Basoglu, Turkey

Investigating the Effects of Transcranial Stimulation to Advance Stroke Rehabilitation

Stroke is a leading cause of death and long-term disability worldwide. More than 70% of stroke survivors experience motor impairments, often resulting in difficulties in daily activities, such as walking, reaching and grasping objects. Regaining upper-limb motor function is key to quality of life and for reducing the high annual costs due to stroke. Research indicates that upper-limb motor function recovery depends on the plasticity of neural circuits controlling movement. Beta activity (β, ~13-30 Hz) in the sensorimotor cortex has been associated with brain plasticity and has been proposed to play a pivotal role in human movement and movement disorders. This activity attenuates during movement execution, known as event-related desynchronization (β-ERD), and temporarily increases after the end of movement, known as event-related synchronization (β-ERS). β-ERD and β-ERS are reliably observed during active and passive movement, movement imagination and movement observation. Changes in movement-related β-ERD and β-ERS have been linked to motor learning, and motor dysfunction in neurological conditions, such as stroke. Studies have shown that stroke survivors with upper limb impairments exhibit significantly lower beta activity compared to healthy individuals, and recovery-related improvements in motor function are accompanied by increases in both sensorimotor β-ERD and β-ERS. Therefore, modulation of movement-related beta activity (i.e., β-ERD and β-ERS) holds great promise for promoting motor function after stroke. Non-invasive brain stimulation (NIBS) can be applied during movements to increase plasticity and enhance motor learning and function. However, prior studies have delivered NIBS using a relatively broad approach; modulating general cortical excitability rather than enhancing specific endogenous oscillations in the brain. Transcranial alternating current stimulation (tACS) is a safe and well-tolerated type of NIBS which provides an option for modulating specific frequencies of brain oscillations by delivering a low-intensity sinusoidal electrical current to the brain at a specific frequency. Therefore, this study will deliver beta-tACS to the ipsilesional motor cortex (M1) aiming to modulate sensorimotor beta activity during upper limb movement in stroke survivors. This study will investigate whether functionally timed beta-tACS has the potential to enhance motor recovery, by assessing whether stimulation delivered at the end of the movement improves upper limb movement (accuracy, smoothness and hand function) and increases the modulation of beta activity. Additionally, the investigators will evaluate whether the effectiveness of the stimulation relates to baseline neuroimaging and neurophysiological measures. Identifying correlates of intervention responsiveness will help future studies to target patients who are most likely to benefit.

Capillary OGTT Study

A Study to Assess the Effectiveness and Safety of Pacritinib in Patients With VEXAS Syndrome (PAXIS)

This study is a randomized, multicenter, double-blind, placebo-controlled phase 2 study (Part 1) followed by an open-label treatment period (Part 2) designed to evaluate the efficacy and safety of pacritinib for the prevention of VEXAS flares after glucocorticoid (GC) taper. The study will enroll patients ≥18 years with inflammatory VEXAS syndrome receiving ongoing GC therapy for ≥4 consecutive weeks, requiring between 15 and 45 mg daily (of prednisone / prednisolone or equivalent) at the time of enrollment (randomization). Patients will be randomized 1:1:1 to receive pacritinib dose A (n=26), pacritinib dose B plus placebo (n=26), or placebo (n=26) for up to 24 weeks during a double-blind treatment period, followed by treatment with pacritinib during an open-label treatment period for up to 48 weeks, and a 30-day post-End of Treatment (EOT) follow-up period. Randomization will be stratified by prescribed GC dose on the day of randomization. All outcomes will be reported by treatment arm, and pair-wise comparison between each pacritinib arm and placebo will be performed in the double-blind treatment period. Patients who complete the double-blind treatment period at End of Week 24 or meet Early Failure criteria at End of Week 12 will transition to an open-label pacritinib treatment period through End of Week 48. In addition, if a study arm closes due to interim futility or safety, all patients currently randomized to that arm will transition to open-label treatment. Study termination is planned approximately 1 year from the first dose of the last patient.

