Frankfurt/main, Germany

High-intensity Interval Training Combined with Muscle-strength Training in Older Women

Capillary OGTT Study

Muscle Mass, Quality, and the Menopause: Sex-specific Strategies to Mitigate Sarcopenia in Ageing Populations

The age-related loss of muscle mass and function (sarcopenia) inevitably results in physical frailty and functional impairments, such as difficulty raising from a chair, dressing, and preparing meals. With a rapidly growing aged population (those >65y increasing from 18% of the population in 2016, to 26% by 2066), sarcopenia represents one of the largest problems facing health care services. Excess healthcare costs associated with sarcopenia are rapidly growing and were estimated to be £2.5 billion in 2016. There is an urgent need to develop strategies to mitigate sarcopenia to reduce healthcare costs and improve health and wellbeing with age. These strategies must be targeted, as evidence suggests that there is sexual dimorphism in ageing and the development of sarcopenia. Sarcopenia develops earlier in women, resulting in greater levels of physical disability that includes difficulties in walking, getting out of a chair, and eating, compared with men. The mechanistic sex differences with ageing are unclear, yet the earlier prevalence of sarcopenia in women coincides with the menopause. In addition, physical disability can be further exacerbated by an increase in adiposity during the menopause in the face of decreasing muscle mass. This change in body composition includes ectopic fat infiltration into muscle that is associated with decreased muscle performance, however, currently, there is a lack of understanding as to how these changes in body composition occur. Understanding the underlying mechanisms that bring about change in physiological systems is key in the development of interventions. Muscle mass is controlled by the balance between muscle protein synthesis (MPS) and muscle protein breakdown (MPB). With age, many of the signals that increase MPS (i.e., nutrient intake and activity) become less effective, resulting in negative protein balance and muscle loss. Since muscle loss is accelerated after the menopause in women, there must be a greater imbalance between MPS and MPB. The measurement of MPS and MPB can be achieved using stable isotope tracer techniques that can be followed throughout the body. However, there is a lack of research into the mechanistic effects of the menopause on muscle mass regulation. In addition to measures of muscle protein turnover, the investigators have recently used stable isotope tracer techniques alongside MRI scanning to image deuterium incorporation within lipid. the investigators will use these techniques to image newly created fat to further understanding of body composition changes in post-menopausal women. Resistance exercise therapy (RET) currently offers the most effective strategy to mitigate muscle mass loss and improve body composition with ageing, by increasing MPS, promoting muscle hypertrophy, and building strength8. However, older women display blunted muscle hypertrophy in response to RET (when compared to younger women, and older men), and it is not known how the menopause affects hypertrophic responses to exercise. Further, for any intervention to have a meaningful impact, it must be effectively incorporated by postmenopausal women into their daily lives. The investigators have conducted an evaluation of physical activity interventions for post-menopausal women, which revealed that women going through the menopause want more evidence-based guidance on how much and what type of exercise they should be doing, and on whether exercise can alleviate menopausal symptoms and prevent muscle loss. Aims: To investigate the effects of the menopause on muscle mass regulation, changes in body composition, and assess the acceptability and effectiveness of RET.

Clinical Experience of Maintaining Patient Safety in Hospital

The National Institute for Health and Care Excellence clinical guidance CG161 recommends that all patients admitted to hospital over the age of 65 and those with specific underlying conditions between the age of 50 and 64 are considered at high risk of falls and a documented falls risk assessment is undertaken on admission. However, whilst advising the use of an appropriate multifactorial risk assessment (MFA) NICE also acknowledges that there is no evidence of the efficacy of most falls prevention methods in hospital and that high quality randomised controlled trials (RCT) conducted in the UK are required to improve the existing evidence base. Falls are referred to as accidents but statistically they have been shown not to demonstrate a pattern of chance which suggests a causal process. Contributing factors leading to falls have been recognised as; postural stability, gait, sensory deficit, neuromuscular impairment, psychological conditions, impact of medications, environmental risks and medical risks such as stroke and cardiac issues. Significant research has been undertaken in relation to falls in the community and as such there are useful clinical guidelines published by both NICE and World Falls Guidelines for preventing and managing patients falls in their home. Whilst patients may be at less risk in their own environment, when admitted to hospital usually single or multiple risk factors apply, even if only for a limited period due to the nature of their presenting condition. It is therefore necessary to assess all patients who are admitted to hospital to establish the level of risk they face and to prescribe interventions with the goal of preventing an accidental fall. In the UK, 30 - 50% of accidental falls in hospital lead to some injury and 1-3% of those sustain a fracture. In-patient falls are a significant cause of morbidity and mortality, with an estimated 247,000 occurring annually at a cost of £2.3billion to the NHS. In-patient falls have consistently been the biggest single category of reported incidents since the 1940's. Little has changed in the 39 years since the that paper and with falls accounting for 85% of all hospital acquired conditions in the USA it is safe to say this is a global issue. A recent Australian study estimated that the annual cost of attempts to prevent in-hospital falls across six health services consumed AU$590 million per year in resources. The areas of greatest investment were 18% physiotherapy, 14% 24 hour observation, 12% falls assessments and 11% falls prevention alarms and there is a lack of quality research to support their efficacy as falls prevention strategies. The generalisable level of success of these strategies is still not known. It seems that health services across the world are investing time and effort in strategies for which there is an absence of evidence. The recently published World Guidelines for Falls Prevention has confirmed there remains no research supporting the use of technology such as falls alarms or nonslip socks (NSS) in hospitals and as such recommends only standard falls prevention methods. As a result of increasing reimbursement costs for hospital treatments, in 2008 the Centres for Medicaid & Medicare Services, health insurance companies in the United States of America (US), removed reimbursement to hospitals for costs incurred by patient falls and any associated trauma resulting in increasing financial burden to hospitals. The impact on staff suffering 'second victim phenomena' as a result of adverse incidents and the cost to patients who suffer pain, disability, and death is incalculable.

