bims-curels 2024-03-24 papers

bims-curels

Biomed News

on Leigh syndrome

Issue of 2024–03–24
seven papers selected by
Cure Mito Foundation

Nocturnal vestibular stimulation using a rocking bed improves a severe sleep disorder in a patient with mitochondrial disease.
Ensuring Stakeholder Feedback in the Design and Conduct of Clinical Trials for Rare Diseases: ISCTM Position Paper of the Orphan Disease Working Group.
Patient listening on social media for patient-focused drug development: a synthesis of considerations from patients, industry and regulators.
Patient engagement with psychological safety.
Mitochondrial genes modulate the phenotypic expression of congenital scoliosis syndrome caused by mutations in the TBXT gene.
Utilization of EHRs for clinical trials: a systematic review.
Mitochondrial variants of complex I genes associated with leprosy clinical subtypes.

J Sleep Res. 2024 Mar 18. e14153

Nocturnal vestibular stimulation using a rocking bed improves a severe sleep disorder in a patient with mitochondrial disease.

Alexander Breuss, Marco Strasser, Jean-Marc Nuoffer, Andrea Klein, Eveline Perret-Hoigné, Christine Felder, Ruth Stauffer, Peter Wolf, Robert Riener, Matthias Gautschi.

  Mitochondrial diseases are rare genetic disorders often accompanied by severe sleep disorders. We present the case of a 12-year-old boy diagnosed with a severe primary mitochondrial disease, exhibiting ataxia, spasticity, progressive external ophthalmoplegia, cardiomyopathy and severely disrupted sleep, but no cognitive impairment. Interestingly, his parents reported improved sleep during night train rides. Based on this observation, we installed a rocking bed in the patient's bedroom and performed different interventions, including immersive multimodal vestibular, kinesthetic and auditory stimuli, reminiscent of the sensory experiences encountered during train rides. Over a 5-month period, we conducted four 2-week nocturnal interventions, separated by 1-week washout phases, to determine the subjectively best-perceived stimulation parameters, followed by a final 4-week intervention using the optimal parameters. We assessed sleep duration and quality using the Mini Sleep Questionnaire, monitored pulse rate changes and used videography to document nocturnal interactions between the patient and caregivers. Patient-reported outcome measures, clinical examinations and personal outcomes of specific interests were used to document daytime sleepiness, restlessness, anxiety, fatigue, cognitive performance and physical posture. In the final 4-week intervention, sleep duration increased by 25%, required caregiver interactions reduced by 75%, and caregiving time decreased by 40%. Subjective fatigue, assessed by the Checklist Individual Strength, decreased by 40%, falling below the threshold of severe fatigue. Our study suggests that rocking beds could provide a promising treatment regime for selected patients with persistent severe sleep disorders. Further research is required to validate these findings in larger patient populations with sleep disorders and other conditions.

Keywords:  Somnomat Casa; alternative treatment; auditory stimulations; kinesthetic stimulation; mitochondrial disease; mitochondrial disease management; mitochondrial disease with an associated severe sleep disorder; robotic bed; rocking bed; sensory experiences; sleep disorder; stimulation; vestibular stimulation

DOI:  https://doi.org/10.1111/jsr.14153
Innov Clin Neurosci. 2024 Jan-Mar;21(1-3):21(1-3): 52-60

Ensuring Stakeholder Feedback in the Design and Conduct of Clinical Trials for Rare Diseases: ISCTM Position Paper of the Orphan Disease Working Group.

Gahan J Pandina, Joan Busner, Lucas Kempf, Joan Fallon, Larry D Alphs, Maria T Acosta, Anna-Karin Berger, Simon Day, Judith Dunn, Victoria Villalta-Gil, Margaret C Grabb, Joseph P Horrigan, William Jacobson, Judith C Kando, Thomas A Macek, Manpreet K Singh, Arielle D Stanford, Silvia Zaragoza Domingo.

The 1983 Orphan Drug Act in the United States (US) changed the landscape for development of therapeutics for rare or orphan diseases, which collectively affect approximately 300 million people worldwide, half of whom are children. The act has undoubtedly accelerated drug development for orphan diseases, with over 6,400 orphan drug applications submitted to the US Food and Drug Administration (FDA) from 1983 to 2023, including 350 drugs approved for over 420 indications. Drug development in this population is a global and collaborative endeavor. This position paper of the International Society for Central Nervous System Clinical Trials and Methodology (ISCTM) describes some potential best practices for the involvement of key stakeholder feedback in the drug development process. Stakeholders include advocacy groups, patients and caregivers with lived experience, public and private research institutions (including academia and pharmaceutical companies), treating clinicians, and funders (including the government and independent foundations). The authors articulate the challenges of drug development in orphan diseases and propose methods to address them. Challenges range from the poor understanding of disease history to development of endpoints, targets, and clinical trials designs, to finding solutions to competing research priorities by involved parties.

