bims-polgdi 2026-04-26 papers

bims-polgdi

Biomed News

on POLG disease

Issue of 2026–04–26
thirty papers selected by
Luca Bolliger, lxBio

Mitochondria at the heart of aging: structure, function, and failure.
Proteolytic control of mitochondrial protein translocases.
Cholesterol overload promotes mitochondria-mediated apoptosis with impaired mitochondrial unfolded protein response and mitophagy in SH-SY5Y cells.
New Understanding and Treatment of Adult Mitochondrial Dysfunction: An Example of Personalized Precision Medicine.
iPSC generation from PBMCs of a MELAS patient for mitochondrial dysfunction studies.
Proteostasis at the mitochondrial outer membrane: Quality control of mitochondrial protein transport.
RNA Sequencing Resolves Cryptic Pathogenic Variants in Mitochondrial Disease.
Role of mitochondrial translation in modulating inflammatory disease outcome: current knowledge and future perspectives.
Study on Leigh syndrome caused by SURF1 gene mutations and its mechanisms.
Architectural and translational perspectives on clinical decision support systems for rare disease diagnosis: a scoping review.
Targeting mitochondrial quality control in Alzheimer's disease: Mechanisms and therapeutic potential of phytomedicines.
Endothelial NAD+ depletion drives vascular senescence and neuroinflammation via mtDNA-cGAS/STING-CD38 signaling in Alzheimer's disease.
The 'mitochondrial guardian' α-amyrin links colourful fruit consumption to cognitive resilience.
Systematic identification of rare disease patients in electronic health records enables evaluation of clinical outcomes.
Consideration of the limitations of cost-effectiveness analysis for severe-rare disease drugs and potential solutions: a structured literature review.
Mitochondrial dysfunction triggers a maladaptive peroxisomal response driving lipid accumulation.
Altered mitochondrial ultrastructure in salivary epithelial cells of patients with Sjögren's disease is associated with mitochondrial DNA release and increased activation of pattern recognition receptors: potential use of tofacitinib as therapy.
Orphan Drugs and Diseases: A Systematic Review.
A rapid HPLC method to simultaneously quantify therapeutic thiols and monitor their disulfide exchange reactions with cystine.
Biomimetic mitochondria-targeted drug delivery system for the treatment of inflammatory bowel disease.
Disulfidptosis in Neurodegenerative Diseases: From Redox Imbalance to Neuronal Dysfunction.
Telethon Undiagnosed Disease Program: Structured approach to solving rare childhood-onset genetic diseases.
Enhancing research and development to innovate neonatology and improve newborn health.
Lessons from human neuroimaging on the developing cerebellum in health and disease.
Automating evaluation of LLM-generated responses to patient questions about rare diseases.
Large Language Models as Physician Recommenders: Limitations, Alternatives, and the Path Toward Hybrid AI Systems.
Trailblazing Person-Centred Care: Lessons From a Hospital Cluster-Wide Retreat to Co-Design Approaches to Person-Centred Care in Singapore.
Benefits and adverse effects of ketogenic diet treatment in pediatric patients with inborn errors of metabolism.
Mitochondrial dysfunction in sleep deprivation.
Deeptaxim: Comprehensive classification analysis for taxonomic datasets using image-based deep-learning models.

J Transl Med. 2026 Apr 24.

Mitochondria at the heart of aging: structure, function, and failure.

Hany E Marei.



Keywords:  Aging; Mitochondria; Mitochondrial biogenesis; Mitochondrial dysfunction; Mitophagy; NAD+; Oxidative stress; PGC-1α; Rejuvenation; Sirtuins

DOI:  https://doi.org/10.1186/s12967-026-08047-8
Protein Sci. 2026 May;35(5): e70553

Proteolytic control of mitochondrial protein translocases.

Lara Kroczek, Thomas Langer.

  Mitochondria are essential organelles that drive numerous cellular processes, including energy metabolism, ion homeostasis, and programmed cell death. This functional versatility relies on a highly dynamic proteome whose composition is continuously remodeled to meet changing cellular and environmental demands. Central to this remodeling are mitochondrial proteases (termed mitoproteases), which maintain protein quality and regulate mitochondrial function through selective processing and degradation events. Their activity ensures rapid degradation of regulatory proteins and dynamically adjusts components of multiprotein complexes. Among their most critical targets are elements of the mitochondrial protein import machinery. By modulating translocase stability and by processing preproteins during translocation, mitoproteases enable precise control over the organelle's proteome, aligning mitochondrial function with the cell's metabolic state. This review discusses how mitoproteases maintain translocase integrity and dynamically regulate mitochondrial protein import and the mitochondrial proteome.

Keywords:  mitochondrial proteases; mitochondrial protein import; mitochondrial remodeling; protein quality control

DOI:  https://doi.org/10.1002/pro.70553
Food Chem Toxicol. 2026 Apr 20. pii: S0278-6915(26)00180-8. [Epub ahead of print] 116106

Cholesterol overload promotes mitochondria-mediated apoptosis with impaired mitochondrial unfolded protein response and mitophagy in SH-SY5Y cells.

Juhyun Chung, Je Won Ko, Young Hye Kwon.

  Cholesterol accumulation in the brain has been implicated in mitochondrial dysfunction and neurodegeneration; however, its specific effects on mitochondrial quality control pathways, including the mitochondrial unfolded protein response (UPRmt) and mitophagy, remain poorly defined. In this study, SH-SY5Y human neuroblastoma cells were treated with 25 or 50 μg/mL water-soluble cholesterol for 24 h. UPRmt, mitophagy, and inflammasome activation were assessed using molecular and cellular approaches, including immunoblotting, quantitative RT-PCR, and fluorescence-based imaging. Cholesterol treatment increased intracellular cholesterol levels up to 1.7-fold and induced dose-dependent cytotoxicity and apoptosis. UPRmt was suppressed, as evidenced by reduced expression of mitochondrial chaperones and proteases. In parallel, cholesterol impaired mitophagy by disrupting autophagic flux, leading to the accumulation of damaged mitochondria. This was accompanied by increased cytosolic mitochondrial DNA (mtDNA), caspase 1 activation, and interleukin-1β secretion. These findings indicate that impaired mitochondrial clearance promotes mtDNA release, thereby linking mitochondrial dysfunction to inflammasome activation. Collectively, cholesterol overload disrupts UPRmt and mitophagy, thereby promoting mitochondrial dysfunction, inflammasome activation, and neuronal apoptosis.

Keywords:  Apoptosis; Cholesterol; Inflammasome; Mitochondria; Mitophagy; SH-SY5Y cells; UPRmt

DOI:  https://doi.org/10.1016/j.fct.2026.116106
Am J Med. 2026 Apr 17. pii: S0002-9343(26)00288-3. [Epub ahead of print]

New Understanding and Treatment of Adult Mitochondrial Dysfunction: An Example of Personalized Precision Medicine.

Gabriela R Esnaola, Edward J Goetzl.

