bims-curels 2023-08-27 papers

bims-curels

Biomed News

on Leigh syndrome

Issue of 2023‒08‒27
23 papers selected by
Cure Mito Foundation

Leigh Syndrome Spectrum: A Portuguese Population Cohort in an Evolutionary Genetic Era.
Aiding the Adoption of Master Protocols by Optimizing Patient Engagement.
Advances in mitochondrial DNA base editing technology.
Toward representative genomic research: the children's rare disease cohorts experience.
Characterising meaningful patient and public involvement in the pharmaceutical industry research setting: a retrospective quality assessment.
Development of Precision Therapies for Rare Inborn Errors of Metabolism: Functional Investigations in Cell Culture Models.
Realising the potential of gene therapies for rare and ultra-rare inherited diseases.
A patienthood that transcends the patient: An analysis of patient research partners' narratives of involvement in a Canadian arthritis patient advisory board.
Mitochondrial disorders due to m.3243A>G not meeting diagnostic criteria for MELAS require comprehensive work-up.
Treatment of a patient with severe lactic acidosis and multiple organ failure due to mitochondrial myopathy: A case report.
Impact of Physical Activity Counselling on Children with Medical Conditions and Disabilities and Their Families.
Mitochondrial impairment and synaptic dysfunction are associated with neurological defects in iPSCs-derived cortical neurons of MERRF patients.
Engaging Patients and Caregivers to Develop a Patient-Centered Agenda for Comparative Effectiveness Research Focused on the Treatment of Complex Knee Problems.
Patient and public involvement in health research from researchers' perspective.
Rare diseases: why is a rapid referral to an expert center so important?
Development of brain organoid technology derived from iPSC for the neurodegenerative disease modelling: a glance through.
Putting the Patient Back into Patient Advocacy.
Series: Public engagement with research. Part 4: Maximising the benefits of involving the public in research implementation.
Mitochondrial DNA in Human Diversity and Health: From the Golden Age to the Omics Era.
'Working relationships' across difference - a realist review of community engagement with malaria research.
Navigating the Rare Neurotransmitter Disease Diagnosis: Insights from Patients and Health Care Professionals.
Do not biopsy the MELAS brain.
Leigh-like syndrome with progressive cerebellar atrophy caused by novel HIBCH variants.

Genes (Basel). 2023 Jul 27. pii: 1536. [Epub ahead of print]14(8):

Leigh Syndrome Spectrum: A Portuguese Population Cohort in an Evolutionary Genetic Era.

Manuela Schubert Baldo, Célia Nogueira, Cristina Pereira, Patrícia Janeiro, Sara Ferreira, Charles M Lourenço, Anabela Bandeira, Esmeralda Martins, Marina Magalhães, Esmeralda Rodrigues, Helena Santos, Ana Cristina Ferreira, Laura Vilarinho.

  Mitochondrial diseases are the most common inherited inborn error of metabolism resulting in deficient ATP generation, due to failure in homeostasis and proper bioenergetics. The most frequent mitochondrial disease manifestation in children is Leigh syndrome (LS), encompassing clinical, neuroradiological, biochemical, and molecular features. It typically affects infants but occurs anytime in life. Considering recent updates, LS clinical presentation has been stretched, and is now named LS spectrum (LSS), including classical LS and Leigh-like presentations. Apart from clinical diagnosis challenges, the molecular characterization also progressed from Sanger techniques to NGS (next-generation sequencing), encompassing analysis of nuclear (nDNA) and mitochondrial DNA (mtDNA). This upgrade resumed steps and favored diagnosis. Hereby, our paper presents molecular and clinical data on a Portuguese cohort of 40 positive cases of LSS. A total of 28 patients presented mutation in mtDNA and 12 in nDNA, with novel mutations identified in a heterogeneous group of genes. The present results contribute to the better knowledge of the molecular basis of LS and expand the clinical spectrum associated with this syndrome.

Keywords:  NGS; clinical spectrum; leigh syndrome; mitochondrial disorders; mutational spectrum

DOI:  https://doi.org/10.3390/genes14081536
Ther Innov Regul Sci. 2023 Aug 24.

Aiding the Adoption of Master Protocols by Optimizing Patient Engagement.

Raymond A Huml, Deborah Collyar, Zoran Antonijevic, Robert A Beckman, Ruben G W Quek, Jingjing Ye.

