Kriviy%20rih, Ukraine

My MS and My Menstrual Cycle

4D-150 in Patients With Macular Neovascularization Secondary to Age-Related Macular Degeneration

Therapeutic Effects of Electrical Vestibular Stimulation (EVS) on Balance and Gait

Background and Rationale Standing balance and stable gait are maintained through the integration of sensory feedback from the visual, somatosensory (muscle, skin, tendon, and joint receptors), and vestibular systems. The quality of this feedback, and the ability of the central nervous system (brain and spinal cord) to integrate these signals and generate appropriate motor responses dictates balance and gait performance. Age-related balance decline, clinically known as presbystasis, is one of the most visible and debilitating signs of aging. More than 60 million people in the U.S. over the age of 40 live with age-related balance impairments that increase their risks of fall-related injuries and make it increasingly difficult to continue living actively and independently. 1-in-3 adults above the age of 65 falls each year and falls are the leading cause of death in seniors. But there are less than 20,000 clinical specialists in the U.S. with the tools to diagnose balance impairments, so for most people, little is done to address declining balance until after a fall-related injury occurs. The solution offered to most older adults is a mechanical balance aid such as a walker, whose prolonged use only further destabilizes balance. Vestibular dysfunction has been identified as the primary cause of balance decline in more than 55% of adults over age 50, or around 34 million people in the U.S. This dysfunction impacts both the peripheral vestibular organs in the inner ear and central vestibular processing in the brain, and it has also been linked to cognitive decline. Current therapeutic options to restore lost balance function are limited to high-risk surgical vestibular implants. The current standard of care is exercise-based therapy that aims to help compensate for vestibular balance decline, but there remains a critical gap: no widely available non-invasive solution exists to restore lost vestibular function or prevent further deterioration. A growing body of research indicates that low-level, non-invasive electrical stimulation of the vestibular balance system (EVS) can induce neuroplastic changes at both cellular and circuit levels, effectively restoring peripheral and central vestibular functions. Restored vestibular function has also been linked to restored cognitive function. The investigators have developed a novel sub-threshold wideband stochastic EVS (swsEVS) neuroplastic stimulation, which targets peripheral and central vestibular pathways. Multiple studies have demonstrated that the swsEVS frequencies and current levels are safe, comfortable, well-tolerated, and have no adverse side effects. These studies have also demonstrated that a therapeutic treatment protocol with 18 twenty-minute swsEVS sessions delivered over a 5-6-week period resulted in significant improvements in balance performance in otherwise healthy adults aged 50-98 years old. These improvements are attributed to neuroplastic restoration of both peripheral and central vestibular function. The observed improvements persisted for at least 3-6 months and were sufficient to recategorize high fall risk individuals to lower fall risk. Objectives With the proposed pre-clinical study, the investigators aim to determine the safety, feasibility, efficacy, and persistence of the above non-invasive swsEVS to improve balance and gait performance in healthy individuals across the lifespan. Specifically, our objective is to measure balance and gait performance before, during and after exposure to single sessions and across repeated sequences of swsEVS at multiple study partner sites. The investigators predict that swsEVS-induced neuroplasticity may promote recovery of vestibular function via documented mechanisms that include: 1) regeneration of vestibular hair cells; 2) an increase in synaptic gain in the vestibular system, 3) an increase in vestibular afferent/efferent nerve fibre conductivity and excitability, and 4) increased central neural integration of sensory signals (vestibular, visual, somatosensory) for motor control. As such, our main hypothesis with this research is that exposure to repeated sequences of swsEVS will enhance balance and gait performance (e.g., walking cadence, stability, etc.). A secondary objective of this study is to determine if changes in vestibular function are accompanied by measurable changes in cognitive function. Finally, a tertiary objective of this research is to determine if swsEVS has any potential benefit for participants suffering from occasional headaches. There is some anecdotal evidence that EVS could help with headaches, particularly for so-called "vestibular migraines"; however, to date this has not been formally studied. Participants Healthy young and older adult participants (18 - 100 years of age) will be recruited in this study. Participants will be recruited at each study site from their local community by word of mouth, study ad postings, and the UCalgary Participate website. All participants will be given detailed written and oral explanations of experimental goals and procedures, and the protocol will be approved by UCalgary's Clinical Health Research Ethics Board (CHREB). Participants will provide written informed consent prior to participation. Methodology Participation in this experiment will involve 18 testing sessions over a 5-6- week period, as well as 3-week, 6-week, 3-month, and 6-month follow up sessions. Each testing and follow-up session will last under 1-hour. The proposed project will employ six primary techniques: (i) electrical vestibular stimulation (swsEVS); (ii) accelerometry; (iii) smartphone app-based gait and balance tests; (iv) clinician-administered Functional Gait Assessments; (v) static and dynamic balance tests using an instrumented balance platform; (vi) cognitive assessments. swsEVS test administrators