Drug-induced Liver Injury: Itching Study

In Idiosyncratic drug-induced liver injury (DILI), the adverse effect is unexpected from the known pharmacological action of the agent. The incidence of DILI is estimated as between 14-19 per 100,000 inhabitants; a population-based study in Europe reported the annual incidence as 19.1 per 100,000. Despite its rarity, idiosyncratic DILI accounts for 7-15% of the cases of acute liver failure in Europe, although many cases resolve quickly. DILI is the most frequent reason for the market withdrawal of an approved drug. In addition, DILI occurs in association with many drugs and shows heterogeneity. There are no markers that can effectively pre-empt and prevent DILI or monitor the severity and course of the adverse event. It is also emerging that immunotherapy regimens devised for cancer treatment are associated with increased risk of DILI development. Further characterisation and understanding of this is urgently needed to distinguish from other causes and develop more effective treatments. Age, smoking, metabolic syndrome, co-morbidity and other yet unidentified factors may generate an environment of oxidative stress that contributes to DILI. Therefore, 'in-depth phenotyping' is needed to develop a refined understanding of drug-related factors, host genetic and environmental risk factors linked to disease characteristics that would enable us to pre-empt and treat DILI. Further work is also needed to identify patients who may benefit from new treatments becoming available, so identification and analysis of certain sub-groups is of value. Based on the pattern of liver biochemistry at the time of initial presentation, DILI is classified as cholestatic, hepatocellular or mixed type. Pruritus (itching) occurs in a proportion of patients with cholestatic and mixed pattern of DILI. Most DILI manifestations resolve within 3 months following the prompt withdrawal of the causative medication, but symptoms persist for 6 months in 18.8% and for 1 year in 12.4%; persistence of symptoms are more common in cholestatic pattern of DILI. Those with persistent DILI have significantly lower SF-36 quality of life scores at baseline and during follow-up. Research is needed to identify patients who may benefit from new treatments becoming available, so identification and analysis of certain sub-groups is of value. DILI is the second most common cause of itching in adult Hepatology, after biliary obstruction. Cholestatic or mixed pattern of DILI is associated with chronicity as well as reduced quality of life. There is currently limited data available on the incidence and impact of pruritus in DILI. Although therapeutics targeting bile acid pathways have been deployed to tackle cholestatic pruritus in primary biliary cholangitis (PBC), their application in cholestatic DILI requires investigation. Further, there is now also effective treatment that have been licensed to improve quality of life of patients with itching as well as potentially improving natural history of cholestatic conditions.

A PROspective Faecal MIcrobiota tranSplantation Trial to Improve outcomEs in Patients With Cirrhosis

