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.

The purpose if this study is to maintain the SPD Biobank with urine samples from cycles in which conception occurred and ones where conception did not occur, together with associated sample information including demographic and clinical data e.g. menses days, volunteer age and reproductive hormone concentrations. Study volunteers, seeking to conceive will be recruited to the study after providing written informed consent. All volunteers will be provided with a CE marked Clearblue Ovulation product to help them pinpoint their most fertile time and aid conception and be required to collect daily early morning urine samples throughout the study until pregnancy is confirmed or their next menstrual period starts. Volunteers will be required to keep a daily diary of menses, sample collection and pregnancy test results. The study will last for up to 3 consecutive menstrual cycles if not pregnant and up to sample day 60 if pregnant. Urine samples will be received in the clinical laboratory and will be tested for the presence of hormones related to pregnancy and fertility, then aliquoted and stored in the SPD Biobank at -80˚C until required for product development or evaluation purposes.

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.

Ischaemic heart disease (IHD) includes coronary artery disease (or 'coronary heart disease 'CHD') and ischaemic with no obstructive coronary arteries (INOCA). Coronary angiography is standard care for the evaluation of symptomatic patients and known or suspected coronary artery disease. A considerable proportion e.g. \>1 in 3, of patients undergoing invasive coronary angiography for known or suspected angina do not have obstructive epicardial coronary artery disease. The CorMicA pilot study involved prospective enrolment of patients referred for clinically indicated coronary angiography during a 12-month period (2016-2017) in the West of Scotland). 391 patients were enrolled, 185 (47%) had no obstructive coronary disease and 151 were randomised in a clinical trial of stratified medicine based on invasive tests of coronary vascular function. A high proportion (\~4 in 5) of these patients had a diagnosis of INOCA due to a disorder of coronary vasomotion including microvascular- and/or vasospastic angina. The trial provided preliminary evidence that stratified medicine, as an adjunct to standard angiography-guided management, has potential to improve symptoms and quality of life. The mechanisms involved changes in diagnosis, treatment and lifestyle measures. The CorMicA investigators were the first group to introduce stratified medicine for the management of ischaemic heart disease. Limitations of the CorMicA study included the setting (mainly single centre), partial blinding, short-term follow-up (primary outcome at 6 months) and the sample size. Acetylcholine reactivity testing was used to assess the susceptibility to coronary spasm (microvascular and/or macrovascular). Although acetylcholine is a naturally occurring substance, current formulations are not licensed for parenteral administration. Further, clinicians should have training and experience before implementing acetylcholine coronary reactivity testing. These considerations present a barrier to adoption in daily practice, which becomes all the more relevant given INOCA is generally under-recognised. A diagnostic coronary guidewire is already widely used in standard care and, unlike reactivity testing using acetylcholine, a guidewire has transferable potential to support stratified medicine during routine practice. This is especially the case for ad-hoc follow-on testing when obstructive coronary artery disease is excluded. The vasoactive responses to acetylcholine reflect endothelial and vascular smooth muscle cell effects, which may overlap with the vasoactive responses to adenosine (non-endothelial dependent). Calcium channel blocker therapy is indicated for the functional endotypes associated with impaired vasodilatation and/or vasoconstriction. This raises the possibility that acetylcholine testing may not be routinely required as an adjunctive test to coronary angiography and instead could be reserved for selected cases, or in specialist centres. Instead, the diagnostic guidewire approach may be sufficient as a routine, first line test for the evaluation of INOCA during daily practice. Anatomical imaging using coronary angiography is the standard of care and clinicians may determine any diagnosis based on all of the available information and their clinical judgement. This approach avoids the need for additional tests. With this approach, the patient's symptoms in response to empirical therapy can be assessed during follow-up and the treatment can be revised as clinically appropriate. In daily practice, adoption of adjunctive tests of coronary function is very low and, in the absence of large, multicentre trials, coronary angiography with or without adjunctive tests of coronary vascular function may be considered reasonable, reflecting equipoise. iCorMicA is a multicentre, prospective, randomised, double-blind, sham-controlled, parallel-group, end-point (patient reported outcome measures (PROMS), health outcomes, health economics) trial and registry. The investigators aim to determine whether stratified medical therapy, guided by a guidewire-based interventional diagnostic procedure (IDP) at the time of invasive coronary angiography (i.e. functional angiography), improves outcomes in patients with known or suspected angina but no obstructive coronary artery disease. Symptoms of angina or angina-equivalent are determined according to the Rose and/or Seattle Angina questionnaires. The IDP utilises principles of thermodilution to measure coronary vascular function (IMR, CFR, RRR), which aid clinicians in establishing a diagnosis of microvascular angina, vasospastic angina, mixed (both), or none, as per Coronary Vasomotion Disorders International Study Group (COVADIS) criteria. The feasibility, safety, efficacy and effect on healthcare resource utilisation of stratified medicine will be tested in multiple hospitals in different countries in Europe. Participants with no obstructive epicardial coronary artery disease (coronary stenosis \<50% and/or FFR \>0.80) are eligible for randomisation (1:1) to either the intervention (IDP-guided, results disclosed) or blinded control (IDP undertaken but results not disclosed, standard of care) group. Medical therapy will be informed according to the clinical diagnosis (endotype). Patients in the intervention group with abnormal coronary vascular function may undergo repeated evaluations to assess the response to intracoronary therapy e.g. calcium channel blocker, enabling a personalised treatment plan. Patients who are ineligible for randomisation (e.g. obstructive coronary artery disease) may be entered into a prospective clinical registry, with individuals from each site invited to undergo similar follow-up assessments as the randomised participants. Trial participants will be blinded to treatment group. The clinicians responsible for on-going care will also be blinded. Following invasive management, patients and clinicians will be advised of the diagnosis (endotype) but not the randomised group. The endotype will be informed by the IDP in the intervention group but not in the control group (sham procedure). Medical therapy and lifestyle measures are linked to the endotype and informed by contemporary practice guidelines. Therefore, optimal guideline-directed medical care according to the endotype is intended to be the same, regardless of the group allocation. The sample size is 1500 randomised participants. The minimum follow-up duration is 12 months from the last participant recruitment. Follow-up will continued in the longer term including, where feasible, electronic case record linkage. The primary outcome measure is the Summary Score of the Seattle Angina Questionnaire at 12 months. Secondary outcomes include other Patient Reported Outcome Measures (PROMS) to describe other aspects of health and wellbeing. These include EQ-5D-5L, Illness perception (Brief IPQ), Treatment satisfaction (TSQM), Duke Activity Status Index (DASI), the International Physical Activity Questionnaire (IPAQ-SF) short-form and a pain questionnaire. Additional objectives include the wider evaluation of the safety and diagnostic utility of the IDP in a multicentre, multinational setting, and the effects of stratified medicine on the rates of major adverse cardiovascular events by randomised group. The registry will represent a parallel control group. Scientific analyses of circulating biomarkers will be performed to better understand the pathophysiology of INOCA.

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.