bims-curels 2023-12-17 papers

bims-curels

Biomed News

on Leigh syndrome

Issue of 2023–12–17
ten papers selected by
Cure Mito Foundation

Red Flags in Primary Mitochondrial Diseases: What Should We Recognize?
#HowNotToDoPatientEngagement: the engaging with purpose patient engagement framework based on a twitter analysis of community perspectives on patient engagement.
The Orphan Drug Act at 40: Legislative Triumph and the Challenges of Success.
Patient/public perceptions on engagement with a medical school: What needs to happen to support authentic and sustained participation.
Morally Problematic Situations Encountered by Adults Living With Rare Diseases.
Ndufs4 KO mice: A model to study comorbid mood disorders associated with mitochondrial dysfunction.
Opening up ideas: an advent calendar for patient and public engagement in clinical trials research.
Ultra-rare ultra-care: Assessing the impact of caring for children with ultra rare diseases.
Prevalence and Clinical Characteristics of Mitochondrial DNA Mutations in Korean Patients With Sensorineural Hearing Loss.
Delivering Digital Health Solutions that Patients Need: A Call to Action.

Int J Mol Sci. 2023 Nov 25. pii: 16746. [Epub ahead of print]24(23):

Red Flags in Primary Mitochondrial Diseases: What Should We Recognize?

Federica Conti, Serena Di Martino, Filippo Drago, Claudio Bucolo, Vincenzo Micale, Vincenzo Montano, Gabriele Siciliano, Michelangelo Mancuso, Piervito Lopriore.

  Primary mitochondrial diseases (PMDs) are complex group of metabolic disorders caused by genetically determined impairment of the mitochondrial oxidative phosphorylation (OXPHOS). The unique features of mitochondrial genetics and the pivotal role of mitochondria in cell biology explain the phenotypical heterogeneity of primary mitochondrial diseases and the resulting diagnostic challenges that follow. Some peculiar features ("red flags") may indicate a primary mitochondrial disease, helping the physician to orient in this diagnostic maze. In this narrative review, we aimed to outline the features of the most common mitochondrial red flags offering a general overview on the topic that could help physicians to untangle mitochondrial medicine complexity.

Keywords:  mitochondria; primary mitochondrial diseases; rare diseases; red flags

DOI:  https://doi.org/10.3390/ijms242316746
Res Involv Engagem. 2023 Dec 13. 9(1): 119

#HowNotToDoPatientEngagement: the engaging with purpose patient engagement framework based on a twitter analysis of community perspectives on patient engagement.

Brianna Dunstan, Francine Buchanan, Alies Maybee, Aisha Lofters, Ambreen Sayani.

   BACKGROUND: Evaluation of patient engagement practices are frequently researcher-driven, researcher-funded, and asymmetric in power dynamics. Little to no literature on patient experiences in patient engagement exist that is are not framed by institutionally-driven research inquiries (i.e., from the lens of a research team lead, or healthcare administrative setting). Understanding these perspectives can help us understand: (i)what matters to patients when they are engaged in research; (ii)why it matters to them, and(iii) how to improve patient engagement practices, so that the needs and priorities of patients are consistently met.
METHODS: This is a patient partner-initiated study. Study authors (including patient partners) conducted a conventional and summative content analysis of textual data retrieved from a highly engaged conversation on Twitter regarding the hashtags #HowNotToDoPatientEngagement and #HowToDoPatientEngagement posted between February 2018 to June 2021. Twitter is a microblogging platform that allows for free-flowing discussions between users not pre-bound by specific community groupings (like within that of Facebook).
RESULTS: A total of 276 tweets were retrieved from 178 separate contributors across seven geographical locations. Four stakeholder groups were identified. We generated 24 codes, nine subthemes and five overarching themes: respect, support, collaboration, inclusivity and impact. Four of these themes are closely aligned with the Strategy for Patient Oriented (SPOR) Patient Engagement framework. We identify impact as a separate and new theme.
INTERPRETATION: Based on our findings we offer the Engaging with Purpose Patient Engagement Framework that defines and describes respect, support, collaboration, inclusivity and impact as five key pillars of meaningful patient engagement.

Keywords:  Framework; Patient advisory; Patient engagement; Patient engagement framework; Patient perspective

DOI:  https://doi.org/10.1186/s40900-023-00527-1
Milbank Q. 2023 Dec 12.