There is an evolving crisis of chronic liver disease (CLD) in the UK and it is the only major chronic disease which is on the rise. The advanced stages of CLD, known as cirrhosis (a hardening and scarring of the liver), is the third biggest cause of death and loss of working life years behind heart disease and self-harm. People die from cirrhosis young with more than 1 in 10 in their 40s. Patients with cirrhosis are very susceptible to infections, antibiotics become ineffective and patients may become infected with 'super bugs'. There is an urgent need for antibiotic-free approaches. The body contains trillions of microscopic organisms called bacteria which play an important role in keeping us healthy. Many of these bacteria live within our bowel and help our immune system fight infection. There are increased numbers of 'unfriendly' bowel bacteria in patients with cirrhosis which emit substances that are harmful to health and disrupt the immune system. It could be beneficial to replace the unfriendly bowel bacteria in patients with cirrhosis with bacteria donated from a healthy person by performing a type of bowel bacteria transplant (known as faecal microbiota transplantation or FMT). The PROFIT trial was recently performed as a preliminary trial of FMT which was placed into the bowel with the help of a flexible camera (endoscopy). The study showed FMT was safe with no serious side effects, but patients told us they would prefer to take tablets rather than have an endoscopy. The chief investigator and her team have therefore made a capsule which contains dried stool from a healthy donor. Participants will need to take 5 of these capsules to achieve the same dose. The PROMISE clinical trial is to test whether treating patients with FMT capsules will reduce the likelihood of them getting an infection by measuring the time it takes to develop an infection resulting in hospital admission. This will be compared to a 'dummy' capsule that contains no FMT (placebo). Patients will be selected at random to have FMT treatment or placebo and both the study team and the patients will not know which treatment they are taking. Participants will need to take 5 capsules every 3-months. Participants will continue treatment for a total of 21-months or until they develop their first infection leading to hospital admission and will be followed-up for a maximum of 2-years. This study will also examine if having FMT will reduce the side effects of cirrhosis and if it has beneficial effects on the liver and immune system. The investigator team will study whether it reduces hospital admissions, the incidence of 'super-bug' infections and death. Laboratory studies will look at whether FMT treatment will help the immune system fight infection. The World Health Organisation describes the resistance of bacteria to the effects of antibiotics as one of the biggest threats to global health. The discovery of new antibiotics has not kept pace. The government's white paper proposes a 5-year plan to tackle resistance to antibiotics. Consultation with our patient co-applicant, patient advisory group, The British Liver Trust and Guts UK Charity have highlighted recurrent hospitalisation, over-use of antibiotics and fear of acquiring a 'super-bug' as being important priorities to patients. The results and study findings will be published in conjunction with patient support groups, the wider media and the NHS. The investigator will ensure the research impacts on the management of patients with CLD and shapes policy and guideline development.

Revumenib in Combination With Azacitidine + Venetoclax in Patients NPM1-mutated or KMT2A-rearranged AML

A Study of Maribavir in Adults With Post-transplant Cytomegalovirus (CMV) Infection

This study will include two main periods of retrospective data collection from medical charts: the pre-index period and the post-index period. The index date is defined as the date of initiation of maribavir dosing, as documented in the medical records. The pre-index period covers the time from the transplant date to the index event, while the post-index period starts at the index event and ends at the date of chart abstraction, death, or loss to follow-up, whichever comes first.

VirtuAl Technology to Improve the Management of Perianal Crohn's (VAMP) - PROSPECTIVE

