bims-curels Biomed News
on Leigh syndrome
Issue of 2023–10–29
eightteen papers selected by
Cure Mito Foundation
  1. Clinical Approaches for Mitochondrial Diseases.
  2. Prevalence of patient partner authorship and acknowledgment in child health research publications: an umbrella review.
  3. A novel mouse model of mitochondrial disease exhibits juvenile-onset severe neurological impairment due to parvalbumin cell mitochondrial dysfunction.
  4. High-throughput single-cell analysis reveals progressive mitochondrial DNA mosaicism throughout life.
  5. Incorporation of patient and public involvement in statistical methodology research: a survey assessing current practices and attitudes of researchers.
  6. The value of co-creating a clinical outcome assessment strategy for clinical trial research: process and lessons learnt.
  7. Diversity in patient and public involvement in healthcare research and education-Realising the potential.
  8. Maximizing the value of patient and public involvement in the digital health co-design process: A qualitative descriptive study with design leaders and patient-public partners.
  9. The INSIGHT project: reflections on the co-production of a quality recognition programme to showcase excellence in public involvement in health and care research.
  10. Zebras Among Us: Advocating for the 30 Million Americans Living with Rare Disease.
  11. Phenotypic heterogeneity of the mitochondrial DNA A8344G variant presenting with dorsal midbrain syndrome.
  12. Mitochondrial heteroplasmy as a cause of cell-to-cell phenotypic heterogeneity in clonal populations.
  13. IRDiRC Drug Repurposing Guidebook: making better use of existing drugs to tackle rare diseases.
  14. Mobilizing Patient and Public Involvement in the Development of Real-World Digital Technology Solutions: Tutorial.
  15. The role of patient organisations in research and development: Evidence from rare diseases.
  16. Mitochondrial DNA Release Is Induced by Apoptotic Stress and Drives the SASP.
  17. Exploring patient perspectives on how they can and should be engaged in the development of artificial intelligence (AI) applications in health care.
  18. Clinical holds for cell and gene therapy trials: Risks, impact, and lessons learned.
  1. Cells. 2023 Oct 20. pii: 2494. [Epub ahead of print]12(20):
    Clinical Approaches for Mitochondrial Diseases.
    Seongho Hong, Sanghun Kim, Kyoungmi Kim, Hyunji Lee.
      Mitochondria are subcontractors dedicated to energy production within cells. In human mitochondria, almost all mitochondrial proteins originate from the nucleus, except for 13 subunit proteins that make up the crucial system required to perform 'oxidative phosphorylation (OX PHOS)', which are expressed by the mitochondria's self-contained DNA. Mitochondrial DNA (mtDNA) also encodes 2 rRNA and 22 tRNA species. Mitochondrial DNA replicates almost autonomously, independent of the nucleus, and its heredity follows a non-Mendelian pattern, exclusively passing from mother to children. Numerous studies have identified mtDNA mutation-related genetic diseases. The consequences of various types of mtDNA mutations, including insertions, deletions, and single base-pair mutations, are studied to reveal their relationship to mitochondrial diseases. Most mitochondrial diseases exhibit fatal symptoms, leading to ongoing therapeutic research with diverse approaches such as stimulating the defective OXPHOS system, mitochondrial replacement, and allotropic expression of defective enzymes. This review provides detailed information on two topics: (1) mitochondrial diseases caused by mtDNA mutations, and (2) the mechanisms of current treatments for mitochondrial diseases and clinical trials.
    Keywords:  clinical trials; mitochondrial diseases; mitochondrial therapy
    DOI:  https://doi.org/10.3390/cells12202494
  2. J Clin Epidemiol. 2023 Oct 21. pii: S0895-4356(23)00272-X. [Epub ahead of print]
    Prevalence of patient partner authorship and acknowledgment in child health research publications: an umbrella review.
    Shelley Vanderhout, Dawn P Richards, Nancy Butcher, Kim Courtney, Stuart G Nicholls, Dean Fergusson, Beth Potter, Manav Bhalla, Pascale Nevins, Grace Fox, Valentina Ly, Monica Taljaard, Colin Macarthur.
       OBJECTIVE: Children and families are increasingly involved as equal partners in child health research, however, considerations around authorship have received little attention and there is limited guidance on the topic. Our objective was to determine the frequency and nature of patient partner authorship and/or acknowledgement among articles focused on patient engagement in child health research.