  The principal cellular energy-generating pathways of mitochondria used to produce adenosine triphosphate (ATP) are oxidative phosphorylation and β-oxidation of fatty acids. Under anaerobic conditions, glycolysis in the cytoplasm is an alternative mechanism for production of ATP. Mitochondrial diseases result from one or more of the over 350 mutations in mitochondrial DNA (10%) or nuclear DNA (90%) that cause defective mitochondrial ATP production. The most common manifestations in adults with mitochondrial DNA mutations are diminished vision, myopathy, cardiomyopathy, neuropathy, encephalopathy and diabetes. Uncommonly there are stroke-like syndromes. The most common manifestations in adults with nuclear DNA mutations are neuropathy with prominent ataxia, ophthalmoplegia, dysarthria, myopathy, cardiomyopathy, liver disease, neuroendocrine and renal cell tumors, and hypoglycemia. Adults, especially the elderly, may only develop manifestations in the course of stressful illnesses that unmask these mutations. Children may require mitochondrial transfer or gene editing therapy. These mutations should be sought in leukocytes or muscle tissue in adults who do not respond to usual treatment for severe stressful illnesses as they may benefit from newly-approved medications.

Keywords:  Oxidative phosphorylation; anaerobic glycolysis; fatty acid β-oxidation; gene editing; mitochondrial transfer; reactive oxygen species (ROS)

DOI:  https://doi.org/10.1016/j.amjmed.2026.04.018
Stem Cell Res. 2026 Apr 16. pii: S1873-5061(26)00088-7. [Epub ahead of print]94 103992

iPSC generation from PBMCs of a MELAS patient for mitochondrial dysfunction studies.

Gautam Sharma, Abhay Srivastava, Cheryl Rockman-Greenberg, Sanjiv Dhingra.

Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like episodes (MELAS) is a multisystemic mitochondrial disorder primarily caused by a heteroplasmic point mutation at mitochondrial DNA (mtDNA) position 3243 (m.3243A > G) in the MT-TL1 gene, which encodes mitochondrial tRNA^Leu(UUR). In this study, we report the successful reprogramming of peripheral blood mononuclear cells (PBMCs) from a male patient diagnosed with MELAS into induced pluripotent stem cells (iPSCs). This patient-specific iPSC platform enables investigation into the relationship between heteroplasmy levels and disease manifestation and provides a valuable tool for screening potential therapeutic strategies aimed at mitigating mitochondrial dysfunction in MELAS.

DOI: https://doi.org/10.1016/j.scr.2026.103992
Protein Sci. 2026 May;35(5): e70587

Proteostasis at the mitochondrial outer membrane: Quality control of mitochondrial protein transport.

Shunsuke Matsumoto, Suzuka Ono, Toshiya Endo.

  Mitochondria are enclosed by a double-membrane structure composed of the outer and inner membranes, and this architectural organization underlies their diverse cellular functions. In particular, the mitochondrial outer membrane serves as an essential interface between the cytosol and the mitochondrial interior, regulating the flux of proteins, lipids, small molecules, and ions through the coordinated activities of its resident proteome. Consequently, structural and functional defects of outer membrane proteins are subject to continuous surveillance, and aberrant proteins are rapidly recognized and degraded. Defects in precursor translocation or translation can lead to the stalling of precursor proteins at the primary protein import gate, the TOM complex. Such situations are resolved by multiple quality control systems operating across both the mitochondria and the cytosol. In addition, proteins normally destined for the endoplasmic reticulum or peroxisomes may be mistargeted to mitochondria, and these mislocalized proteins are likewise managed through dedicated mechanisms that promote their degradation or re-targeting. In this review, we summarize current insights into the molecular factors and mechanisms that maintain proteostasis at the mitochondrial outer membrane.

Keywords:  mitochondria; outer membrane; protein degradation; quality control; re‐targeting

DOI:  https://doi.org/10.1002/pro.70587
Ann Clin Transl Neurol. 2026 Apr 25.

RNA Sequencing Resolves Cryptic Pathogenic Variants in Mitochondrial Disease.

Zhimei Liu, Xin Duan, Fatemeh Peymani, Jia Wang, Chengjia Bao, Chaolong Xu, Ying Zou, Zixuan Zhang, Yunxi Zhang, Tongyue Li, Martin Pavlov, Junling Wang, Minhan Song, Tianyu Song, Xiaodi Han, Mingxi Sun, Danmin Shen, Ruoyu Duan, Huafang Jiang, Manting Xu, Holger Prokisch, Fang Fang.

   OBJECTIVE: Mitochondrial diseases are the most common inherited metabolic disorders, characterized by pronounced clinical and genetic heterogeneity that complicates molecular diagnosis. Although DNA-based sequencing approaches have become standard in genetic testing, up to half of patients remain without a definitive diagnosis. We aimed to perform RNA sequencing (RNA-seq) of patient-derived skin fibroblasts to enhance the molecular diagnostic efficacy of mitochondrial disease in undiagnosed cases in China.
METHODS: We performed RNA-seq on skin fibroblasts from 140 pediatric patients with suspected mitochondrial disease who remained genetically undiagnosed after whole exome sequencing (WES). Aberrant RNA expression and splicing were identified using the detection of RNA outliers pipeline (DROP). Based on WES findings, patients were stratified into a candidate group (n = 28), in which RNA-seq evaluated the pathogenicity of WES-identified variants of uncertain significance and an unsolved group (n = 112), in which RNA-seq was used to pinpoint candidate genes. In six cases where RNA-seq identified the aberrant RNA event but WES did not detect the causative variants, whole genome sequencing (WGS) was performed.
RESULTS: Integrative RNA-seq, WES, and WGS analysis resulted in a genetic diagnosis in 25% of patients overall (20/28 [71%] in the candidate group; 15/112 [13%] in the unsolved group). Aberrant splicing explained most candidate-group diagnoses, including variants misclassified by in silico predictors such as SpliceAI. 14% of protein-truncating variants predicted to undergo nonsense-mediated decay (NMD) escaped degradation, highlighting the functional limits of current predictions. The variants identified in the unsolved cohort included synonymous, missense, deep intronic, near-splice-site variants, and large deletions. The most frequent among them was a recurrent synonymous East Asian founder mutation in ECHS1, accounting for seven cases. Interestingly, across 233 pathogenic variants associated with aberrant RNA phenotypes compiled from this study and prior reports, half were noncoding and half were coding variants.
CONCLUSION: RNA-seq substantially enhances molecular diagnosis in mitochondrial disease by exposing cryptic splicing, regulatory, and NMD-escape events invisible to DNA sequencing alone. These data advocate transcriptome analysis as an essential component of comprehensive genomic diagnostics in neurometabolic disease.

Keywords:  RNA sequencing; mitochondrial diseases; pediatric; whole‐exome sequencing; whole‐genome sequencing

DOI:  https://doi.org/10.1002/acn3.70379
J Biol Chem. 2026 Apr 16. pii: S0021-9258(26)00327-3. [Epub ahead of print] 111455

Role of mitochondrial translation in modulating inflammatory disease outcome: current knowledge and future perspectives.

Swarnali Basu, Rukshar Khan, Shiva Sharma, Priyanka Prajapati, Veena Ammanathan, Sumit Rungta, Amit Lahiri.

