Fatty Acid Oxidation Disorder

This randomized, triple-blind, placebo-controlled study will evaluate the efficacy of Diaberine, a berberine-based nutraceutical, in aiding blood sugar regulation and metabolism in 80 participants over 24 weeks.

Data will be abstracted through medical record review ensuring inclusion only of data from participants meeting all the inclusion criteria and none of the censoring criteria. Data will be collected retrospectively from study sites, including medical clinics, hospitals and academic medical centers.

The study will assess long-term safety of mRNA-3927. Participants with PA who were previously enrolled and completed the end-of-treatment (EOT)/early termination (ET) visit of the mRNA-3927-P101 study will have the option to enroll into this extension study provided all eligibility criteria have been met. The study will include 2 periods: 1) Treatment Period and 2) Follow-up Period (90 days after the EOT visit). All participants will enter the study receiving mRNA-3927 at the same dose and at the same dosing interval last received in the mRNA-3927-P101 study.

This study is being conducted to obtain short-term and long-term clinical safety information from adult and pediatric patients treated for hyperammonemia due to Methylmalonic Acidemia (MMA) and Propionic Acidemia (PA). This is an observational/non-interventional study. Patients will be treated per the prescribing information and routine medical practice. Only available data will be collected as part of the study including developmental outcomes, details of treatment with Carbaglu® and other treatments for hyperammonemia including dietary and protein management, plasma ammonia levels, pregnancy and maternal complications, adverse effects on the developing fetus and neonate, adverse effects on the infant through first year of life.

Study Description: Caregivers will be invited to participate in surveys and interviews to assess their cognitions and emotions about caregiving, caregiving burden, and caregiving or support network systems during the life of the Care Recipient. The study will also include a bereavement component, in which families who have experienced the death of a Care Recipient may choose to participate. In addition, biomarkers may be evaluated in consenting individuals to assess genetic susceptibility to stress and stress-related dysregulations in the endocrine and immune systems. Objectives: The primary objective of this study is to investigate the natural history of family caregiver stress over time, providing opportunity to understand the social, psychological, behavioral, and biological factors that characterize caregivers response to long-term caregiving during the life and after death of a Care Recipient with a chronic medical condition. Endpoints: To assess the change over time in terms of social, psychological, behavioral, and biological factors associated with caregiving.

Polycystic Ovarian Syndrome is a point of concern these days in female population around the world.The patients feel psychological and mentally unhealthy. PCO effects around 6- 14% of women worldwide. PCOS is characterized by hormonal dis-regulation and hyperinsulinemia. Improvements in sex hormones and insulin sensitivity in PCOS women, either through lifestyle changes or through pharmaceutical intervention, have consistently resulted in a marked improvement in the reproductive and metabolic abnormalities in PCOS Commonly prescribed treatment for PCOS include oral contraceptives (OCPs), metformin, pioglitazone, estrogen, GnRH agonist, myo-inositol, letrozole and clomiphene citrate. Despite their effectiveness in symptom relief and ovulation induction, these treatments are associated with adverse effects including weight gain, cardiac issues, lactic acidosis, dysmenorrhea, and abdominal discomfort (Hussain et al., 2022). Given the limitations of conventional drugs, Herbal therapies are gaining attention for their multi-targeted ability to restore natural hormonal balance, improve ovulation and offer symptom relief with minimal side effects (Hussain et al., 2022). In this context, the present study is designed to explore the therapeutic benefits of a novel polyherbal formulation that includes Momordica charantia L., Linum usitatissimum, Symplocos racemose bark, Allium cepa L., Tribulus terrestris, and eggshell. These ingredients were selected based on their various pharmacological properties that are relevant to the pathophysiology of PCOS. This study will evaluate the safety and effectiveness of Melats P in achieving a successful menstruation regulation in PCOS women.We will recruit 3 groups , First group with conventional treatment (Metformin ) , Second with Alternative medicine having a herbal Formulation ( Melats P) and Third group patients will receive both Conventional (Metformin) and Herbal Formulationn (Melats P).

This is a single-arm study to investigate 1-year treatment related mortality (TRM) in patients with life threatening non-malignant and malignant hematologic disorders who do not have a matched related donor for allogeneic transplantation.

Hematopoietic stem cell transplantation (HSCT) from a healthy donor can cure or alleviate a broad spectrum of non-malignant disorders (NMD). Although reduced-intensity conditioning (RIC) regimens promise decreased treatment-related morbidity and mortality, graft failure and infections are limiting the use of RIC in chemotherapy-naive patients. Dr. Szabolcs have completed several trials to evaluate a novel RIC regimen of alemtuzumab, hydroxyurea, fludarabine, melphalan, and thiotepa. The last trial at UPMC Children's Hospital of Pittsburgh of a highly effective and biologically rational chemotherapy-based RIC regimen paired with simple alemtuzumab dosing strata was tested and resulted in outstanding survival and remarkably low rates of graft failure. The favorable outcome described may serve as a toxicity and efficacy reference for emerging gene therapy strategies as well. This prospective collection of clinical data will allow the investigators to further assess engraftment, GVHD, immunosuppressant use and overall survival in this patient population.