    STUDY DESIGN: In this umbrella review, we searched MEDLINE, Embase, APA PsycINFO, Cochrane Database of Systematic Reviews, CINAHL, and Web of Science for systematic/scoping reviews on patient engagement in child health research. Individual articles included in eligible reviews comprised the sample of articles for analysis and were examined to identify patient partner authorship. Descriptive statistics were used to quantify patient partner authorship and/or acknowledgement and to summarize article characteristics.
    RESULTS: Twelve systematic/scoping reviews met eligibility criteria, from which 230 individual articles were examined. In 16/230 (7%) articles, there was at least one patient partner author, and in 6/230 (3%) articles, patient partners were included as group authors. Within article Acknowledgements sections, patient partners were acknowledged by name in 41/230 (18%) articles, and anonymously or as a group in 98/230 (43%) articles. Patient partner authorship and/or acknowledgement was more frequent among articles published more recently (after 2015) and among articles where patient engagement was explicitly reported in the article.
    CONCLUSION: Patient partners were more likely to be acknowledged than listed as an author on articles on patient engagement in child health research. Understanding patient partner preferences about authorship and acknowledgement, examination of the unique aspects of child and youth authorship and developing supports to empower patient partner authorship are needed.
    Keywords:  acknowledgement; author; patient and public involvement; patient engagement
    DOI:  https://doi.org/10.1016/j.jclinepi.2023.10.012
  3. Commun Biol. 2023 Oct 23. 6(1): 1078
    A novel mouse model of mitochondrial disease exhibits juvenile-onset severe neurological impairment due to parvalbumin cell mitochondrial dysfunction.
    Elizaveta A Olkhova, Carla Bradshaw, Alasdair Blain, Debora Alvim, Doug M Turnbull, Fiona E N LeBeau, Yi Shiau Ng, Gráinne S Gorman, Nichola Z Lax.
      Mitochondrial diseases comprise a common group of neurometabolic disorders resulting from OXPHOS defects, that may manifest with neurological impairments, for which there are currently no disease-modifying therapies. Previous studies suggest inhibitory interneuron susceptibility to mitochondrial impairment, especially of parvalbumin-expressing interneurons (PV+). We have developed a mouse model of mitochondrial dysfunction specifically in PV+ cells via conditional Tfam knockout, that exhibited a juvenile-onset progressive phenotype characterised by cognitive deficits, anxiety-like behaviour, head-nodding, stargazing, ataxia, and reduced lifespan. A brain region-dependent decrease of OXPHOS complexes I and IV in PV+ neurons was detected, with Purkinje neurons being most affected. We validated these findings in a neuropathological study of patients with pathogenic mtDNA and POLG variants showing PV+ interneuron loss and deficiencies in complexes I and IV. This mouse model offers a drug screening platform to propel the discovery of therapeutics to treat severe neurological impairment due to mitochondrial dysfunction.
    DOI:  https://doi.org/10.1038/s42003-023-05238-7
  4. Sci Adv. 2023 Oct 27. 9(43): eadi4038
    High-throughput single-cell analysis reveals progressive mitochondrial DNA mosaicism throughout life.
    Angelos Glynos, Lyuba V Bozhilova, Michele Frison, Stephen Burr, James B Stewart, Patrick F Chinnery.
      Heteroplasmic mitochondrial DNA (mtDNA) mutations are a major cause of inherited disease and contribute to common late-onset human disorders. The late onset and clinical progression of mtDNA-associated disease is thought to be due to changing heteroplasmy levels, but it is not known how and when this occurs. Performing high-throughput single-cell genotyping in two mouse models of human mtDNA disease, we saw unanticipated cell-to-cell differences in mtDNA heteroplasmy levels that emerged prenatally and progressively increased throughout life. Proliferating spleen cells and nondividing brain cells had a similar single-cell heteroplasmy variance, implicating mtDNA or organelle turnover as the major force determining cell heteroplasmy levels. The two different mtDNA mutations segregated at different rates with no evidence of selection, consistent with different rates of random genetic drift in vivo, leading to the accumulation of cells with a very high mutation burden at different rates. This provides an explanation for differences in severity seen in human diseases caused by similar mtDNA mutations.
    DOI:  https://doi.org/10.1126/sciadv.adi4038
  5. Res Involv Engagem. 2023 Oct 27. 9(1): 100
    Incorporation of patient and public involvement in statistical methodology research: a survey assessing current practices and attitudes of researchers.
