Dk-2730, Herlev, Denmark

An Extension and Crossover Vaccination Study on the Immune Response and Safety of a Vaccine Against Respiratory Syncytial Virus Given to Adults 60 Years of Age and Above Who Participated in RSV OA=ADJ-006 Study

A Study to Assess Efficacy and Safety of Efgartigimod PH20 SC in Adults With Ocular Myasthenia Gravis

Promotion of Nurses' Lower Extremity Health by Foot(at)Work Intervention

Investigation of VAP-1 Expression and Tissue Blood Flow by PET-MRI in Patients With Crohn's Disease

Patients with a strong suspicion of small bowel's CD after the colonoscopy and laboratory studies will be recruited to study protocol in the outpatient gastroenterology clinic of Turku University Hospital. After the signed informed consent patients will undergo combined [68Ga]Ga-DOTA-Siglec-9 and [15O]H2O PET/MRE, the MRE being part of their clinical diagnostics. If the MRE shows no signs/or mild inflammation of small intestine CD patients will be directed to small bowel capsule endoscopy (SBCE), which is routine in this clinical suspicion. The patients will also have routine blood samples taken. A complete blood count (CBC), C-reactive protein (CRP), creatinine, alanine aminotransferase (ALAT), alkaline phosphatase (AFOS) and albumin will be analysed from each patient's blood sample, calprotectin and faecal microbiota will be analysed from stool. The tissue samples for (immuno)histological evaluation, proteome-wide mass spectrometry allowing sensitive site-specific detection of ADP-ribosylation and structural protein analysis will also be obtained in primary ileocolonoscopy (biopsies from the bowel wall). Before the PET study starts, the patients will undergo screening procedures with physical examination, chemistry panel (electrolytes, creatinine, liver function), and acute phase reactants (ESR, CRP) and urine tests. In addition, serum/plasma biomarker sample, serum sample for soluble VAP-1 analysis, whole blood RNA sample, and whole blood DNA sample for gene variant analyses will be collected. In the combined PET/MRE scanning the study subjects lay in the prone position on the PET scanner bed, and the area of interest (AOI) is positioned in the gantry and in the field of view. [68Ga]Ga-DOTA-Siglec-9 and [15O]H2O PET/MRE imaging will be performed in the fasting state (at least 6 hours). The patients will be instructed to avoid caffeinated drinks during the last 24-hours before the study. A catheter will be inserted in an antecubital vein for injection of PET radiopharmaceutical. Another catheter will be inserted in the opposite radial or antecubital vein for blood sampling and the subjects will be placed in supine position in the PET/MRE scanner, arms next to the body. Ideally, urinary bladder should be empty before PET/MRE scan. The uptake of tracer will be measured using PET and MRE will be performed for anatomical reference. After PET scans, the patients with CD will be treated and followed by gastroenterologist according to the current guidelines.

A Study on the Immune Response, Safety and the Occurrence of Respiratory Syncytial Virus (RSV)-Associated Respiratory Tract Illness After Administration of RSV OA Vaccine in Adults 60 Years and Older

The Effect of Cancer Treatments on Speech Perception in Noise, Cognition, and Hearing-Related Quality of Life

The study will assess the effects of four different types of cancer treatments on speech perception in noise, hearing thresholds, cognition, and hearing-related quality of life over a follow-up period of 3 years. The speech perception in noise will be assessed using the Finnish matrix sentence test. Other hearing measures include transient and distortion product otoacoustic emissions, impedance audiometry and pure-tone audiometry extending to high frequencies (0.125kHz - 16kHz). Hearing-related quality of life will be assessed using Speech, Spatial, and Qualities 12 -questionnaire, Vanderbilt Fatigue Scale 10 -questionnaire and Tinnitus Handicap Index. Cognitive functions will be assed using Functional Assessment of Cancer Therapy - Cognitive Function (FACT-Cog) questionnaire and neuropsychological tests. The neuropsychological tests included in the study are Continuous Performance Test, Continuous Auditory Test of Attention, Trail Making Test A & B, Stroop Test, Coding and Digit span tasks from the Wechsler Adult Intelligence Scale - Fourth Edition, Word List task from Wechsler Memory Scale III, and Controlled Oral Word Association Test. Neuropsychological assessments will be conducted at baseline and 1 year and 3 years after the end of the treatments. All other assessments will be conducted at baseline and at 3-4 months, 1 year, and 3 years after the end of the initial treatments.