will also collect information about any adverse events during each visit and since the last visit. Participants will also complete questionnaires upon entering and exiting the study to assess the prevalence and severity of headaches, cognition, dizziness, level of physical activity, as well as to determine if these headaches are causing any notable disability. (i) Electrical Vestibular Stimulation (EVS) involves electrically activating the peripheral vestibular system by passing small electrical currents through electrodes placed on the mastoid processes (behind the ears) via battery powered, constant current isolated stimulators. This non-invasive, safe and painless bioelectronic stimulation technique commonly utilizes either a stochastic signal (white noise) or monopolar or bipolar square- or sine-wave pulses. EVS typically used different bandwidths of stimulation, from broad-band (0-1 kHz) to narrow-band (0-2 Hz).EVS may also be applied at different stimulation amplitudes, ranging from those that are below the level of evoking any sensation by the participant ("sub-threshold"; typically < 0.5 mA), to those that evoke overt vestibular sensations and balance responses ("supra-threshold"; > 0.5 mA). The swsEVS neuroplastic restoration in the present study delivers subthreshold, wideband, stochastic stimuli via 2 pairs of disposable single-use electrodes attached to each mastoid and the back of the neck. EVS does not ever exceed +/- 3 mA (hardware and software limited), giving it an excellent safety profile across a large and growing body of scientific literature. (ii) Accelerometry: Participants will be instrumented with wearable accelerometers (Phybrata Sensor; PROTXX Inc.) on their head over top of the right mastoid process, as well as on the top of each foot. The sensor placed on the head has been validated as a measure of gait and balance performance in multiple previous studies. The sensors placed on the top of the foot will be used to reconstruct step-by-step foot placement kinematics during gait testing. Sensors attached to the head will be affixed to the skin with disposable double-sided medical adhesive tape, after cleaning the skin with an alcohol swab. Sensors applied to the foot during gait testing will be affixed with medical tape. The accelerometers automatically collect and relay the kinematic data to a smartphone app-based system. (iii) Smartphone App-Based Gait and Balance Testing: Gait and balance assessments will be performed using a smartphone app developed by PROTXX Inc. The app guides the user through the experimental procedures through on-screen instructions and auditory beeps. Investigators will use the app to perform assessments of quiet standing (3 x 2 min intervals of standing still and relaxed with their arms at their sides; 1 min eyes open, 1 min eyes closed), as well as the standard Timed Up and Go (TUG) task and an over-ground walking task. For the TUG task, participants will start seated in a chair, then when prompted by the app, will stand up, walk 3 m forward to a pilon on the floor, turn around 180 degrees, then return to the chair and sit down. For the over-ground walking task, participants will simply start standing with their toes over a tape line on the floor, then they will walk forward (< 50') to an end target pilon. (iv) Functional Gait Assessment (FGA): The investigators will have trained clinicians administer the FGA, which involves timing 10 different tests of mobility, including: 1) level surface walking (20'), 2) 'change-in-gait-speed' task alternating between 'slow' and 'fast' speeds (5' each), 3) walking with horizontal head turns every 3 steps (20'), 4) walking with vertical head turns every 3 steps (20'), 5) walking with pivot turn to reverse direction and stop (5'), 6) walking with a step over a 9" obstacle (i.e., the height of 2 shoe boxes), 7) walking with narrow base of support (i.e., stepping 'heel-to-toe') for 10 steps, 8) walking with eyes closed (20'), 9) walking backwards (20'), and 10) walking up and down a set of 4 steps, using a railing if necessary. (v) Cognitive Assessments: Cognitive assessments will utilize paper-based questionnaire forms of the Symbol Digit Matching Task (SDMT) and the Montreal Cognitive Assessment (MoCA). Experiment Overview During their initial intake session at the study site, all participants will undergo EVS threshold testing to determine normalized levels of EVS that result in balance perturbations. This EVS threshold testing will be carried out by administering very low currents (starting at ~0.1 mA) to participants standing with their eyes closed and increasing the current level across trials until an EVS balance threshold is determined. During all 18 subsequent testing sessions, participants will perform gait and balance tests administered via a smartphone app (see below) before and after a single continuous session of swsEVS (<20 min). During each swsEVS session, participants will alternate between sitting, standing on the hard floor, and standing on a foam pad, with intervals of having their eyes open and closed. An investigator will always be nearby the participants to protect them from falling and provide postural support if needed. Cognitive testing and headache questionnaires will be completed during the first and last of the 18 treatment sessions. During the 3-week, 6-week, 3-month, and 6-month follow up sessions, participants will repeat gait and balance tests to assess the persistence of any performance improvements measured after the 18 testing sessions. Statistical Design To determine the therapeutic efficacy of repeated EVS sessions, dependent variables will be submitted to repeated measures ANCOVA with stimulation type ('sub-threshold', 'supra-threshold') and sex ('male', 'female') as between subject factors, and age as a covariate. Further exploratory analysis of relationships between age and different dependent variables will be performed using Pearson correlations. An alpha level of 0.05 will be used as the statistical significance threshold for all testing.

