Uxbridge

There is a need for the development of a tool that can help to identify those HF patients at risk of deterioration. The ideal tool would be quick, easy to use, non-invasive, inexpensive and can be performed by any healthcare practitioner or patient themselves (i.e. point of care testing). The Acorai Heart Monitor device is an extended smartphone case equipped with a combination of microphonic sensors, inertial measurement units, electrocardiographic sensors and photoplethysmography sensor, in a configuration that is designed to enhance low frequency sound and seismic signals pertaining to intracardiac pressure. Each sensor technology has been validated to minimize the risk to the patient. Sensor data is collected to provide clinicians with the patients intracardiac pressures. This is performed by placing the monitoring device on the chest, with a small smart-wrist watch, for a period of five minutes in the supine position. A feasibility study showed Acorai device cardiac output measurements correlate highly with the gold standard right heart catheterisation (RHC) cardiac output measurement. Intracardiac pressure monitoring is important in HF patients. Studies also show that raised right atrial pressure and pulmonary capillary wedge pressure are predictors of worse outcomes with increased risk of death, cardiovascular hospitalisation or transplantation. Clinicians can only gather intracardiac pressure measurements by undertaking a RHC procedure with fluoroscopy guidance. However, this is an invasive procedure, with radiation exposure, that carries risks including bleeding, stroke, infection and pneumothorax. This is a prospective, observational, single-site, non-randomised, non-significant risk, single arm, clinical investigation designed to collect non-invasive cardiac output measurements from the Acorai Heart Monitor device The objective of the study is to assess the feasibility of the Acorai ICPM system to predict survival and hospitalisation at 1 year in hospitalised heart failure patients deemed medically fit for discharge.

The study consists of 2 parts, each with its own participant cohort * Part A: double-blind treatment with open-label extension (OLE) * Part B: open-label treatment. Participants will be enrolled in only one part of the study.

This study will look at the safety of curative radiotherapy to the prostate and lymph glands given in 5 visits, in men with high risk localised prostate cancer. The purpose of the research is to test an advanced type of external beam radiotherapy called stereotactic body radiotherapy (also known as SBRT) in 1128 participants with high risk localised prostate cancer (that is, prostate cancer that has not spread beyond the prostate gland but is at high risk of growing quickly or spreading). Importantly, this treatment delivers a potentially curative dose of radiotherapy in only 5 treatments over two weeks. Half the participants in the trial will receive radiotherapy to the prostate, the other half will have radiotherapy to the prostate as well as the surrounding lymph nodes. The investigators will follow patients in the trial for at least three and half years to see which treatment is best. The investigators will be looking at whether it is safe to give this treatment by reviewing any side-effects that occur and also assessing whether giving SBRT to the lymph nodes as well as the prostate reduces the chance of prostate cancer returning. The treatment will take place at NHS radiotherapy centres that are experienced in giving SBRT and radiotherapy to the pelvic nodes, and have been quality assured to deliver these treatments

This study is researching an experimental drug called odronextamab (referred to as study drug), in combination with lenalidomide. The study is focused on participants who have one of two types of cancer: follicular lymphoma (FL) or marginal zone lymphoma (MZL) that has come back after treatment (called "relapsed"), or did not respond to treatment (called "refractory"). FL and MZL are subtypes of Non-Hodgkin 's lymphoma (NHL). This study will be made up of two parts (Part 1 not randomized, Part 2 randomized - controlled). The aim of Part 1 of the study is to see how safe and tolerable the study drug is when used in combination with lenalidomide, in participants with FL or MZL, and to determine the dose of the study drug to be used in Part 2 of this study. This combination is considered "first-in-human" as it has not been tested as a combination treatment in humans before. The aim of Part 2, of the study is to assess how well the combination of the study drug and lenalidomide works compared to the combination of rituximab (called "the comparator drug") and lenalidomide. The combination of comparator drug and lenalidomide is the current standard-of-care treatment for relapsed/refractory FL and/or MZL. Standard-of-care means the usual medication expected and used when receiving treatment for a condition. The study is looking at several other research questions, including: * What side effects may happen from taking the study drug in combination with lenalidomide * How much study drug is in the blood at different times * Whether the body makes antibodies against the study drug (which could make the study drug less effective or could lead to side effects) * The impact from the study drug on quality-of-life and ability to complete routine daily activities

