bims-curels 2023-06-04 papers

Issue of 2023–06–04
five papers selected by
Cure Mito Foundation

Ann Neurol. 2023 May 31.

Expert panel curation of 113 primary mitochondrial disease genes for the Leigh syndrome spectrum.

NICHD ClinGen U24 Mitochondrial Disease Gene Curation Expert Panel

OBJECTIVE: Primary mitochondrial diseases (PMDs) are heterogeneous disorders caused by inherited mitochondrial dysfunction. Classically defined neuropathologically as subacute necrotizing encephalomyelopathy, Leigh syndrome spectrum (LSS) is the most frequent manifestation of PMD in children, but may also present in adults. A major challenge for accurate diagnosis of LSS in the genomic medicine era is establishing gene-disease relationships (GDRs) for this syndrome with >100 monogenic causes across both nuclear and mitochondrial genomes.
METHODS: The Clinical Genome Resource (ClinGen) Mitochondrial Disease Gene Curation Expert Panel (GCEP), comprising 40 international PMD experts, met monthly for 4 years to review GDRs for LSS. The GCEP standardized gene curation for LSS by refining the phenotypic definition, modifying the ClinGen Gene-Disease Clinical Validity Curation Framework to improve interpretation for LSS, and establishing a scoring rubric for LSS.
RESULTS: The GDR with LSS across the nuclear and mitochondrial genomes was classified as definitive for 31/114 gene-disease relationships curated (27%); moderate for 38 (33%); limited for 43 (38%); and 2 as disputed (2%). Ninety genes were associated with autosomal recessive inheritance, 16 were maternally inherited, 5 autosomal dominant, and 3 X-linked.
INTERPRETATION: GDRs for LSS were established for genes across both nuclear and mitochondrial genomes. Establishing these GDRs will allow accurate variant interpretation, expedite genetic diagnosis of LSS, and facilitate precision medicine, multi-system organ surveillance, recurrence risk counselling, reproductive choice, natural history studies and eligibility for interventional clinical trials. This article is protected by copyright. All rights reserved.

DOI: https://doi.org/10.1002/ana.26716

Orphanet J Rare Dis. 2023 05 29. 18(1): 129

Healthcare resource utilization of patients with mitochondrial disease in an outpatient hospital setting.

Sameen Haque, Karen Crawley, Rupendra Shrestha, Deborah Schofield, Carolyn M Sue.

BACKGROUND AND OBJECTIVES: Mitochondrial diseases present as multi-system disorders requiring a comprehensive multidisciplinary approach. The data on healthcare resource utilization associated with mitochondrial diseases and the clinical drivers of these costs are limited including for the out-patient setting where the majority of the clinical care for mitochondrial disease patients occurs. We performed a cross-sectional retrospective study of out-patient healthcare resource utilization and costs for patients with a confirmed diagnosis of mitochondrial disease.
METHODS: We recruited participants from the Mitochondrial Disease Clinic in Sydney and stratified them into three groups: those with mitochondrial DNA (mtDNA) mutations (Group 1), those with nuclear DNA (nDNA) mutations and the predominant phenotype of chronic progressive external ophthalmoplegia (CPEO) or optic atrophy (Group 2) and those without a confirmed genetic diagnosis but clinical criteria and muscle biopsy findings supportive of a diagnosis of mitochondrial disease (Group 3). Data was collected through retrospective chart review and out-patient costs were calculated using the Medicare Benefits Schedule.
RESULTS: We analyzed the data from 91 participants and found that Group 1 had the greatest average out-patient costs per person per annum ($838.02; SD 809.72). Neurological investigations were the largest driver of outpatient healthcare costs in all groups (average costs per person per annum:-Group 1: $364.11; SD 340.93, Group 2: $247.83; SD 113.86 and Group 3: $239.57; SD 145.69) consistent with the high frequency (94.5%) of neurological symptoms. Gastroenterological and cardiac-related out-patient costs were also major contributors to out-patient healthcare resource utilization in Groups 1 and 3. In Group 2, ophthalmology was the second-most resource intensive specialty ($136.85; SD 173.35). The Group 3 had the greatest average healthcare resource utilization per person over the entire duration of out-patient clinic care ($5815.86; SD 3520.40) most likely due to the lack of a molecular diagnosis and a less customized management approach.
CONCLUSION: The drivers of healthcare resource utilization are dependent on the phenotype-genotype characteristics. Neurological, cardiac, and gastroenterological costs were the top three drivers in the out-patient clinics unless the patient had nDNA mutations with predominant phenotype of CPEO and/or optic atrophy wherein ophthalmological-related costs were the second most resource intensive driver.

