Bedford

This study is a prospective, observational, multi-country, multi-Centre, single-arm registry designed to evaluate the clinical safety and performance of VIVO ISAR, Polymer Free Sirolimus Eluting Coronary Stent System. The study population is made up of subjects who have undergone PCI using VIVO ISAR and are receiving standard of care short DAPT treatment (≤ 3 months) . Subjects will be screened by site teams and offered the opportunity to participate in the registry after their procedure. Rationale for this study is to evaluate clinical outcomes and collect data of the Polymer Free Sirolimus Eluting Coronary Stent in real world CAD patients with follow-up at 1 month, 3 months and 12 months. All medications and procedures to be used/ performed in this registry are commonly used/performed for clinical indications as part of standard of care and have well-defined safety profiles. The study does not influence the choice of device utilized nor does it alter the routine standard of care. After a patient has been treated with the Vivo ISAR, informed consent will be requested and the eligible patient will be registered in the study. Baseline data will be completed using medical notes. All recruited subjects will then be followed as per routine practice together with telephonic follow-up at 30 days, 3 months and 12 months from the baseline PCI procedure date. The 30 day, 3 months and 12 month telephonic follow up will consist of a verbally report of the DAPT anticoagulation medications continued, about any lab assessments that might have happened, recording of any adverse events, and any interventional treatment that has occurred since previous contact.

CALCIO is a multicentre, prospective, observational cohort study that will collect real world data on the use of intravascular Lithotripsy (IVL) with the Shockwave IVL system to disrupt calcified femoropopliteal and crural lesions in patients with chronic limb-threatening ischemia (CLTI). The primary objective of CALCIO is to understand the effectiveness of IVL in promoting wound healing and preventing amputation. The secondary objectives of CALCIO are to evaluate the immediate effectiveness of the treatment in restoring vessel patency as well as its safety and impact on patients' quality of life.

The objective of this study is to collect and evaluate long-term clinical and radiographic outcomes data in order to better understand the safety and performance of the shoulder arthroplasty over time. This study will follow subjects long-term for a minimum of 10-years, without an early-term restriction on the amount of time they will be followed.

This is a disease registry, which is an organized system using non-interventional methods to collect data on a patient population defined by a particular disease, exposure, or condition, and which is followed over time. Non-interventional means that after participants enrollment, participants will be treated according to the routine clinical treatment decision by the physician. The registry will not impose any treatment or procedure for participants.

An automated strategy for identifying abnormalities in head scans could address the unmet clinical need for faster abnormality identification times, potentially allowing for early intervention to improve short- and long-term clinical outcomes. Radiologist shortages and increased demand for MRI scans lead to delays in reporting, particularly in the outpatient setting. Furthermore, there is a wide variation in the management of incidental findings (IFs) discovered in 'healthy volunteers.' The routine reporting of 'healthy volunteer' scans by a radiologist poses logistical and financial challenges. It would be valuable to devise automated strategies to reliably and accurately identify IFs, potentially reducing the number of scans requiring routine radiological review by up to 90%, thus increasing the feasibility of implementing a routine reporting strategy. Deep learning is a novel technique in computer science that automatically learns hierarchies of relevant features directly from the raw inputs (such as MRI or CT) using multi-layered neural networks. A deep learning algorithm will be trained on a large database of head MRI scans to recognize scans with abnormalities. This algorithm will be trained to classify a subset of these scans as normal or abnormal and then tested on an independent subset to determine its validity. If the tested neural network demonstrates high diagnostic accuracy, future research participants and patients may benefit, as not all institutions currently review their research scans for incidental findings and clinical scans may not be reported for weeks in some cases. In both research and clinical scenarios, an algorithm could rapidly identify abnormal pathology and prioritize scans for reporting. In summary, the aim is to develop a deep learning abnormality detection algorithm for use in both research and clinical settings.