  Master protocols (MPs) are an important addition to the clinical trial repertoire. As defined by the U.S. Food and Drug Administration (FDA), this term means "a protocol designed with multiple sub-studies, which may have different objectives (goals) and involve coordinated efforts to evaluate one or more investigational drugs in one or more disease subtypes within the overall trial structure." This means we now have a unique, scientifically based MP that describes how a clinical trial will be conducted using one or more potential candidate therapies to treat patients in one or more diseases. Patient engagement (PE) is also a critical factor that has been recognized by FDA through its Patient-Focused Drug Development (PFDD) initiative, and by the European Medicines Agency (EMA), which states on its website that it has been actively interacting with patients since the creation of the Agency in 1995. We propose that utilizing these PE principles in MPs can make them more successful for sponsors, providers, and patients. Potential benefits of MPs for patients awaiting treatment can include treatments that better fit a patient's needs; availability of more treatments; and faster access to treatments. These make it possible to develop innovative therapies (especially for rare diseases and/or unique subpopulations, e.g., pediatrics), to minimize untoward side effects through careful dose escalation practices and, by sharing a control arm, to lower the probability of being assigned to a placebo arm for clinical trial participants. This paper is authored by select members of the American Statistical Association (ASA)/DahShu Master Protocol Working Group (MPWG) People and Patient Engagement (PE) Subteam. DahShu is a 501(c)(3) non-profit organization, founded to promote research and education in data science. This manuscript does not include direct feedback from US or non-US regulators, though multiple regulatory-related references are cited to confirm our observation that improving patient engagement is supported by regulators. This manuscript represents the authors' independent perspective on the Master Protocol; it does not represent the official policy or viewpoint of FDA or any other regulatory organization or the views of the authors' employers. The objective of this manuscript is to provide drug developers, contract research organizations (CROs), third party capital investors, patient advocacy groups (PAGs), and biopharmaceutical executives with a better understanding of how including the patient voice throughout MP development and conduct creates more efficient clinical trials. The PE Subteam also plans to publish a Plain Language Summary (PLS) of this publication for clinical trial participants, patients, caregivers, and the public as they seek to understand the risks and benefits of MP clinical trial participation.

Keywords:  Basket trials; Clinical trials; Master protocol; Patient; Patient engagement; Patient-reported outcomes; Plain language summary; Platform trials; Umbrella trials

DOI:  https://doi.org/10.1007/s43441-023-00570-w
Yi Chuan. 2023 Aug 20. 45(8): 632-642

Advances in mitochondrial DNA base editing technology.

Rui-Jia Song, Lu Han, Hai-Feng Sun, Bin Shen.

  Mitochondria, the energy factories of higher eukaryotes, provide energy (ATP) for life activities through aerobic respiration. They possess their own genome, mitochondrial DNA (mtDNA), which encodes 37 genes. Mutations in mtDNA cause mitochondrial diseases, and more than 100 pathogenic mutations have been identified in human mtDNA, with a total incidence rate of about 1/5000. In recent years, advances in CRISPR-based base editing technology have enabled accurate editing of nuclear genes. However, it remains a challenge to achieve precise base editing on mtDNA due to the difficulty of guide RNA in the CRISPR system passing through the mitochondrial double-membrane. In 2020, David R. Liu's group at Harvard University reported a double-stranded DNA deaminase DddA from Burkholderia cenocepacia, which was fused with the programmable transcription activator-like effector (TALE) and uracil glycosylase inhibitor (UGI) to develop DddA-derived cytosine base editors (DdCBEs). Using DdCBEs, they were able to achieve specific and efficient C?G to T?A conversion on mtDNA for the first time. In this review, we summarize the recent progress of mitochondrial base editing technology based on DddA and prospect its future application prospects. The information presented may facilitate interested researchers to grasp the principles of mitochondrial base editing, to use relevant base editors in their own studies, or to optimize mitochondrial base editors in the future.

Keywords:  base editing; mitochondrial DNA; mitochondrial diseases

DOI:  https://doi.org/10.16288/j.yczz.23-045
Ther Adv Rare Dis. 2023 Jan-Dec;4:4 26330040231181406

Toward representative genomic research: the children's rare disease cohorts experience.

Zoë J Frazier, Eurnestine Brown, Shira Rockowitz, Ted Lee, Bo Zhang, Abigail Sveden, Nancy L Chamberlin, Kira A Dies, Annapurna Poduri, Piotr Sliz, Maya Chopra.