Pharmacogenetic-Guided Antidepressant Prescribing in Adolescents With Anxiety and Depression

Goal: To test the efficacy of pharmacogenetic-guided antidepressant prescribing for adolescents with depression. Background: For an adolescent with depression and anxiety, antidepressant medication is prescribed, often in combination with psychotherapy. The class of antidepressants recommended for use is selective serotonin reuptake inhibitors (SSRIs) with fluoxetine recommended as the first-line medication, and four other SSRIs recommended for consideration (sertraline, citalopram, escitalopram, fluvoxamine) if the adolescent does not respond or tolerate fluoxetine. For most adolescents, medication prescribing, and monitoring will be managed by a primary care physician or community pediatrician rather than by a mental health care provider, and guidelines exist to support this management. However, current prescribing guidelines/recommendations do not account for SSRI metabolism phenotypes that could change whether the SSRI selected is efficacious or tolerated. Our team of researchers, clinician scientists, patient partners, and primary care providers has designed a trial to test the impact of accounting for metabolism phenotypes, through pharmacogenetic-guided antidepressant prescribing, on adolescent outcomes, experiences, and health care utilization. Principal Question: Compared to current prescribing guideline/recommendation informed prescribing, does pharmacogenetic-guided prescribing for adolescents with depression and/or anxiety have superior efficacy following 12-weeks of therapy with a SSRI? The Trial: This is a parallel arm randomized controlled trial. Adolescents aged 12-17 years (n=452) who are starting or changing a SSRI for depression and/or anxiety will be randomly allocated to receive pharmacogenetic-guided antidepressant therapy (experimental intervention) or current prescribing guideline/recommendation guided prescribing (control intervention). Participants and prescribing physicians will be blinded to which intervention was received. The primary outcome is depressive symptom remission at 12 weeks measured using the Quick Inventory of Depressive Symptomatology - Adolescent (17-item) (QIDS-A17) and anxiety symptom remission at 12 weeks measures using the Screen for Child Anxiety Related Disorders (SCARED). Secondary outcomes include side effects, role functioning, medication adherence, and health-related quality of life measured 4-, 8-, and 12-weeks after intervention initiation as well as cost-effectiveness.

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.

Sustainable Implementation of the EXCEL Exercise Oncology Program Across Canada

Over the past 4.5 years, the EXCEL Study (HREBA.CC-20-0098, NCT04478851) has been implemented across Canada and has recruited over 1500 individuals living with and beyond cancer. This updated study will streamline the program to essential baseline screening and testing (for safe and effective program delivery), simplify outcome assessments (for participants to see changes and for program evaluation), and increase the reach to include more urban centres to encourage more healthcare provider (HCP) buy-in with a simplified referral process (i.e. no patient screening required from HCPs to determine eligibility, based on location). This updated program is based off of the Alberta Cancer Exercise (ACE) Program (HREBA.CC-24-0252). Thus, we are modifying the original EXCEL ethics to will reduce the participant burden with less patient-reported-outcomes and fewer follow-ups, which will allow more focus on program implementation, evaluation, and sustainability. Continued effort and training to establish the clinic-to-community model will be enhanced with stronger relationships and referrals from the cancer care system and the HCPs, which will continue to work towards a 'patient-centered care approach'.

Feasibility Trial for a Right Ventricular Failure Platform Trial

This study is an investigator-initiated, open label, prospective, multi-centre, phase 2, randomized control trial. This CRAVE feasibility trial will seek to establish the feasibility of a larger platform trial for testing multiple interventions in various domains to improve right ventricular function. In this feasibility trial, 30 participants with pulmonary hypertension and right heart failure with be randomized 1:1:1 to empagliflozin 10 mg daily + standard of care, ranolazine twice daily + standard of care, or standard of care alone. Participant outcomes (medical records review) will be followed for 16 weeks after randomization.

