterioration of health of participants, impacted adversely on their socio-economic positions and affected access to food and essential supplies. In addition, government public health messaging was considered confusing and inadequate. Conclusions: This study highlights the need for pathways into services which support marginalised groups to remain accessible during periods of restrictions and essential supplies and food to be mapped and protected for marginalised individuals within our local communities.
  • Digest of Evidence 9, The Human Bone

    Clark, J.; Garner-Lahire, J.; Spall, C.; Toop, N.; Curtis-Summers, Shirley (2021-06)
  • Patient Perspectives on Factors Affecting Direct Oral Anticoagulant Use for Stroke Prevention in Atrial Fibrillation

    Medlinskiene, Kristina; Richardson, S.; Fylan, Beth; Stirling, K.; Rattray, Marcus; Petty, Duncan (2021-05-10)
    Introduction: Oral anticoagulant therapy choices for patients with atrial fibrillation (AF) expanded in the last decade with the introduction of direct oral anticoagulants (DOAC). However, the implementation of DOACs was slow and varied across different health economies in England. There is limited evidence on the patient role in the uptake of new medicines, including DOACs, apart from considering their demographic and clinical characteristics. Hence, this study aimed to address the gap by exploring the view of patients with AF on factors affecting DOAC use. Methods: A qualitative study using semi-structured interviews was conducted in three health economies in the North of England. Adult patients (>18 years) diagnosed with non-valvular AF, prescribed an oral anticoagulant (vitamin K antagonist or DOAC), and able to give written consent were recruited. Data were collected between August 2018 and April 2019. Audio recorded interviews were transcribed verbatim and analyzed using the framework method. Results: Four themes with eleven subthemes discussed identified factors affecting the use of DOACs. They were linked to limited healthcare financial and workforce resources, patient involvement in decision-making, patient knowledge about DOACs, safety concerns about oral anticoagulants, and oral anticoagulant therapy impact on patients' daily lives. Lack of a) opportunities to voice patient preferences and b) information on available therapy options resulted in some patients experiencing difficulties with the prescribed therapy. This was reported to cause negative impact on their daily lives, adherence, and overall satisfaction with the therapy. Conclusion: Greater patient involvement in decision-making could prevent and resolve difficulties encountered by some patients and potentially improve outcomes plus increase the uptake of DOACs.
  • Probing cytochrome P450 (CYP) bioactivation with chloromethylindoline bioprecursors derived from the duocarmycin family of compounds

    Ortuzar, N.; Karu, K.; Presa, Daniela; Morais, Goreti R.; Sheldrake, Helen M.; Shnyder, Steve D.; Barnieh, Francis M.; Loadman, Paul M.; Patterson, Laurence H.; Pors, Klaus; et al. (2021-06-15)
    The duocarmycins belong to a class of agent which has great potential for use in cancer therapy. Their exquisite potency means they are too toxic for systemic use, and targeted approaches are required to unlock their clinical potential. In this study, we have explored seco-OH-chloromethylindoline (CI) duocarmycin-based bioprecursors for their potential for cytochrome P450 (CYP)-mediated cancer cell kill. We report on synthetic and biological explorations of racemic seco-CI-MI, where MI is a 5-methoxy indole motif, and dehydroxylated analogues. We show up to a 10-fold bioactivation of de-OH CI-MI and a fluoro bioprecursor analogue in CYP1A1-transfected cells. Using CYP bactosomes, we also demonstrate that CYP1A2 but not CYP1B1 or CYP3A4 has propensity for potentiating these compounds, indicating preference for CYP1A bioactivation.
  • How can the potential of the duocarmycins be unlocked for cancer therapy?