  Background: Due to racial, cultural, and linguistic marginalization, some populations experience disproportionate barriers to genetic testing in both clinical and research settings. It is difficult to track such disparities due to non-inclusive self-reported race and ethnicity categories within the electronic health record (EHR). Inclusion and access for all populations is critical to achieve health equity and to capture the full spectrum of rare genetic disease.Objective: We aimed to create revised race and ethnicity categories. Additionally, we identified racial and ethnic under-representation amongst three cohorts: (1) the general Boston Children's Hospital patient population (general BCH), (2) the BCH patient population that underwent clinical genomic testing (clinical sequencing), and (3) Children's Rare Disease Cohort (CRDC) research initiative participants.
Design and Methods: Race and ethnicity data were collected from the EHRs of the general BCH, clinical sequencing, and CRDC cohorts. We constructed a single comprehensive set of race and ethnicity categories. EHR-based race and ethnicity variables were mapped within each cohort to the revised categories. Then, the numbers of patients within each revised race and ethnicity category were compared across cohorts.
Results: There was a significantly lower percentage of Black or African American/African, non-Hispanic/non-Latine individuals in the CRDC cohort compared with the general BCH cohort, but there was no statistically significant difference between the CRDC and the clinical sequencing cohorts. There was a significantly lower percentage of multi-racial, Hispanic/Latine individuals in the CRDC cohort than the clinical sequencing cohort. White, non-Hispanic/non-Latine individuals were over-represented in the CRDC compared to the two other groups.
Conclusion: We highlight underrepresentation of certain racial and ethnic populations in sequencing cohorts compared to the general hospital population. We propose a range of measures to address these disparities, to strive for equitable future precision medicine-based clinical care and for the benefit of the whole rare disease community.

Keywords:  electronic medical record; ethnicity; genetic testing; genomic research; health equity; race; racial disparity; representation

DOI:  https://doi.org/10.1177/26330040231181406
BMJ Open. 2023 08 23. 13(8): e071339

Characterising meaningful patient and public involvement in the pharmaceutical industry research setting: a retrospective quality assessment.

Sally-Anne Dews, Adit Bassi, Sean Buckland, Lucy Clements, Rachel Daley, Angela Davies, Sophie Evett, Samantha Howland, Emma Kinloch, Berkeley Phillips, Gareth Powell, Jennifer Preston, Kamil Sterniczuk, Natalie Bohm.

  OBJECTIVES: Patient and public involvement (PPI) in clinical research has a well-established infrastructure in the UK, and while there has been good progress within pharmaceutical-industry-sponsored research, further improvements are still needed. This review aims to share learnings from quality assessments of historical PPI projects within Pfizer UK to inform future projects and drive PPI progress in the pharmaceutical industry.DESIGN AND SETTING: Internal assessments of Pfizer UK PPI projects were conducted to identify all relevant projects across the medicines development continuum between 2017 and 2021. Five sample projects were developed into case studies.
OUTCOME MEASURE: Retrospective quality assessments were performed using the Patient Focused Medicines Development (PFMD) Patient Engagement Quality Guidance (PEQG) tool. Recommendations for improvement were developed.
RESULTS: Retrospective case study analysis and quality framework assessment revealed benefits of PPI to both Pfizer UK and to external partners, as well as challenges and learnings to improve future practice. Recommendations for improvement based on these findings focused on processes and procedures for PPI, group dynamics and diversity for PPI activities, sharing of expertise, the importance of bidirectional and timely feedback, and the use of understandable language in materials.
CONCLUSIONS: PPI in medicines development is impactful and beneficial but is still being optimised in the pharmaceutical industry. Using the PFMD PEQG tool to define gaps, share learnings and devise recommendations for improvement helps to ensure that PPI is genuine and empowering, rather than tokenistic. Ultimately, these recommendations should be acted on to further embed PPI as an integral part of medicines development and health research within the pharmaceutical industry. This article includes a plain language summary in the supplement.

Keywords:  MEDICAL EDUCATION & TRAINING; QUALITATIVE RESEARCH; Quality in health care

DOI:  https://doi.org/10.1136/bmjopen-2022-071339
J Inherit Metab Dis. 2023 Aug 22.

Development of Precision Therapies for Rare Inborn Errors of Metabolism: Functional Investigations in Cell Culture Models.

Miroslava Didiasova, Antje Banning, Ritva Tikkanen.

  Due to the low number of patients, rare genetic diseases are a special challenge for the development of therapies, especially for diseases that result from numerous, patient-specific pathogenic variants. Precision medicine makes use of various kinds of molecular information about a specific variant, so that the possibilities for an effective therapy based on the molecular features of the variants can be elucidated. The attention to personalized precision therapies has increased among scientists and clinicians, since the "single drug for all patients" approach does not allow the classification of individuals in subgroups according to the differences in the disease genotype or phenotype. This review article summarizes some approaches of personalized precision medicine that can be used for a cost-effective and fast development of therapies, even for single patients. We have focused on specific examples on inborn errors of metabolism, with special attention on drug repurposing. Furthermore, we provide an overview of cell culture models that are suitable for precision medicine approaches. This article is protected by copyright. All rights reserved.

Keywords:  drug repurposing; inborn errors of metabolism; pathogenic variants; personalized medicine; precision medicine; rare diseases

DOI:  https://doi.org/10.1002/jimd.12674
Hum Gene Ther. 2023 Aug 25.

Realising the potential of gene therapies for rare and ultra-rare inherited diseases.

Claire Booth, Alessandro Aiuti.