Mitochondrial translation is crucial for maintaining cellular respiration, energy balance, calcium signaling, apoptosis, immune surveillance, and the regulation of inflammatory responses. This specialized process, involving mitochondrial rRNAs, tRNAs, mitoribosomes, and nuclear-encoded translation factors, ensures the synthesis of mitochondrially encoded proteins that support oxidative phosphorylation. The mitochondrial translation cycle is tightly regulated by RNA-binding proteins, mitochondrial unfolded protein response, and stress-responsive pathways such as mTOR, particularly during metabolic shifts and immune activation. Emerging evidence highlights mitochondrial translation as a critical modulator of inflammation. In this review, we describe the alteration in mitochondrial-specific translation dynamics in immune cells, its adaptation to stress, and its interplay with organelle-wide signaling via mito-nuclear and mito-cytosolic communication. We focus on the alterations in mitochondrial translation machinery including mitoribosomal proteins, rRNA, tRNA synthetases or other regulatory factors linked to inflammatory diseases, including neurodegeneration, IBD, metabolic and cardiovascular disorders. We further examine how mitochondrial translation influences immune responses through mitochondrial DNA/RNA release, activation of mitochondrial damage-associated molecular patterns, and inflammasomes such as NLRP3. Collectively, mitochondrial translation functions as an immune centric-checkpoint that presents promising therapeutic target for intervention in inflammation-driven diseases.

DOI: https://doi.org/10.1016/j.jbc.2026.111455
Front Neurol. 2026 ;17 1793054

Study on Leigh syndrome caused by SURF1 gene mutations and its mechanisms.

Chunmei Wang, Longlong Lin, Yuanfeng Zhang, Simei Wang, Xiaona Luo, Xuqin Chen.

  Leigh syndrome (LS) is a prevalent mitochondrial encephalomyopathy in childhood, triggered by mutations in mitochondrial DNA (mtDNA) or nuclear DNA (nDNA). The protein encoded by the SURF1 gene localizes to the inner mitochondrial membrane and is involved in the biosynthesis of the cytochrome c oxidase (COX) complex. We enrolled 5 children harboring SURF1 gene variants whose clinical manifestations were highly consistent with LS. The clinical characteristics and potential pathogenic mechanisms of the disease were elucidated by systematic analysis of their clinical data. Among the 5 patients, 4 were female and 1 was male, with ages ranging from 13 months to 2 years and 7 months. Next-generation sequencing (NGS) results revealed 6 variant sites in the SURF1 gene among the 5 patients, of which 2 were known variants and 4 were unreported novel variants, namely c.314-317delTGCC (p.L105Qfs*7), c.588+1_588+3delGTA (splicing), c.655G>T (p.Glu219), and c.515+3G>C. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was performed on the peripheral blood of 4 patients, and the results demonstrated that the messenger RNA (mRNA) expression level of the SURF1 gene was significantly lower than that in their parents. Using 10 healthy children as controls, we analyzed the ratios of mitochondria-related NADH-ubiquinone oxidoreductase core subunit 1 (ND1), Cytochrome c oxidase subunit I (COX1), Cytochrome c oxidase subunit II (COX2), NADH-ubiquinone oxidoreductase chain 4 (ND4), Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) was used as a nuclear reference gene. Mitochondrial DNA content was determined by measuring the ND1/GAPDH ratio using RT-qPCR, and further verified with COX1, COX2, and ND4. These ratios were all significantly decreased, indicating reduced mitochondrial DNA (mtDNA) copy number/mtDNA depletion. Iterative Threading ASSEmbly Refinement (I-TASSER)-based three-dimensional (3D) structural analysis indicated that all 6 variant sites induced alterations in the spatial structure of the SURF1 protein. The SURF1 protein is a hydrophilic protein, protein hydrophobicity and stability analyses showed that the 4 unreported novel variants could reduce the hydrophilicity, increase the hydrophobicity, and decrease the structural stability of the protein. The Saccharomyces cerevisiae Homolog of Yeast 1 (Shy1) domain serves as the key structural basis for SURF1 to exert its mitochondrial functions. We found that all 6 variant sites in the SURF1 gene were located within the Shy1 domain.

Keywords:  Chinese children; Leigh syndrome; Shy1 domain; mitochondrial DNA depletion; splice-site variant

DOI:  https://doi.org/10.3389/fneur.2026.1793054
Int J Med Inform. 2026 Apr 16. pii: S1386-5056(26)00182-6. [Epub ahead of print]215 106442

Architectural and translational perspectives on clinical decision support systems for rare disease diagnosis: a scoping review.

Erdener Özçetin, Sümeyye Ebrar Baş, Furkan Özpay.

   BACKGROUND: Rare diseases remain difficult to diagnose because of phenotypic heterogeneity, limited clinical familiarity, and fragmented health data infrastructures. Clinical decision support systems (CDSS) have emerged as promising tools to support earlier recognition and more consistent diagnostic reasoning. However, the literature spans diverse technological paradigms, making it difficult to understand how these systems collectively contribute to clinical decision-making and their translational implementation.
OBJECTIVE: This scoping review aimed to map diagnostic CDSS developed for rare disease diagnosis and to examine how data infrastructures, phenotype-driven reasoning frameworks, and artificial intelligence-based approaches contribute to clinical decision support and their translation into practice.
METHODS: A PRISMA-ScR-guided scoping review was conducted. Searches were performed primarily in PubMed (MEDLINE), with supplementary screening in Google Scholar; the final search was completed on 30 November 2025. Records were screened in two stages and eligible studies were charted according to CDSS type, data sources, analytical methods, validation strategies, explainability features, interoperability elements, and reported evidence of clinical integration. Findings were synthesized using a taxonomy-based thematic approach rather than through quantitative pooling.
RESULTS: The reviewed literature clustered into four main technological paradigms: information-retrieval systems, phenotype- and ontology-driven reasoning tools, data-driven predictive models based on EHRs and AI methods, and interoperable infrastructures such as federated learning and knowledge graphs. In addition, a separate group of studies addressed clinical evaluation and translation readiness across these paradigms. Across these areas, the field showed substantial methodological diversity, but evidence for external validation, workflow-level integration, and real-world clinical implementation remained limited. Interoperability, explainability, and governance were recurring challenges across paradigms.
CONCLUSIONS: Rare disease CDSS research is moving from isolated diagnostic tools toward broader, interconnected diagnostic ecosystems. Progress toward clinically actionable implementation will depend on standardized data representations, stronger cross-institutional validation, explainable outputs aligned with clinical workflows, and interoperable infrastructures supported by appropriate governance. This review provides a taxonomy and conceptual framework to support the translational development of rare disease diagnostic CDSS.

Keywords:  Artificial intelligence; Clinical decision support systems; Diagnostic reasoning; Electronic health records; Phenotype ontology; Rare diseases

DOI:  https://doi.org/10.1016/j.ijmedinf.2026.106442
Pharmacol Res. 2026 Apr 21. pii: S1043-6618(26)00117-9. [Epub ahead of print]228 108202

Targeting mitochondrial quality control in Alzheimer's disease: Mechanisms and therapeutic potential of phytomedicines.

Zhongying Lin, Shun Zhang, Miao Sun.