    Lucy Abell, Francesca Maher, Samina Begum, Sarah Booth, Jonathan Broomfield, Sangyu Lee, Ellesha Smith, Rachael Stannard, Lucy Teece, Elpida Vounzoulaki, Hannah Worboys, Laura J Gray.
       BACKGROUND: Patient and public involvement (PPI) ensures that research is designed and conducted in a manner that is most beneficial to the individuals whom it will impact. It has an undisputed place in applied research and is required by many funding bodies. However, PPI in statistical methodology research is more challenging and work is needed to identify where and how patients and the public can meaningfully input in this area.
    METHODS: A descriptive cross-sectional research study was conducted using an online questionnaire, which asked statistical methodologists about themselves and their experience conducting PPI, either to inform a grant application or during a funded statistical methodology project. The survey included both closed-text responses, which were reported using summary statistics, and open-ended questions for which common themes were identified.
    RESULTS: 119 complete responses were recorded. Individuals who completed the survey displayed an even range of ages, career lengths and positions, with the majority working in academia. 40.3% of participants reported undertaking PPI to inform a grant application and the majority reported that the inclusion of PPI was received positively by the funder. Only 21.0% of participants reported undertaking PPI during a methodological project. 31.0% of individuals thought that PPI was "very" or "extremely" relevant to statistical methodology research, with 45.5% responding "somewhat" and 24.4% answering "not at all" or "not very". Arguments for including PPI were that it can provide the motivation for research and shape the research question. Negative opinions included that it is too technical for the public to understand, so they cannot have a meaningful impact.
    CONCLUSIONS: This survey found that the views of statistical methodologists on the inclusion of PPI in their research are varied, with some individuals having particularly strong opinions, both positive and negative. Whilst this is clearly a divisive topic, one commonly identified theme was that many researchers are willing to try and incorporate meaningful PPI into their research but would feel more confident if they had access to resources such as specialised training, guidelines, and case studies.
    Keywords:  Methodology; Patient and public involvement (PPI); Survey
    DOI:  https://doi.org/10.1186/s40900-023-00507-5
  6. Res Involv Engagem. 2023 Oct 24. 9(1): 98
    The value of co-creating a clinical outcome assessment strategy for clinical trial research: process and lessons learnt.
    Thomas Morel, Karlin Schroeder, Sophie Cleanthous, John Andrejack, Geraldine Blavat, William Brooks, Lesley Gosden, Carroll Siu, Natasha Ratcliffe, Ashley F Slagle.
       BACKGROUND: In support of UCB pharmaceutical research programs, the aim of this research was to implement a novel process for patient involvement in a multidisciplinary research group to co-create a clinical outcome assessment strategy to accurately reflect the experience of people living with early-stage Parkinson's. Patient experts were an integral part of the decision-making process for patient-reported outcome (PRO) research and instrument development.
    METHODS: In partnership with two patient organizations (Parkinson's UK and the Parkinson's Foundation), 6 patient experts were recruited into a multidisciplinary research group alongside clinical, patient engagement and involvement, regulatory science, and outcome measurement experts. The group was involved across two phases of research; the first phase identified what symptoms are cardinal to the experience of living with early-stage Parkinson's and the second phase involved the development of PRO instruments to better assess the symptoms that are important to people living with early-stage Parkinson's. Patient experts were important in performing a variety of roles, in particular, qualitative study protocol design, conceptual model development, and subsequent co-creation of two PRO instruments.
    RESULTS: Involving people with Parkinson's in PRO research ensured that the expertise of these representatives from the Parkinson's community shaped and drove the research; as such, PRO instruments were being developed with the patient at the forefront. Working with patient experts required considerable resource and time allocation for planning, communication, document development, and organizing meetings; however, their input enriched the development of PRO instruments and was vital in developing PRO instruments that are more meaningful for people with Parkinson's and clinicians.
    CONCLUSIONS: Conducting PRO research, in the context of clinical development involving pharmaceutical companies, requires balancing regulatory and scientific rigor with tight time constraints. Incorporating a multi-stakeholder perspective, which included patient experts as joint investigators, had a strong positive impact on our research, despite the logistical complexities of their involvement. Due to the input of patient experts, the innovative clinical outcome assessment strategy and the co-created novel PRO instruments were more relevant and holistic to the patient experience of early-stage Parkinson's.