Recruitment A treating clinician from collaborating healthcare Trust will inform the patients about the study and ask if they are interested. If so, they will provide them with the participant information sheet and ask if the chief investigator (CI) can contact them. Following this, the CI will contact the patient and manage consent. Once recruited, an assessor will visit the participants in their home to conduct the Action Research Arm Test (ARAT) and nine-hole-peg-test (9HPT) and Stroke Specific Quality of Life Questionnaire (SSQoL) baseline assessment. After the baseline assessment, the CI will contact the participants to schedule pre-intervention assessments and the 15 sessions over three-weeks. The CI will schedule all assessment and EEG lab visits with participants and Dr Maidhof. Music Intervention Equipment for music intervention delivery will be brought to the participants' homes and will comprise: Untuned percussion, iPad, guitar. The iPad and percussion will facilitate every type of hand, finger and arm movement and all movement sequences required to perform activities of daily living. Exercises will progress to facilitate greater range and frequency of movement and complexity (number of instruments or screen targets hit in a sequence) without compromising quality (i.e. avoiding the introduction of compensatory movements). Music intervention training and supervision The PI will train the music therapist in the music intervention protocol and instruct on how to assess participants in the first session in order to establish the starting exercise - he will provide supervision throughout the treatment period. Treatment fidelity The participants will be given a questionnaire prior to the first baseline data collection, to record any other interventions, for example pharmacological, that they may be using or due to use. The participants will also be asked to keep a log of activities during each phase of the study. This is to ensure that any changes that occur can be analysed in relation to other activities and interventions, and treatment related changes can be more robustly examined. The music therapist delivering the intervention will keep a log of the content of each session, noting which exercises were completed, duration, breaks and any modification of exercises such as tempo adjustment, spatial arrangement of equipment. EEG data collection EEG will be measured on a day before the intervention starts and after it has stopped. Upon arrival, the participants will be asked to fill out a brief questionnaire about handedness, caffeine consumption during the last 24 hours, and other diagnosis relevant for the EEG recording. After the participant's head size is measured, the EEG cap (R-net, Brainproducts, Germany, GmbH) will be prepared and fitted, which will take about 5-15 minutes. After ensuring good signal quality, the different parts of the study will be explained to the participant. These consist of: 1. a resting-state recording, during which the participant is asked to sit in a relaxed position with eyes closed for 5-10 min. 2. a tapping task during which the participant is asked to perform simple self-paced movements on a muted drum pad and piano keyboard every 3-5 seconds, whereby the following movements will be executed about 100 times: a) tapping with index finger and b) performing bilateral gross movements with the whole arm. The duration of this task is about 30 minutes including breaks if needed. During the tapping tasks, participants will be wearing earplugs/noise cancelling headphones in order to block any auditory feedback from their tapping movements. A green circle in the middle of the screen appears after about 3 seconds after their last tap, indicating that they can perform the next tap. After each tap, the circle turns red indicating that participants should wait with their next tap. The participant is instructed to look at the circle in the middle of the screen and to avoid any excessive eye movements, especially shortly before and after each tap. 3. a Working memory task, during which one of five letters is presented repeatedly on a computer screen in front of the participant. The letter is either the rare target stimulus, or one of four frequent non-target stimuli. The participant is asked to press a button with their unaffected hand whenever a target stimulus has been perceived. There are 200 trials, divided into five blocks. The target stimulus will appear randomly 40 times, and frequent non-target stimuli 160 times. Including participant-controlled breaks between blocks, this will take 5-8 minutes. After ensuring that the participants understood the procedure and have no further questions, the recording will begin. The participant will be monitored by the EEG engineer in an observation booth with a video camera, and the participant can signal any time if they need a break, drink or anything else. The researchers will take care that the participant feels comfortable in a friendly and welcoming atmosphere throughout the measurement. Primary data analysis EEG data analysis As this is a single-case series, only descriptive statistics and data visualisation (e.g. bar charts and boxplots) will be used to describe pre- and post-treatment changes in arm function and EEG measures. With regards to EEG measures, the mean frontal alpha asymmetry (FAA) and its standard deviation will be computed following published guidelines. After a current source density transformation will have been applied, artefact-free 1s epochs of EEG data will be Hanning-windowed and subjected to a Fast Fourier Transformation. Alpha power for each epoch will be calculated as the band (8-13 