    Jukes, Zoë; Morais, Goreti R.; Loadman, Paul M.; Pors, Klaus (2021-02)
    The duocarmycins belong to a class of agent that has fascinated scientists for over four decades. Their exquisite potency, unique mechanism of action, and efficacy in multidrug-resistant tumour models makes them attractive to medicinal chemists and drug hunters. However, despite great advances in fine-tuning biological activity through structure-activity relationship studies (SARS), no duocarmycin-based therapeutic has reached clinical approval. In this review, we provide an overview of the most promising strategies currently used and include both tumour-targeted prodrug approaches and antibody-directed technologies.
  • Luminal Bioavailability of Orally Administered ω-3 PUFAs in the Distal Small Intestine, and Associated Changes to the Ileal Microbiome, in Humans with a Temporary Ileostomy

    Nana, G.; Mitra, S.; Watson, H.; Young, C.; Wood, H.M.; Perry, S.L.; Race, Amanda D.; Quirke, P.; Toogood, G.J.; Loadman, Paul M.; et al. (2021-05)
    Background: Oral administration of purified omega-3 (ω-3) PUFAs is associated with changes to the fecal microbiome. However, it is not known whether this effect is associated with increased PUFA concentrations in the gut. Objectives: We investigated the luminal bioavailability of oral ω-3 PUFAs (daily dose 1 g EPA and 1g DHA free fatty acid equivalents as triglycerides in soft-gel capsules, twice daily) and changes to the gut microbiome, in the ileum. Methods: Ileostomy fluid (IF) and blood were obtained at baseline, after first capsule dosing (median 2 h), and at a similar time after final dosing on day 28, in 11 individuals (median age 63 y) with a temporary ileostomy. Fatty acids were measured by LC–tandem MS. The ileal microbiome was characterized by 16S rRNA PCR and Illumina sequencing. Results: There was a mean 6.0 ± 9.8-fold and 6.6 ± 9.6-fold increase in ileal EPA and DHA concentrations (primary outcome), respectively, at 28 d, which was associated with increased RBC ω-3 PUFA content (P ≤ 0.05). The first oral dose did not increase the ileal ω-3 PUFA concentration except in 4 individuals, who displayed high luminal EPA and DHA concentrations, which reduced to concentrations similar to the overall study population at day 28, suggesting physiological adaptation. Bacteroides, Clostridium, and Streptococcus were abundant bacterial genera in the ileum. Ileal microbiome variability over time and between individuals was large, with no consistent change associated with acute ω-3 PUFA dosing. However, high concentrations of EPA and DHA in IF on day 28 were associated with higher abundance of Bacteroides (r2 > 0.86, P < 0.05) and reduced abundance of other genera, including Actinomyces (r2 > 0.94, P < 0.05). Conclusions: Oral administration of ω-3 PUFAs leads to increased luminal ω-3 PUFA concentrations and changes to the microbiome, in the ileum of individuals with a temporary ileostomy.
  • The effect of photoperiod and high fat diet on the cognitive response in photoperiod-sensitive F344 rats

    McLean, Samantha L.; Yun, Haesung; Tedder, Andrew; Helfer, Gisela (2021)
    In many species, seasonal changes in day length (photoperiod) have profound effects on physiology and behavior. In humans, these include cognitive function and mood. Here we investigated the effect of photoperiod and high fat diets on cognitive deficits, as measured by novel object recognition, in the photoperiod-sensitive F344 rat, which exhibits marked natural changes in growth, body weight and food intake in response to photoperiod. 32 male juvenile F344 rats were housed in either long or short photoperiod and fed either a high fat or nutrient-matched chow diet. Rats were tested in the novel object recognition test before photoperiod and diet intervention and re-tested 28 days after intervention. In both tests during the acquisition trials there was no significant difference in exploration levels of the left and right objects in the groups. Before intervention, all groups showed a significant increase in exploration of the novel object compared to the familiar object. However, following the photoperiod and diet interventions the retention trial revealed that only rats in the long photoperiod-chow group explored the novel object significantly more than the familiar object, whereas all other groups showed no significant preference. These results suggest that changing rats to short photoperiod impairs their memory regardless of diet. The cognitive performance of rats on long photoperiod-chow remained intact, whereas the high fat diet in the long photoperiod group induced a memory impairment. These findings suggest that rats exposed to long photoperiod have different cognitive responses to rats exposed to short photoperiod and high fat diet.
  • A Simple Subjective Evaluation of Enface OCT Reflectance Images Distinguishes Glaucoma From Healthy Eyes