The Orphan Drug Act at 40: Legislative Triumph and the Challenges of Success.

Peter Saltonstall, Heidi Ross, Paul T Kim.

  Policy Points The Orphan Drug Act (ODA) was the result of patient advocacy and by many measures has been strikingly successful. However, approximately 95% of the more than 7,000 known rare diseases still have no US Food and Drug Administration-approved treatment. The ODA's success led to sustained criticism of high drug prices, often for products that have orphan drug indications. Critics misconstrue the ODA's intent and propose reducing its incentives instead of pursuing policies focused on addressing broader prescription drug price challenges that exist in both the orphan and nonorphan drug market. Patients and their families will continue to defend the purpose and integrity of the ODA and to drive investments into rare disease research and clinical development.

Keywords:  FDA; orphan drug; rare diseases

DOI:  https://doi.org/10.1111/1468-0009.12680
Med Teach. 2023 Dec 10. 1-8

Patient/public perceptions on engagement with a medical school: What needs to happen to support authentic and sustained participation.

Angela Towle, Kenneth Ong, Lucy Wang, Cathy C Kline.

   PURPOSE: Patient/public involvement in health professional education is increasing but remains episodic, narrowly focused, reliant on individual enthusiasts, and lacks supportive institutional infrastructure. There is little evidence-informed practical guidance on how to take a more strategic and formal approach. We undertook a qualitative study to learn from patients and the public how medical schools could engage in an authentic and sustainable way.
METHODS: In 2022 we conducted eight focus groups with patients and members of community organizations. Participants were asked about experiences and perceptions of what needs to happen to enable and support them to participate in medical education, barriers to authentic engagement, and how they might be overcome. Recordings were transcribed and data coded inductively. A summary report was circulated to participants for validation of findings.
RESULTS: The focus groups were attended by 38 participants representing a wide variety of perspectives. Participants provided practical suggestions that we categorized into six major themes: inviting participation; preparing for participation; supporting participation; increasing and supporting diversity; recognizing participation; institutional buy-in and support.
CONCLUSIONS: Individual instructors can enhance authentic patient engagement through recruitment, support and recognition practices. Institutional commitment is required to sustain and widen participation through funding, policies and infrastructure.

Keywords:  Community engagement; patient and public involvement

DOI:  https://doi.org/10.1080/0142159X.2023.2289843
AJOB Empir Bioeth. 2023 Dec 14. 1-14

Morally Problematic Situations Encountered by Adults Living With Rare Diseases.

Ariane Quintal, Élissa Hotte, Annie-Danielle Grenier, Caroline Hébert, Isabelle Carreau, Yves Berthiaume, Eric Racine.

   BACKGROUND: Rare diseases are generally poorly understood from scientific and medical standpoints due, to their complexity and low prevalence. As a result, individuals living with rare diseases struggle to obtain timely diagnoses and suitable care. These clinical difficulties add to the physical and psychological impacts of living with chronic and often severe medical conditions. From the standpoint of pragmatist ethics, the morally problematic situations that adults living with rare diseases experience matter crucially. However, there is little known about these experiences.
METHODS: A survey study was conducted with 121 adults living with rare diseases in Québec, Canada, to identify morally problematic situations encountered in the healthcare system and everyday life as part of a participatory action research project. Morally problematic situations elicited internal tensions and constraints to agency.
RESULTS: Adults living with rare diseases experienced morally problematic situations of stigmatization, disbelief, and sometimes abuse in the healthcare system. These situations were compounded by diagnostic delays, inadequate care, and suboptimal follow-up, and led some individuals to opt-out of medical care. In their personal lives, these individuals sometimes found themselves in situations of physical and financial dependency. They often also had to give up professional occupations, academic training, or life projects.
CONCLUSIONS: Adults living with rare diseases experience important morally problematic situations navigating the healthcare system and their everyday lives, some of which could be alleviated through interventions developed through future participatory action research.

Keywords:  Rare diseases; community-based participatory research; ethics; pragmatism; pragmatist ethics; surveys and questionnaires

DOI:  https://doi.org/10.1080/23294515.2023.2274587
Pharmacol Biochem Behav. 2023 Dec 07. pii: S0091-3057(23)00176-4. [Epub ahead of print]234 173689

Ndufs4 KO mice: A model to study comorbid mood disorders associated with mitochondrial dysfunction.