    Keywords:  Clinical outcome assessment; Co-creation; Early-stage Parkinson’s; Outcome measure; PEIRS-22; Parkinson’s disease; Patient and public involvement; Patient engagement; Patient expert; Patient-focused drug development; Patient-reported outcomes
    DOI:  https://doi.org/10.1186/s40900-023-00505-7
  7. Health Expect. 2023 Oct 23.
    Diversity in patient and public involvement in healthcare research and education-Realising the potential.
    Sarah Hatch, Jim Fitzgibbon, Amanda Jayne Tonks, Liz Forty.
       BACKGROUND: Patient and public involvement (PPI) is an increasing priority in health-related research and education. Attracting and supporting people from different demographic groups to give up their time and get involved is important to help ensure that all parts of society are empowered, represented and their voices heard in decisions that may affect their health and quality of life.
    OBJECTIVES: (1) To determine if a demographically diverse cross-section of society would be interested in contributing to healthcare research and education. (2) To understand factors that can act as barriers and enablers to effective and diverse PPI.
    METHOD: PPI survey data was collected via engagement events, with the aim of scoping interest in PPI from a diverse public. A Focus Group study involving members of the public, academic and professional service staff, was then conducted to gain a deeper understanding around the barriers and enablers of diversity within PPI.
    RESULTS: 71% of a diverse rich public indicated they would like to get involved in healthcare research and teaching. 76% of survey respondents indicated that they would be happy to share a personal or family experience of healthcare. The two biggest factors impacting on our cohort getting involved are' availability of time' and 'being aware of PPI opportunities'. These factors may disproportionally affect specific groups. Shared and individual PPI enablers and barriers were identified across all stakeholder groups within the Focus Group Study, as well as generic and novel factors that would impact on an institutions' ability to improve PPI diversity.
    CONCLUSION: These data points confirm a demographically diverse public's appetite to get involved in academic health research and teaching. This needs to be recognised and harnessed to ensure public contributor networks are representative of society. Equality Impact Assessments should be undertaken in relation to all PPI opportunities. There is a need to recognise the investment of time and resources required to build mutually beneficial relationships with diverse communities as well as the development of inclusive 'fit for purpose' PPI infrastructures to support the uptake of diverse PPI contributors.
    PUBLIC CONTRIBUTION: This study involved members of the public responding to a short survey. Public contributors made up one of the three focus groups. The School of Medicine lead public contributor was also involved in the preparation of this manuscript.
    Keywords:  diverse patient/public; health research and education; involvement
    DOI:  https://doi.org/10.1111/hex.13896
  8. PLOS Digit Health. 2023 Oct;2(10): e0000213
    Maximizing the value of patient and public involvement in the digital health co-design process: A qualitative descriptive study with design leaders and patient-public partners.
    Paula Voorheis, Jeremy Petch, Quynh Pham, Kerry Kuluski.
      Digital health interventions have enormous potential to support patients and the public in achieving their health goals. Nonetheless, many digital health interventions are failing to effectively engage patients and the public. One solution that has been proposed is to directly involve patients and the public in the design process of these digital health interventions. Although there is consensus that involving patients and the public in collaborative design is valuable, design teams have little guidance on how to maximize the value of their collaborative design work. The main objective of this study was to understand how the value of patient and public involvement in digital health design can be maximized, from the perspective of design leaders and patient-public partners. Using a qualitative descriptive methodology, we conducted semi-structured interviews with 19 design leaders and 9 patient-public partners. Interviewees agreed that involving patients and the public was valuable, however, they questioned if current collaborative methods were optimized to ensure maximal value. Interviewees suggested that patient and public collaborative design can add value through four different mechanisms: (1) by allowing the design process to be an empowering intervention itself, (2) by ensuring that the digital health intervention will be effectively engaging for users, (3) by ensuring that the digital health intervention will be seamlessly implemented in practice, and (4) by allowing patient-public collaborations extend beyond the initial product design. Overall, interviewees emphasized that although collaborative design has historically focused on improving the digital health product itself, patients and the public have crucial insights on implementation planning as well as how collaborative design can be used as its own empowering intervention. The results of this paper provide clarity about the ways that patient and public collaborative design can be made more valuable. Digital health design teams can use these results to be more intentional about their collaborative design approaches.