Rare and ultra-rare diseases have been central to the field of gene therapy since its earliest stage, and we are now witnessing more and more effective treatments entering the clinical realm for patients in need. However, despite promising results across a range of rare diseases, transformative gene therapies may not be available and accessible to patients for non-medical reasons. Traditional regulatory and commercialisation pathways to licensed products seem to be prohibitive for ultra-small patient populations. Here we highlight some of the challenges of delivering gene therapies in rare diseases and discuss innovative solutions being proposed by the gene therapy community.

DOI: https://doi.org/10.1089/hum.2023.127
J Health Serv Res Policy. 2023 Aug 26. 13558196231197288

A patienthood that transcends the patient: An analysis of patient research partners' narratives of involvement in a Canadian arthritis patient advisory board.

Graham G Macdonald, Jenny Leese, Alison M Hoens, Sheila Kerr, Wendy Lum, Lianne Gulka, Laura Nimmon, Linda C Li.

  OBJECTIVES: Incorporating the perspectives of patients and public into the conduct of research has the potential to make scientific research more democratic. This paper explores how being a patient partner on an arthritis patient advisory board shapes the patienthood of a person living with arthritis.METHODS: An analysis was undertaken of the narratives of 22 patient research partners interviewed about their experiences on the Arthritis Patient Advisory Board (APAB), based in Vancouver, Canada.
RESULTS: Participants' motivations to become involved in APAB stemmed largely from their desire to change their relationship with their condition. APAB was a living collective project in which participants invested their hope, both for their own lives as patients and for others with the disease.
CONCLUSIONS: Our findings highlight how the journeys of patient partners connect and integrate seemingly disparate conceptions of what it means to be a patient. One's experience as a clinical 'patient' transforms into the broader notion of civic patienthood.

Keywords:  Patient engagement in research; civic patienthood; patient journey

DOI:  https://doi.org/10.1177/13558196231197288
Eur Heart J Case Rep. 2023 Aug;7(8): ytad294

Mitochondrial disorders due to m.3243A>G not meeting diagnostic criteria for MELAS require comprehensive work-up.

Josef Finsterer, Sounira Mehri.

DOI: https://doi.org/10.1093/ehjcr/ytad294
World J Clin Cases. 2023 Aug 06. 11(22): 5398-5406

Treatment of a patient with severe lactic acidosis and multiple organ failure due to mitochondrial myopathy: A case report.

Ling Chen, Tian-Kui Shuai, Yu-Wei Gao, Min Li, Peng-Zhong Fang, Waydhas Christian, Li-Ping Liu.

  BACKGROUND: Mitochondrial myopathy is a rare genetic disease with maternal inheritance that may involve multiple organ systems. Due to the lack of typical characteristics, its clinical diagnosis is difficult, and it is often misdiagnosed or even missed.CASE SUMMARY: The patient was a young college student. When he presented at the hospital, he had severe lactic acidosis, respiratory failure, and shock with multiple organ dysfunction syndrome (MODS). He was treated by mechanical ventilation, veno-arterial extracorporeal membrane oxygenation, and other organ support. However, his condition continued to worsen. After a thorough and detailed medical and family history was taken, a mitochondrial crisis was suspected. A muscle biopsy was taken. Further genetic testing confirmed a mitochondrial gene mutation (TRNL1 3243A>G). The final diagnosis of mitochondrial myopathy was made. Although there is no known specific treatment, intravenous methylprednisone and intravenous immunoglobulin were started. The patient's shock eventually improved. The further course was complicated by severe infection in multiple sites, severe muscle weakness, and recurrent MODS. After 2 mo of multidisciplinary management and intensive rehabilitation, the patient could walk with assistance 4 mo after admission and walk independently 6 mo after admission.
CONCLUSION: More attention should be paid to mitochondrial myopathy to avoid missed diagnosis and misdiagnosis.

Keywords:  Case report; Extracorporeal membrane oxygenation; Hyperlactatemia; Mitochondrial crisis; Mitochondrial myopathy; Multiple organ dysfunction syndrome

DOI:  https://doi.org/10.12998/wjcc.v11.i22.5398
Children (Basel). 2023 Jul 27. pii: 1293. [Epub ahead of print]10(8):

Impact of Physical Activity Counselling on Children with Medical Conditions and Disabilities and Their Families.

Hannah C Cummings, Jordan Merkas, Jenna Yaraskavitch, Patricia E Longmuir.