Virtual Pulmonary Rehabilitation Program for COPD Patients; a Pilot Study

The e-PURE study is an investigator initiated study, which aims to evaluate the feasibility, effectiveness, and long-term outcomes of a digital pulmonary rehabilitation program designed for patients with Chronic Obstructive Pulmonary Disease (COPD) in Southwest Finland. This pilot study assesses patient adherence, lung function, exercise capacity, quality of life, and the program's potential impact on healthcare utilization. COPD is a common disease, affecting mostly elderly, with significant impact on life expectancy and quality of life. Pulmonary rehabilitation (PR) is an essential intervention for COPD patients, known to enhance health-related quality of life and reduce symptoms like shortness of breath. Traditional PR programs are underutilized due to accessibility barriers, with less than 1% of COPD patients in Canada and 3.7% in the U.S. attending such programs. The COVID-19 pandemic exacerbated these challenges by halting in-person PR programs. Virtual PR offers a promising, non-inferior alternative. The e-PURE study responds to this need by rolling out a digital rehabilitation program developed by a multidisciplinary team of healthcare professionals. This is a single-arm observational pilot study enrolling up to 50 COPD patients. The rehabilitation program spans around 12 weeks, with follow-up assessments at 16 and 26 weeks post-enrolment. Patients undergo a tailored rehabilitation plan that includes individualized exercise routines, nutritional counselling, and smoking cessation support. Progress is reported through questionnaires and clinical evaluations such as the 6-minute walk test. The primary outcome measure is the improvement in distance during the 6-minute walk test after the program, compared to baseline. Secondary outcomes include patient satisfaction, changes in the St. George Respiratory Questionnaire, and healthcare resource utilization (hospital readmissions, emergency visits). The pilot study will identify whether a larger follow-up study is feasible, and indicate the number of patients to recruit.

Pooled Human Plasma vs Crystalloid in The Management of Children Undergoing Instrumented Spinal Fusion for Scoliosis