  Alzheimer's disease (AD) is a neurodegenerative disorder driven partly by mitochondrial dysfunction, notably the failure of mitochondrial quality control (MQC). Phytochemicals have emerged as multi-target agents capable of restoring MQC, offering a promising therapeutic avenue. This review outlines how dysregulated MQC contributes to AD pathogenesis and summarizes the current evidence on phytochemicals that target key MQC processes-including mitochondrial dynamics, biogenesis, mitophagy, oxidative stress, and apoptosis-to exert neuroprotection. In AD, MQC is broadly impaired, characterized by suppressed biogenesis, excessive mitochondrial fission, defective mitophagy, oxidative stress, and calcium dyshomeostasis. Phytochemicals counter these defects through diverse mechanisms: restoring fission-fusion balance, enhancing biogenesis and mitophagic clearance, attenuating oxidative stress via Nrf2 activation, and inhibiting mitochondria-dependent apoptosis by modulating Bcl-2 family proteins and caspases. Despite these promising preclinical findings, several challenges remain, including poor bioavailability, limited blood-brain barrier penetration, lack of standardized preparations, and insufficient clinical validation. This review provides a mechanistic rationale for targeting MQC in AD and highlights future directions for translating phytochemical-based strategies into effective therapies.

Keywords:  Alzheimer’s disease; Mitochondrial quality control; Multi-target therapy; Neuroprotection; Phytochemicals

DOI:  https://doi.org/10.1016/j.phrs.2026.108202
Alzheimers Dement. 2026 Apr;22(4): e71423

Endothelial NAD+ depletion drives vascular senescence and neuroinflammation via mtDNA-cGAS/STING-CD38 signaling in Alzheimer's disease.

Qing-Hua Luo, Fang Li, Li Yang, Han-Qing Pan, Wen-Ping Zhu, Ping Hu, Chu-Ming Tao, Min Yin, Si Zhang, Qiu-Ye Liao, Zhi-Hao Chen, Hong-Xin Shu, Xin-Yi Zhu, Teng-Feng Yan, Xu Liu, Jiang-Long Tu, Xin-Gen Zhu.

   BACKGROUND: Endothelial dysfunction has emerged as early and pivotal event in Alzheimer's disease (AD), yet the molecular mechanisms linking vascular aging to neuroinflammation remain elusive.
METHODS: We used APP/PS1 mice and amyloid beta (Aβ)-challenged brain endothelial cells (BECs) to understand the mechanisms of nicotinamide adenine dinucleotide (NAD+) deficiency, and its relationship with endothelial senescence and neuroinflammation in AD pathology. Nicotinamide riboside supplementation was administered to APP/PS1 mice to determine whether restoration of NAD+ homeostasis mitigates AD-related vascular and inflammatory pathology.
RESULTS: NAD+ deficiency induced voltage-dependent anion channel 1 (VDAC1) oligomerization, mitochondrial DNA (mtDNA) leakage, and cGAS/STING-IRF3 activation, promoting endothelial senescence and SASP production with NAD+-consuming enzyme CD38 upregulation. Senescent BECs triggered IL-6-dependent microglial activation. NR treatment restored mitochondrial integrity, suppressed cGAS-STING signaling, and reduced neuroinflammation, improving vascular function and cognition.
DISCUSSION: Aβ-driven NAD+ deficiency initiates a VDAC1-mtDNA-cGAS/STING cascade that promotes endothelial senescence and neurovascular inflammation in AD pathology, and amplifies neuroinflammation through BEC-microglia crosstalk, highlighting NAD+ restoration as a promising AD therapeutic strategy.

Keywords:  Alzheimer's disease; NAD+ supplementation; cGAS/STING pathway; endothelial senescence; neuroinflammation

DOI:  https://doi.org/10.1002/alz.71423
Autophagy. 2026 Apr 23.

The 'mitochondrial guardian' α-amyrin links colourful fruit consumption to cognitive resilience.

Shu-Q Cao, Juan Ignacio Jiménez-Loygorri, Patricia Boya, Evandro F Fang.

  Mitochondrial quality control is essential for maintaining neuronal function and resilience during aging, yet pharmacological strategies that effectively restore mitophagy to maintain mitochondrial homeostasis remain limited. Emerging evidence suggests that dietary molecules may influence mitochondrial health, although the underlying mechanisms are largely unknown. Here, we summarize our recent finding whereby we have identified a robust mitophagy inducer: α-amyrin (αA). This molecule is a lipid-like pentacyclic triterpenoid abundant in edible plants, such as passion fruit. Mechanistically, αA targets dual leucine zipper kinase (DLK), a neuron-enriched stress kinase that plays a central role in axonal degeneration signaling. Under pathological stress, DLK activates the degeneration mediator SARM1, which can sequester the key autophagy/mitophagy protein ULK1 leading to compromised autophagy and mitophagy. By specifically binding to DLK, αA releases ULK1 from SARM1-mediated restriction and promotes ULK1-dependent mitophagy, restoring mitochondrial homeostasis. This mechanism reveals the DLK-SARM1-ULK1 cascade as a previously underappreciated regulatory interface linking neuronal stress signaling to mitochondrial surveillance pathways. More broadly, these findings introduce lipid-like dietary molecules as potential "mitochondrial guardians" that preserve organelle integrity through physiological activation of mitophagy. Targeting the DLK-SARM1-ULK1 axis with such molecules may represent a promising strategy for maintaining mitochondrial health and mitigating neurodegenerative processes associated with aging.

Keywords:  DLK; ULK1; lipid-like molecule; mitophagy; α-amyrin

DOI:  https://doi.org/10.1080/15548627.2026.2664599
Sci Rep. 2026 Apr 18.

Systematic identification of rare disease patients in electronic health records enables evaluation of clinical outcomes.

N3C Consortium

  Identifying rare disease (RD) patients in electronic health records (EHRs) is difficult, as most of the over 10,000 RDs are not adequately captured by standard coding systems. To address this, we developed a semi-automated workflow to map RDs to SNOMED-CT and ICD-10 codes, enabling improved RD identification across EHR systems. The optimized workflow yielded 88.4% true RD codes in a subset of 1,715 manually curated diseases. Using this workflow and starting with 12,003 GARD IDs mapped to ORPHANET, we obtained 12,081 SNOMED-CT and 357 ICD-10 codes representing 6,342 RDs, organized into 30 ORPHANET linearization classes. We applied these codes to the National COVID Cohort Collaborative (N3C) dataset of over 21 million patients. Among these patients, 8.46 million were identified as COVID-19 positive, of which 4.8 million were used in analyses. Among these, 316,836 (6.55%) had a preexisting RD. Logistic regression, adjusted for age and BMI, revealed that most RD classes were significantly associated with increased odds of severe COVID-19 outcomes. Notably high odds of mortality were observed for rare cardiac (OR = 4.07) and otorhinolaryngologic diseases (OR = 4.00). Hospitalization risk was also elevated across all RD classes, with the highest odds seen in otorhinolaryngologic (OR = 4.31) and endocrine diseases (OR = 3.38). This approach enables scalable RD patient identification in EHRs and highlights the need for tailored healthcare strategies to improve outcomes in RD populations.

Keywords:  COVID-19 outcomes; ICD-10; N3C; Rare disease; Rare diseases mappings; Retrospective analysis; SNOMED-CT

DOI:  https://doi.org/10.1038/s41598-026-43020-x
Health Econ Rev. 2026 Apr 18.

Consideration of the limitations of cost-effectiveness analysis for severe-rare disease drugs and potential solutions: a structured literature review.

Jia Pan, Anastasios Skroumpelos, Anouska Jha, Urs Arnet, Rachel Kewley, Johannes Michel, Ashleys C Humphries, Rogier Klok.