  Physical activity counselling can target cognitive-affective participation barriers, but counselling benefits for children with medical conditions/disabilities were unknown. This study investigated successes, challenges, and the impact of physical activity counselling on children and their families. One-on-one semi-structured interviews were completed with 7 patients (2 male/5 female, aged 13-17) and 4 parents who participated in 2-8 weekly counselling sessions (2015-2020). Interviews were recorded and transcribed verbatim for inductive thematic analyses. Counselling encouraged positive mindset changes (viewing physical activity more holistically, making it "more fun and manageable", helping them to "learn how to love moving and doing sports"). Participants felt strong support (feeling heard, validated, and provided with "hope… that we can still achieve things… even though it may seem like there's limitations"). Counselling was viewed positively. The intent to improve active lifestyle attitudes and confidence was reflected in positive, primarily cognitive-affective (motivation for activity, "more general skills of having a positive attitude towards physical activity and the willingness to try new things") outcomes. More sessions, additional resources to keep, and follow-up after counselling completion were recommended to support behaviour change. Future research should evaluate enhanced counselling services and comparing children who have and have not received such counselling.

Keywords:  behaviour therapy; child; counselling; exercise; health promotion; patient satisfaction

DOI:  https://doi.org/10.3390/children10081293
J Biomed Sci. 2023 Aug 21. 30(1): 70

Mitochondrial impairment and synaptic dysfunction are associated with neurological defects in iPSCs-derived cortical neurons of MERRF patients.

Yu-Ting Wu, Hui-Yi Tay, Jung-Tse Yang, Hsiao-Hui Liao, Yi-Shing Ma, Yau-Huei Wei.

  BACKGROUND: Myoclonic epilepsy with ragged-red fibers (MERRF) syndrome is a rare inherited mitochondrial disease mainly caused by the m.8344A > G mutation in mitochondrial tRNALys gene, and usually manifested as complex neurological disorders and muscle weakness. Currently, the pathogenic mechanism of this disease has not yet been resolved, and there is no effective therapy for MERRF syndrome. In this study, MERRF patients-derived iPSCs were used to model patient-specific neurons for investigation of the pathogenic mechanism of neurological disorders in mitochondrial disease.METHODS: MERRF patient-derived iPSCs were differentiated into excitatory glutamatergic neurons to unravel the effects of the m.8344A > G mutation on mitochondrial bioenergetic function, neural-lineage differentiation and neuronal function. By the well-established differentiation protocol and electrophysiological activity assay platform, we examined the pathophysiological behaviors in cortical neurons of MERRF patients.
RESULTS: We have successfully established the iPSCs-derived neural progenitor cells and cortical-like neurons of patients with MERRF syndrome that retained the heteroplasmy of the m.8344A > G mutation from the patients' skin fibroblasts and exhibited the phenotype of the mitochondrial disease. MERRF neural cells harboring the m.8344A > G mutation exhibited impaired mitochondrial bioenergetic function, elevated ROS levels and imbalanced expression of antioxidant enzymes. Our findings indicate that neural immaturity and synaptic protein loss led to the impairment of neuronal activity and plasticity in MERRF neurons harboring the m.8344A > G mutation. By electrophysiological recordings, we monitored the in vivo neuronal behaviors of MERRF neurons and found that neurons harboring a high level of the m.8344A > G mutation exhibited impairment of the spontaneous and evoked potential-stimulated neuronal activities.
CONCLUSIONS: We demonstrated for the first time the link of mitochondrial impairment and synaptic dysfunction to neurological defects through impeding synaptic plasticity in excitatory neurons derived from iPSCs of MERRF patients harboring the m.8344A > G mutation. This study has provided new insight into the pathogenic mechanism of the tRNALys gene mutation of mtDNA, which is useful for the development of a patient-specific iPSCs platform for disease modeling and screening of new drugs to treat patients with MERRF syndrome.

Keywords:  AMPARs; Disease modeling; Electrophysiological activity; Excitatory neurons; MERRF syndrome; Neurological defect; Synaptic plasticity; Synaptophysin; iPSCs; mtDNA mutation

DOI:  https://doi.org/10.1186/s12929-023-00966-8
J Knee Surg. 2023 Aug 21.

Engaging Patients and Caregivers to Develop a Patient-Centered Agenda for Comparative Effectiveness Research Focused on the Treatment of Complex Knee Problems.

Lisa A Royse, Sandi Strother, Matt Trachsel, David R Mehr, Kimberly Hoffman, James L Cook.