The primary clinical objective of the clinical study is to determine and compare cardiac microstructural phenotypes by cardiac MRI in patients and healthy controls and their relationship to cardiac structure/function with our MRI technologies. Aim 1: What are the myocardial microstructure phenotypes in both patients with cardiovascular disease and healthy cohorts? Are they linked to other prevalent macro structure and functional abnormalities? The hypothesis is that the investigators can develop the next generation cardiac MRI exam that is faster, more robust, and more efficient for clinic use. The enrolled subjects will do ONE of the following: • Receive an extended clinical cardiac MRI exam. An MRI is an imaging technique used in radiology to make an accurate picture of the body. In this study the investigators will be focusing on the heart. The participant's routine clinical cardiac MRI exam will be extended by up to 25 min to perform a truncated research cardiac MRI protocol. The extended clinical cardiac MRI will take approximately one hour in total. The investigators may review the medical records to follow-up their medical status up to 5 years after start of the study. OR: • Receive a research cardiac non-contrast MRI exam. An MRI is an imaging technique used in radiology to make an accurate picture of the body. In this study the investigators will be focusing on the heart. The research cardiac MRI will take approximately one to two hours in total. The investigators may review the medical records to follow-up their medical status up to 5 years after start of the study Optionally, if the subjects agree, the blood samples will be collected: • Give blood sample for research purpose only. The blood draw is used to correlate the clinical blood biomarkers to the cardiac MRI data to help us better understand and validate the clinical utility of the novel cardiac MRI techniques. The blood draws should approximately take 20 minutes. The blood draw will take place in the doctor's office or at Mellen center private preparation by a registered nurse or approved technician. The blood will be stored with a unique code at Cleveland Clinic BioRepository for up to 10 years, and disposed following Cleveland Clinic guidelines. It may be used for future research in the Cleveland Clinic. Only members of the research team will have access to the participant's samples. For healthy control: • Only one cardiac MRI is needed, and it will be non-contrast MRI.