Keywords: Health care costs; Health resources; Health services; Mitochondrial diseases; Mitochondrial disorders; Outpatients

DOI: https://doi.org/10.1186/s13023-023-02746-x

Health Expect. 2023 May 30.

Examining how study teams manage different viewpoints and priorities in patient-centered outcomes research: Results of an embedded multiple case study.

Maureen E Maurer, Tandrea Hilliard-Boone, Karen Frazier, Laura Forsythe, Rachel Mosbacher, Kristin L Carman.

INTRODUCTION: Limited evidence exists about which patient and stakeholder engagement practices support or hinder study teams as they negotiate different viewpoints in decisions about the design and conduct of patient-centered outcomes research.
METHODS: We applied a multiple-embedded descriptive case study design for six studies funded by the Patient-Centered Outcomes Research Institute (PCORI). We interviewed 32 researchers and stakeholder partners, including patients, caregivers and clinicians, and reviewed documents related to each study (e.g., publications, and progress reports submitted to PCORI).
FINDINGS: Overall, researchers reported that incorporating different viewpoints was a strength or opportunity to learn rather than something to be avoided or dreaded. Across cases, different viewpoints and priorities, often related to ethical or pragmatic considerations, emerged between researchers and stakeholders, between stakeholder groups (e.g., patients and clinicians) or within groups (e.g., amongst researchers). Examples of navigating different viewpoints arose across study phases. The length of time to resolve issues depended on how strongly people disagreed and the perceived importance or impact of decisions on the study. All cases used collaborative decision-making approaches, often described as consensus, throughout the study. Interviewees described consensus as using negotiation, compromise or working towards an agreeable decision. To encourage consensus, cases actively facilitated group discussions with an openness to diverse opinions, remained flexible and open to trying new things, referenced a ground rule or common goal and delegated decisions to partners or smaller workgroups. When viewpoints were not easily resolved, cases used different approaches to reach final decisions while maintaining relationships with partners, such as elevating decisions to leadership or agreeing to test out an approach. No one engagement structure (e.g., advisory group, coinvestigator) stood out as better able to manage different viewpoints. Teams adjusted engagement structures and behaviours to facilitate an overall culture of inclusion and respect. Partners acknowledged the intentional efforts of researchers to incorporate their perspectives, navigate challenges and communicate the value of partner input.
CONCLUSION: By using collaborative decision-making in the early stages and throughout the study, researchers built trust with partners so that when decisions were difficult to resolve, partners still felt listened to and that their input mattered.
PATIENT OR PUBLIC CONTRIBUTION: Members of the PCORI Patient Engagement Advisory Panel in 2019-2020 provided input into the design of the study, including the research questions and approaches to data collection and analysis.

Keywords: comparative effectiveness research; conflict resolution; consensus; patient and public involvement; patient and stakeholder engagement; patient-centered outcomes research; team science

DOI: https://doi.org/10.1111/hex.13765

Neurology. 2023 Jun 02. pii: 10.1212/WNL.0000000000207402. [Epub ahead of print]

Efficacy and Safety of Elamipretide in Individuals With Primary Mitochondrial Myopathy: The MMPOWER-3 Randomized Clinical Trial.