    DOI:  https://doi.org/10.1371/journal.pdig.0000213
  9. Res Involv Engagem. 2023 Oct 25. 9(1): 99
    The INSIGHT project: reflections on the co-production of a quality recognition programme to showcase excellence in public involvement in health and care research.
    Steven Blackburn, Rachele Hine, Samantha Fairbanks, Phillip Parkes, Darren Murinas, Andrew Meakin, Robert Taylor, Linda Parton, Marilyn Jones, Jessica Tunmore, Jennifer Lench, Nicola Evans, Katharine Lewney, Lucy O'Mara, Anthony A Fryer.
       BACKGROUND: The quality of Patient and Public Involvement (PPI) in healthcare research varies considerably and is frequently tokenistic. We aimed to co-produce the Insight | Public Involvement Quality Recognition and Awards programme, based on the UK Standards for Public Involvement (UKSPI) alongside an incremental scale designed by Expert Citizens (a lived experience-led community group), to incentivise and celebrate continuous improvement in PPI.
    METHODS: We used Task and Finish Groups (19/44 [43%] public contributor membership) to co-produce the programme which we piloted in three organisations with different healthcare research models. We used surveys and review sessions to capture learning and reflections.
    RESULTS: We co-created: (1) A Quality descriptor matrix comprising four incremental quality levels (Welcoming, Listening, Learning, Leading) for each UKSPI standard. (2) An assessment framework including guidance materials, self-assessment form and final report template. (3) An assessor training package. (4) The quality awards event format and nomination form. These materials were modified based on pilot-site feedback. Of survey respondents: 94.4% felt they had made at least 'Some' personal contribution (half said 'Quite a lot'/'A great deal'), 88.9% said they were 'Always'/'Often' able to express their views freely and, 100% stated the programme would have 'A lot of impact'/'Quite a bit of impact'. During the project, we identified the importance of taking time to explain project aims and contributor roles, adapting to the needs of individual contributors and, using smaller bespoke sessions outside the main Task and Finish Groups.
    CONCLUSIONS: We co-produced and piloted a quality recognition programme to incentivise and celebrate continuous quality improvement in PPI. One public contributor stated, "I feel strongly that the Insight framework and awards will raise awareness of the [public involvement] work going on in many community settings. [It] is likely to result in better sharing of positive practice, incentivising research groups of any size to start work or to improve the quality of [PPI] could be one of the main benefits. I'm excited that if this initiative takes off, regionally and then in the longer term nationally, it could be a significant step in advancing the [public] voice."
    Keywords:  Appreciative inquiry; Co-production; Public involvement; Quality improvement; UK Standards for Public Involvement
    DOI:  https://doi.org/10.1186/s40900-023-00508-4
  10. Med Sci Educ. 2023 Oct;33(5): 1239-1242
    Zebras Among Us: Advocating for the 30 Million Americans Living with Rare Disease.
    Eric L Wan, Yehuda Elkaim, William Gao, Robin Yoon.
      Nearly 30 million (about 1 in 10) Americans have a rare disease. On average, rare disease patients wait 6 years for an accurate and definitive diagnosis and see as many as 12 specialists along their diagnostic journey. In this brief article, we highlight some of what is being done across patient care, medical education, policy, and innovation in order to improve the diagnostic and treatment journeys of rare disease patients. We hope that members of the medical education community will appreciate this call to action and engage in the rare disease space.
    Keywords:  Advocacy; Health policy; Innovation; Medical education; Medical professionalism; Rare disease
    DOI:  https://doi.org/10.1007/s40670-023-01856-2
  11. Am J Ophthalmol Case Rep. 2023 Dec;32 101938
    Phenotypic heterogeneity of the mitochondrial DNA A8344G variant presenting with dorsal midbrain syndrome.
    Megan Kasetty, Michael Altman.
       Purpose: To describe a neuro-ophthalmic presentation of a phenotypically heterogeneous mitochondrial DNA variant.
    Observations: A 10-year-old female with gross motor developmental delay, absence seizures and ataxia subacutely developed poor near acuity and asthenopia. She was found to have accommodative insufficiency, impaired supraduction and convergence retraction nystagmus leading to a diagnosis of dorsal midbrain syndrome. Brain MRI showed highly symmetrical lesions involving the dorsal pons. Genetic testing revealed a previously undiagnosed mitochondrial DNA (mtDNA) pathogenic variant, adenine to guanine at nucleopeptide pair 8344 (A8344G).