The development of the vEUA tool is a significant advancement in the management of perianal Crohn's disease fistulas. Mismanagement of fistulas can lead to significant complications, such as abscesses, scarring, and delayed healing. Additionally, multiple surgeries can cause damage to the anal sphincter muscles, leading to incontinence and other issues. With the vEUA tool, surgeons can now have a more precise and accurate understanding of the fistula anatomy before conducting the examination under anaesthesia. This approach can significantly reduce the risk of misdiagnosis and subsequent complications. The tools 3D visualization capability allows surgeons to assess the extent of the fistula, its location, and any associated abscesses or inflammation. This information is essential for planning the surgery and ensuring that the procedure is as minimally invasive as possible. In addition to improving surgical planning, the vEUA tool can also enhance post-operative care. The 3D model generated by the tool can be used to monitor the healing process and ensure that the fistula has healed correctly. This approach reduces the need for multiple follow-up surgeries and promotes faster healing. With the vEUA tool, surgeons can better plan the surgery to avoid damaging the muscles, promoting faster healing and reducing the risk of long-term complications. Overall, the development of the vEUA tool represents a significant breakthrough in the management of Crohn's disease and perianal fistulas. The tool's ability to provide a more precise and accurate understanding of the fistula's anatomy will reduce the risk of misdiagnosis, promote faster healing, and improve patient outcomes. vEUA generates a disease activity score based on T2 enhancement and a volumetric measurement of the fistula tract, providing a more detailed analysis of the fistula and surrounding structures. RESEARCH QUESTION / AIM(S) Our proposed investigation aims to generate early clinical usage data to assess the feasibility of the vEUA approach. Our findings will feed into a larger multicentre study at a later date. In this early-stage investigation, we aim to answer the question: Does vEUA improve the surgeon's confidence in and ability to manage all fistula tracts and drain all collections in perianal Crohn's disease at surgery? In addition, we aim to gain insight into the following supplementary questions that will feed into future projects: - Can vEUA be used effectively by trained radiologists? - How long does it take a radiologist to perform a vEUA? - What concerns do patients have over the vEUA system? How does viewing a vEUA report change their perception of their disease, their treatment and their ability to provide informed consent? (Answered through our PPIE work packages and survey). - Is there any indication that the vEUA system reduces the likelihood of a patient requiring multiple operations to control sepsis and fistula tracts? - Does the use of vEUA translate to improved disease control and a subsequent improvement in quality of life for patients? The purpose of answering these questions is to determine whether the quality of care afforded to perianal Crohn's patients can be meaningfully improved by the vEUA system. These data will highlight which patients will benefit most from vEUA. It is possible that this technology will be most useful for those with more complex disease, i.e., multiple fistula tracts or deep collections, thus ensuring value for money in the future through correct patient selection to vEUA. 30 patients will be prospectively recruited to this vEUA feasibility study, 15 to standard care and 15 randomised to the vEUA technology, and assess outcome data as outlined below to guide future studies and assess the acceptability of the vEUA technology to patients and clinicians. Standard care (SC) will be defined as a written MRI report by a qualified radiologist followed by EUA and intervention as per surgeon's findings. Interventions will include one or combinations of: lay open of fistula, insertion of seton into the fistula tract and / or drainage of abscess. vEUA-enhanced care will be defined as having a vEUA performed by the radiologist following a MRI using the same unmodified sequence from the SC arm (in addition to a written radiology report). The surgeon will then be given unlimited access to the vEUA interactive report via standard PC hardware. The surgeon will then perform the EUA and intervention as per SC but with the additional insight garnered from the vEUA interactive report. We will also monitor the time taken to mark up and produce the vEUA and compare this to the time taken to produce a standard MRI report. OUTCOME MEASURES: These will include: 1. Baseline inflammatory bowel disease (IBD) specific patient outcome measures will be collected on recruitment, including: - IBD quality of life (IBDQ) scores - The Crohn's Anal Fistula Quality of Life (CAF-QoL) scale - Hospital Anxiety and Depression Scale (HADS) - Incontinence (Vaizey / St. Marks) score 2. Baseline clinical outcome measures will be assessed including: - Perianal Disease Activity Score (PDAI) - Number of surgical interventions (EUAs) in previous 3 months - Number of antibiotic courses in previous 3 months 3. Biochemical disease activity will be measured by: - C-reactive protein (CRP) - Faecal calprotectin These outcome measures will be re-captured again at 3 months postoperatively and exploratory analyses will be undertaken. We will use baseline variables to predict postoperative response. 4. An evaluation of surgical confidence and opinion will be used to assess surgical confidence prior to commencement of the procedure, surgeons will be asked to propose and document a likely pre-operative plan based on their understanding of the anatomy of the disease from the information available through either a standard MRI report or vEUA. Their confidence in this plan will be scored using a Likert scale from 1 (no confidence) to 10 (extremely confident). Immediately following surgery, surgeons will again be asked to complete a questionnaire to include interventions completed, adherence to pre-operative plan scored from 1 (no adherence to plan) to 10 (exact plan followed) and their confidence in having adequately and safely identified and treated all fistula and collections with each aspect scored from 1 (no confidence) to 10 (extremely confident). 5. An evaluation of patient opinion will help us understand the benefit of vEUA in describing and explaining disease anatomy to the patient and in obtaining informed consent for surgical intervention. Patients will be presented with a decisional conflict scale10 to evaluate their personal uncertainty related to their surgery after consultation with a surgeon. A 16-question, 5-response category (strongly disagree to strongly agree) traditional decisional conflict scale will be to assess whether the patient feels they are making an effective decision (i.e., the decision is informed, values-based and likely to be implemented). Results will be compared between patients shown their vEUA and those randomised to SC. 6. A radiological assessment of surgical quality will allow assessment of disease control at surgery. Patients will undergo a repeat MRI scan of the pelvis at 4 weeks post-procedure to look for undrained collections, the size of any remaining collections or untreated fistula i.e., those not laid open or with a seton in-situ. MRI scans will be reviewed by an adjudication radiology / surgical panel to compare the relative successes of SC and vEUA in achieving disease control. We hope to establish utilising these data that vEUA is safe and effective in improving the care of patients with perianal Crohn's.

AZD0486 as Monotherapy in Participants With Relapsed/Refractory (R/R) B-cell NHL

This is a modular, Phase II, multicenter, single-arm, open-label study to evaluate the efficacy and safety of AZD0486 monotherapy administered as an intravenous (IV) infusion in participants with relapsed or refractory B-NHL. The purpose of this study is to determine the efficacy and safety of AZD0486 administered at the RP2D in adults 18 to 80 years of age with relapsed or refractory B-NHL.