   BACKGROUND: Rare diseases affect more than 400 million people globally with only a small number having currently approved treatments. Drugs for rare diseases (medications developed to treat conditions affecting small patient populations), which may include innovative drugs (medications with novel mechanisms/new active ingredients) can face access challenges as they are often found not to be cost-effective under conventional health technology assessment methods. In this review we provide a comprehensive and up-to-date understanding of challenges associated with the economic evaluation of innovative drugs for severe-rare diseases, and any proposed solutions and associated barriers to solution adoption.
METHODS: This review included searches of electronic databases and select health technology assessment agency websites to identify relevant publications, guidelines or recommendations from 1st January 2014 to 29th July 2024. A pre-authorised protocol, including detailed eligibility criteria, was used to ensure robust methodology in the capture of materials. Relevant data extracted from included publications were synthesised thematically to support identification of the most prominent concepts within current literature.
RESULTS: Of the 1,803 records identified, 31 publications and eight health technology assessment guidance were included. Main challenges were related to the utilitarian principle underlying cost-effectiveness analysis, the limited scope of the quality-adjusted life year and the value elements assessed. Associated solutions included the incorporation of a societal willingness-to-pay or inclusion of equity in healthcare decision making, reduced weighting of the economic evaluation in resource allocation, consideration of additional value elements, and introducing a quality-adjusted life year weighting or alternative measures of health outcomes. While some payers have implemented modifications to economic evaluation guidelines in an attempt to address the challenges, for example including the consideration of additional value elements, the solutions employed are not consistent across payers and often do not address the root issue. Economic evaluation as part of health technology assessment therefore remains challenging for manufacturers of drugs for rare diseases.
CONCLUSION: Conventional methods of economic evaluation contribute to the access challenge for innovative drugs for rare diseases. Collaboration between payers, manufacturers, and healthcare decision makers to foster greater understanding of how to evolve and adopt these novel solutions will be key to ensuring timely patient access.

Keywords:  Cost-effectiveness; Economic evaluation; Health technology assessments; Limitations

DOI:  https://doi.org/10.1186/s13561-026-00771-7
Redox Biol. 2026 Apr 14. pii: S2213-2317(26)00164-3. [Epub ahead of print]93 104166

Mitochondrial dysfunction triggers a maladaptive peroxisomal response driving lipid accumulation.

Patrícia Coelho, Pedro Dionísio, Vilma Sardão Oliveira, Roberto A Dias, Matthias E Futschik, Robin Klemm, Ira Milosevic, Nuno Raimundo.

  Mitochondria and peroxisomes communicate to maintain lipid homeostasis, but how the latter adjust to mitochondrial dysfunction remains unclear. Here, we show that loss of complex I subunit NDUFS4 in mouse fibroblasts leads to impaired mitochondrial fatty acid oxidation, resulting in the accumulation of triacylglycerol and lipid droplet (LD) expansion. In this context, peroxisomal biogenesis is upregulated, but their β-oxidation capacity is impaired, suggesting an adaptive yet ineffective response. Additionally, lipid overload using a very-long-chain fatty acid (VLCFA) leads to peroxisomal proliferation but prevents LD expansion when peroxisomal β-oxidation is compromised. The data demonstrated that proper peroxisomal processing is necessary for lipid storage under mitochondrial stress conditions. Our findings reveal a peroxisomal maladaptive remodelling response that fails to compensate for mitochondrial dysfunction, leading to disruptions in LD homeostasis. We propose a critical axis involving peroxisomes-LD-mitochondria that buffers metabolic stress in mitochondrial diseases.

Keywords:  Complex I dysfunction; Lipid homeostasis; Mitochondria-peroxisome crosstalk; NDUFS4-KO; Peroxisomes

DOI:  https://doi.org/10.1016/j.redox.2026.104166
Ann Rheum Dis. 2026 Apr 17. pii: S0003-4967(26)00208-6. [Epub ahead of print]

Altered mitochondrial ultrastructure in salivary epithelial cells of patients with Sjögren's disease is associated with mitochondrial DNA release and increased activation of pattern recognition receptors: potential use of tofacitinib as therapy.

Patricia Carvajal, Isabel Castro, Félix Urra, Sergio Aguilera, Sergio González, Claudio Molina, Salvador Campos, Gonzalo Ramírez, Cristopher Chávez, Juan Gutiérrez, María José Yáñez, María-Julieta González, María-José Barrera.

OBJECTIVES: This study aimed to analyse structural and functional mitochondrial alterations, the release of mitochondrial DNA (mtDNA), and the activation of inflammatory signalling pathways that can be reversed by tofacitinib in the salivary glands (SG) of patients with Sjögren's disease (SjD).
METHODS: SG from patients with SjD and controls, as well as from mice with SjD treated with or without tofacitinib, were analysed. We determined the mitochondrial ultrastructure, the presence of mtDNA in the cytosol, and the levels and localisation of pattern recognition receptors (PRRs) that recognise mtDNA. The adenosine triphosphate (ATP) levels and oxygen consumption rate (OCR) were measured to evaluate mitochondrial respiration in frozen SG. We also evaluated the OCR in human submandibular gland cells incubated with interferon-gamma (IFN-γ), tofacitinib, or both.
RESULTS: Increased mtDNA release into the cytosol was observed in SG epithelial cells of patients with SjD. This change was linked with increased PRR activation (cyclic GMP-AMP synthase, Z-DNA-binding protein 1, and nucleotide-binding oligomerisation domain-like receptor protein 3) and decreased mitochondrial transcription factor A (TFAM). Similar mitochondrial ultrastructural alterations and increased PRR activation were observed in the SG of the SjD mouse model. These changes were reversed by tofacitinib. Interestingly, increased activity of electron transport chain complexes was observed in SG of patients with SjD, which could be modulated by IFN-γ, as observed in vitro. We also found that tofacitinib stabilised mitochondrial function at basal conditions in vitro, counteracting the mitochondrial adaptations induced by IFN-γ.
CONCLUSIONS: Taken together, these results suggest that mitochondrial alterations are linked with inflammation and support the potential use of tofacitinib in patients with SjD.

DOI: https://doi.org/10.1016/j.ard.2026.03.022
J Pharm Bioallied Sci. 2026 Apr-Jun;18(2):18(2): 93-95

Orphan Drugs and Diseases: A Systematic Review.

Heena Dixit Tiwari, Manoj Kumar Sahoo, M R Murali, Rahul Tiwari, Kamatham Manjusha, M C Prashant.

  Rare diseases, though individually infrequent, collectively affect over 300 million people worldwide. The development of orphan drugs to treat these conditions is hampered by regulatory inconsistencies, high costs, and limited clinical trial populations. To systematically review the current landscape of orphan drugs and rare diseases, focusing on definitions, therapeutic approaches, health economic evaluations, and stakeholder perspectives. A systematic review was conducted using 70 reference-screened articles, out of which 10 were selected based on relevance to rare diseases or orphan drug policy, economics, or clinical management. Study types included systematic and scoping reviews, observational studies, and health economic evaluations. Data extraction focused on definitions, healthcare roles, cost analyses, and clinical outcomes. Definitions of rare diseases varied globally, impacting drug approval processes. Economic evaluations revealed disparities in funding orphan drugs. Studies emphasized the growing role of pharmacists and stakeholders in therapeutic access. High-cost burdens, ethical considerations, and diagnostic advancements were recurring themes. Pediatric and syndromic rare conditions, like Duchenne muscular dystrophy and Turner syndrome, were notably covered. Effective rare disease care requires harmonized definitions, ethical pricing models, interdisciplinary healthcare roles, and evidence-based policies to ensure equitable access and sustainability.