Hz) value sum and the alpha asymmetry scores will be computed by taking the differences between the natural-log transformed power values of frontal electrodes F4 and F3. The averaged FAA and its standard deviation of the baseline recording will be descriptively compared to the post-treatment recording (visually and in percentage relative change). Analysis of sensorimotor cortical activity during the self-paced finger and hand tapping tasks, as indexed by event-related oscillatory power in alpha (8-12 Hz) and beta (18-22 Hz) frequency bands, as well as coherence between brain areas, will follow the procedures as described in published research. Artefact-free band-pass filtered (and squared) data in the alpha and beta frequency bands will be segmented into 4s epochs with 2s before and 2s after each tap, with a baseline ranging from 1.5s to 1s before the tap. Three spatial clusters will be used to increase the signal-to-noise ratio: central (electrodes Fz, Fcz, and Cz), ipsilesional, and contralesional. In case of right-sided motor deficits, the ipsilesional cluster would include electrodes C3, F3, and Fc3, and the contralesional cluster would include electrodes C4, F4, and Fc4 (vice versa for left-sided motor deficits). Mean alpha- and beta power during the tapping tasks pre- and post-intervention and standard deviations will be plotted and any changes in mean power will be calculated as percentage relative change. The P300 component of the event-related potential will be analysed according to established routines in the literature. After artifact cleaning based on independent component analysis and bandpass filtering (0.1-25 Hz), data will be segmented into 1s epochs with a baseline ranging from 200ms to 0ms before stimulus onset. Artifact-free trials of target and non-target stimuli with correct behavioural responses will be baseline corrected and averaged. To assess any pre-post differences, averaged ERPs will be plotted. In addition, pre-post differences in mean amplitude of the P300 component, measured at electrode Pz in a time window of ca. 300ms (centered around the peak amplitude), will be expressed in percentage relative change. Secondary Data Analysis Action Research Arm Test data will be presented in a box plot, showing scores in the categories of Grasp, Grip, Pinch, Gross at the four data collection timepoints. Pre-/post-intervention period scores in each category will be shown in a graph. Means of measurements pre-intervention, post-intervention will be compared to measurements of data from baseline. Deviations from baseline will be tested by t-tests. Ethical and regulatory considerations Assessment and management of risk Below is a list of identified ethical risks and how they will be managed during the study: * Capacity: The participants will have capacity to consent when screened by CCS NHS trust. Staff will be aware of any capacity issues for a potential participant, because they will have delivered community stroke rehabilitation to them. Capacity will be monitored throughout the study. If it is judged that the participant loses capacity during the study, they will be withdrawn from the study. * Withdrawal: Irrespective of stage, participants will have the right to withdraw at any point during the study without their healthcare or rights being affected. This can be done by contacting a member of the research team. Participants have the right to refuse any or all parts of the study. * Reading/writing impairment: Individuals that are functionally unable to read or visually impaired can participate in the study, researchers will describe each section of the information sheet and consent form to the potential participant. In these cases, consent will be taken orally and counter-signed by a third party (e.g. spouse or carer). * Video: The participant will be video recorded whilst undergoing EEG using a university device. Video data will be password protected, encrypted and stored on the Anglia Ruskin OneDrive. If the participant has consented, the video will be used for publication or other output. * The participants will have the option to be videoed during sessions in their home, whilst they complete the music exercises. This is in order that the researchers can more closely monitor how they are performing the movements and refine the exercises, and so that they can disseminate the research. * Reimbursement: The participants are entitled to reimbursement for travel to the music therapy center EEG lab. There will be two lab visits. * Incidental EEG findings: The EEG equipment and the research team are not certified for medical diagnosis, however during routine EEG data quality checks they might detect suspicious grapho-elements that might require further investigations. In such a case, the general practitioner will be informed (if consent has been given). * Participants will not be asked to provide personal identifiable data during the study, except for the purposes of consent and for contact purposes, and these data will be kept separate from video data. Research data will be pseudo-anonymised, therefore not directly identifiable. All data will be stored securely (password protected) on university servers for the duration of the study. As the research is occurring within the community, data may be temporarily stored elsewhere; for example, in a navigation system to find the participant's home. All data will be encrypted irrespective of storage location, and deleted once transferred to the university servers. * Anonymised data will be stored on the Anglia Ruskin University OneDrive server, which is GDPR compliant, and can only be accessed by authorised members of the research team.