Background DMO is a leading cause of sight loss in people living with diabetes (PLWD). Considering the prevalence of DMO (7%) and diabetes (\~4.8 million), around 336,000 PLWD have DMO in the UK. With its increasing incidence, DMO will continue to be a burden to society. In DMO, fluid collects at the macula, the area that gives central vision, leading to sight loss. As fluid accumulates, the macula thickens. This is measured in microns (μm) with optical coherence tomography (OCT) scans. A measure of central retinal subfield thickness (CRT) is obtained with OCT scans when DMO is diagnosed, guiding treatment selection. National Institute for Health and Care Excellence (NICE) guidance advises intraocular injections of anti-VEGF for PLWD presenting with severe (CRT ≥400μm) centre involved DMO. For PLWD presenting with milder forms of centre involved DMO (CRT \<400μm), NICE advises macular laser because it is as effective as anti-VEGFs but costs less. Most patients presenting to UK Hospital Eye Services (HES) have DMO with CRT ≥400μm and are treated with anti-VEGFs. Currently, as per standard practice, anti-VEGFs are given monthly initially (loading dose) and then typically every 1-3 months until the macula dries, even if CRT falls to below 400μm. In 72% of people on anti-VEGFs, the fluid remains until at least the second year of treatment. Trials have shown that after 5 years, 38-48% of participants still require anti-VEGFs either because DMO remains or because it recurs after clearing once anti-VEGFs are stopped. Most patients on anti-VEGFs need follow-up for life. Anti-VEGFs are expensive and carry potential harms including increased intraocular pressure, retinal detachment, cataract, and infection (endophthalmitis). The latter, although rare, can lead to total blindness. Furthermore, intraocular injections cause discomfort to many patients during administration and for hours thereafter and elicit anticipatory stress responses. Research has shown that a significant proportion of patients (25%) experience high levels of preprocedural anxiety, and nearly 10% report high levels of pain. Other experiences of treatment burden, not commonly assessed in previous studies, have been found to be important including time and functional disruption associated with intravitreal injections. Moreover, HES are unable to cope with the demand and injections are not being given in a timely manner, which has a negative impact on outcomes and the cost-effectiveness of the treatment. Finding ways to reduce the number of injections to optimise patient experience and maximise adherence is a goal pursued worldwide. Trials comparing anti-VEGFs with standard macular laser have shown superior efficacy of anti-VEGFs against laser in severe DMO. These trials included predominantly eyes with very thickened retinas (e.g. \>460μm in RISE and RIDE and \>479μm in VIVID and VISTA. When anti-VEGFs were used in combination with macular laser in some of these trials, combined treatment (anti-VEGFs and macular laser) did not appear to be superior to anti-VEGFs alone. However, macular laser was not necessarily applied when CRT had gone below 400μm following anti-VEGFs. It would be at this stage that macular laser would have more chance to be effective, as its penetration through the neurosensory retina and areas of macular oedema, and subsequently, its uptake by the retinal pigment epithelium (RPE) would be more adequate when compared with its likely reduced penetration and effect on the RPE when the macula is very thickened by marked DMO. Rationale DAME will be a pragmatic trial comparing clinical- and cost-effectiveness, side effects and participant experience and acceptability of combined treatment with anti-VEGFs + Subthreshold Macular Laser (SML) for participants who present with severe DMO and are treated initially with anti-VEGF, with the SML applied after CRT falls to \<400μm (when laser has more chance to succeed), versus the current standard of care of continuing with anti-VEGF monotherapy even when the CRT falls below 400μm if DMO is present. DAME follows from the DIAMONDS trial, which showed that SML, which does not damage the macula, is as effective to treat DMO of \<400μm as