    Conclusion and importance: The authors describe a unique, neuro-ophthalmic manifestation of mitochondrial disease in a pediatric patient. This report discusses the phenotypic heterogeneity of the mtDNA A8344G variant, which may include 'stroke-like episodes' involving the brainstem, thus presenting with ophthalmic manifestations.
    Keywords:  Dorsal midbrain syndrome; Metabolic stroke; Mitochondrial disorder; Pediatric neuro-ophthalmology; Pediatric stroke
    DOI:  https://doi.org/10.1016/j.ajoc.2023.101938
  12. Front Cell Dev Biol. 2023 ;11 1276629
    Mitochondrial heteroplasmy as a cause of cell-to-cell phenotypic heterogeneity in clonal populations.
    Dmitry A Knorre.
      
    Keywords:  heterogeneity; heteroplasmy; mitochondrial dysfuncion; mtDNA; pathogenicity threshold; retrograde signaling; yeast
    DOI:  https://doi.org/10.3389/fcell.2023.1276629
  13. Nat Rev Drug Discov. 2023 Oct 23.
    IRDiRC Drug Repurposing Guidebook: making better use of existing drugs to tackle rare diseases.
    Anneliene Hechtelt Jonker, Simon Day, Michela Gabaldo, Heather Stone, Martin de Kort, Daniel J O'Connor, Anna Maria Gerdina Pasmooij.
      
    DOI:  https://doi.org/10.1038/d41573-023-00168-9
  14. J Med Internet Res. 2023 Oct 27. 25 e44206
    Mobilizing Patient and Public Involvement in the Development of Real-World Digital Technology Solutions: Tutorial.
    Mobilise-D consortium
      Although the value of patient and public involvement and engagement (PPIE) activities in the development of new interventions and tools is well known, little guidance exists on how to perform these activities in a meaningful way. This is particularly true within large research consortia that target multiple objectives, include multiple patient groups, and work across many countries. Without clear guidance, there is a risk that PPIE may not capture patient opinions and needs correctly, thereby reducing the usefulness and effectiveness of new tools. Mobilise-D is an example of a large research consortium that aims to develop new digital outcome measures for real-world walking in 4 patient cohorts. Mobility is an important indicator of physical health. As such, there is potential clinical value in being able to accurately measure a person's mobility in their daily life environment to help researchers and clinicians better track changes and patterns in a person's daily life and activities. To achieve this, there is a need to create new ways of measuring walking. Recent advancements in digital technology help researchers meet this need. However, before any new measure can be used, researchers, health care professionals, and regulators need to know that the digital method is accurate and both accepted by and produces meaningful outcomes for patients and clinicians. Therefore, this paper outlines how PPIE structures were developed in the Mobilise-D consortium, providing details about the steps taken to implement PPIE, the experiences PPIE contributors had within this process, the lessons learned from the experiences, and recommendations for others who may want to do similar work in the future. The work outlined in this paper provided the Mobilise-D consortium with a foundation from which future PPIE tasks can be created and managed with clearly defined collaboration between researchers and patient representatives across Europe. This paper provides guidance on the work required to set up PPIE structures within a large consortium to promote and support the creation of meaningful and efficient PPIE related to the development of digital mobility outcomes.
    Keywords:  digital mobility measures; digital mobility outcomes; patient engagement; patient involvement; public-private partnership; real-world mobility; research consortium
    DOI:  https://doi.org/10.2196/44206
  15. Soc Sci Med. 2023 Oct 17. pii: S0277-9536(23)00689-5. [Epub ahead of print]338 116332
    The role of patient organisations in research and development: Evidence from rare diseases.
    Arianna Gentilini, Marisa Miraldo.
      Patient organisations play an increasingly crucial role in the pharmaceutical sector, yet their impact on innovation remains unexplored. We estimate the impact of patient organisations on R&D activity in the context of rare diseases in Europe using a proprietary dataset that maps clinical trials from discovery to phase III across 29 countries, 1893 indications, and 30 years (1990-2019). By applying difference-in-differences and event study methodologies to a panel of 1,646,910 unique R&D observations, we find that country-indication pairs with at least one operating patient organisation have a higher rate of R&D activity compared to those without, with stronger effect in more prevalent rare diseases compared to ultra-rare conditions. We observe a lag in effects from patient organisation introduction, suggesting it takes approximately five years for these organisations to affect R&D activity. Overall, our work suggests that patient organisations play an important role in steering R&D efforts in rare diseases. Further research is needed to better understand mechanisms driving this effect and the potential impact of patient organisations on existing health inequities.
