Ashford

The research study is being done to see if ziltivekimab can be used to treat people who were admitted to hospital because of a heart attack. Ziltivekimab might reduce development of heart disease, thereby preventing new heart attacks or strokes. Participants will either get ziltivekimab (active medicine) or placebo (a dummy medicine which has no effect on the body). Which treatment participants get is decided by chance. The chance of getting ziltivekimab or placebo is the same. The participant will need to inject the study medicine into a flat skin surface in there stomach, thigh, or upper arm once every month. Ziltivekimab is not yet approved in any country or region in the world. It is a new medicine that doctors cannot prescribe. The study will last for about 2 years.

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.

COMET is a phase III prospective multi-centre open label two-arm randomised controlled trial with an internal pilot and masked outcome assessments. Administration of cooling therapy cannot be masked. All babies born at or after 36 weeks and requiring prolonged resuscitation at birth (defined as continued resuscitation at 10 minutes after birth or 10-minute Apgar score less than 6) or those with severe birth acidosis (defined as any occurrence of: pH =\<7.00 or Base deficit \>=16mmol/l in any cord or baby gas sample within 60 minutes of birth) and admitted to the neonatal unit will started on aEEG or EEG as a part of standard clinical care. Neonatal doctors or advanced nurse practitioners (clinical team) will screen for eligibility using a structured neurological examination performed between 1 to 6 hours after birth. Once parental consent is obtained, babies will be randomised to whole-body hypothermia or targeted normothermia within 6 hours of birth, using a web-based program. Initial assessment and randomisation (and initiation of whole-body hypothermia or targeted normothermia) will occur at the hospital of birth. The babies in both arms, who are born at a non-cooling centre (LNU or SCBU) will be then transferred to the nearest cooling centre (NICU) within 8 hours of birth for continued care. Whole-body hypothermia (33.5±0.5°C) will be initiated within 6 hours of birth and continued for 72 hours using a servo-controlled cooling machine at the nearest available neonatal intensive care unit (cooling centre). Passive cooling methods will not be allowed. Whole-body hypothermia to 33.5±0.5°C for 72 hours is the duration and depth of cooling that is standard for babies with moderate or severe HIE in high income countries. To administer this intervention babies will be kept on a cooling mattress or blanket circulating a coolant/water, a rectal temperature probe will be inserted, and overhead radiant warmers will be switched off. The cooling device will be set to hypothermia mode and body temperature will be rapidly reduced to 33.5°C from 37.0°C and maintained within the target range of 33°C to 34°C. In the Normothermia (Control group), the rectal temperature will be maintained at 37.0±0.5°C for the first 88 hours and any hyperthermia will be treated with a standardised protocol. Four hourly axillary temperature will be recorded during the first 88 hours. Babies in the control group who develop seizures (level 1 or level 2) and progress to moderate HIE between 6 to 24 hours may be treated with whole-body cooling for 72 hours as clinical care, although this is expected to occur in less than 5%. Conventional MRI using standard 3D T1-weighted and 2D T2-weighted sequences and diffusion weighted imaging will be performed prior to discharge home. The follow-up assessment will be done when the recruited babies are 24 (±2) months of age. The assessment will be carried out using the Bayley Scales of Infant and Toddler Development IV. It is a validated and standardized scoring system that assesses development in three domains, that is cognition, language, and motor development. In addition, all infants will have a detailed neurological examination, including Gross Motor Function Classification System (GMFCS) for cerebral palsy, vision, and hearing assessment. Babies who die (the mortality rate is expected to be less than 1% in mild HIE) or who cannot be assessed with the Bayley-IV due to severe disability will be allocated a Cognitive Scale Composite score one point below the basal test score (i.e., score of 54). In all infants, PARCA-R (online or face to face) will be completed by the parents immediately prior to the Bayley IV assessments and CBCL (face to face only) after the Bayley IV assessments. The data will be collected into a paper case report form (CRF) initially and then entered into electronic database at the participating sites. Data will include ante-natal, birth, and neonatal clinical information including gestational age, birth weight, gender, Apgar scores, birth history, delivery room resuscitation to assess the baseline comparability of the groups, core body temperature for assessment of intervention, details of the hospital course, laboratory investigations and MR imaging for safety monitoring, and neurodevelopmental outcomes at 24 (±2) months of age for primary outcome evaluation.

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.