The Dragon PLC Trial (DRAGON-PLC)

Primary liver cancer (PLC) is the third most common cause of cancer death worldwide. Surgical resection is the mainstay for a curative approach as contemporary chemotherapy and immune-based therapies only lead to a median survival of 10-14 months. A complete surgical resection increases the median survival to 42 months (range 32-52 months). However, PLC is mainly diagnosed at an advanced stage and >70% of PLC patients are ineligible for an immediate surgical approach. There are different reasons that make a patient ineligible for surgery, one important reason is the risk of liver failure after the surgery due to a small remnant liver. This study aims to improve the oncological, radiological and surgical strategy to allow more patients to undergo liver resection safely, to improve quality of life and to extend overall survival at acceptable costs. Adequate function of the future liver remnant (FLR) is a prerequisite for surgical resectability. This is necessary in order to avoid liver failure after surgery, a major cause of morbidity (38%) and mortality (27%). To mitigate this risk, regenerative strategies based on preoperative calculation of the FLR volume and function are essential. Patients with technically resectable disease but predicted insufficient FLR volume or function are referred to as primarily unresectable or potentially resectable (PU/PR). These patients can undergo strategies that capitalize on the regenerative capacity of the liver which aim to preoperatively increase the FLR volume and function in order to allow surgery. Many of the patients that are primarily unresectable due to an insufficient FLR can become ultimately and safely resectable after the induction of adequate FLR-hypertrophy by the current standard, portal vein embolisation (PVE). However, 25% of patients do not show sufficient FLR growth after PVE and are unable to safely undergo resection. A new approach has been developed to improve this. Combined portal and hepatic vein embolisation (PVE/HVE) has great promise in terms of increasing FLR growth, resection rate (RR), safety and potentially, overall survival. Establishing PVE/HVE as the new standard could result in increased survival and a better quality of life (QoL) for patients.