Randomised, phase II/III 3 stage trial to evaluate the safety and efficacy of the addition of olaparib to platinum-based neoadjuvant chemotherapy in breast cancer patients with TNBC and/or gBRCA. Disease under investigation: Breast Cancer Purpose of clinical trial: To establish if the addition of olaparib to neoadjuvant platinum-based chemotherapy for Triple Negative Breast Cancer (TNBC) and/or germline BRCA (gBRCA) breast cancer is safe and improves efficacy. Trial Design: Open label, randomised, 3-stage Phase II/III Sample Size: Minimum of 780 patients (including at least 220 gBRCA patients equally allocated to the control and the selected research arm). Non Investigational Medicinal Products: Prophylactic granulocyte-colony stimulating factor (G-CSF) to be given as per local practice and 3 cycles of anthracyclines as per local practice. Treatment period: A minimum of 21 weeks of chemotherapy followed by surgery. Procedures: Screening \& enrolment Eligible patients with early breast cancer will be registered and consented for screening: BRCA mutation test Tumour Infiltrating Lymphocytes(TILs) score Cytokeratin 5/6 (CK5/6), Epidermal Growth Factor Receptor (EGFR) +/-, Androgen Receptor (AR) status by Immunohistochemistry (IHC). Standard assessment prior to chemotherapy Standard staging to exclude metastatic disease. When eligibility is confirmed, patients will be randomised via a web-based central system which will allocate each patient a unique randomisation number associated with one of the treatment arms. PARTNERing Pathway - For those patients who still have residual disease after receiving neoadjuvant chemotherapy +/- olaparib there is the opportunity to be screened to a sub-study to receive a further two cycles of chemotherapy consisting of Duralumab and AZD6738. End of Trial: For patients, the end of trial is after the last follow-up visit or contact with the research team planned 10 years after surgery. Procedures for safety monitoring during trial: Pharmacovigilance will be performed by the PARTNER Trial Office. Also, the Trial Management Group and the Independent Data and Safety Monitoring Committee will regularly review the patient safety data. Criteria for discontinuation of trial treatment on safety grounds: Severe toxicity or inter-current illness, requiring cessation in the judgement of patient's clinician. Patient within 4 weeks has not recovered from toxicity to an extent that allows further treatment. Patient unable to comply with trial procedures. Disease progression while on trial treatment. Patient becomes pregnant.

RESOLVE is a pragmatic, cluster-randomised, open-label study designed to evaluate in real-world conditions the comparative effectiveness of two default dialysate sodium concentrations. Dialysis sites will be randomised in a 1:1 ratio to a default dialysate sodium concentration of 137mmol/l or 140mmol/l. 'Default' is defined as the use of the allocated dialysate sodium for ≥ 90% of delivered dialysis sessions in the unit. All other care will be according to standard local practices as determined by the site. Outcomes will be assessed on individual patients dialysing at those sites. Sites will be asked to consent to participation while waiver or opt-out consent will be sought for individual patients. It is anticipated that site accrual will occur over 5-7 years with average study duration expected to be approximately 2-5 years. The actual length of the study will be end-point determined.