    Cheloni, Riccardo; Dewsbery, S.D.; Denniss, Jonathan (2021-05-25)
    Purpose: We present a subjective approach to detecting glaucomatous defects in enface images and assess its diagnostic performance. We also test the hypothesis that if reflectivity changes precede thickness changes in glaucoma there should be reduced correlation between the modalities in glaucoma compared to controls. Methods: Twenty glaucoma participants and 20 age-matched controls underwent high-resolution OCT scans of one eye. 4 μm-thick enface slabs were constructed through the retina. Enface indices were depths of first gap in visible retinal nerve fiber bundles (RNFBs) and last visible bundle, subjectively evaluated in six sectors of a 3.5 mm circle around the optic disc. Retinal nerve fiber layer thickness (RNFLT) along the same circle was extracted at angles corresponding to enface indices. Between-group differences were tested by linear mixed models. Diagnostic performance was measured by partial receiver operating characteristic area (pAUC). Results: First gap and last visible bundle were closer to the inner limiting membrane in glaucoma eyes (both P < 0.0001). Enface indices showed excellent diagnostic perfor mance (pAUCs 0.63–1.00), similar to RNFLT (pAUCs 0.63–0.95). Correlation between enface and RNFLT parameters was strong in healthy (r = 0.81–0.92) and glaucoma eyes (r = 0.73–0.80). Conclusions: This simple subjective method reliably identifies glaucomatous defects in enface images with diagnostic performance at least as good as existing thickness indices. Thickness and reflectivity were similarly related in healthy and glaucoma eyes, providing no strong evidence of reflectivity loss preceding thinning. Objective analyses may realize further potential of enface OCT images in glaucoma. Translational Relevance: Novel enface OCT indices may aid glaucoma diagnosis.
  • Effects of Chemical and Radiation Sterilisation on the Biological and Biomechanical Properties of Decellularised Porcine Peripheral Nerves

    Holland, J.D.R.; Webster, G.; Rooney, P.; Wilshaw, Stacy-Paul; Jennings, L.M.; Berry, H.E. (2021-06)
    There is a clinical need for novel graft materials for the repair of peripheral nerve defects. A decellularisation process has been developed for porcine peripheral nerves, yielding a material with potentially significant advantages over other devices currently being used clinically (such as autografts and nerve guidance conduits). Grafts derived from xenogeneic tissues should undergo sterilisation prior to clinical use. It has been reported that sterilisation methods may adversely affect the properties of decellularised tissues, and therefore potentially negatively impact on the ability to promote tissue regeneration. In this study, decellularised nerves were produced and sterilised by treatment with 0.1% (v/v) PAA, gamma radiation (25-28 kGy) or E Beam (33-37 kGy). The effect of sterilisation on the decellularised nerves was determined by cytotoxicity testing, histological staining, hydroxyproline assays, uniaxial tensile testing, antibody labelling for collagen type IV, laminin and fibronectin in the basal lamina, and differential scanning calorimetry. This study concluded that decellularised nerves retained biocompatibility following sterilisation. However, sterilisation affected the mechanical properties (PAA, gamma radiation), endoneurial structure and basement membrane composition (PAA) of decellularised nerves. No such alterations were observed following E Beam treatment, suggesting that this method may be preferable for the sterilisation of decellularised porcine peripheral nerves.
  • Using experience-based co-design with patients, carers and healthcare professionals to develop theory-based interventions for safer medicines use

    Fylan, Beth; Tomlinson, Justine; Raynor, D.K.; Silcock, Jonathan (2021)
    Background: Experience-Based Co-Design (EBCD) is a participatory design method which was originally developed and is still primarily used as a healthcare quality improvement tool. Traditionally, EBCD has been sited within single services or settings and has yielded improvements grounded in the experiences of those delivering and receiving care. Method: In this article we present how EBCD can be adapted to develop complex interventions, underpinned by theory, to be tested more widely within the healthcare system as part of a multi-phase, multi-site research study. We begin with an outline of co-design and the stages of EBCD. We then provide an overview of how EBCD can be assimilated into an intervention development and evaluation study, giving examples of the adaptations and research tools and methods that can be deployed. We also suggest how to appraise the resulting intervention so it is realistic and tractable in multiple sites. We describe how EBCD can be combined with different behaviour change theories and methods for intervention development and finally, we make suggestions about the skills needed for successful intervention development using EBCD. Conclusion: EBCD has been recognised as being a collaborative approach to improving healthcare services that puts patients and healthcare staff at the heart of initiatives and potential changes. We have demonstrated how EBCD can be integrated into a research project and how existing research approaches can be assimilated into EBCD stages. We have also suggested where behaviour change theories can be used to better understand intervention change mechanisms.
  • A non-randomised feasibility study of an intervention to optimise medicines at transitions of care for patients with heart failure