The CACHE Study: Coronary Artery Care in HaEmophilia

Background and Rationale Haemophilia, ageing and cardiovascular disease It is only relatively recently, due to the development of both effective and safe replacement therapies, that there is an aging population with haemophilia. This represents new challenges with respect to managing comorbidities. Cardiovascular disease (CVD) is the leading cause of death globally in the general population, and as people with haemophilia (PWH) age they are also at risk of developing CVD which poses particular challenges due to the opposing risks of bleeding, from haemophilia and antithrombotic treatments, versus thrombosis. Better understanding of the risks of atherosclerosis in PWH is crucial in order to best support aging PWH; and it has been identified as a research priority by patients and healthcare professionals. Although mortality from cardiovascular disease in PWH has historically been about 40% less than the general population, it remains unclear whether this is because people with haemophilia develop atherosclerosis more slowly than the general population or whether deficiency of FVIII/FIX protects from formation of an occlusive thrombus at time of atherosclerotic plaque rupture. As FVIII is produced and stored within endothelial cells lining the blood vessels and FIX is produced in the liver, it may also be that FVIII and FIX deficiencies have different effects on the rates of atherosclerosis. The most informative studies of atherosclerosis in PWH to-date used ultrasound to measure carotid and femoral intima-media thickness and computed tomography (CT) to derive coronary artery calcium scores. The first study measured carotid and femoral intima-media thickness (IMT) and brachial flow-mediated dilatation (FMD) as markers of atherosclerosis and endothelial dysfunction respectively in 51 obese PWH, and 42 obese and 50 matched non-obese male patients. All the PWH had haemophilia A (33% severe, moderate 16%, mild 50%), HIV was excluded, and the mean age was 50 +/-13 years. Carotid IMT was increased in obese as compared with non-obese subjects, but no difference was found in mean carotid and femoral IMT between obese PWH and obese control individuals. Thirty-five per cent of the obese PWH and 29% of the obese controls had an atherosclerotic plaque, irrespective of the severity of haemophilia. Brachial FMD was comparable between obese PWH and obese controls. The second study evaluated the presence and extent of atherosclerosis by coronary artery calcification score (CACS) derived from computed tomography and carotid IMT in 69 PWH (51 haemophilia A, 18 haemophilia B; 40% severe, 11% moderate, 49% mild). This again showed that CACS and carotid IMT were similar to controls and that the extent of atherosclerosis was related to traditional cardiovascular risk factors. Although these studies suggest PWH develop atherosclerosis at a similar rate to the general population; they are severely limited by the quality of the imaging techniques, patient numbers and relatively young patient age (average 50 years). Cardiology guidelines recommend using a risk score to calculate cardiovascular risk over time and engaging patients in discussing modifiable risk factors. These scores have been used in PWH. A Dutch/UK cohort used both the QRISK(R)2 and SCORE algorithms. The predicted 10-year QRISK(R)2 risk was significantly higher in PWH than in the general population (8.9 vs. 6.7%), indicating more unfavourable cardiovascular risk profiles; and the increased risk became apparent after the age of 40 years. In contrast a study of 100 PWH in Europe compared to 200 aged-matched controls, found no significant difference in the 10-year cardiovascular mortality risk >10% between PWH and controls using SCORE. Other studies have looked at individual cardiac risk factors and PWH had higher rates of hypertension than expected for the general population. Critically whether the cardiac risk algorithm conveys the same actual CVD risk and is valid in PWH is not known. Oxford University Hospitals has the ability to explore CVD risk and atherosclerosis in haemophilia with a proof of concept project due to having both a large haemophilia centre and the only UK photon-counting cardiac CT scanner. Photon-counting cardiac CT Coronary computed tomography angiography (CCTA) is a sensitive and widely used, non-invasive imaging modality for diagnosing coronary artery disease (CAD) and recent clinical guidelines have expanded its use as a first-line diagnostic tool in the management of chest pain of recent onset, suggestive of typical/atypical angina or non-anginal chest pain with electrocardiographic changes. However, conventional CCTA identifies only anatomically significant coronary artery stenoses which are found in <50% of all patients referred for this test. Importantly, the majority of acute coronary syndromes are caused by unstable but non-obstructive atherosclerotic plaques, which cannot be identified by conventional CCTA or other non-invasive diagnostic tests detecting coronary luminal stenosis or stress-induced myocardial ischaemia. In the normal population, early detection of cardiovascular disease and subsequent optimisation has been associated with reduced cardiovascular mortality. This has led to the development by our study investigators of the perivascular fat attenuation index (FAI or FAIPVAT), a novel imaging biomarker which detects vascular inflammation in the human coronary arteries using images from routine CCTA scans and is predictive of cardiovascular risk. The FAI relies on the discovery that inflammatory signals released by the diseased coronary artery, inhibit adipogenesis and trigger lipolysis in the perivascular adipose tissue (PVAT), shifting perivascular CT attenuation from the lipid towards that of the aqueous phase. Vascular inflammation is a driver of coronary atherosclerotic plaque formation, and a characteristic feature of atherosclerotic plaque rupture, leading to acute coronary syndromes including myocardial infarction. The causal role of inflammation in vascular disease pathogenesis has recently been documented by the CANTOS trial, which demonstrated that specific targeting of residual inflammatory risk improves clinical outcomes. In the CRISP-CT study, recently published in the Lancet, our investigators demonstrated that FAIPVAT predicts all-cause and cardiac mortality over and above clinical risk factors and the current interpretation of CCTA. These findings are validated in two large and substantially different "real-life" prospective cohorts of patients undergoing clinically-indicated CCTA, one in Europe and the other in the United States, demonstrating similar predictive value. Oxford University Hospitals has a newly-installed state of the art, photon-counting CT scanner, capable of performing CCTA to assess atherosclerotic burden and peri-vascular FAI. By incorporating an updated detector, single photons can be converted directly into electrical signals, removing the need for a two-step conversion process which is used in conventional CT scanners. This allows for higher resolution images than conventional CT at a given radiation exposure and therefore offers the opportunity to assess in detail the cardiovascular risk associated with haemophilia. Oxford Haemophilia Centre The Oxford Haemophilia Centre is one of the largest in the UK. The haemophilia team look after 190 PWH over the age of 40 years (range 40-88 years), of which 146 are over the age of 45 years, and 117 over the age of 50 years. Of PWH >45 years: 45 have severe haemophilia, 14 moderate haemophilia, 87 mild haemophilia; 77% have haemophilia A. Comorbidities are common and approximately 50% have hypertension and 7% atrial fibrillation. In those >65years, 6% have known ischaemic heart disease, 6% history of ischaemic stroke, and 4% peripheral vascular disease. In order to help answer the question of whether PWH develop atherosclerosis at a similar rate to the general population with similar known cardiac risk factors, and whether there is a difference in the stability of the plaques, the investigators will use this state-of-the-art cardiac imaging technique to look in detail at atherosclerosis in aging patients with haemophilia and compare how this imaging data correlates with standard cardiovascular risk scores such as QRISK. As a comparison to general population, imaging data and standard cardiovascular risk factors will be compared to anonymised control scans from other studies at the University of Oxford with matching for age, gender, and exposure to cardiovascular risk factors (smoking, hypertension, high cholesterol, diabetes, family history). These data could pave the way for future multi-centre clinical studies with increased numbers of PWH (especially through close regional haemophilia centres and potentially reducing age of screening), extension to other common bleeding disorders such as von Willebrand disease, and ultimately impact on clinical care for people with bleeding disorders (cardiac screening); as well as further translational research studies into the role of factor VIII and factor IX in the pathogenesis of atherosclerosis.