Abused and neglected children are at extremely high lifetime risk of psychiatric disorder placing a huge burden on health/social care services and society. Virtually all 92,000 children adopted or fostered in the UK have suffered abuse or neglect, therefore risking profoundly negative outcomes in important areas of development including problematic social relationships, academic underachievement and involvement in crime. These disadvantages can lead to negative spirals of poor health and social inequality. Early intervention can greatly improve their life chances, yet there are no adequate psychosocial treatment strategies or care pathways to address the needs of maltreated children. Psychiatric problems of maltreated children are characterised by complexity. They have experienced extreme environmental risk and are at higher genetic risk than peers. Many also struggle to develop and maintain healthy family relationships. Neurodevelopmental disorders such as Attention Deficit/Hyperactivity Disorder (ADHD) and Autism often co-exist with disorders arising from the abuse and neglect such as Conduct Disorder, Attachment Disorders and Post Traumatic Stress Disorder (PTSD) with devastating consequences for lifelong mental health and development. To reflect this complexity, research team uses the overarching term Maltreatment-Associated Psychiatric Problems (MAPP). The proposed project is a three-phase development and exploratory trial of Clinical and cost-effectiveness of Dyadic Developmental Psychotherapy (DDP) for abused and neglected children with MAPP and their parents compared to Service as Usual (SAU). The data will be collected in 3 phase trial, through a mixture of qualitative and quantitative methods. Phase 1 Months 1-9 (9 months) The first phase will focus on intervention and context optimisation that will take place in 3 sites, each representing one of the UK DDP service delivery contexts: NHS, Social Services and Private Practice. The research questions will be addressed through 24-36 qualitative interviews, and focus groups as well as review meetings at each site, with practitioners and managers involved in delivery of DDP and SAU. The research team will require input from the services practitioners and managers but also Young Peoples' Advisory Groups (YPAG) and Patient, Public, Commissioner Involvement (PPCI) groups. Phase 2 Months 10-26 (17 months) To examine the research questions, and minimise bias, the proposed design is a single-blind randomised controlled trial, with two-groups. The aim of this phase will be to respond to research questions such as what are recruitment and retention rates over 6 months; are the trial assessments and interventions acceptable to parents and professionals; are there functional data collection systems enabling future cost effectiveness analysis. This phase will also assess fidelity to the DDP model and whether the care pathways to CAMHS are maintained throughout. The research team will aim to recruit around 60 families. The potential participants will be identified and approached by their usual service provider. The usual service research administrator will ensure eligible families receive the study participant information leaflet to learn about the study. Once the interest of the family to take part in the trial is confirmed, a research nurse will contact interested families 24 hours later, to discuss the study further and seek consent. Families that confirm their willingness to participate will be invited for two study visits one at baseline, shortly after joining study and second visit after 12 months. On completion of the baseline data collection, consenting families will be individually randomised 1:1 to DDP or SAU, stratified by site. Individuals who consent to take part will have an equal chance of being randomised to either group. One group will be included in the DDP intervention. The second group will take part in the Services as Usual. The research assistant with responsibility for collecting the data will not know which group participants have been allocated to until the end of the study. The intervention will be delivered by the participant's usual health care team. Beside the randomised controlled trial, the data will be collected through qualitative research activities to explore social context supporting/hindering child mental health, optimising the contexts of, and processes for, DDP delivery. Process evaluation Qualitative work in phase 2 has three main aims: 1. To keep abreast of issues and themes uncovered in Phase 1 in the three feasibility trial sites, to ensure ongoing compliance with guidelines for safe DDP delivery and to explore the social context supporting/hindering child mental health in each site including drivers and barriers to optimal DDP/SAU delivery. 6-10 interviews/focus groups will be conducted with therapists, managers and families across the sites. 