1. Background 1.1. Rare diseases Rare diseases are defined as serious diseases which affect only a very small number of people compared to the general population. The more than 8.000 different rare diseases most often affect children and encompass an enormous heterogenous clinical spectrum associated mostly with a chronic or progressive disease course. In addition to the clinical and economic burden of a chronic disease, patients with rare diseases faces also the "rare disease burden" which describes associated problems caused by rarity of the disease. 1-3While advances in rare disease research have significantly improved the diagnostic and therapeutic strategies in rare diseases, psychosocial care is still not part of routine care in rare diseases. 4 1.2. Own previous work The investigator team is highly experienced in both, the molecular characterization 5-16 and the clinical care 17-21 of rare and ultra-rare diseases and in psychosocial care 22-27 of pediatric patients in acute and chronic stress situations. Based on this experience the investigators developed a psycho-educational intervention program for children and adolescents affected by a rare disease named "Education \& Care in RARE" Figure 1. Education \& Care in RARE (https://www.youtube.com/watch?v=R3fr-q-6JIw) is a short-term, structured, resource-oriented and child-friendly psychoeducation program for children and adolescents with rare diseases. It promotes knowledge and competence on rare diseases in children in order to reduce the psychosocial rare disease burden and to improve individual self-competence in managing the rare disease and to improve their quality of life. Education \& Care in RARE can be used for all pediatric rare diseases. This has the great advantage that users only need to be trained in the use of one program. Figure 1 Education \& Care in RARE is used during clinical care at the outpatient clinic for clinical genetics, Department of Pediatrics and Adolescent Medicine, Division of Pediatric Pulmonology, Allergology and Endocrinology. Education \& Care in RARE is currently not available in routine care outside of this specialized outpatient clinic. Affected children who have completed Education \& Care in RARE during clinical care, have rated this as a very helpful and supportive program. To date, there has been no study on the effectiveness of Education \& Care in RARE. 2. Aims and hypotheses of the study 2.1. Aims This study aims to investigate the efficacy of Education \& Care in RARE on knowledge about rare diseases and on mental health well-being in pediatric rare disease patients. As a primary objective the investigators will evaluate \> The effect of Education \& Care in RARE on participants' self-rating scales regarding knowledge about rare diseases and well-being, compared to a control group. As secondary objectives the investigators will evaluate * The effect of Education \& Care in RARE on expert-rating scales regarding participants' knowledge about rare diseases and competences to cope with rare-disease specific challenges, compared to a control group. * The effect of Education \& Care in RARE on generic Quality of Life and mental health well-being questionnaires, compared to a control group. * Moderating effects (such as age, rare disease diagnosis, additional diagnosis) on the efficacy of Education \& Care in RARE * The long-term effect of Education \& Care in RARE on participants' knowledge about rare diseases and on mental health well-being. * Differences in Quality of Life and mental health well-being of children and adolescents with rare disease, compared to norm data. * Since this is the first study on Education \& Care in RARE, we will also evaluate the satisfaction with the intervention for the intervention groups and for the applying experts. 2.2. Hypotheses Specifically, the investigators will test the following hypotheses: Primary hypothesis: • H1: Education \& Care in RARE will have a different impact on the change in rare disease specific knowledge and well-being (Rare Disease Specific Self-Rating Scale), between the study time points T0 and T1, in the intervention group compared to the waitlist control group. Secondary hypotheses: * H2: Education \& Care in RARE will have a different impact on the change in experts' opinion regarding participant's knowledge and competences (Rare Disease Specific Expert-Rating Scale), between the study time points T0 and T1, in the intervention group compared to the waitlist control group. * H3: Education \& Care in RARE will have a different impact on the change of Quality of Life (KINDLR self-report) and mental-health well-being (SDQR self-report), between the study time points T0 and T1, in the intervention group compared to the waitlist control group. * H4: Participants' age (H4a), educational level (H4b), and intellectual ability (H4c) will moderate the effect of Education \& Care in RARE on participants' rare diseases knowledge and well-being (Rare Disease Specific Self-Rating Scale, Rare Disease Specific Expert-Rating Scale). Education \& Care in RARE will have stronger effects for older participants, participants with higher educational levels and participants with normal intellectual ability. * H5: Education \& Care in RARE will have a different impact on the long-term change in knowledge and well-being (Rare Disease Specific Self-Rating Scale, H5a), experts' opinion regarding participant's knowledge and competences (Rare Disease Specific Expert-Rating Scale, H5b) and change of Quality of Life (KINDLR self-report, KINDLR third-party-report, H5c) and mental-health well-being (SDQR self-report, SDQR third-party-report, H5d) , between the study time points T0 and T2 in the intervention group. H6: Rare diseases affect Quality of Life (KINDLR self-report, KINDLR third-party-report) and mental-health well-being (SDQR self-report, SDQR third-party-report,) in pediatric rare disease patients, at T0 in the intervention and in the waitlist control group, compared to norm data. 3. Originality and scientific innovation During a 6-year period, from 2018-2024 at MUW, based on the expertise of a highly specialized, multiprofessional and multidisciplinary expertise team, the investigators invented Education \& Care in RARE: https://www.youtube.com/watch?v=R3fr-q-6JIw Education \& Care in RARE is the first targeted psychoeducational program which can be applied in all 8.000 rare diseases. This has the great advantage that users only need to be trained in the use of one program. Education \& Care in RARE is a short-term, structured, resource-oriented and child-friendly psychoeducation program for children and adolescents with rare diseases. It promotes knowledge and competence on rare diseases in children in order to reduce the psychosocial rare disease burden and to improve individual self-competence in managing the rare disease and to improve their quality of life. Education \& Care in RARE can be used for all pediatric rare diseases. 4. Research design 4.1. Type of study This study is a prospective 2-arm waitlist randomized controlled trial, that will test the efficacy of a targeted psychoeducation with Education \& Care in RARE in pediatric rare diseases patients. Participants will be randomly assigned (1:1 allocation) to either the intervention group, which benefits from the Education \& Care in RARE program, or a waiting list control group that will also receive the Education \& Care in RARE intervention after the intervention group finishes it. The 2 independent groups (IG versus WLG) will be evaluated at different measurement times (in IG: baseline T0, the postintervention time point T1, and 3-6 month follow-up T2; in WLG baseline T0 and T1, the postintervention time point T2, and 3-6 month follow-up T3). 