Daniël J van Rensburg, Zander Lindeque, Brian H Harvey, Stephan F Steyn.

  The Ndufs4 knockout (KO) mouse is a validated and robust preclinical model of mitochondrial diseases (specifically Leigh syndrome), that displays a narrow window of relative phenotypical normality, despite its inherent mitochondrial complex I dysfunction and severe phenotype. Preclinical observations related to psychiatric comorbidities that arise in patients with mitochondrial diseases and indeed in Leigh syndrome are, however, yet to be investigated in this model. Strengthening this narrative is the fact that major depression and bipolar disorder are known to present with deficits in mitochondrial function. We therefore screened the behavioural profile of male and female Ndufs4 KO mice (relative to heterozygous; HET and wildtype; WT mice) between postnatal days 28 and 35 for locomotor, depressive- and anxiety-like alterations and linked it with selected brain biomarkers, viz. serotonin, kynurenine, and redox status in brain areas relevant to psychiatric pathologies (i.e., prefrontal cortex, hippocampus, and striatum). The Ndufs4 KO mice initially displayed depressive-like behaviour in the tail suspension test on PND31 but not on PND35 in the forced swim test. In the mirror box test, increased risk resilience was observed. Serotonin levels of KO mice, compared to HET controls, were increased on PND36, together with increased tryptophan to serotonin and kynurenine turnover. Kynurenine to kynurenic acid turnover was however decreased, while reduced versus oxidized glutathione ratio (GSH/GSSG) was increased. When considering the comorbid psychiatric traits of patients with mitochondrial disorders, this work elaborates on the neuropsychiatric profile of the Ndufs KO mouse. Secondly, despite locomotor differences, Ndufs4 KO mice present with a behavioural profile not unlike rodent models of bipolar disorder, namely variable mood states and risk-taking behaviour. The model may elucidate the bio-energetic mechanisms underlying mood disorders, especially in the presence of mitochondrial disease. Studies are however required to further validate the model's translational relevance.

Keywords:  Monoamines; Mood; Oxidative stress; Tryptophan metabolism

DOI:  https://doi.org/10.1016/j.pbb.2023.173689
Res Involv Engagem. 2023 Dec 11. 9(1): 118

Opening up ideas: an advent calendar for patient and public engagement in clinical trials research.

Nicola L Harman, Kerrie McGiveron, Catrin Tudur Smith, Paula R Williamson, Heather Barrington.

  The involvement of patients and the public in research is now an expectation in research with funders requesting a clear plan of involvement and engagement. In the United Kingdom involvement typically focuses on research prioritisation, design and delivery, in contrast activities that share the results of research or research methods more generally are considered to be engagement. Clinical trials tend to concentrate on involvement activities with less emphasis on engagement. To promote engagement activities in the context of clinical trials we asked people attending the 2022 International Clinical Trials Methodology Conference to share ideas on how we can best engage with patients and the public. Responses were reviewed and 22 themes identified. One suggestion was to create an advent calendar and so these 22 themes plus two from the authors were used as a daily tweet from the 1st to the 24th December 2022. Here we share these ideas and draw comparisons between engagement activities in research and traditions of the Christmas period. The ideas shared are not intended as a definitive list but instead a novel way to start discussions between experts by experience, researchers, health professionals and communities to facilitate co-production of meaningful engagement strategies.

Keywords:  Clinical trials; Clinical trials methodology; Patient and public engagement; Patient and public involvement

DOI:  https://doi.org/10.1186/s40900-023-00530-6
Eur J Paediatr Neurol. 2023 Dec 06. pii: S1090-3798(23)00187-3. [Epub ahead of print]48 78-84

Ultra-rare ultra-care: Assessing the impact of caring for children with ultra rare diseases.

Jan Domaradzki, Dariusz Walkowiak.