A Platform Trial for Gram Negative Bloodstream Infections

BALANCE+ is an adaptive platform trial evaluating multiple treatment options in patients admitted to the hospital due to Gram negative bloodstream infections (BSIs). It focuses on both cross-cutting and subgroup-specific questions, using an open-label, pragmatic design embedded in routine care. BALANCE+ addresses the significant health concern of BSIs, which have high morbidity and mortality rates, exacerbated by the global public health threat of antimicrobial resistance (AMR). With rising resistance rates and limited new drug development, effective treatment strategies for BSIs remain under-researched. BALANCE+ follows the BALANCE trial, which evaluated duration of antibiotic treatment, and aims to further investigate critical questions in managing Gram-negative BSIs. This platform trial will explore various aspects of BSI treatment, including antibiotic de-escalation, oral antibiotic choices, central line management, treatment of specific pathogens, and the necessity of follow-up blood cultures. BALANCE+ is using Bayesian methods without a fixed sample size. Interim analyses will occur after every 1000th patient in each domain, and then for every 200th patient thereafter. The trial will stop if futility or superiority thresholds are met, or if a domain reaches its ceiling sample size (2500 patients for most domains and 4000 for the beta-lactam versus non-beta-lactam domain) without meeting a stopping threshold. A vanguard pilot trial involving over 150 patients at 9 hospitals across Canada confirmed the feasibility of the BALANCE+ trial. The main trial will include patients from the vanguard pilot phase since there has been no major change in the overall study design and domains. The adaptive design allows for interim analyses and adjustments by adding or removing domains as per the statistical analysis plan, enhancing the trial's efficiency and relevance.

UPTAKE - Virtual Care: Virtual Home Hospital With Remote Monitoring to Reduce Acute Care Hospitalization

1. Background and Rationale Acute kidney injury (AKI) is a common and serious complication in hospitals. A major care gap for survivors of AKI is the fragmentation of care that exists as they transition from the hospital to their home. This contributes to a high risk of adverse long-term outcomes, including prolonged hospitalization, high rates of readmission, cardiovascular events, infections, progression to chronic kidney disease (CKD), kidney failure requiring dialysis, and death. To address this challenge, the investigators are implementing multi-component digital health solutions including Computerized Clinical Decision Support (CDS) and Digital Remote Patient Monitoring (dRPM) through Virtual Care (VC) programs in Alberta to reduce length of hospital stay and readmission rates and improve long-term outcomes after AKI. Evidence of the effectiveness of the two digital health solutions is available from Alberta and international clinical trials. Our team previously implemented a computerized CDS intervention for AKI risk assessment and prevention and achieved improved AKI prevention and reduced AKI incidence after cardiac procedures across the province. The investigators will use a similar approach to identify high risk patients with AKI and provide recommendations to improve the quality of their care, which is well suited to the evolving digital health infrastructure in Alberta. Providing hospital-level care at home through Virtual Care (VC) teams has been shown to reduce mortality and readmission rates. Alberta's VC program have existed in both Edmonton and Calgary since 2018 and have reported lower readmission rates, Emergency Department (ED) visits and use of Emergency Medical Services than observed with usual care. Patients reported that the program helped them regain their independence and function. Alberta's VC programs have implemented dRPM technology, which has been further associated with fewer days in hospital and emergency department visits. Patients reported better quality of care using this technology. The framework for dRPM and complex care planning is already in place in Alberta's Virtual Care programs. The investigators intend to utilize these programs to improve transitions of care through early facilitated discharge and enhanced follow-up of patients with AKI at high risk of hospital readmission, who require frequent monitoring and more intensive care strategies during this vulnerable period of transition in care. 2. Research Question and Objectives - Implement and evaluate a transition of care intervention for patients with AKI. - Integrate digital health solutions that can achieve levels of monitoring and care in a patient's own home that are comparable to acute care, while transitioning care to the community setting. - Reduce the length of hospital stay and risk of hospital readmission for people with AKI. - Improve the long-term outcomes after hospitalization with AKI. 3. Methods The investigators will evaluate implementation initially in a Vanguard phase to establish feasibility and acceptability of the intervention, followed by an evaluation of implementation and effectiveness of the intervention in a larger Multicenter Randomized Controlled Trial (RCT). High risk patients with AKI and a predicted risk of readmission or death ≥20% will be identified using a Best Practice Alert (BPA) in Connect Care and participants will be randomized to care with or without virtual monitoring through the VC programs. All patients will receive the same baseline interventions refined in the Vanguard phase, while the intervention arm will additionally receive VC with dRPM following discharge. High risk patients in the intervention arm will be navigated through the transition of care pathway by a trained nurse navigator. Patients will receive dRPM kits, and biometric data will be automatically uploaded to the web-based monitoring platform and reviewed by the nurse navigator. Patients will receive regular virtual assessments via telephone or videoconferencing (via the tablet) after in-patient discharge. Blood tests will be drawn at home by community paramedics as deemed necessary by the clinical team to assess kidney function and monitor for complications of AKI. Should concerns be identified that warrant in-person assessment, paramedic care teams will be sent for assessment and/or intervention. Upon completion of the intervention patients will be assessed for readiness to move to the subacute arms of the program and return to their primary care provider. If ongoing nephrologist or other specialist care is required, the nurse navigator will ensure appropriate follow up is arranged.

A Study of Sequential Therapy With Daplusiran/Tomligisiran (DAP/TOM) Followed by Bepirovirsen in Participants Living With Chronic Hepatitis B (CHB)