MMPOWER-3 Trial Investigators

BACKGROUND AND OBJECTIVES: Primary Mitochondrial Myopathies (PMMs) encompass a group of genetic disorders that impair mitochondrial oxidative phosphorylation, adversely impacting physical function, exercise capacity, and quality of life (QoL). Current PMM standards-of-care address symptoms, with limited clinical impact, constituting a significant therapeutic unmet need. We present data from MMPOWER-3, a pivotal, phase-3, randomized, double-blind, placebo-controlled clinical trial that evaluated the efficacy and safety of elamipretide in participants with genetically-confirmed PMM.
METHODS: Following screening, eligible participants were randomized 1:1 to receive either 24weeks of elamipretide 40mg/day or placebo subcutaneously. Primary efficacy endpoints included change from baseline to Week 24 on the distance walked on the 6-minute Walk Test (6MWT), and Total Fatigue on the Primary Mitochondrial Myopathy Symptom Assessment (PMMSA). Secondary endpoints included Most Bothersome Symptom Score on the PMMSA, NeuroQoL Fatigue Short Form scores, and the Patient- and Clinician-Global Impression of PMM Symptoms.
RESULTS: Participants (N=218) were randomized (n=109 elamipretide; n=109 placebo). Mean age was 45.6 year (64% women; 94% white). The majority of participants (n=162 [74%]) had mitochondrial DNA (mtDNA) mutations, with the remainder having nuclear DNA (nDNA) defects. At screening, the most frequent bothersome PMM symptom on the PMMSA was tiredness during activities (28.9%). At baseline, mean distance walked on the 6MWT was 336.7±81.2 meters, mean score for Total Fatigue on the PMMSA was 10.6±2.5, and mean T-score for the Neuro-QoL Fatigue Short Form was 54.7±7.5. The study did not meet its primary endpoints assessing changes in the 6MWT and PMMSA Total Fatigue Score (TFS). Between the participants receiving elamipretide versus placebo, the difference in the Least Squares Mean (SE) from baseline to Week 24 on distance walked on the 6MWT was -3.2 (95% confidence interval,-18.7,12.3; p=0.69) meters and on the PMMSA Total Fatigue Score was -0.07 (95% confidence interval,-0.10,0.26; p=0.37). Elamipretide treatment was well-tolerated with most adverse events being mild to moderate in severity.
DISCUSSION: Subcutaneous elamipretide treatment did not improve outcomes in the 6MWT and PMMSA TFS in patients with PMM. However, this phase-3 study demonstrated that subcutaneous elamipretide is well-tolerated.
TRIAL REGISTRATION INFORMATION: Trial registered with clinicaltrials.gov, Clinical Trials Identifier: NCT03323749; submitted on October 12, 2017;first patient enrolled October 9, 2017. https://clinicaltrials.gov/ct2/show/NCT03323749?term=elamipretide&draw=2&rank=9 CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that elamipretide does not improve the 6 minute walk test or fatigue at 24 weeks compared to placebo in patients with primary mitochondrial myopathy.

Keywords: elamipretide; exercise intolerance; myopathy; primary mitochondrial disease; primary mitochondrial myopathy

DOI: https://doi.org/10.1212/WNL.0000000000207402

Front Public Health. 2023 ;11 1144027

The immaturity of patient engagement in value-based healthcare-A systematic review.

Michael van der Voorden, Wim S Sipma, Margriet F C de Jong, Arie Franx, Kees C T B Ahaus.

Introduction: In recent years, Value-Based Healthcare (VBHC) has been gaining traction, particularly in hospitals. A core VBHC element is patient value, i.e., what matters most to the patient and at what cost can this be delivered. This interpretation of value implies patient engagement in patient-doctor communication. Although patient engagement in direct care in the VBHC setting is well described, patient engagement at the organizational level of improving care has hardly been studied. This systematic review maps current knowledge regarding the intensity and impact of patient engagement in VBHC initiatives. We focus on the organizational level of a continuous patient engagement model.
Methods: We performed a systematic review following PRISMA guidelines using five electronic databases. The search strategy yielded 1,546 records, of which 21 studies were eligible for inclusion. Search terms were VBHC and patient engagement, or similar keywords, and we included only empirical studies in hospitals or transmural settings at the organizational level.
Results: We found that consultation, using either questionnaires or interviews by researchers, is the most common method to involve patients in VBHC. Higher levels of patient engagement, such as advisory roles, co-design, or collaborative teams are rare. We found no examples of the highest level of patient engagement such as patients co-leading care improvement committees.
Conclusion: This study included 21 articles, the majority of which were observational, resulting in a limited quality of evidence. Our review shows that patient engagement at the organizational level in VBHC initiatives still relies on low engagement tools such as questionnaires and interviews. Higher-level engagement tools such as advisory roles and collaborative teams are rarely used. Higher-level engagement offers opportunities to improve healthcare and care pathways through co-design with the people being served. We urge VBHC initiatives to embrace all levels of patient engagement to ensure that patient values find their way to the heart of these initiatives.

Keywords: co-design; co-production; communication; patient engagement; patient perspective; quality improvement; value-based healthcare (VBHC)

DOI: https://doi.org/10.3389/fpubh.2023.1144027