   BACKGROUND: We sought to assesses the impact of caring for children with ultra rare diseases (URDs) on family carers and to analyse the way these experiences differ among the caregivers of children diagnosed through prenatal or newborn screening, and those with symptom-based diagnosis.
METHODS: A total of 200 caregivers of 219 URDs children completed an on-line survey regarding the challenges and experiences of caregivers of URDs children.
RESULTS: The majority of URD caregivers felt burdened by their children's health problems, emotional and behavioural changes. 46.5% reported feelings of care overload, 43% coped poorly with the stress, and many experienced a variety of feelings of distress towards the role of caregiver. While most caregivers struggled with the diagnostic odyssey and were dissatisfied with the healthcare services for URD children, caregivers of children diagnosed through prenatal or newborn screening were significantly less burdened than the parents of children with symptom-based diagnoses.
CONCLUSION: Although caregivers of URDs children experience physical and emotional strain, they are often neglected by the healthcare system. A bio-psychosocial approach to URDs should therefore also include family caregivers' physical and psychosocial needs. Apart from financial and emotional support, enhancing access to genetic testing and newborn screening should be prioritised.

Keywords:  Caregiving burden; Children; Experiences; Family caregivers; Genetic testing and newborn screening; Ultra rare disease

DOI:  https://doi.org/10.1016/j.ejpn.2023.12.003
J Korean Med Sci. 2023 Dec 11. 38(48): e355

Prevalence and Clinical Characteristics of Mitochondrial DNA Mutations in Korean Patients With Sensorineural Hearing Loss.

Sun Young Joo, Seung Hyun Jang, Jung Ah Kim, Se Jin Kim, Bonggi Kim, Hye-Youn Kim, Jae Young Choi, Heon Yung Gee, Jinsei Jung.

   BACKGROUND: Mutations in mitochondrial DNA (mtDNA) are associated with several genetic disorders, including sensorineural hearing loss. However, the prevalence of mtDNA mutations in a large cohort of Korean patients with hearing loss has not yet been investigated. Thus, this study aimed to investigate the frequency of mtDNA mutations in a cohort of with pre- or post-lingual hearing loss of varying severity.
METHODS: A total of 711 Korean families involving 1,099 individuals were evaluated. Six mitochondrial variants associated with deafness (MTRNR1 m.1555A>G, MTTL1 m.3243A>G, MTCO1 m.7444G>A and m.7445A>G, and MTTS1 m.7471dupC and m.7511T>C) were screened using restriction fragment length polymorphism. The prevalence of the six variants was also analyzed in a large control dataset using whole-genome sequencing data from 4,534 Korean individuals with unknown hearing phenotype.
RESULTS: Overall, 12 of the 711 (1.7%) patients with hearing loss had mtDNA variants, with 10 patients from independent families positive for the MTRNR1 m.1555A>G mutation and 2 patients positive for the MTCO1 m.7444G>A mutation. The clinical characteristics of patients with the mtDNA variants were characterized by post-lingual progressive hearing loss due to the m.1555A>G variant (9 of 472; 1.9%). In addition, 18/4,534 (0.4%) of the Korean population have mitochondrial variants associated with hearing loss, predominantly the m.1555A>G variant.
CONCLUSION: A significant proportion of Korean patients with hearing loss is affected by the mtDNA variants, with the m.1555A>G variant being the most prevalent. These results clarify the genetic basis of hearing loss in the Korean population and emphasize the need for genetic testing for mtDNA variants.

Keywords:  Mitochondrial DNA; Restriction Fragment Length Polymorphism; Sensorineural Hearing Loss

DOI:  https://doi.org/10.3346/jkms.2023.38.e355
Ther Innov Regul Sci. 2023 Dec 11.

Delivering Digital Health Solutions that Patients Need: A Call to Action.

Veronica Popa, Jan Geissler, Rebecca Vermeulen, Elizabeth Priest, Katherine Capperella, Gözde Susuzlu, Sharon F Terry, Nicholas Brooke.

  Digital health solutions have the potential to complement traditional healthcare approaches and deliver improved health outcomes, but there are system-wide challenges that need to be addressed. These include fragmentation of the digital health landscape, regulatory processes that lack the agility to accommodate the fast pace of digital health advances, and inadequate transparency around data sharing and data governance. All of these challenges have led to mistrust, limited understanding and sharing of best practices, a lack of digital education and awareness, and insufficient patient and public engagement and involvement. In this paper, we argue that for digital health solutions to fulfil their potential, there needs to be a significant increase in early, meaningful, and sustained engagement with the people they intend to benefit. The uptake as well as the impact of digital solutions created in partnership with patients for patients are greater and more relevant to the communities they address.

Keywords:  Digital data governance; Digital health; Patient engagement; Patient involvement; Patient-centric design

DOI:  https://doi.org/10.1007/s43441-023-00592-4