Introduction Total blood loss including intraoperative, drain output, and hidden blood loss equals to 40% of blood volume in patients undergoing posterior spinal fusion for paediatric spinal deformities. Despite the perioperative use of tranexamic acid and gelatine matrix with human thrombin, 14% of patients with adolescent idiopathic scoliosis (AIS) and 73% of patients with neuromuscular scoliosis (NMS) require allogenic red blood cell infusion (Soini et al. NASSJ 2022). Early use of pooled human plasma (PHP) may reduce total blood loss in these patients, but there are no studies in the paediatric population undergoing major surgery on this subject. Objective To compare pooled human plasma (PHP, OCTAPLAS) vs. crystalloid (PLASMALYTE, comparator) for intraoperative bleeding, drain output, and hidden blood loss as well as the sum of these components (total blood loss) in children undergoing posterior spinal fusion for AIS. Adverse events will be recorded and reported as minor (skin reaction) or major (severe allergic reaction, transfusion related acute lung injury, TRALI; deep surgical site infection, neurologic injury). The investigators hypothesize that the use of PHP in the early perioperative management will reduce intraoperative blood loss (primary outcome), drain output, and hidden blood loss accounting for total blood loss and reduce the need for perioperative allogenic red blood cell infusion (secondary outcome) without increasing the risk for adverse events. Additionally, postoperative pain (opioid consumption and pain score, secondary outcome) may be decreased. Outcomes Primary outcome is intraoperative blood loss (blood loss in mL after wound closure). Secondary outcomes include need for allogenic red blood cell infusion (percentage of patients at hospital release, health-related quality of life (Scoliosis Research Society 24 outcome questionnaire), postoperative pain (48-hour opioid consumption, pain visual analogue score), operative time (hours), drain output (mL), hidden blood loss (mL), hospital stay, and complications (skin reactions, TRALI, deep surgical site infection). Disease specific Scoliosis Research Society (SRS)-24 questionnaires are filled out preoperatively, at 6 months and 24 months during postoperative outpatient clinic visits. Study design A randomized, double-blinded, multicenter (Helsinki and Turku University Hospitals, Finland) clinical trial according to CONSORT criteria. After randomization, patients will be given in a blinded fashion (except for anaesthesia nurse) either 10 ml/kg (maximal dose 400 ml) pooled human plasma (OCTAPLAS or 10ml/kg (maximal dose 400 ml) crystalloid (PLASMALYTE) as an intravenous 1-hour infusion, as part of the standard anaesthesia of scoliosis surgery, starting at one hour before incision. Scoliosis surgery is a complex procedure, in addition to standard pharmacological treatment and anaesthesiologic control of blood pressure, surgical technique significantly affects blood loss during surgery. To dependently determine the effectiveness of OCTAPLAS to reduce blood loss, the operating room needs to be blinded for intervention. Selection of study population Trial subjects consist of individuals who are planned to undergo PSF for scoliosis as standard practice. Individuals are 10 to 21 years of age. The study population consists of adolescents with idiopathic scoliosis (over 45 degrees) and neuromuscular scoliosis (over 50 degrees). All individuals are required to give informed consent either by patient, legal representative/parent, or both, when appropriate. Patients under legal age of independent consent (less than 15 or 18) need parents' or caretakers' consent in addition to their own consent. Some neuromuscular scoliosis patients are not capable of giving their own informed consent. In that case the consent is given only by the child´s legal representative or parent. Suitability for this trial is determined by the need of surgical intervention for scoliosis, thus the patient population who would benefit from the treatment under investigation includes individuals who are minors or are not capable of giving informed consent, thus inclusion of this patient population in this investigation is justified. The clinical trial is essential with respect to incapacitated subjects and data of comparable validity cannot be obtained in clinical trials on persons able to give informed consent, or by other research methods, and the incapacitated subjects have received the information referred to in Article 29(2) in a way that is adequate in view of their capacity to understand. The sponsor considers that the conditions for the inclusion of incapacitated subjects in the trial, as laid out in Art 31 of the CTR, are considered fulfilled. Inclusion criteria Subjects meeting all the criteria below may be included in the study. To be eligible for inclusion, each subject must meet each of the following criteria at Screening and must continue to fulfil these criteria at Baseline (Visit 1). Patients will be included in the study if they fulfil the following criteria: - Written informed consent. - Aged between 10 and 21 years of age - Scoliosis requiring posterior scoliosis surgery using all pedicle screw technique for AIS (>45-degree major curve) or NMS (>50-degree major curve); - Normal whole spine MRI except for the spinal deformity (only for patients with adolescent idiopathic scoliosis as patients with neuromuscular scoliosis do not typically undergo MR images as they would need general anaesthesia). Exclusion criteria Subjects are excluded from the study if any of the following criteria is met at Screening or at Baseline: - Immunoglobulin A-deficiency - Need for anteroposterior surgery - Need for three column vertebral resection - Smoking - Diabetes mellitus - Abnormalities in blood coagulation (thromboplastin time below above or below of normal values, 70-130%) - Blood trombosytes less than 150 x E9/l - Body mass index over 40 - Allergy or hypersensitivity to study medications or their ingredients - Pregnancy or breast-feeding, aim of becoming pregnant during the study. - Participation in another study and receipt of any other investigational agent during 2 year period of current investigation - Inability to provide written informed consent - Any significant disease or disorder which, in the opinion of the investigator, may either put the subject at risk by participation in the study, or may influence the result of the study. - A history of drug or alcohol use that, in the opinion of the investigator, would interfere with adherence to study requirements. - Known history of, or documented positive hepatitis B or C or HIV infection - Prior or concurrent malignancy 12 - Aspartate transaminase (AST) or alanine transaminase (ALT) ≥ 3 x upper-limit of normal - Creatinine clearance (CrCl) < 60 ml/min measured by 24-hour urine collection or estimated from the Cockcroft and Gault formula - Clinically significant ECG findings as judged by the investigator - Amiodarone medication - Hyperkalemia - Renal insufficiency - AV-block - Metabolic or respiratory alkalosis - Hypochlorhydria - Hypersensitivity for active component or additives - Contraception requirements: Combined hormonal contraception should be stopped 4 weeks prior to receiving IMP. Progestin-only contraceptives including pills, implant and intrauterine system, and Copper IUD) and sexual abstinence are allowed forms of contraception. Withdrawal Patient can withdraw from trial at any point at will. The infusion is administered during anesthesia and primary outcome can be evaluated in all patients. Randomization and blinding The randomization is carried out by research coordinator, using a computer-generated method (www.sealedenvelope.com), in 1:1 allocation ratio. Randomization aims at equal distribution of the active treatment throughout the study period and between the different centres. To balance the groups, stratification will be conducted according to centre (Helsinki vs. Turku), developmental disability (Yes vs. No), and weight (less than 60 kg vs. 60 kg or more). The study will be conducted in a double-blind fashion. Study treatment assignment will be blinded for both the investigators and the subject. At each local investigation site, a defined group of trained, unblinded personnel will be responsible for preparing the intravenous study drug and for delivering the drug to blinded personnel involved in the subsequent patient treatment and care. The person preparing the drug will not participate in other aspects of the study. The blind can be broken in case a significant medical adverse event occurs (such as suspected allergic reaction). Any intentional or unintentional breaking of the blind will be recorded and reported to the sponsor as soon as possible. Blinding and coding lists saved are managed in secure database and under the responsibility of the Chief Investigator, who has access to this database. In case of unblinding is needed, the unblinding process is conducted as follows: Criteria for Unblinding: Unblinding will be performed only if it is deemed essential for the immediate clinical management of a participant. Unblinding may be initiated if a serious adverse event (SAE) occurs that, in the investigator's judgment, requires knowledge of the treatment assignment to make critical decisions for patient care. Procedure for Unblinding: The investigator should first attempt to contact the trial's chief investigator or research coordinator to discuss the need for unblinding. If the chief investigator or research coordinator agrees that unblinding is necessary, the randomization code will be accessed. If the chief investigator or research coordinator cannot be reached in a reasonable time frame, the investigator may proceed to unblind, documenting the reason and the time. Accessing the Randomization Code: The randomization code is securely stored in a sealed envelope at the trial site in patient folder and in an electronic randomization system accessible only by authorized personnel. The investigator or treating physician must log the details of the unblinding event, including the date, time, and rationale for unblinding, in the participant's medical record, from where it transferred eCRF. Surgery Surgery - Posterior surgery for scoliosis will be conducted according to current standard. Surgical planning of implant placement and the need for Ponte procedures will be carried out preoperatively. Each patient will be placed in the prone position and the posterior elements will be exposed using electrocautery. Ponte osteotomy will be conducted as described previously (Ponte et al, 1985). After full facetectomies, ligamentum flavum and laminae are resected for 5 mm posteriorly at three adjacent levels. The deformity will be corrected using bilateral segmental pedicle screw instrumentation and by en bloc vertebral column derotation. Spinal fusion is carried out using autograft acquired from facetectomies and osteotomies with bone graft extenders (iFactor, Cerapedics, Ic., Westminster, CO). Spinal cord monitoring (MEP, SSEP, lumbar nerve root EMG with or without pedicle screw stimulation) will be undertaken in all patients. A single subfascial drain (Hemovac Ch14; Zimmer, Warsaw, Indiana) will be placed and kept for 24 hours post-operatively. A sterile wound dressing will be applied at the end of surgery. All patients will be mobilized using a standardized protocol: sitting on the day of surgery, minimum four steps on 1st postoperative day (AIS), and progressively increasing walking distance with an aim to discharge patients on 4th -5th postoperative day. Discharge criteria include ability to walk independently (AIS) or sit independently (NMS), no need for opioid prescription, and ability to empty bladder spontaneously without a significant urinary retention (>200 mL). Anaesthesia All patients will have total intravenous anaesthesia including dexmedetomidine, propofol and remifentanil-infusions. Mean arterial pressure will be kept between 65 mmHg and 75 mmHg during surgery and for the first 24 hours postoperatively. Cefuroxime and Vancomycin will be used as antibiotic prophylaxis. All patients will receive pain control by oral long-acting Targiniq™ twice daily along with on demand short-acting oral oxycodone. The analgesic management also includes regular oral paracetamol. All patients will receive an intravenous bolus of tranexamic acid (30 mg/kg, maximum dose 1500 mg) within 30 minutes before incision and then an infusion (10 mg/kg/h, maximum dose 500 mg/h) during surgery. Intraoperative blood loss will be measured and recorded as the amount of blood collected in the cell saver, surgical wound dressings will be weighed during surgery, excluding any irrigation with saline. Allogenic red blood cells will be transfused according to a threshold level of Hb 80 g/L during surgery or during the hospital stay. Pooled frozen human plasma will be given according to randomization or if the blood loss exceeds 50% of the patient's total blood volume (safety criteria). Platelets will be infused if the blood loss is more than 100% of the blood volume. The estimated blood volume will be calculated using a formula of 70 ml/kg x weight (kg). Arterial gas analyses will be performed minimum twice intraoperatively and at the postoperative recovery unit to rule out hyponatremia and hyperkalemia. Vasopresssin is not part of our standardized anaesthesia protocol. Assessment Day 1 of the trial is day of the surgery, and the trial medication and placebo will be given to patients. During surgery Intraoperative blood loss is determined by weighting of surgical folds and measurement of surgical suction collection. Mean arterial pressure (MAP), systolic arterial pressure (SAP), diastolic arterial pressure (DAP), heart rate, blood oxygen saturation, BIS/SQI, body temperature and noradrenalin infusion (μg/kg/min) is recorded at anaesthesia induction, after patient positioning in prone position on operating table, after surgical incision, after implantation of screws and rods, after