standard laser, which produces a burn. Although DIAMONDS participants had poor glycaemic control (mean HbA1c 8.5%), most maintained excellent sight and fulfilled driving standards throughout their 2-year follow-up. Those treated with SML needed, on average, only two sessions of laser, with clinic visits every 3-4 months and only 18% received rescue treatment with anti-VEGFs, with an average total cost of care of £898 per participant (similar to the cost of the drug in a single anti-VEGF injection). The hypothesis for DAME is that treating people with severe DMO (CRT ≥400μm) initially with anti-VEGFs and then, when CRT goes below 400μm, continuing with SML every 2-3 months until DMO clears will be as effective but more cost-effective, have fewer side effects and be preferred by people with DMO when compared to continuing with anti-VEGF monotherapy. If SML allows people initially treated with anti-VEGFs to maintain the characteristic early vision gains that are observed following the first few anti-VEGF injections this new strategy could become the new standard of care for people with severe DMO and be implemented worldwide. Potential benefits would include fewer injections with subsequent reduction in inconvenience, stress, harms and costs, and fewer clinic visits, which will facilitate patient's compliance with the treatment and reduce costs and inconvenience to people with severe DMO. A Cochrane network meta-analysis found that anti-VEGFs improve vision in DMO but concluded "evidence from RCTs may not apply to real-world practice where people are often undertreated and under-monitored". In this regard, a large cohort study from Moorfields Eye Hospital found that half of the patients with DMO treated with anti-VEGFs achieved vision of 70 ETDRS letters at 1.9 months of initiating this therapy but, in 50% of these, vision dropped below this by 14.7 months (i.e. visual gain was not maintained). Similarly, a "real world" analysis of 28,658 eyes of participants with DMO treated with anti-VEGFs found that eyes with good vision at baseline (before initiating anti-VEGF therapy), were at risk of visual loss a year following treatment initiation, highlighting that outcomes observed in anti-VEGF trials are not reproduced in clinical practice. Rationale for the Intervention Macular laser is likely to be effective in combination with anti-VEGFs in people initially presenting with ≥400μm DMO if the macula laser is applied after the CRT has gone below 400μm following anti-VEGFs. A Single Technology Appraisal by NICE found that for people presenting with DMO and CRT of \<300μm, there was no statistically significant difference in efficacy between anti-VEGFs and laser, but laser was more cost-effective. When CRT was between 300μm and 400μm, there were gains in vision of 7 ETDRS letters with anti-VEGFs and 4 ETDRS letters with macular laser, a statistically significant difference but of doubtful clinical relevance; and macular laser dominated in cost-effectiveness. A randomised trial by the Diabetic Retinopathy Clinical Research Network (Protocol V) including people presenting with DMO and good vision (median 85 ETDRS letters), with CRT of \<400μm (median 290μm and 299μm in aflibercept and macular laser arms, respectively) and median HbA1c of 7.6% showed comparable efficacy between aflibercept and macular laser, with 16% and 17% of participants experiencing improvement in best corrected visual acuity (BCVA) of \>5 ETDRS letters at 2 years. The DIAMONDS trial showed that macular laser is effective and cost-effective for treating people presenting with DMO and CRT \<400μm. Participants who had good vision (median 82 ETDRS letters), median CRT of 331μm and median HbA1c of 8.5% (i.e. more severe disease than those included in Protocol V) maintained good sight throughout the 2-year follow-up (mean change in vision of less than 3 ETDRS letters) with 18% of participants experiencing an improvement in BCVA of \>5 ETDRS letters at two years. In clinical practice, macular laser is offered only to people presenting with new DMO with CRT \<400μm but not routinely to those who have started anti-VEGFs, even if, at some point, their CRT is \<400μm. The proposed strategy (initial anti-VEGF therapy for people presenting with severe DMO with CRT of ≥400μm followed by macular laser after CRT goes below 400μm) would likely allow participants to achieve visual acuity improvement (which often occurs following the first few anti-VEGF injections but is less frequently observed after macular laser monotherapy) but without the need to continue with anti-VEGF injections long-term. The DAME PPI Group felt that participants would be likely to prefer this new proposed strategy (anti-VEGF followed by SML). The DIAMONDS trial in people presenting with DMO of \<400μm showed that SML, which