Complex articular cartilage loss in the knee is being diagnosed more frequently and earlier in life, and patients are faced with major decisions regarding invasive surgical interventions at increasingly younger ages. There is a critical unmet need to provide patient-centered comparative effectiveness research for the hundreds of thousands of patients faced with these treatment decisions each year. Toward filling the need, we developed the Patient AdvisoR Team iN Orthopaedic ReSearch (PARTNORS) program. We recruited a diverse group of patients and caregivers with lived experiences in dealing with complex knee problems to define patient-centered research priorities for comparative biological and artificial knee surgery research for middle-aged adults. Adapting the Stakeholder Engagement in Question Development and Prioritization Method, PARTNORS defined a 20-question list of patient-centered research questions of factors influencing a patients' choice between biological and artificial knee surgeries. The highest prioritized research question related to functional level postsurgery as it relates to daily activities and recreational activities. The second highest prioritized research questions related to insurance coverage and financial costs. Other prioritized research areas included caregiving needs, implant longevity, recovery and rehabilitation time, patient satisfaction and success rates, individual characteristics, and risks. By engaging a group of patients and caregivers and including them as members of a multidisciplinary research team, comparative effectiveness research that includes patient-centered factors that go beyond typical clinical success indicators for knee surgery can be designed to allow physicians and patients to work together toward evidence-based shared decisions. This shared decision-making process helps to align patients' and health care team's goals and expectations to improve outcomes.

DOI: https://doi.org/10.1055/s-0043-1772608
Health Expect. 2023 Aug 21.

Patient and public involvement in health research from researchers' perspective.

Toril B Røssvoll, Jan H Rosenvinge, Kristin Liabo, Tove A Hanssen, Gunn Pettersen.

  BACKGROUND: Patient and public involvement (PPI) is increasingly considered an integral part of health research, and the focus has shifted from why we need PPI to how users can be involved in a meaningful way. The rationale for investigating experiences with PPI from the perspective of occupational therapy (OT)-trained researchers' originates in the interrelationship between the inclusive approach to knowledge production, and participation and inclusion as core tenets of OT. The aim of this study was to explore PPI in health research from the perspective of OT-trained researchers.METHOD: Semi-structured individual interviews were conducted online with nine Norwegian researchers. The interviews were analysed using reflexive thematic analysis.
RESULTS: Professional background and clinical experience from person-centred OT formed the foundation for how these researchers approached and facilitated PPI in their research. Valuing experiential knowledge and facilitating PPI to be meaningful for public collaborators were highlighted as essential for PPI to have an impact. The need to balance mutual expectations, requirements for research, and what might be possible to achieve within a research study were found to be vital.
CONCLUSION: Collaborative clinical experience constituted a sound foundation for implementing PPI in research. The occupational perspective underlines the importance of acknowledging experiential knowledge as essential to facilitating meaningful PPI. Challenges related to requirements for research and culture for implementing PPI were addressed by clarifying roles and expectations.
PATIENT OR PUBLIC CONTRIBUTION: Three public collaborators were involved in developing the aims, the interview guide, and the data analysis. They all had previous experience being involved in research.

Keywords:  occupational therapist; participation; patient and public involvement; reflexive thematic analysis

DOI:  https://doi.org/10.1111/hex.13853
BMC Health Serv Res. 2023 Aug 23. 23(1): 904

Rare diseases: why is a rapid referral to an expert center so important?

Tina Willmen, Lukas Willmen, Anne Pankow, Simon Ronicke, Heinz Gabriel, Annette Doris Wagner.

  BACKGROUND: Patients with rare diseases usually go through years of diagnostic odysseys. The large number of rare diseases and the associated lack of expertise pose a major challenge to physicians. There are few physicians dealing with patients with rare diseases and they usually work in a limited number of specialized centers. The aim of this study was to evaluate the diagnostic efficiency of an expert center.METHODS: The diagnostic pathway of 78 patients of the outpatient clinic for rare inflammatory systemic diseases with renal involvement was analyzed retrospectively. For this purpose, each examination day was documented with the corresponding examinations performed from the onset of initial symptoms. Three time points were considered: The time when patients first visited a physician with symptoms, the time when patients consulted an expert, and the time when they received the correct diagnosis. In addition, it was documented whether the diagnosis could be made without the expert, or only with the help of the expert. The examinations that confirmed the diagnosis were also documented for each patient.
RESULTS: A correct diagnosis was made without the help of the expert in only 21% of cases. Each patient visited an average of 6 physicians before consulting the expert. Targeted diagnostics enabled the expert to make the correct diagnosis with an average of seven visits, or one inpatient stay. However, referral to the expert took an average of 4 years.
CONCLUSION: The data show that rapid and targeted diagnostics were possible in the expert center due to the available expertise and the interdisciplinary exchange. Early diagnosis is of great importance for many patients, as an early and correct therapy can be decisive for the course of the disease.

Keywords:  Diagnostic odysseys; Diagnostics; Prevention; Rare diseases; Target-oriented diagnostic procedures

DOI:  https://doi.org/10.1186/s12913-023-09886-7
Front Mol Neurosci. 2023 ;16 1173433

Development of brain organoid technology derived from iPSC for the neurodegenerative disease modelling: a glance through.

Amirah Syamimi Jusop, Kalaiselvaan Thanaskody, Gee Jun Tye, Sylvia Annabel Dass, Wan Safwani Wan Kamarul Zaman, Fazlina Nordin.