correction of scoliosis and after wound closure. Patient haemoglobin concentration and haematocrit is recorded at end of surgery, 4 hours, and 8 hours after surgery. Pain visual analogue scale (VAS 0-10) is recorded at 4 and 8 hours after end of surgery. Day 2 to 5 are the 1st to 3rd postoperative days. Patients are hospitalised at surgical ward. At day 2 to 5 patient haemoglobin concentration and hematocrit is recorded. At day 2 wound drain is removed and total drain output is recorded. PCA pump is removed at day 3 and total oxycodone consumption is recorded. Peroral oxycodone consumption is recorded at day 4 to 5. Pain VAS is recorded at day 2 to 4. Nausea, skin rash and other possible other adverse reactions are recorded. Scoliosis radiographs, SRS-24 questionnaire, Pain VAS, adverse events, and pain medication are recorded at 6 and 24 months. End of Trial Trial ends 24 months after surgery of the last participant. The Sponsor and/or the trial steering committee have the right at any time to terminate the study for clinical or administrative reasons. The end-of-trial is the date of the last visit of the last subject. The end of study visit includes assessment of primary and secondary outcome measures, assessments of safety and compliance with study treatments, and recording of concomitant medications. Unblinded interim analysis will be conducted after enrollment of 50% of the predetermined number of patients. If the experimental group shows >20% higher intraoperative blood loss, >20% higher incidence of blood transfusions or >20% higher complication rate, as compared to comparator the trial will be terminated. The analysis and possible recommendation of study termination will be made by independent external DSMB. Description of treatment OCTAPLAS is a solvent/detergent (S/D) treated, pooled human plasma indicated for replacement of multiple coagulation factors in patients with acquired deficiencies due to liver disease or who are undergoing cardiac surgery or liver transplantation; and plasma exchange in patients with thrombotic thrombocytopenic purpura (TTP). OCTAPLAS is infused based on ABO-blood group compatibility. OCTAPLAS is marketed in the Member States of the Union. The marketing authorisations include major surgery. 10 ml/kg OCTAPLAS (maximal dose 400 ml) is infused in 60-minute infusion prior to surgical infusion. This should increase the patient's plasma coagulation factor levels by approximately 15-25%, resulting in lower intraoperative blood loss. PLASMALYTE Injection is a sterile, nonpyrogenic intravenous solution which does not contain bacteriostatic or antimicrobial agents or added buffers. 19 PLASMALYTE Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) administered intravenously has value as a source of water, electrolytes, and calories. One litre has an ionic concentration of 140 mEq sodium, 5 mEq potassium, 3 mEq magnesium, 98 mEq chloride, 27 mEq acetate, and 23 mEq gluconate. The osmolarity is 294 mOsmol/L (calc). Normal physiologic osmolarity range is 280 to 310 mOsmol/L. The caloric content is 21 kcal/L. PLASMALYTE is marketed in the Member States of the European Union. The marketing authorisations include major surgery. 10 ml/kg (maximal dose 400 ml) PLASMALYTE is infused in 60-minute infusion prior to surgical infusion. PLASMALYTE A serves as placebo. PLASMALYTE is the standard crystalloid used in the participating investigation sites. The study medication will be supplied to pharmacy by Helsinki and Turku University hospitals and retrieved at the end of the study. The investigator is responsible for the control of the treatments under investigation. Adequate records for the receipt and disposition of the IMP will be maintained. The investigator will use a standard prescription manner of the institution and the research nurse will collect the medication from the pharmacy. Accountability and subject compliance with study treatments will be assessed by maintaining dispensing and return records. Safety reporting Adverse events will be reported according to Common Terminology Criteria for adverse effects (CTCAE, V.5, 2017) and graded as an assessment of the causal relationship to the investigational medicinal product. The PI or a delegated physician is responsible for registering and reporting AE/AR or serious AEs or serious ARs (SAE/SAR). All assessments will be documented in HUSeCRF and registered at the in-hospital treatment daily and follow-up visit at 3 months and 24 months post-surgery. Thereafter, the safety registration and reporting will be finalised. A SAE/SAR will be reported to the chief investigator within 24 hours after the PI becomes aware of event. If the PI at one of the participating sites suspects a suspected unexpected serious adverse reaction, they will inform the chief investigator with 24 hours. SUSARs will be reported to Fimea with CIOMS form, which transfers them to EudraVigilance database. If the event is fatal or life threatening, the event will be reported immediately. Any event that is neither fatal nor life threatening is reported within 7 days of the investigators' knowledge of such an event. In the case of a event, all participating investigators will be informed of the event, and any consequences related to the execution of the trial will be communicated. Data Safety Monitoring Board The investigators and institutions involved in this clinical trial are under clinical trial-related safety monitoring. Independent Data Safety Monitoring Board (DSMB) evaluates risks and if necessary the efficacy of investigational product. DSMB recommends the sponsor either to continue or terminate the ongoing investigation. The DSMB is composed of paediatric orthopaedic surgeon, paediatrician, paediatric anaesthesiologist and biostatistician, all members of DSMB are experienced in clinical research involving underage patients. All trial documents are available to the public at the European Medicines Agency website Clinical Trials Information System (CTIS) database. If protocol deviations occur, these are reported from PIs to the chief investigator as soon as possible and noted in the eCRF separately. Statistics The sample size has been evaluated with significance level (alpha) 5%, power (1-beta) 70% with expected mean blood loss in Plasmalyte group (NMS 1085 ml (SD 1049), AIS 554 ml (SD 349) and Octaplas (NMS 700ml, AIS 409). Expected blood loss is derived from institutional treatment registry (Soini et al NASSJ 2022). Allowing 5% lost to follow-up 97 patients for both groups are required. The statistical analyses are adjusted using linear mixed model with developmental disability diagnosis and weight as independent variables. Intention to treat analysis set is used for primary and secondary outcomes and safety analysis set for AEs. Data handling Data are collected locally and reported continuously after every visit to an electronic Case Report Form (HUSeCRF). The PIs at each investigative site are responsible for data entry into the HUSeCRF and for the validity of the data collected.