1 in 7 infants born in the United Kingdom will require treatment on a Neonatal unit to treat conditions, which vary in there level of severity. Treatments and interventions aimed at supporting the unwell neonate have associated risks and the evidence underpinning them can range from limited to substantial. There is a degree of uncertainty in Neonatology, which can be very stressful for parents and clinicians alike. Parents need to be supported by the clinical team in making many complicated clinical decisions, a skill that requires robust communication of risks, benefits and alternatives. In 2019 the British Association of Perinatal Medicine released a framework of care advocating Shared Decision Making (SDM) as the optimal process for making clinical decisions on neonatal units. This model builds upon the "informed decision" models by putting a greater emphasis on involving parents in key decisions regarding the treatment of their babies medical condition. Evidence has demonstrated that SDM can improve parental satisfaction and reduce anxiety and the likelihood of feeling regret. In order to support parents in the SDM process, clinicians need to be able to provide impartial information encompassing the proposed intervention, intended benefit, potential risks and alternatives. Whilst clinicians may have preconceptions on the information that they think should be provided, there is limited evidence in the literature of what are the most important concepts and themes that parents would expect to be conveyed during the SDM process. ShAPE is a qualitative study that aims to

Background: Gallstone disease affects 10-15% of people in the United Kingdom (UK) and over 65,000 patients undergoing cholecystectomy each year, costing the National Health Service (NHS) over 110 million. There is increasing evidence suggesting differences in the gut microbiome of patients with gallstone disease compared to those without (including reduced diversity, decreased prevalence of beneficial and increased prevalence of pathogenic bacteria) but there are only a handful of small scale studies exploring the development of gallstone disease complications and patient outcomes to date. Hypothesis and Objectives: This pilot study aims to understand the profile of the gut microbiome in adult patients diagnosed with gallstone disease and its relationship with patient outcomes including: Patients who develop complications of gallstone disease(including but not limited to biliary colic, cholangitis, cholecystitis, pancreatitis and gallstone ileus) following diagnosis and Patients who develop post-operative complications including short (hospital stay, wound healing etc) and intermediate (development of post-cholecystectomy diarrhoea) outcomes. Design and Methods: A prospective cohort design will be used to collect data from 75 adult patients presenting to East Kent University Hospitals NHS Foundation Trust Hospitals with newly diagnosed gallstone disease following confirmatory imaging investigations. Data will be collected from electronic patient records including clinical history and diagnostic investigations, anthropometry, blood and imaging results (if taken as part of routine clinical care) for the initial presentation and subsequent readmissions/planned follow-up timepoints. Stool samples will be collected from patients either during admission or at home at each timepoint. Samples will be returned by post to the research team where they will be stored and analysed. Patients will also be asked to provide a 3 day food diary card Patients will have a sample collected at time of diagnosis and then at 6 monthly intervals whilst awaiting cholecystectomy. A pre-operative sample will be required within 6 weeks of any surgical intervention. Following cholecystectomy an immediate post-operative sample (within the first week) will be collected as well as a sample at 6 months. Clinical and Scientific Impact: At least 20% of those patients awaiting cholecystectomy experience complications, costing the NHS over £25 million per year. Therefore, there is a huge need to understand mechanisms behind the development of complications and to reduce the symptom burden for patients as well as the financial burden for the NHS. This study is the crucial first step in identifying differences in the gut microbiome between patients who experience complications (both pre and post-op) and those who do not. Once differences are discovered the next step will be to use the information discovered to determine interventions to reduce the development of these complications.

COMPLETE-2 STUDY OBJECTIVES 1. To determine whether a strategy of physiology-guided complete revascularization is non-inferior to a strategy of angiography-guided complete revascularization on the efficacy composite outcome of cardiovascular (CV) death, new myocardial infarction (MI) or ischemia-driven revascularization (IDR). 2. To determine whether a physiology-guided complete revascularization strategy is superior to an angiography-guided complete revascularization strategy in reducing the safety composite outcome of clinically significant bleeding, stroke, stent thrombosis or contrast-associated acute kidney injury.

Observational, multicentre, international retrospective and prospective cohort study. Since this is an observational study, a formal sample size is not necessary. At least 500 prospectively recruited patients and 500 historical cases will be enrolled. Patient data will be collected at the following time-points: * First SCAD event visit (retrospectively on chart review) * First follow-up: at time of enrolment * Yearly follow-up: up to 1, 2, 3, 4 and 5 years post enrolment or until study completion Approximately 30 countries and 120 sites will participate in this registry.