    Keywords:  Innovation; Patient organisations; Pharmaceutical markets; Rare diseases; Research and development
    DOI:  https://doi.org/10.1016/j.socscimed.2023.116332
  16. Cancer Discov. 2023 Oct 27. OF1
    Mitochondrial DNA Release Is Induced by Apoptotic Stress and Drives the SASP.
      Minority mitochondrial outer membrane permeabilization (miMOMP) during senescence drives the SASP.
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2023-169
  17. BMC Health Serv Res. 2023 Oct 26. 23(1): 1163
    Exploring patient perspectives on how they can and should be engaged in the development of artificial intelligence (AI) applications in health care.
    Samira Adus, Jillian Macklin, Andrew Pinto.
       BACKGROUND: Artificial intelligence (AI) is a rapidly evolving field which will have implications on both individual patient care and the health care system. There are many benefits to the integration of AI into health care, such as predicting acute conditions and enhancing diagnostic capabilities. Despite these benefits potential harms include algorithmic bias, inadequate consent processes, and implications on the patient-provider relationship. One tool to address patients' needs and prevent the negative implications of AI is through patient engagement. As it currently stands, patients have infrequently been involved in AI application development for patient care delivery. Furthermore, we are unaware of any frameworks or recommendations specifically addressing patient engagement within the field of AI in health care.
    METHODS: We conducted four virtual focus groups with thirty patient participants to understand of how patients can and should be meaningfully engaged within the field of AI development in health care. Participants completed an educational module on the fundamentals of AI prior to participating in this study. Focus groups were analyzed using qualitative content analysis.
    RESULTS: We found that participants in our study wanted to be engaged at the problem-identification stages using multiple methods such as surveys and interviews. Participants preferred that recruitment methodologies for patient engagement included both in-person and social media-based approaches with an emphasis on varying language modalities of recruitment to reflect diverse demographics. Patients prioritized the inclusion of underrepresented participant populations, longitudinal relationship building, accessibility, and interdisciplinary involvement of other stakeholders in AI development. We found that AI education is a critical step to enable meaningful patient engagement within this field. We have curated recommendations into a framework for the field to learn from and implement in future development.
    CONCLUSION: Given the novelty and speed at which AI innovation is progressing in health care, patient engagement should be the gold standard for application development. Our proposed recommendations seek to enable patient-centered AI application development in health care. Future research must be conducted to evaluate the effectiveness of patient engagement in AI application development to ensure that both AI application development and patient engagement are done rigorously, efficiently, and meaningfully.
    Keywords:  Application development; Artificial intelligence; Patient engagement; Patient perspective; Qualitative research
    DOI:  https://doi.org/10.1186/s12913-023-10098-2
  18. Mol Ther Methods Clin Dev. 2023 Dec 14. 31 101125
    Clinical holds for cell and gene therapy trials: Risks, impact, and lessons learned.
    Carolyn A Wills, Daniela Drago, Robert G Pietrusko.
      The recent increase in cell and gene therapies being developed has been coupled with a disproportionate increase in Food and Drug Administration (FDA)-mandated clinical holds. Aiming to better understand causes and secondary effects of these clinical holds on biotechnology companies, we analyzed 33 clinical holds that were publicly announced from January 2020 to December 2022. Approximately 80% of the analyzed clinical holds were formally lifted by the close of our study after an average of 6.2 months, and several trials have had significant clinical success following a hold. CAR T cell therapies accounted for nine holds, Lentiviral and AAV-based gene therapies accounted for five and 15 holds, respectively, and other cell and gene therapies accounted for four holds. The most common trigger was an adverse event or patient death. To remove a hold, protocol amendments were the most requested resolution by FDA. While there is no way to guarantee a therapy will not be placed on clinical hold, especially following unexpected adverse events, some deficiencies are avoidable. Utilizing FDA-provided resources on regulations and expectations for cell and gene therapy investigational new drug applications, inclusion of an external safety monitoring board, and a proactive risk assessment plan may prevent a clinical hold or result in a shortened duration.
    Keywords:  FDA; IND; cell and gene therapy; clinical hold; regulatory submissions
    DOI:  https://doi.org/10.1016/j.omtm.2023.101125
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