SEDentary Lifestyle, Mortality and Major Adverse Clinical Outcomes in Chronic KIDney Disease

The prevalence of chronic kidney disease (CKD) and patients on maintenance dialysis is increasing, and affected patients are at elevated risk of premature death and adverse cardiovascular events. Frailty is a term used to describe aging related attenuation of physical, mental, psychological and cognitive performance. Frailty is common in patients with CKD. Frailty is associated with increased mortality, hospitalization and falls in both the general population and in CKD. Treatment of frailty is challenging due to its multidimensional nature and the old age and comorbidity of the affected patients. In spite these challenges, physical rehabilitation and training programs have been shown to successfully improve the prognosis of patients with CKD. The investigators hypothesize that marked frailty is associated with a weak prognosis in spite renal replacement therapy and kidney transplantation. Because advanced predialysis stage CKD carries a high risk of adverse events and kidney transplants available are scarce, it is imperative to identify those elderly CKD stage 5 patients that benefit from initiating renal replacement therapy and those who are unlikely to benefit to avoid futile intensive treatment when it does not improve prognosis or quality of life. The investigators expect that the progression of frailty may up to a point be hindered using a simple physical exercise program that can be produced cost effectively to aid a large number of patients. The trial aims to examine the benefits of an individual physical training education program in advanced CKD. In addition to the controlled trial setting the study examines the association between measures of frailty, physical and psychological capability assessed at study inclusion (baseline) and incident hospitalization, mortality, renal replacement therapy (RRT) and major adverse cardiovascular events during follow-up.