  Neurodegenerative diseases are adult-onset neurological conditions that are notoriously difficult to model for drug discovery and development because most models are unable to accurately recapitulate pathology in disease-relevant cells, making it extremely difficult to explore the potential mechanisms underlying neurodegenerative diseases. Therefore, alternative models of human or animal cells have been developed to bridge the gap and allow the impact of new therapeutic strategies to be anticipated more accurately by trying to mimic neuronal and glial cell interactions and many more mechanisms. In tandem with the emergence of human-induced pluripotent stem cells which were first generated in 2007, the accessibility to human-induced pluripotent stem cells (hiPSC) derived from patients can be differentiated into disease-relevant neurons, providing an unrivaled platform for in vitro modeling, drug testing, and therapeutic strategy development. The recent development of three-dimensional (3D) brain organoids derived from iPSCs as the best alternative models for the study of the pathological features of neurodegenerative diseases. This review highlights the overview of current iPSC-based disease modeling and recent advances in the development of iPSC models that incorporate neurodegenerative diseases. In addition, a summary of the existing brain organoid-based disease modeling of Alzheimer's disease was presented. We have also discussed the current methodologies of regional specific brain organoids modeled, its potential applications, emphasizing brain organoids as a promising platform for the modeling of patient-specific diseases, the development of personalized therapies, and contributing to the design of ongoing or future clinical trials on organoid technologies.

Keywords:  Alzheimer’s disease; assembloids; brain organoids; disease modeling; induced pluripotent stem cells (iPSCs); neurodegenerative disease

DOI:  https://doi.org/10.3389/fnmol.2023.1173433
J Pediatr Gastroenterol Nutr. 2023 Aug 24.

Putting the Patient Back into Patient Advocacy.

Simon S Rabinowitz.

DOI: https://doi.org/10.1097/MPG.0000000000003926
Eur J Gen Pract. 2023 Dec;29(1): 2243037

Series: Public engagement with research. Part 4: Maximising the benefits of involving the public in research implementation.

Laura Swaithes, Laura Campbell, Sibyl Anthierens, Magdalena Skrybant, Dieuwke Schiphof, Helen French, Maarten de Wit, Steven Blackburn, Krysia Dziedzic.

  This final article in the four-part series focuses on the often neglected yet important role of the public in implementing research in General Practice and Primary Care more broadly. Experience in implementation of findings from research with public engagement in Primary Care has highlighted how partnership working with patients and the public is important in transitioning from 'what we know' from the evidence-base to 'what we do' in practice. Factors related to Primary Care research that make public engagement important are highlighted e.g. implementing complex interventions, implementing interventions that increase health equity, implementing interventions in countries with different primary healthcare system strengths. Involvement of patients and public can enhance the development of modelling and simulation included in studies on systems modelling for improving health services. We draw on the emerging evidence base to describe public engagement in implementation and offer some guiding principles for engaging with the public in the implementation in General Practice and Primary Care in general. Illustrative case studies are included to support others wishing to offer meaningful engagement in implementing research evidence.

Keywords:  Patient and public involvement; general practice; implementation; knowledge mobilisation

DOI:  https://doi.org/10.1080/13814788.2023.2243037
Genes (Basel). 2023 Jul 27. pii: 1534. [Epub ahead of print]14(8):

Mitochondrial DNA in Human Diversity and Health: From the Golden Age to the Omics Era.

Candela L Hernández.

  Mitochondrial DNA (mtDNA) is a small fraction of our hereditary material. However, this molecule has had an overwhelming presence in scientific research for decades until the arrival of high-throughput studies. Several appealing properties justify the application of mtDNA to understand how human populations are-from a genetic perspective-and how individuals exhibit phenotypes of biomedical importance. Here, I review the basics of mitochondrial studies with a focus on the dawn of the field, analysis methods and the connection between two sides of mitochondrial genetics: anthropological and biomedical. The particularities of mtDNA, with respect to inheritance pattern, evolutionary rate and dependence on the nuclear genome, explain the challenges of associating mtDNA composition and diseases. Finally, I consider the relevance of this single locus in the context of omics research. The present work may serve as a tribute to a tool that has provided important insights into the past and present of humankind.

Keywords:  aDNA; aging; diseases; forensics; haplogroup; human population genetics; longevity; mitogenome; phylogeny; phylogeography

DOI:  https://doi.org/10.3390/genes14081534
Wellcome Open Res. 2022 ;7 13

'Working relationships' across difference - a realist review of community engagement with malaria research.

REAL team: Mary Chambers, Phaik Yeong Cheah, Al Davies, Kate Gooding, Dorcas Kamuya, Vicki Marsh, Noni Mumba, Deborah Nyirenda, and Paulina Tindana.