does not produce any deleterious functional or structural changes in the retina, is as effective as standard laser, which produces a burn. A systematic review on SML for DMO identified 5 small (30-56 eyes in total in each trial) randomised trials comparing anti-VEGFs alone with anti-VEGFs + SML. In 4 of these trials, no statistically significant differences in BCVA were found between treatment groups, whereas in one a significant improvement in BCVA was observed only in the combined anti-VEGF+SML group. A statistically significantly reduced number of anti-VEGF injections was required in the anti-VEGF+SML group in 3 of the 4 trials in which this outcome was investigated. None of the trials included other important outcomes such as health-related and visual-related quality of life, participant-reported experience, adverse events, or costs. The CRT in these trials varied (means of 494-513μm, 462-457μm, 458-470μm, 466-451μm, 433-458μm) and the SML was applied after randomisation (i.e. not when CRT had gone below 400μm following anti-VEGFs). Rationale for the Comparator The comparator in DAME will be the current standard of care for these patients: continuing with anti-VEGF monotherapy until DMO fully clears or if it recurs after having previously dried, based on OCT scans. Sites will use the type of anti-VEGF they routinely use in their standard clinical practice. Research Hypothesis DAME will test whether, in people presenting with severe DMO (CRT ≥400μm) who are initially treated with anti-VEGFs, treatment with SML (intervention) after their CRT has decreased to \<400μm is equivalent (equivalence margin +/- 5 Early Treatment Diabetic Retinopathy Study \[ETDRS\] letters) to continuing anti-VEGF monotherapy (control, comparator = standard of care) for preserving/improving BCVA in the study eye at 104 weeks (primary outcome). Aim To conduct a pragmatic randomised equivalence trial to assess clinical- and cost-effectiveness, safety, participant experience and acceptability of SML applied after CRT is \<400μm following initial anti-VEGF injections, compared to continued anti-VEGF monotherapy, in people who originally presented with severe DMO (CRT ≥400μm). DAME includes an assessment of service providers and planners of factors that enable sustainable delivery of the service to participants, assuming a positive trial result, after the study. Objectives In people initially presenting with severe DMO (CRT ≥400μm) who receive treatment with anti-VEGFs and once their macular CRT, as determined on OCT scans, has decreased to \<400μm: 1. To determine if the clinical effectiveness of anti-VEGFs and SML is equivalent to anti-VEGF monotherapy 2. To determine the cost-effectiveness of anti-VEGFs and SML compared to anti-VEGF monotherapy 3. To evaluate the participant experience and acceptability of anti-VEGFs and SML compared to antiVEGF monotherapy 4. To evaluate the post-trial implementation and scalability of anti-VEGFs and SML Study Design Pragmatic, allocation-concealed, single-masked (outcome assessors), multicentre, randomised, equivalence trial with an internal pilot. Internal Pilot An internal pilot will be conducted over the first 6 months of recruitment, to assess feasibility of recruitment and determine if the study should continue to a full trial. Progression criteria will be assessed 6 months after the first participant is randomised. The target recruitment will be an average of one participant per month per open site. With staggered opening of sites, it is anticipated that by 6 months after the first participant is randomised, 16% of the required sample size would be met. Therefore, the internal pilot recruitment target is 42. Criteria for progression to the full trial are GREEN (Average recruitment rate/site/month: 1; number of sites opened: 12; number of participants recruited: 42): Progress to full trial. AMBER (0.5-0.99; 6-11; 21-41): Discuss feasibility with the TSC and NIHR and develop a recovery plan to reach the recruitment target and evaluate options to improve recruitment, including number of eligible participants identified, percentage of these randomised and reasons for non-randomisation, review of site recruitment performance, and a review of recruitment procedures. RED (\<0.5; \<6; \<21): Decision cessation of the trial with the TSC and NIHR. Setting At least 20 HES across the UK, with catchment areas that cover diverse populations. Sequence Generation Eligible participants who provide consent will be randomised 1:1 to receive SML or continue with antiVEGF monotherapy. Minimisation will be used to balance allocation of participants across trial arms for centre, duration of DMO (≤1year, \>1year), number of doses of anti-VEGFs received before randomisation (1-6; 7-12), type of anti-VEGF used (ranibizumab, ranibizumab-biosimilar, Brolucizumab, aflibercept, or faricimab) before randomisation, which will be continued throughout the trial unless lack of efficacy is observed and rescue treatment is needed, presenting BCVA \[BCVA ≥ 69 ETDRS letters (Snellen equivalent ≥ 20/40; logMAR ≥ 0.3), 24-68 ETDRS letters (Snellen equivalent ≤20/50-20/320; logMAR 0.4-1.2) and CI-DMO (Yes, No). Allocation Concealment and Implementation An automated system with the allocation concealed to the ophthalmologist or designee randomising the participant will be used to generate the random allocation sequence. After informed consent, participants will be randomised via an automated web-based system. Each participant will be allocated their own unique trial identifier during the randomisation process, which will be used throughout the study for participant identification. Recruitment People that may become a potential participant in this trial (i.e. people with DMO ≥400μm eligible for anti-VEGFs and being started on this treatment) will be identified by the clinical assessment team through referrals to HES, through electronic databases or logbooks, or whilst in clinic. A member of the care team will introduce the study to them at any time during their first year of anti-VEGF therapy, which might be before their CRT has gone below 400μm. Participants expressing interest in taking part will be given further verbal and written details by a member of the research team, including the DAME Participant Information Leaflet (PIL). After anti-VEGF treatment is initiated and when the CRT is below 400μm the participant, if eligible based on the DAME eligibility criteria, could be enrolled and randomised (once consented appropriately). When someone consents to join DAME, they will be asked if they agree to be approached at a later date to be invited to take part in a focus group discussion, so that they can be approached and consented when these focus groups are organised. Participants will also be asked if following completion of DAME, data collected as part of their standard care, can be reviewed for future follow-up studies. Participants will be randomised only when their DMO has improved and the CRT is \<400μm following treatment with anti-VEGFs. Enrolment can happen at any time after the CRT has gone below 400μm provided that it is still within one year of initiating anti-VEGF therapy. Screening Participants attending clinic for a routine appointment will be screened to check for eligibility. All participants screened for the study will be documented, including reasons for not being enrolled for those not recruited. A minimal dataset will be recorded (including age, sex at birth, sexual orientation, ethnicity and partial postcode, to determine if there are differences with those willing to participate). Informed Consent The study will be conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki. Eligible participants may only be included in the trial after written informed consent is obtained. Sample Size DAME is powered to demonstrate equivalence of treatment strategies for the primary outcome, which will be assessed 104 weeks after randomisation. Based on two one-sided t-tests at the 2.5% significance level, a 10 ETDRS letter standard deviation (SD) and an equivalence margin of +/- 5 ETDRS letters, with a significance level of 2.5% and power of 90%, a total of 210 participants would be required. Allowing for 20% dropout, will require 264 participants. The proposed sample size of 132 per group will also be sufficient to detect a mean difference between groups of 39.5μm in CRT (based on a SD of 86.8) and 6.85 in NEI-VFQ-25 (based on a SD of 15.1) at 104 weeks, which are important secondary outcomes on this study. These differences in CRT and NEI-VFQ scores are both clinically relevant differences. Nested Process Evaluation to Assess Implementation and Scalability Aspects Post-Trial A process evaluation will collect qualitative data from service providers and managers across sites using i) Focus groups or individual interviews with clinical, nursing and service management leads (or their representatives) across participating sites. Focus groups (analogous to those described above) or 1:1 interviews will be offered to participants, and applied depending on feasibility, preference and timeliness. They will be carried out when sites/participants have had experience with the intervention. The aim is to recruit a minimum of two participants per site for these focus groups/interviews, purposefully selected to have an overview of how the service was introduced and implemented in their hospital and wider knowledge of service setup and funding considerations for eye care. ii) Implementation strategy analysis will be conducted after the focus groups/interviews. This will be driven by the ERIC framework (Expert Recommendations for Implementing Change). This will lead to a DAME implementation toolkit, assuming a positive result (i.e. new tested SML pathway is shown to be beneficial). Data from the nested process evaluation will be subjected to a framework analysis, guided by the Consolidated Framework for Implementation Research (CFIR). CFIR allows formal categorisation of emerging barriers or drivers into specific categories - broadly including external and internal context of the service, people involved and the process of implementation and also the actual clinical intervention itself. To ensure representativeness and local relevance, the analysis will create and include new codes for data that do not fit into existing CFIR categories. For the implementation strategy analysis, the CFIR (and any further) categories of barriers to implementation that participants report will be deductively matched to, firstly, the reported strategies they used to implement the new intervention and also further potential strategies as per the ERIC framework. These will formulate the DAME implementation toolkit, which will articulate explicitly barriers to be expected in setting up and delivering the service and what activities and initiatives could be undertaken to mitigate them and sustain delivery in a NHS setting. The toolkit will include how to select what strategies might be relevant for each NHS adopting site (i.e. how to appraise local barriers and match those to implementation strategies as revealed by the trial's process evaluation). Study Within a Trial (SWAT) A variety of summaries of the results of DAME will be prepared and understanding and potential impact of these will be compared with a variety of stakeholders (including participants in DAME, members of the public, ophthalmologists, policy makers (e.g. those engaged in guideline production) and medical students). They will be required to give consent before taking part in the SWAT. The findings will inform dissemination plans and provide evidence for dissemination plans in other trials. The format of these summaries will be determined when the results of DAME and their potential implications are known. However, they may include a plain language summary, scientific summary, short abstract, infographic, podcast, and its associated script.

Background: The presence of cancer in the axillary lymph nodes on needle biopsy in patients with early stage breast cancer before neoadjuvant chemotherapy (NACT) has been the determinant of the need for axillary treatment (in the form of axillary lymph node dissection (ALND) or axillary radiotherapy (ART)) after completion of NACT. Treatment to the axilla damages lymphatic drainage from the arm and patients can subsequently develop lymphoedema, restricted shoulder movement, pain, numbness, and other sensory problems. As more effective chemotherapy is now available that results in complete eradication of cancer in the axilla in around 40 to 70% of patients, extensive axillary treatment might no longer be necessary in patients with no evidence of residual nodal disease. Aim: To assess whether, omitting further axillary treatment (ALND and ART) for patients with early stage breast cancer and axillary nodal metastases on needle biopsy, who after NACT have no residual cancer in the lymph nodes on sentinel node biopsy, is non-inferior to axillary treatment in terms of disease free survival (DFS) and results in reduced risk of lymphoedema at 5 years. Methods: Study design: A pragmatic, phase 3, open, randomised, multicentre trial and embedded economic evaluation in which participants will be randomised in a 1:1 ratio. Study population: T1-3N1M0 breast cancer patients aged 18 years or older, with needle biopsy proven nodal metastases, who after NACT have no residual cancer in the lymph nodes on dual tracer sentinel node biopsy and removal of at least 3 lymph nodes (sentinel nodes and marked involved node). Intervention: All participants will receive human epidermal growth factor receptor 2 (HER2)-targeted treatment, endocrine therapy and radiotherapy to breast or chest wall, if indicated according to local guidelines. Patients in the intervention group will not receive further axillary treatment (ALND or ART), whereas those receiving standard care will receive axillary treatment (ALND or ART) as per local guidelines. Follow-up is annually for at least 5 years. Outcomes: The co-primary outcomes are disease free survival(DFS) and self-reported lymphoedema defined as 'yes' to the two questions participants will be asked - 'arm heaviness during the past year' and 'arm swelling now' from the Lymphoedema and Breast Cancer Questionnaire at 5 years. Secondary outcomes: arm function assessed by the QuickDASH (disabilities of the arm, shoulder and hand) questionnaire; health