    Fylan, Beth; Ismail, Hanif; Hartley, S.; Gale, C.P.; Farrin, A.J.; Gardner, Peter H.; Silcock, Jonathan; Alldred, D.P. (2021-03)
    Heart failure affects 26 million people globally, and the optimal management of medicines is crucial for patients, particularly when their care is transferred between hospital and the community. Optimising clinical outcomes requires well-calibrated cross-organisational processes with staff and patients responding and adapting to medicines changes. The aim of this study was to assess the feasibility of implementing a complex intervention (the Medicines at Transitions Intervention; MaTI) co-designed by patients and healthcare staff. The purpose of the intervention was to optimise medicines management across the gaps between secondary and primary care when hospitals handover care. The study objectives were to (1) assess feasibility through meeting specified progression criteria to proceed to the trial, (2) assess if the intervention was acceptable to staff and patients, and (3) determine whether amendment or refinement would be needed to enhance the MaTI. The feasibility of the MaTI was tested in three healthcare areas in the North of England between July and October 2017. Feasibility was measured and assessed through four agreed progression to trial criteria: (1) patient recruitment, (2) patient receipt of a medicines toolkit, (3) transfer of discharge information to community pharmacy, and (4) offer of a community pharmacy medicines review/discussion or medicines reconciliation. From the cardiology wards at each of the three NHS Acute Trusts (sites), 10 patients (aged ≥ 18 years) were recruited and introduced to the 'My Medicines Toolkit' (MMT). Patients were asked to identify their usual community pharmacy or nominate a pharmacy. Discharge information was transferred to the community pharmacy; pharmacists were asked to reconcile medicines and invited patients for a medicines use review (MUR) or discussion. At 1 month following discharge, all patients were sent three questionnaire sets: quality-of-life, healthcare utilisation, and a patient experience survey. In a purposive sample, 20 patients were invited to participate in a semi-structured interview about their experiences of the MaTI. Staff from hospital and primary care settings involved in patients' care were invited to participate in a semi-structured interview. Patient and staff interviews were analysed using Framework Analysis. Questionnaire completion rates were recorded and data were descriptively analysed. Thirty-one patients were recruited across three sites. Eighteen staff and 18 patients took part in interviews, and 19 patients returned questionnaire sets. All four progression to trial criteria were met. We identified barriers to patient engagement with the intervention in hospital, which were compounded by patients' focus on returning home. Some patients described not engaging in discussions with staff about medicines and lacking motivation to do so because they were preoccupied with returning home. Some patients were unable or unwilling to attend a community pharmacy in person for a medicines review. Roles and responsibilities for delivering the MaTI were different in the three sites, and staff reported variations in time spent on MaTI activities. Staff reported some work pressures and staff absences that limited the time they could spend talking to patients about their medicines. Clinical teams reported that recording a target dose for heart failure medicines in patient-held documentation was difficult as they did not always know the ideal or tolerable dose. The majority of patients reported receiving the patient-held documentation. More than two-thirds reported being offered a MUR by their community pharmacists. Delivery of the Medicines at Transitions Intervention (MaTI) was feasible at all three sites, and progression to trial criteria were met. Refinements were found to be necessary to overcome identified barriers and strengthen delivery of all steps of the intervention. Necessary changes to the MaTI were identified along with amendments to the implementation plan for the subsequent trial. Future implementation needs to take into account the complexity of medicines management and adaptation to local context.

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