Keywords: Orphan disease; clinical trials; drug development research; key stakeholders; patient experience
Front Med (Lausanne). 2024 ;11 1274688

Patient listening on social media for patient-focused drug development: a synthesis of considerations from patients, industry and regulators.

Philipp Cimiano, Ben Collins, Maria Carmela De Vuono, Thierry Escudier, Jürgen Gottowik, Matthias Hartung, Mathias Leddin, Bikalpa Neupane, Raul Rodriguez-Esteban, Ana Lucia Schmidt, Cornelius Starke-Knäusel, Maarten Voorhaar, Krzysztof Wieckowski.

  Patients, life science industry and regulatory authorities are united in their goal to reduce the disease burden of patients by closing remaining unmet needs. Patients have, however, not always been systematically and consistently involved in the drug development process. Recognizing this gap, regulatory bodies worldwide have initiated patient-focused drug development (PFDD) initiatives to foster a more systematic involvement of patients in the drug development process and to ensure that outcomes measured in clinical trials are truly relevant to patients and represent significant improvements to their quality of life. As a source of real-world evidence (RWE), social media has been consistently shown to capture the first-hand, spontaneous and unfiltered disease and treatment experience of patients and is acknowledged as a valid method for generating patient experience data by the Food and Drug Administration (FDA). While social media listening (SML) methods are increasingly applied to many diseases and use cases, a significant piece of uncertainty remains on how evidence derived from social media can be used in the drug development process and how it can impact regulatory decision making, including legal and ethical aspects. In this policy paper, we review the perspectives of three key stakeholder groups on the role of SML in drug development, namely patients, life science companies and regulators. We also carry out a systematic review of current practices and use cases for SML and, in particular, highlight benefits and drawbacks for the use of SML as a way to identify unmet needs of patients. While we find that the stakeholders are strongly aligned regarding the potential of social media for PFDD, we identify key areas in which regulatory guidance is needed to reduce uncertainty regarding the impact of SML as a source of patient experience data that has impact on regulatory decision making.

Keywords:  patient experience data; patient-focused drug development; real-world evidence; regulatory decision making; social media listening

DOI:  https://doi.org/10.3389/fmed.2024.1274688
Dialogues Health. 2023 Dec;3 100153

Patient engagement with psychological safety.

Tatsuya Fukami.

  Psychological safety is a multidimensional, dynamic phenomenon that concerns team members' perception of whether it is safe to take interpersonal risks at work. It is particularly important within health care teams who need to work interdependently to coordinate safe patient care within a highly complex, variable and high-stakes work environment. High levels of psychological safety have clear benefits for patient safety by improving the delivery of clinical care and promoting health care providers' job satisfaction and well-being. Feeling psychologically safe can enable team members to engage in speaking up behavior, such as asking questions, pointing out mistakes, or reporting errors. Several studies have explored psychological safety in health care teams and its impact on patient safety. These studies have highlighted the importance of psychological safety in health care organizations and provided strategies for promoting psychological safety. Psychological safety in health care involvement with patients can improve patient engagement.

Keywords:  Patient engagement; Patient safety; Professionalism; Psychological safety; Shared decision making

DOI:  https://doi.org/10.1016/j.dialog.2023.100153
Gene. 2024 Mar 16. pii: S0378-1119(24)00269-5. [Epub ahead of print] 148388

Mitochondrial genes modulate the phenotypic expression of congenital scoliosis syndrome caused by mutations in the TBXT gene.

Olfa Alila-Fersi, Amel Tej, Marwa Maalej, Marwa Kharrat, Lamia Boughamoura, Jihen Chouchen, Abdelaziz Tlili, Faiza Fakhfakh.

   BACKGROUND: Congenital scoliosis (CS) is a spinal disorder caused by genetic-congenital vertebral malformations and may be associated with other congenital defects or may occur alone. It is genetically heterogeneous and numerous genes contributing to this disease have been identified. In addition, CS has a wide range of phenotypic and genotypic variability, which has been explained by the intervention of genetic factors like modifiers and environment genes. The aim of the present study was to determine the possible cause of CS in a Tunisian patient and to examine the association between mtDNA mutations and mtDNA content and CS.
METHODS: Here we performed Whole-Exome Sequencing (WES) in a patient presenting clinical features suggestive of severe congenital scoliosis syndrome. Direct sequencing of the whole mitochondrial DNA (mtDNA) was also performed in addition to copy number quantification in the blood of the indexed case. In silico prediction tools, 3D modeling and molecular docking approaches were used.
RESULTS: The WES revealed the homozygous missense mutation c.512A > G (p.H171R) in the TBXT gene. Bioinformatic analysis demonstrated that the p.H171R variant was highly deleterious and caused the TBXT structure instability. Molecular docking revealed that the p.H171R mutation disrupted the monomer stability which seemed to be crucial for maintaining the stability of the homodimer and consequently to the destabilization of the homodimer-DNA complex. On the other hand, we hypothesized that mtDNA can be a modifier factor, so, the screening of the whole mtDNA showed a novel heteroplasmic m.10150T > A (p.M31K) variation in the MT-ND3 gene. Further, qPCR analyses of the patient's blood excluded mtDNA depletion. Bioinformatic investigation revealed that the p.M31K mutation in the ND3 protein was highly deleterious and may cause the ND3 protein structure destabilization and could disturb the interaction between complex I subunits.
CONCLUSION: We described the possible role of mtDNA genetics on the pathogenesis of congenital scoliosis by hypothesizing that the presence of the homozygous variant in TBXT accounts for the CS phenotype in our patient and the MT-ND3 gene may act as a modifier gene.