Keywords:  Healthcare policy; orphan drugs; pharmacoeconomics; rare diseases; systematic review

DOI:  https://doi.org/10.4103/jpbs.jpbs_937_25
Orphanet J Rare Dis. 2026 Apr 22.

A rapid HPLC method to simultaneously quantify therapeutic thiols and monitor their disulfide exchange reactions with cystine.

Azhidhack Hadjipour, Gayatri Gayatri, Patrice Rioux, Oisín N Kavanagh.



Keywords:  Cysteamine; Cystinosis; Cystinuria; Disulfide exchange; Rare disease; Therapeutic thiols

DOI:  https://doi.org/10.1186/s13023-026-04363-w
J Control Release. 2026 Apr 22. pii: S0168-3659(26)00330-5. [Epub ahead of print] 114927

Biomimetic mitochondria-targeted drug delivery system for the treatment of inflammatory bowel disease.

Fuya Jia, Yudi Deng, Yiwen Xu, Jiahui Wu, Sijie Liu, Yuan Huang.

  Mitochondria play a pivotal role in regulating inflammation and maintaining intestinal microenvironmental homeostasis during the progression of inflammatory bowel disease (IBD). However, to date, only a limited number of orally deliverable systems capable of mitochondrial targeting have been reported for IBD therapy. Existing approaches, such as charge- or ligand-dependent targeting peptides, were susceptible to physiological variations and exhibited suboptimal mitochondrial targeting efficiency. Here, we develop a hybrid membrane-based strategy incorporating two complementary functional modules: (i) M2 macrophage membranes, which enable inflammation-associated targeting; (ii) mitochondrial membranes, which facilitate mitochondrial targeting through membrane fusion. Encapsulated within a sodium alginate-carboxymethyl chitosan hydrogel, the melatonin-loaded hybrid membrane-coated nanoparticles (RC@MEL) arrive at colon following oral administration. Upon colonic release, RC@MEL are efficiently internalized by inflamed epithelial cells and macrophages, where the mitochondrial membrane coating facilitate fusion with mitochondria, achieving effective mitochondrial targeting. This subcellular delivery effectively scavenges mitochondrial ROS, promotes macrophage repolarization, enhances tight junction repair, and contributes to the restoration of gut microbiota homeostasis in both acute and chronic colitis models. Overall, this work establishes a mitochondria-targeting oral delivery strategy for IBD treatment and provides a generalizable design framework for subcellular-targeted therapeutics in inflammatory diseases.

Keywords:  Hybrid membrane; IBD therapy; Mitochondria targeting; Oral delivery; ROS-scavenging

DOI:  https://doi.org/10.1016/j.jconrel.2026.114927
Behav Brain Res. 2026 Apr 22. pii: S0166-4328(26)00218-4. [Epub ahead of print] 116242

Disulfidptosis in Neurodegenerative Diseases: From Redox Imbalance to Neuronal Dysfunction.

Caizhen Shi, Kunpeng Jia, Yanjie Guo, Shenghao Qian, Bingbing Wang, Yue Qiu, Li Dan, Zhuokun Dang, Kun Xue, Feng Gao, Lin Zhao.

  Disulfidptosis is a recently identified form of regulated cell death driven by disulfide stress and cytoskeletal collapse under conditions of impaired reducing capacity. Neurodegenerative diseases (NDs), including Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis, are characterized by oxidative stress, mitochondrial dysfunction, metabolic impairment, protein aggregation, and cytoskeletal instability-features that may provide a permissive intracellular context for disulfidptosis. However, its occurrence and pathological relevance in these disorders remain incompletely understood. In this review, we examine the potential involvement of disulfidptosis in neurodegenerative diseases from a disease-centered perspective. We emphasize that current evidence is largely indirect and based on mechanistic overlap rather than direct experimental validation in neural systems. Accordingly, we distinguish between direct evidence, indirect mechanistic support, and pathophysiological plausibility. We further discuss cell-type-specific susceptibility across neurons and glial cells, analyze its relationship with other cell death pathways, and consider potential therapeutic implications. Overall, disulfidptosis is best regarded as a context-dependent and emerging mechanism that may contribute to neuronal vulnerability under specific metabolic and redox constraints. Clarifying its disease relevance will be essential for determining its significance in neurodegeneration and its potential as a therapeutic target.

Keywords:  cell death; disulfidptosis; mitochondria; neurodegenerative diseases; protein aggregation; redox imbalance

DOI:  https://doi.org/10.1016/j.bbr.2026.116242
Genet Med Open. 2026 ;4 104394

Telethon Undiagnosed Disease Program: Structured approach to solving rare childhood-onset genetic diseases.

Telethon Undiagnosed Disease Study group

   Purpose: Many children with severe genetic disorders remain undiagnosed despite advanced genomic technologies. Early diagnosis is vital for prognosis, genetic counseling, and targeted treatment development. This study aims to increase diagnostic rates in complex pediatric cases and foster research into disease mechanisms.
Methods: Launched in 2016, the Telethon Undiagnosed Diseases Program provides a structured, multicenter approach to rare disease diagnosis. Standardized case submission criteria ensured consistent clinical data collection. Children with severe, multisystemic disorders and prior negative genetic tests were eligible. After case approval, trio-based exome sequencing was performed, with regular reanalysis for unsolved cases until December 2024.
Results: Between June 2016 and December 2023, 1338 cases were submitted by 60 clinicians from 22 Italian centers; 1019 were accepted. A definitive genetic diagnosis was achieved in 49% of cases, implicating 330 genes. Most pathogenic variants (70.2%) were de novo, reflecting demographic trends, such as delayed parenthood. The remainder included autosomal recessive or X-linked variants, with homozygosity observed in 9% of patients.
Conclusion: The Telethon Undiagnosed Diseases Program significantly shortened the average diagnostic odyssey of ∼8 years. Children born after 2016 benefited from faster diagnoses. This initiative offers a scalable, cost-effective model for improving diagnosis, guiding treatment, and supporting therapeutic innovation in rare pediatric diseases.

Keywords:  Exome sequencing; Genetic diagnosis; Pediatric genomics; Rare diseases; Undiagnosed Diseases Program

DOI:  https://doi.org/10.1016/j.gimo.2026.104394
Semin Fetal Neonatal Med. 2026 Apr 16. pii: S1744-165X(26)00037-5. [Epub ahead of print] 101735

Enhancing research and development to innovate neonatology and improve newborn health.

Daniele De Luca, Roberta Onesimo, Alexandra Benachi, Satoshi Kusuda, Elizabeth Foglia, Ola Saugstad, Steven Abman.