2. To explore the same topics from Phase 1 in the seven putative Phase 3 trial sites - optimising the contexts of, and processes for, DDP delivery in those sites and examining compliance with the DDP delivery guidelines established in Phase 1. 18-26 interviews/focus groups will be conducted across the sites. 3. To allow selection of 2-4 additional sites for Phase 3. The number of additional sites required for Phase 3 will be decided based on Phase 2 conversion rates from eligible to consented families and on statistical power considerations based on the standard deviation, in Phase 2, of our principle outcome measure. Phase 2 will also adopt case study methodology to focus more specifically on the impact of DDP and SAU. The research team will learn through a more in-depth investigation (individual interviews) about participant experience of DDP/SAU and of journeys through service landscapes from the perspectives of the family, therapists, and other key stakeholders involved in the treatment of and care pathways. A small selection of families (2-3 families) will be invited to take part. Phase 3 Months 27-53 (27 month RCT; (6 month analysis/write-up). The third phase will continue as a single-blind individually randomised controlled superiority definitive trial. The aim of this phase will be to examine the clinical and cost-effectiveness of DDP for improving child mental health, compared to SAU. The principle outcome will be child's mental health at 12 months post randomisation. The research team will aim to recruit additional 180 families, including phase 2. The study population, interventions, randomisation, data collection, measures, model fidelity and procedures will be as described for Phase 2 unless findings from the process evaluation suggest modifications. Qualitative evaluation (process evaluation) will continue at the same intensity as Phase 2, with a similar number of interviews/focus groups (24-36 across all sites), to explore delivery drivers/barriers in each service context. The case studies will continue, involving a further 10-12 interviews, to track development over time. The PPCI group and YPAG will have a crucial role in the Process Evaluation, during this phase, in reviewing the qualitative findings with the Process Evaluation Team (PET) and considering how these findings pragmatically feed into future service delivery. Whether or not DDP is eventually found to be cost-effective over services as usual, the process evaluation will yield important information about how mental health services can be safely delivered for maltreated children in different services contexts (i.e. NHS CAMHS, Social Care and Private Practice).

TRACC Part B: Despite potentially curative surgery +/- adjuvant chemotherapy, a proportional of patients with early stage CRC will experience disease relapse. Current tools for surveillance, e.g., blood sampling for tumour markers (CEA) are neither sensitive nor specific. We hypothesise that detection of mutations in circulating free DNA (cfDNA) in plasma can predict relapse in patients with early stage CRC. Circulating cell free tumour DNA (ctDNA) maintains the same mutations that are present in tumour. In colorectal cancer CRC, primary tumours and\& metastases exhibit high genomic concordance. Therefore the TRACC study TRACC Part B is investigating whether serial blood samples taken from in patients with stage II and III fully resected early stage CRC colorectal cancer that have undergone potentially curative surgery, blood samples to can be used to detect and\& quantify ctDNA may in order to identify minimal residual disease MRD and predict relapse earlier than existing methods. CtDNA may ultimately help identify a subset of patients that are or are unlikely to benefit from adjuvant chemotherapy and could therefore safely spare some patients from receiving unnecessary chemotherapy \& its associated side-effects. TRACC Part C: We hypothesis that ctDNA guided adjuvant chemotherapy administration will enable biomarker driven selection of patients who would and would not benefit from adjuvant chemotherapy and thereby reduce the proportion of patient receiving unnecessary adjuvant chemotherapy, reducing the potential side effects associated with it, but without compromising disease free survival (DFS). : This part of the study will use tThe blood test ctDNA result from a post-operative blood sample willto guide adjuvant chemotherapy treatment decisions. The study aims to demonstrate that athe de -escalation strategy of ctDNA guided adjuvant chemotherapy is non-inferior to standard of care treatment as measured by 3 year DFS in patients with high risk stage II and stage III CRC, in those who have no evidence of MRD (ctDNA negative). after surgery for patients with colorectal cancer who are following the standard of care pathway. Patients are randomised at the post- operative time point to: Arm A (standard of care adjuvant chemotherapy), or Arm B (ctDNA guided adjuvant chemotherapy) arm. For the ct DNA guided arm, patients who are ctDNA negative at this time point will have their chemotherapy de-escalated.