related quality of life assessed using euroqol EQ-5D-5L; axillary recurrence free interval (ARFI); local recurrence; regional (nodal) recurrence; distant metastasis; overall survival; contralateral breast cancer; non-breast malignancy; costs; quality adjusted life years (QALYs) and cost-effectiveness. Sample size: A sample size of 1900 patients would have the ability to demonstrate a 3.5% non-inferiority margin with a 5% 1-sided significance level and 85% power, allowing for 7% non-collection of primary outcome data assuming a 90% 5-year disease free survival rate in the control arm. It would also be able to detect at least a 5% difference in proportion of patients with lymphoedema with 90% power, a 5% 2-sided significance level and allowing for 25% non-collection of primary outcome data over 5 years. Analysis plan: All analyses will be carried out on an intention-to-treat basis to preserve randomisation, avoid bias from exclusions and preserve statistical power. Time to event outcomes, including disease free survival and axillary recurrence free interval, will be assessed using Kaplan-Meier curves and compared using Cox proportional hazards models. The proportion of patients experiencing lymphoedema at 5 years will be compared across trial arms using a chi-squared test and a logistic regression model used to adjust for stratification variables. Arm morbidity and health related quality of life will be scored using the appropriate manuals and assessed using a longitudinal mixed model regression analysis if model assumptions valid or a standardised area-under-the-curve analysis. For economic evaluation, incremental cost per QALY gained at 5 years will be estimated. Timelines for delivery: Total project duration is 120 months based on 6 months for set up; 60 months recruitment period (including an 18 months internal pilot phase); and 54 months for follow up, analysis, writing up and dissemination.

Background and study aims: The aim of this study is to improve the way prostate cancer is diagnosed by looking at two different types of MRI scans and two different types of prostate biopsy (tissue samples). A large study such as this is required to help the NHS decide how to diagnose prostate cancer in the future. If a person is suspected of having prostate cancer, then they are referred by their GP. At the hospital clinic, the participant will then have an MRI scan. If this scan shows that cancer might be present, then the doctor will usually suggest that the patient has a biopsy. There are two ways of doing a prostate MRI. One takes 30-40 minutes and requires a contrast injection called gadolinium (like a dye). This is called long MRI and is most commonly used in the NHS. Gadolinium is safe as it rarely causes any bad reaction but using it means that the scan takes more time. Another type of MRI takes 15-20 minutes and does not use gadolinium contrast. This is called a short MRI. Many studies over the last 5 years have shown that the long and short MRIs are similar in their accuracy in diagnosing important prostate cancer. These studies have not been of high quality or large enough to change NHS practice. Patients with suspicious areas on the MRI are usually advised to have a prostate biopsy. This involves taking tissue samples using a needle. The samples are then looked at under the microscope by a pathologist to see if cancer cells are present. There are two ways of doing a prostate biopsy. One is where the person doing the biopsy decides where to put the biopsy needle by looking at the MRI scans that have been already taken on a computer screen. The needle is guided to the prostate using live ultrasound scans that are shown on a different screen near the patient. The biopsy operator makes a judgement about where to place the biopsy needles. This is called visual registration. Tissue samples from other areas of the prostate that look normal on the MRI scans are also taken to ensure cancer is not missed. The other type of biopsy is called image fusion. During image fusion biopsy, the biopsy operator uses the MRI scans that have been taken beforehand but laid on top of the live ultrasound images during the biopsy. This uses software and takes a few minutes longer to perform. Once the MRI images and ultrasound images are 'fused', the actual biopsies are taken as normal. Studies over the last 5 years have shown mixed results. Some have shown that image fusion biopsy is no better than visual registration biopsy, whilst a few have shown it might make a difference in improving cancer detection. As a result, it is not known for certain which way is better. A large study is needed to show whether the investigators need to do image fusion or not, in order for the NHS to decide whether or not to use it in all hospitals doing prostate biopsies.