Keywords:  Congenital scoliosis; MT-ND3 gene; Molecular docking; TBXT gene; WES

DOI:  https://doi.org/10.1016/j.gene.2024.148388
BMC Med Res Methodol. 2024 Mar 18. 24(1): 70

Utilization of EHRs for clinical trials: a systematic review.

Leila R Kalankesh, Elham Monaghesh.

   BACKGROUND AND OBJECTIVE: Clinical trials are of high importance for medical progress. This study conducted a systematic review to identify the applications of EHRs in supporting and enhancing clinical trials.
MATERIALS AND METHODS: A systematic search of PubMed was conducted on 12/3/2023 to identify relevant studies on the use of EHRs in clinical trials. Studies were included if they (1) were full-text journal articles, (2) were written in English, (3) examined applications of EHR data to support clinical trial processes (e.g. recruitment, screening, data collection). A standardized form was used by two reviewers to extract data on: study design, EHR-enabled process(es), related outcomes, and limitations.
RESULTS: Following full-text review, 19 studies met the predefined eligibility criteria and were included. Overall, included studies consistently demonstrated that EHR data integration improves clinical trial feasibility and efficiency in recruitment, screening, data collection, and trial design.
CONCLUSIONS: According to the results of the present study, the use of Electronic Health Records in conducting clinical trials is very helpful. Therefore, it is better for researchers to use EHR in their studies for easy access to more accurate and comprehensive data. EHRs collects all individual data, including demographic, clinical, diagnostic, and therapeutic data. Moreover, all data is available seamlessly in EHR. In future studies, it is better to consider the cost-effectiveness of using EHR in clinical trials.

Keywords:  Clinical trials; EHR; Electronic Health Record

DOI:  https://doi.org/10.1186/s12874-024-02177-7
Sci Rep. 2024 03 16. 14(1): 6365

Mitochondrial variants of complex I genes associated with leprosy clinical subtypes.

Felipe Gouvea de Souza, Caio S Silva, Gilderlanio S de Araújo, Mayara N Santana-da-Silva, Angélica Rita Gobbo, Moisés Batista da Silva, Pablo Pinto, Patrícia Fagundes da Costa, Claudio Guedes Salgado, Ândrea Ribeiro-Dos-Santos, Giovanna C Cavalcante.

  Leprosy is a chronic bacterial infection mainly caused by Mycobacterium leprae that primarily affects skin and peripheral nerves. Due to its ability to absorb carbon from the host cell, the bacillus became dependent on energy production, mainly through oxidative phosphorylation. In fact, variations in genes of Complex I of oxidative phosphorylation encoded by mtDNA have been associated with several diseases in humans, including bacterial infections, which are possible influencers in the host response to leprosy. Here, we investigated the presence of variants in the mtDNA genes encoding Complex I regarding leprosy, as well as the analysis of their pathogenicity in the studied cohort. We found an association of 74 mitochondrial variants with either of the polar forms, Pole T (Borderline Tuberculoid) or Pole L (Borderline Lepromatous and Lepromatous) of leprosy. Notably, six variants were exclusively found in both clinical poles of leprosy, including m.4158A>G and m.4248T>C in MT-ND1, m.13650C>A, m.13674T>C, m.12705C>T and m.13263A>G in MT-ND5, of which there are no previous reports in the global literature. Our observations reveal a substantial number of mutations among different groups of leprosy, highlighting a diverse range of consequences associated with mutations in genes across these groups. Furthermore, we suggest that the six specific variants exclusively identified in the case group could potentially play a crucial role in leprosy susceptibility and its clinical differentiation. These variants are believed to contribute to the instability and dysregulation of oxidative phosphorylation during the infection, further emphasizing their significance.

Keywords:  Complex I; Heteroplasmy; Leprosy; Mitochondria; mtDNA

DOI:  https://doi.org/10.1038/s41598-024-57191-y