  Neonatology suffers from a chronic lack of innovation, and several neonatal disorders still lack appropriate diagnostic or therapeutic tools. Here, we expand on the recent analysis of this situation by the Lancet Child and Adolescent Commission for the Future of Neonatology, highlighting the similarities between adult and neonatal critical care, the need for greater interdisciplinary collaboration, and the importance of clearly defining neonatology as a distinct specialty. We also discuss the peculiarities of medical devices. We analyse the rarity of neonatal malformative and non-malformative disorders and diseases in light of the opportunities related to the definition of rare disease. We provide a culture-based definition of neonatology and advocate for creating a separate residency program, discussing its benefits in both developed and low-middle-income countries.

Keywords:  Critical care; Innovation; Life support; Rare diseases

DOI:  https://doi.org/10.1016/j.siny.2026.101735
Curr Top Dev Biol. 2026 ;pii: S0070-2153(26)00017-7. [Epub ahead of print]167 335-377

Lessons from human neuroimaging on the developing cerebellum in health and disease.

A J Jain, A M D'Mello.

  The cerebellum is a critical structure for both motor and cognitive behaviors. Although the majority of human neuroimaging research has examined the cerebellum in adults, this "little brain" may be especially pivotal during development. Indeed, the cerebellum has a unique developmental timecourse relative to the cerebral cortex, suggesting that it may play a unique role in the development of motor and cognitive functions. Here, we review the literature on cerebellar development with a focus on neuroimaging studies in humans. We discuss several structural and functional MRI studies that examine the cerebellum across typical development from infancy through adulthood. We also discuss the links between the developmental time course of various cerebellar sub-regions and the emergence of core motor and cognitive functions. Finally, we investigate the consequences of cerebellar differences (and disorders that implicate the cerebellum) on motor control, language and communication, executive function, attention, and affective regulation.

Keywords:  ADHD; Adolescence; Affect; Ataxia; Attention; Attention Deficit Hyperactivity Disorder; Autism; Bipolar; Bipolar Disorder; Cerebellar; Cerebellar Cognitive Affective Syndrome; Cerebellar differences; Cerebellum; Cerebro-cerebellar; Childhood; Cognitive; Communication; Depression; Development; Developmental Dyslexia; Diaschasis; Disorders; Dyslexia; Executive Function; Function; Functional Magnetic Resonance Imaging; Human; Human neuroimaging; Infancy; Language; Lesions; MRI; Magnetic Resonance Imaging; Motor; Neuroimaging; Neuroscience; Pre-mature birth; Psychosis; Rare diseases; Reading; Schizophrenia; Structural Magnetic Resonance Imaging; Subcortical; Tumors; cortico-cerebellar; fMRI

DOI:  https://doi.org/10.1016/bs.ctdb.2026.02.002
JAMIA Open. 2026 Apr;9(2): ooag054

Automating evaluation of LLM-generated responses to patient questions about rare diseases.

Min Zhao, Inez Y Oh, Aditi Gupta, Sally Cohen-Cutler, Kathryn M Harmoney, Albert M Lai, Bryan A Sisk.

   Objectives: Patients with rare diseases often struggle to find accurate medical information, and large language model (LLM)-based chatbots may help meet this need. However, evaluating LLM-generated free-text answers typically requires physician review, which is time-consuming and difficult to scale. This study compared traditional natural language processing (NLP) metrics to emerging LLM-based evaluation approaches for assessing answer quality in the context of Complex Lymphatic Anomalies (CLAs).
Materials and Methods: We compiled 25 common patients' questions about CLAs and generated 175 responses to these questions from seven LLMs. Three expert physicians scored these responses for accuracy. We compared these physician-assigned scores with automated scores, generated by four NLP sentence similarity metrics (BLEU, ROUGE, METEOR, BERTScore) and six LLM evaluators (GPT-4, GPT-4o, Qwen3-32B, DeepSeek-R1-14B, Gemma3-27B, LLaMA3.3-70B). We examined both LLM-based scoring with and without reference answers (reference-guided vs reference-free). We calculated Spearman, Phi, and Kendall's Tau correlation coefficients to assess alignment between automated and physician-assigned scores.
Results: LLM-based evaluation demonstrated stronger alignment with physician-assigned scores than NLP metrics. The reference-guided GPT-4 evaluator achieved the highest correlation with physician-assigned scores (ρ = 0.758), followed by GPT-4o (ρ = 0.727). NLP metrics showed weak to moderate correlations with physician-assigned scores (ρ = 0.240-0.403). Reference-guided scoring outperformed reference-free methods.
Discussion: Reference-guided LLM-based evaluation methods approximate expert physicians' judgment better than traditional NLP metrics, offering an effective, scalable approach for assessing LLM-generated responses to patient questions about rare disease.
Conclusion: LLM-based evaluation, particularly reference-guided scoring with GPT models, can support the scalable development and evaluation of LLM-based rare disease-specific chatbot systems.

Keywords:  Large language models; automated evaluation; natural language processing; rare diseases; vascular anomaly

DOI:  https://doi.org/10.1093/jamiaopen/ooag054
Jt Comm J Qual Patient Saf. 2026 Mar 28. pii: S1553-7250(26)00077-2. [Epub ahead of print]

Large Language Models as Physician Recommenders: Limitations, Alternatives, and the Path Toward Hybrid AI Systems.

Mohammad Mahdi Bagheri Asl, Alejandro M Spiotta.

Digital tools are increasingly used by patients to access health information and navigate care, including choosing clinicians, but the evidence supporting "best doctor" recommendations varies widely across available methods. This manuscript compares the emerging use of consumer-facing large language models (LLMs) for this purpose with four alternative physician-selection strategies: patient networks, expert referrals, consumer rating/search platforms, and outcome-informed artificial intelligence / machine learning (AI/ML) recommender systems. Consumer rating platforms mainly reflect patient experiences rather than technical skills and often show weak or inconsistent links with objective performance measures. General-purpose LLMs may produce convincing rationales that highlight visibility and reputation, but they remain limited by hallucinations, prompt sensitivity, and uncertainty about whether their explanations truly reflect the underlying reasoning. Outcome-informed AI/ML recommender systems could, in theory, incorporate risk-adjusted clinical performance, but they face significant challenges, including unreliable physician-level measurement, incomplete data, residual confounding, and limited transparency, which can undermine trust and informed consent. We suggest that a hybrid system should be seen as a guiding concept and a testable approach rather than a final solution. Such a system could integrate proven, auditable performance measures with transparent patient-preference filters and verifiable, patient-facing explanations. We present key design principles, including clinical relevance, explainability, autonomy, equity, and governance, in line with current US Food and Drug Administration (FDA) guidance related to clinical decision support and adaptive AI life cycle management.

DOI: https://doi.org/10.1016/j.jcjq.2026.03.011
Health Expect. 2026 Apr;29(2): e70594

Trailblazing Person-Centred Care: Lessons From a Hospital Cluster-Wide Retreat to Co-Design Approaches to Person-Centred Care in Singapore.

Xiankun Meng, Amanda Wei Li Tan, Samantha Shi Man Koh, Shanice Shi Hui Ng, Balkhis Puteh, Chien Earn Lee, Esther Li Ping Lim, Luke Sher Guan Low, Stephanie Swee Hong Teo, Andy Gim Hong Sim.