This is a multi-centre, observational study of children with rare inherited cardiac conditions. The focus of the study will be on children with clinically diagnosed cardiomyopathy and their unaffected parents, with collection of baseline demographic data, imaging data, and genotyping data. Children and their parents will been rolled over a 5-year period. Sub-sets of patients with confirmed diagnoses of other heritable cardiovascular diseases with onset \<16 years will also be recruited.These will include children who following evaluation by their clinical multidisciplinary team (which will include a geneticist or genetic counsellor) are likely to have a rare monogenic condition. Other affected family members of eligible patients may be also invited to participate in the study. Information for this study will be collected primarily from investigations performed as part of the participants' routine clinical care including whole genome sequencing commissioned by NHS England. The study will seek consent to access and export this data. Procedures performed as part of this study may include venepuncture and/or saliva collection and carry minimal risk to the patient. Parents of participants that are recruited into the study will donate a blood sample (or saliva sample if unable to provide blood) and consent will be requested for collection of health information and results of relevant investigations carried out as part of their routine clinical care (e.g. an echocardiogram). Other family members that are recruited into the study will donate a blood sample (or saliva sample if unable to provide blood) and consent will be requested for collection of health information. Family members of deceased patients with cardiomyopathy or other inherited cardiac conditions may be asked if they wish to donate stored samples that may have been taken prior to death or as part of a post-mortem examination to establish cause of death. Any discussion with regard to the use of stored samples for this project will be initiated by the clinical care team for the deceased patient and their family to minimise any potential distress to the family. Sub-sets of patients may be asked to donate tissue samples taken as part of their clinical care.

Many patients diagnosed with Early Rectal Cancer (ERC) are currently over-treated. Most patients with confirmed ERC will undergo an MRI, but some are not correctly identified in endoscopy and immediately removed. Of those who undergo MRI, 69% are over-staged and undergo major surgery or unnecessary radiotherapy when local excision surgery to preserve the patients rectum, and quality of life, would have been possible. \<10% of patients with ERC are staged accurately and offered local excision, with the majority who are staged as ERC on MRI still undergoing major surgery, likely due to uncertainty in the staging report. Prof Gina Brown developed a more accurate radiological staging system (PRESERVE) or ERC, whereby T2 tumours are identified and classified according to the degree of preservation of the individual layers of the rectal wall. It has been shown that PRESERVE enabled better identification of ERC suitable for local excision from the expected 30% to 89% accuracy. This improved accuracy was replicated in a further study by training a cohort of 12 radiologists. It is predicted that wider adoption of PRESERVE will result in increased organ-preserving surgery from the current rates of 10% to \>50%.

Community-acquired pneumonia (CAP) that is of sufficient severity to require admission to an intensive care unit (ICU) is associated with substantial mortality. Patients with pneumonia who are being treated in an ICU will receive therapy that consists of many different treatments, as many as 20 or 30. These treatments act together to treat both the infection and its effects on the body. When treating a patient, doctors choose from many different treatments, most of which are known or believed to be safe and effective. However, doctors don't always know which treatment option is the better one, as individuals or groups of individuals may respond differently. This study aims to help doctors understand which treatments work best. This clinical study has been designed in a way that allows the information from patients already in the study to help new patients joining the study. Most studies aren't able to do that. REMAP-CAP has been designed to: * Evaluate multiple treatment strategies, at the same time, in the same patient. * Reach platform conclusions when sufficient data is accrued, rather than when a pre-specified sample size is reached * Utilise data that is already accrued to increase the likelihood that patients within the trial are randomised to treatments that are more likely to be beneficial * New questions can be substituted into the trial as initial questions are answered, meaning that the trial can be perpetual or open-ended * Interactions between interventions in different domains can be evaluated It is reasonable to presume that any pandemic respiratory infection of major significance to public health will manifest as life-threatening respiratory infection including Severe Acute Respiratory illness and severe Community Acquired Pneumonia (CAP) with concomitant admission to hospital, and for some patients, admission to an Intensive Care Unit (ICU). Previous pandemics and more localized outbreaks of respiratory emerging infections have resulted in severe CAP and ICU admission. Previous pandemics and outbreaks of emerging infectious diseases have outlined the urgent need for evidence, preferably from Randomized Controlled Trials (RCTs), to guide best treatment. However, there are substantial challenges associated with being able to organize such trials when the time of onset of a pandemic and its exact nature are unpredictable. As an adaptive platform trial that enrolls patients during the interpandemic period, REMAP-CAP is ideally positioned to adapt, in the event of a respiratory pandemic, to evaluate existing treatments as well as novel approaches.