Total-body Glucose Utilization in Obesity

The study consists of two separate parts: the dose escalation study and the part studying the effects of emotions and insulin on blood flow. All participants will first undergo a screening visit starting with signing an informed consent form. Then they will undergo a physical examination, are interviewed about their medical history. Finally, some routine laboratory tests are collected, and a 75 g oral glucose tolerance test is performed. The participants who are eligibile for the study will continue to the PET studies. The dose escalation study will be completed first. In this 8 participants will be studied once with Siemens Biovision Quadra PET/CT scanner. They will receive eight doses of oxygen-15 labelledradiowater (H2[15O]O) ranging from 25 to 700 MBq, with each dose repeated twice to evaluate repeatability of each dose. These participants will not undergo any further studies. For the other subjects, there will be two more PET study visits. On the first visit, the effects of emotions, evoked by short movie clips or cold exposure of one leg, on whole-body blood flow will studied with oxygen-15 labelled radiowater. Each participant will be studied 8 times in one session, with repeated H2[15O]O boluses of 400 MBq followed by 7.5 min dynamic PET scans with Siemens Biovision Quadra PET/CT scanner and a 5 min recovery and wash-out period. On the other visit the effects of insulin on circulation will be studied by performing a hyperinsulinemic, euglycemic clamp during the PET scan. During the clamp, fast-acting insulin (NovoRapid, NovoNordisk) is administered intravenously at a fixed rate (40 mU/m2 body surface area/min). Plasma glucose is monitored every 5-10 minutes, and 20 % glucose is administered at a varying rate to maintain euglycemia (5.0 mmol/L). At the scanner a fasting H2[15O]O PET/CT scan (400 MBq) will be performed first. After this, the hyperinsulinemic, euglycemic clamp is started, and the radiowater scans are repeated 10 minutes and 50 minutes into the insulin infusion. 60 minutes after the start of clamp, 100 MBq of glucose analogue tracer [18F]fluorodeoxyglucose is administered and a 50 min dynamic PET scan is started. After the scan, insulin infusion is discontinued and participants are monitored until plasma glucose levels are adequate for safe discharge. For a subgroup of participants, skeletal muscle microvascular bloodflow will also be assessed with contrast-enhanced ultrasound performed during fasting and 30 minutes after the start of clamp. The participants will be administered intravenous contrast agent, and after steady plasma concentration is reached (2.5 min), the contrast agent micro bubbles are destroyed with a high-intensity ultrasound signal, and the rate at which small arterioles are refilled is measured. Data will be analysed using in-house developed programs. Regions of interest will be drawn manually for peripheral tissues (skeletal muscle, visceral, brown and subcutaneous adipose tissue, liver, kidney, intestines) and using automated segmentation tools for the brain.