   INTRODUCTION: Person-centred care (PCC) is globally recognised as essential for quality healthcare, yet implementation remains inconsistent in Singapore due to hierarchical structures, time constraints, and fragmented understanding. SingHealth, Singapore's largest public healthcare cluster, initiated a retreat to co-design a unified approach to PCC across its institutions.
OBJECTIVES: The retreat aimed to (1) align stakeholders on PCC's importance; (2) co-develop a locally tailored PCC definition; (3) advance PCC through five workstreams (user experience, research, education, service innovation, strategic partnerships); and (4) provide experiential co-design learning.
METHODS: This qualitative case study employed reflexive thematic analysis to analyse data from a retreat designed using Goffman's frame analysis. The retreat engaged 42 healthcare practitioners, 26 senior management, and 13 patient/caregiver experience experts in a three-phase co-design process. 1. Pre-design: Strategic stakeholder invitation and pre-reading to align perspectives. 2. Generative phase: Creative methods ('Frozen' metaphors, flip cube exercises and patient videos) to explore PCC's 'what' and 'why', followed by live visual scribing, discussion and presentation. 3. Evaluative phase: Visioning exercises, debates on patient autonomy, and development of an implementation matrix.
RESULTS: Four key themes emerged:. 1. Shared responsibility between patients and providers. 2. Communication skills as foundational to PCC. 3. Integration of PCC into systems and culture. 4. Actionable steps, including patient-reported experience measures and new models of care. Tangible outputs included a shared vision- 'Empowering individuals. Everyone matters' and a five-level implementation matrix operationalising PCC at institutional, departmental, and patient-provider levels.
CONCLUSION: The retreat successfully fostered stakeholder alignment and co-designed actionable strategies for PCC. The co-design process successfully revealed nuanced tensions around shared responsibility while generating implementable strategies. This model demonstrates how structured stakeholder engagement can advance PCC in hierarchical healthcare systems.
PATIENT OR PUBLIC CONTRIBUTION: Experience experts (patients and caregivers), constituting 16% of retreat participants, were strategically recruited from established networks. They actively co-designed the PCC definition, participated in world café discussions, informed implementation strategies across five workstreams, co-created the vision statement and validated the final implementation matrix. Their lived experiences critically shaped key themes of this event. One experience expert co-authored this manuscript, reflecting sustained partnership.

Keywords:  Person‐centred care; co‐design; implementation science; organisational change; shared responsibility

DOI:  https://doi.org/10.1111/hex.70594
Adv Clin Exp Med. 2026 Apr 21.

Benefits and adverse effects of ketogenic diet treatment in pediatric patients with inborn errors of metabolism.

Dorota Wesół-Kucharska, Magdalena Alicja Kaczor, Ewa Ehmke Vel Emczyńska-Seliga.

   BACKGROUND: The ketogenic diet (KD) is an established therapeutic option for epilepsy and selected inborn errors of metabolism (IEMs), particularly glucose transporter type 1 deficiency (GLUT1D) and pyruvate dehydrogenase complex deficiency (PDCD). Increasing evidence suggests broader applications of KD in pediatric metabolic disorders; however, data on its safety and efficacy in heterogeneous IEM populations remain limited.
OBJECTIVES: To evaluate the efficacy, clinical benefits, and adverse effects (AEs) of KD in pediatric patients with various IEMs.
MATERIAL AND METHODS: A retrospective analysis was conducted in pediatric patients with IEMs receiving KD treatment. Patients were categorized into 3 groups: 1) other IEMs (n = 7), 2) mitochondrial diseases (MD) (n = 17), and 3) GLUT1D and PDCD (n = 20). The median age at initiation of KD was 37, 53, and 53 months, respectively, and the median duration of KD treatment was 5, 11, and 55 months in groups 1, 2, and 3.
RESULTS: The KD was associated with clinical benefits in 84% of patients. Among children with epilepsy (n = 23), a seizure reduction of >50% was observed in 73.9% of patients, including complete seizure freedom in 4 individuals. Improvements were also noted in muscle tone (27.6%), exercise tolerance (51.2%), ataxia (83.3%), and involuntary movements (60%). Lactate levels decreased in 84.6% of patients with mitochondrial disease and in all patients with PDCD. The KD was discontinued in 12 patients due to insufficient efficacy (n = 5) or AEs (AEs; n = 7). The most common AEs included gastrointestinal (GI) symptoms, dyslipidemia, hyperuricemia, metabolic acidosis, and decreased free carnitine; most were transient. No significant association was found between median β-hydroxybutyrate (BHB) levels and clinical outcomes.
CONCLUSIONS: The KD is an effective and generally well-tolerated therapeutic option in pediatric IEMs, with benefits extending beyond seizure control. Adverse effects are typically manageable, although GI intolerance may limit long-term use. Ketogenic diet should be considered not only for refractory epilepsy but also for selected metabolic indications.

Keywords:  epilepsy; inborn errors of metabolism; ketogenic diet; mitochondrial diseases; pediatric metabolic disorders

DOI:  https://doi.org/10.17219/acem/219994
Metab Brain Dis. 2026 Apr 24. pii: 90. [Epub ahead of print]41(1):

Mitochondrial dysfunction in sleep deprivation.

Meng Zhao, Adeel Ahmed Abbasi, Peijun Li, Peiyuan Lu.



Keywords:  Alzheimer’s disease; Mitochondrial dysfunction; Mitophagy; Neurodegeneration; Oxidative stress; Parkinson’s disease; Sleep deprivation

DOI:  https://doi.org/10.1007/s11011-026-01853-5
Comput Biol Chem. 2026 Apr 20. pii: S1476-9271(26)00188-X. [Epub ahead of print]124(Pt 1): 109063

Deeptaxim: Comprehensive classification analysis for taxonomic datasets using image-based deep-learning models.

U Gulfem Elgun Ciftcioglu, O Ufuk Nalbantoglu.

  Advancements in deep learning have opened new possibilities for the classification of microbiome data, offering solutions to the challenges posed by its complexity and variability. This work explores the application of deep learning techniques for accurate and reliable classification of microbiome data, addressing the challenges of high-dimensionality and sparsity. Focusing on diseases known to be closely linked with gut microbiome alterations, we convert microbiome data into image format using the hierarchical structure of the taxonomic tree (cladogram). Our proposed model, Deeptaxim, leverages 2D-CNN-based Autoencoder, U-Net, and GAN architectures to enhance classification performance across two distinct dataset groups. The primary goals are to (1) utilize cladogram-based image data to capture complex microbial relationships, (2) develop optimized deep learning models for microbiome-based disease classification, (3) assess Deeptaxim's transfer learning capabilities for low-sample datasets, and (4) evaluate its robustness when applied to a broader range of diseases. Our findings demonstrate that the use of taxa-ordered images instead of tabular taxonomic data and employing CNN as a classifier led to superior classification performance compared to conventional methods typically used for taxonomic data. Furthermore, it proved that a model trained on a comprehensive dataset can significantly improve the classification performance on data with fewer examples or different disease types through transfer learning. Proposed model thanks to its NN-based framework, not only facilitates working with alternative datasets but also can be integrated into other NN-based methods as a head/neck module of other models. Thus, Deeptaxim can be adapted, extended, and ported to serve as a wellness index.

Keywords:  CNNs; Deep learning; Microbiome data; Taxonomy; Transfer learning; Wellness index

DOI:  https://doi.org/10.1016/j.compbiolchem.2026.109063