  Background: Community engagement (CE) is increasingly accepted as a critical aspect of health research, because of its potential to make research more ethical, relevant and well implemented. While CE activities linked to health research have proliferated in Low and Middle Income Countries (LMICs), and are increasingly described in published literature, there is a lack of conceptual clarity around how engagement is understood to 'work', and the aims and purposes of engagement are varied and often not made explicit. Ultimately, the evidence base for engagement remains underdeveloped. Methods: To develop explanations for how and why CE with health research contributes to the pattern of outcomes observed in published literature , we conducted a realist review of CE with malaria research - a theory driven approach to evidence synthesis. Results: We found that community engagement relies on the development of provisional 'working relationships' across differences, primarily of wealth, power and culture. These relationships are rooted in interactions that are experienced as relatively responsive and respectful, and that bring tangible research related benefits. Contextual factors affecting development of working relationships include the facilitating influence of research organisation commitment to and resources for engagement, and constraining factors linked to the prevailing 'dominant health research paradigm context', such as: differences of wealth and power between research centres and local populations and health systems; histories of colonialism and vertical health interventions; and external funding and control of health research. Conclusions: The development of working relationships contributes to greater acceptance and participation in research by local stakeholders, who are particularly interested in research related access to health care and other benefits. At the same time, such relationships may involve an accommodation of some ethically problematic characteristics of the dominant health research paradigm, and thereby reproduce this paradigm rather than challenge it with a different logic of collaborative partnership.

Keywords:  Community Engagement; access to health; health research; malaria research; realist review; research benefits; research ethics; stakeholder engagement

DOI:  https://doi.org/10.12688/wellcomeopenres.17192.1
J Inherit Metab Dis. 2023 Aug 25.

Navigating the Rare Neurotransmitter Disease Diagnosis: Insights from Patients and Health Care Professionals.

Ivana Badnjarevic, Kelly Moyer, Mariarita Bertoldi, Thomas Opladen, Lisa Flint.

Since neurotransmitter diseases are ultra orphan disorders, the diagnostic odyssey is markedly longer than for more common rare diseases. To elucidate the diagnostic odyssey, the authors, consisting of patient advocates and experts, designed questionnaires with the aim to evaluate the challenges of proper diagnosis and to identify the areas in need of improvement. Two questionnaires were designed, one for caregivers and one for health care professionals (HCP). The key questions aimed to evaluate the challenges of diagnosis and to identify the areas in need of improvement. A total of 61 patients' parents/caregivers were surveyed, 81% of them noticed symptoms before the age of 6 months, while 75% reported that their child was 12 months or older before a correct diagnosis was made. Notably, 47% of patients had at least one misdiagnosis. A total of 33 health care professionals were surveyed, of which 40% suspected that it may take up to 12 months, and another 39% 12 or more months, for children to be referred to an experienced specialist in their country. Interestingly, a growing trend emerges toward genetic testing. Early testing and improved collaboration between general practitioners and specialists, may shorten the length of time between symptom onset and correct diagnosis for neurotransmitter disorders. There is a growing movement, among affected families from neurotransmitter communities, who are encouraging the expansion of collaborative initiatives between HCP, scientists, and patient support groups. United efforts can significantly improve the diagnostic odyssey for patients and mitigate the protracted suffering being experienced. This article is protected by copyright. All rights reserved.

DOI: https://doi.org/10.1002/jimd.12675
Parkinsonism Relat Disord. 2023 Aug 09. pii: S1353-8020(23)00880-5. [Epub ahead of print] 105801

Do not biopsy the MELAS brain.

Josef Finsterer, Sounira Mehri.



Keywords:  MELAS; Seizures; Stroke-like episode; m.3243A>G; mtDNA

DOI:  https://doi.org/10.1016/j.parkreldis.2023.105801
Hum Genome Var. 2023 Aug 22. 10(1): 23

Leigh-like syndrome with progressive cerebellar atrophy caused by novel HIBCH variants.

Yoshihiro Taura, Takenori Tozawa, Kenichi Isoda, Satori Hirai, Tomohiro Chiyonobu, Naoko Yano, Takahiro Hayashi, Takeshi Yoshida, Tomoko Iehara.

Pathogenic variants in the HIBCH gene cause HIBCH deficiency, leading to mitochondrial disorders associated with valine metabolism. Patients typically present with symptoms such as developmental regression/delay, encephalopathy, hypotonia and dystonia. Brain magnetic resonance imaging (MRI) shows bilateral lesions in the basal ganglia with/without brainstem involvement. Here, we report a case of a Japanese patient with Leigh-like syndrome caused by novel HIBCH variants. Long-term follow-up MRI revealed progressive cerebellar atrophy, which expands the phenotypic spectrum of HIBCH deficiency.

DOI: https://doi.org/10.1038/s41439-023-00251-y