4.2. Intervention Intervention in this study is a targeted psychoeducation for pediatric rare diseases using Education \& Care in RARE. To enable standardized application of the intervention, the implementation and objectives of the intervention using Education \& Care in RARE are defined as followed: 4.2.1. Standardization - application of the intervention * All participating centers completed a one-day workshop to learn how to use the Education \& Care in RARE program. * The intervention (Education \& Care in RARE program) is done in a one-to-one setting (trained member of the medical care team and the pediatric study participant). * Consultation of participant's medical and psychosocial care team, before applying the intervention, to ensure quality-assured knowledge transfer regarding the specific rare disease of the individual study participant. * Execution of the Education \& Care in RARE program from front to back (Chapter 1-4) according to the Education \& Care in RARE Manual * Completion of Education \& Care in RARE within up to 8 weeks. Within this 8-week period a variable number of sessions and a variable duration of the sessions can be used to complete the Education \& Care in RARE program. 4.2.2. Standardization - aims of the intervention Basic learning objectives of the intervention, which should be achieved by the intervention are defined as followed: * Establishment of 3 names for the rare disease * rare disease name within the medical system * rare disease name within the patient's social system * what to say if the patient does not want to talk about the rare disease * Acquisition of knowledge on the underlying rare diseases (eg. knowledge about the emergency card, knowledge about special risk factors, knowledge about etiology, etiology of disease symptoms and healthy body functions) * Acquisition of knowledge on rare diseases in general * Acquisition of competences in dealing with the rare disease in daily life * Emotional relief of the child 4.3. Setting This multicenter trial will be performed at pediatric centers in Austria who are specially experienced in diagnostics and therapeutics of pediatric rare diseases patients. 4.4. Statistical analyses, sample size 4.4.1. Statistical analysis Statistical analysis was planned in cooperation with the Institute of Medical Statistics Center for Medical Data Science, Medical University of Vienna. First a t-test will be applied to test the primary objective: differences of participants' knowledge and well-being (Rare Disease Specific Self-Rating Scale) between the study time points T0 and T1, in the intervention group compared to the waitlist control group. For both groups, mean values and standard deviations will be reported. In case of a skewed distribution, a Wilcoxon test will be computed and median and interquartile range will be reported. The significance level will be set to 0.05. In case of missing values for study time point T1, for the primary analysis, only available cases will be considered. A sensitivity analysis will be performed to compare baseline data of patients with complete data and patients with missing data (descriptive statistics as only a small number of missing values is expected). Tests for secondary endpoints: H2, H3 and H5 (difference in change in expert-rating scales, Quality of Life and mental health well-being, competences and mental health well-being) are analyzed in the same manner as the primary objective. To analyze the independent variables age, educational level and intellectual ability on the change in "Rare Disease Specific Self-Rating Scale", first univariate analyses of covariances (Ancova) will be computed and second a multiple Ancova will be performed with independent variables age, educational level and intellectual ability and group. For the secondary analyses, the significance level will be set to 0.05. No adjustment for multiplicity will be performed and p-values will be interpreted descriptively. Descriptive statistics will be used to summarize baseline characteristics of recruited participants. Baseline characteristics will be presented in a table for the full enrolled sample. In order to test differences at baseline between the two groups with regard to theoretical and practical knowledge, as well as emotion t-tests for independent samples will be performed. The satisfaction with the Education \& Care in RARE program for the intervention groups and for the applying experts (Patient Evaluation of the Education \& Care in RARE program, at T1 and T2). Categorical variables will be presented in absolute frequencies and percentages. Continuous variables will be listed in means and standard deviations and will be presented in tables. Statistical analysis will be performed using SPSS 24 (IBM Corporation, Armonk, NY, USA). 4.4.2. Sample size calculation Sample size calculation was done for the primary study outcome "differences of participants' self-rating scales regarding knowledge about rare diseases and well-being (Rare Disease Specific Self-Rating Scale), before and after intervention with Education \& Care in RARE". Sample size estimation was evaluated using R (Version 4.4.1, library pwr). We based the sample size calculation on parameters derived from some internal pilot data where we observed a standard deviation of 0.55 for the change between T0 and T1 (intervention group). However, as the study population will be very heterogenous (for example over 8.000 potential different rare diseases, high variability of knowledge on the underlying rare disease in the study population…) we consider more conservative estimates for the sample size calculation. These estimates should be considered as vague approximations. Thus, assuming that the standard deviation is equal for the intervention and the control group we performed several sample size calculations for standard deviations 0.55, 0.8, and 1 and several effect sizes (difference of differences) for a two-tailed t-test for independent groups (significance level 0.05 and power 0.8). The results can be found below. Based on this, sample size estimates indicate that we will be able to detect a difference of differences of 0.5 when the standard deviation of the difference in both groups is 0.8 with a sample size of 49 participants in each group and considering a dropout rate of 15%. 4.4.3. Methods of preventing bias Participants will be randomized using an online-randomization (https://www.meduniwien.ac.at/web/mitarbeiterinnen/it-hilfe-support/it4science/plattformen/randomizer/). Patients will be randomized in blocks with random block lengths between 4 and 8 and stratified for center.¬¬ 4.4.5. Recruiting This prospective randomized controlled trial will be performed at several pediatric centers in Austria, which are involved in the diagnostics and care of pediatric rare diseases patients. In participating centers, during routine check-ups, patients who meet the inclusion and exclusion criteria, are invited to take part in the study. Patients and their legal guardians are informed in detail about the study by the treating doctors or psychologist during a personal interview. There is written project information for children and adolescents of different age groups (age in years: 8-10, 11-14, 15-18, more than 18 years) and for parents/caregivers. If there are no more questions, written consent is obtained.