A Study of Zasocitinib in Adults With Psoriatic Arthritis Who Have or Have Not Been Treated With Biologic Medicines

ID93/GLA-SE Vaccination + BCG Challenge

Tuberculosis (TB) remains one of the deadliest infectious diseases worldwide. Key research priorities include the development of an effective vaccine. Currently, the only licensed vaccine against TB is BCG (Bacille Calmette-Guérin). This works well against TB in childhood but is often ineffective in adults. Developing a new TB vaccine is difficult, as it is hard to determine which will be effective. In other diseases, e.g. influenza or malaria, it is possible to experimentally-infect volunteers with the disease to see if the proposed vaccine is effective. This is called a "controlled human challenge or infection model" and is possible in easily treatable or self-limiting diseases. This is not possible with TB, where treatments may be harmful and complex. Using BCG, a live attenuated (weakened) strain of the bacteria that do not cause disease in healthy individuals, the investigators have developed a challenge model to mimic TB infection. Mycobacterium tuberculosis, the bacterium that causes TB, infects people by inhalation into the lungs. Therefore, inhaled BCG more closely imitates TB infection than an injection. Previous studies (TB041 and TB043) and a current study (TB044) in our group used aerosol inhaled BCG in both previously BCG-vaccinated and BCG-naïve volunteers to show that aerosolised BCG could be safely employed, and that BCG could be detected in lung washings two weeks after challenge. A novel TB vaccine (ID93/GLA-SE) has recently undergone clinical trials (phase IIa) to show that it can be given safely to healthy people. Its ability to protect people from TB is currently being investigated. The purpose of this study is to show the safety of this approach and provide preliminary immunogenicity data of this novel TB vaccine (ID93/GLA-SE) in both historically BCG-vaccinated and BCG-naïve volunteers, using an aerosol BCG challenge model. It will involve 48 participants; 12 historically BCG-vaccinated and 12 BCG-naïve participants will initially receive 2 injections of the intramuscular ID93/GLA-SE before challenge with aerosol BCG, while a further 24 participants (12 historically BCG vaccinated) will have aerosol BCG challenge alone. Bronchoscopies will be performed 14 days post aerosol BCG challenge to measure BCG recovered from bronchial samples. Blood samples will be taken to look at potential immunological markers of protection.

Natural History Study for Patients With Nemaline Myopathy in the UK

Current treatments for people living with nemaline myopathy are supportive only. Several potential therapies are in development which may be available in the next 5-10 years. The barrier to these becoming available is that there is little data available on the natural progression (natural history) of nemaline myopathy. This means that it would be difficult to do a clinical trial of a treatment because it is not known which assessments would be useful to measure or what normally happens during the lives of people with NM.This study aims to better define the natural history and disease specific outcome measures and biomarkers. This study will comprehensively evaluate the natural clinical progression of the disease using medical data and examination findings, scales and questionnaires for the assessment of motor function, breathing, swallow function and Quality of life and fatigue. In addition it will collect data on continuous movement and gait analysis using real world data and wearable sensors (Syde and Maiju), blood samples for future genetic and proteomic analysis and respiratory analysis using ventilatory and thoraco-abdominal pattern for paediatric participants.

Carriage to Assess Protection of New Pneumococcal Vaccines - PCV15

This is a Phase IV Double Blind (participant and observer) Placebo Controlled Randomised Controlled Trial (DBRCT) that will assess the superiority of PCV15 against placebo in healthy adults 18-50 years old exposed to an Experimental Human Pneumococcal Challenge (EHPC). Participants will be randomised 1:1 to receive PCV15 or placebo. We estimate a colonisation rate of 60% for the placebo group (84 participants with available endpoints, or up to 106 participants enrolled after adjusting for 20% attrition). One month following randomisation and vaccination with PCV15 or placebo, all participants will be intranasally inoculated with Streptococcus pneumoniae serotype 3 (SPN3). Participants will be inoculated with a pure culture of a well-characterised, fully sequenced amoxicillin-sensitive pneumococcal serotype 3 (Clade Ia, strain LIV014-S3). Follow-up for 28 days will occur in the clinic with assessment of laboratory measures of the acquisition of nasal pneumococcal colonisation and of immune response after which participants will be required to take a 5-day course of antibiotics. Participants will be considered enrolled into the trial at vaccination. Exploratory Nasal Biopsy cohort: From the 106 participants enrolled, 5 participants (not included in the primary endpoint sample size) will be asked to consent for a nasal biopsy procedure during screening visit and a second nasal biopsy 28 days after PCV15 vaccination. This cohort will not be blinded as only PCV15 will be provided. These participants wil not be inoculated and the study will terminate after the second biopsy visit (28 after vaccination). The study is sponsored by the University of Oxford with two sites: Oxford (Centre for Clinical Vaccinology and Tropical Medicine) and Liverpool (Liverpool School of Tropical Medicine). The Experimental Human Pneumococcal Challenge model is well established on both sites.

COmmencing Menopausal HOrmone Replacement Therapy and the Effect on Metabolic-dysfunction Associated Steatotic Liver Disease: a Pilot Mechanistic Study