@article {pmid41760992,
year = {2026},
author = {Hollin, IL and Ilieva, H and Pasinelli, P and Chisholm, L and Heiman-Patterson, T},
title = {Preferences for Healthcare Delivery in Amyotrophic Lateral Sclerosis (ALS): A Survey of Patients and Caregivers in the United States.},
journal = {The patient},
volume = {},
number = {},
pages = {},
pmid = {41760992},
issn = {1178-1661},
abstract = {BACKGROUND AND OBJECTIVES: Amyotrophic lateral sclerosis (ALS) is a rapidly progressive and fatal neurological disease that leads to death within 2-5 years of diagnosis for more than 80% of people living with ALS (PLWALS). The American Academy of Neurology (AAN) developed practice parameters-general principles to guide clinicians in managing ALS-encouraging multidisciplinary care (MDC) but does not recommend specific healthcare delivery models. Three healthcare delivery models have evolved: a traditional model, a triage model, and a non-triage model. This study aims to describe preferences for and satisfaction with various models, among PLWALS and their caregivers (CALS), along with their perceptions of how their care aligns with AAN guidelines.

METHODS: A cross-sectional observational study utilizing a web-based survey was distributed via email to PLWALS and CALS. Three multi-assessment questionnaires were developed and tailored for PLWALS, CALS, and former CALS. Best-worst scaling (object case) data were analyzed using a best-minus-worst approach and descriptive statistics were calculated from means, t-tests and chi-square.

RESULTS: The combined sample included 378 respondents: 254 PLWALS (67.20%) and 124 CALS (32.80%; composed of 79 current caregivers [20.90%] and 45 former caregivers [11.90%]). The mean respondent age was 61.09 years (SD 11.1). The majority of the sample was white (92.86%), insured by Medicare (61.11%), and married/partnered (79.10%). Respondents preferred a non-triage model the most and a traditional model the least; 88.20% (CI: 84.92-91.49) were extremely likely to choose a non-triage model if given the choice and 83.12% (CI: 79.29-86.92) of respondents ranked non-triage as most preferred. A traditional model was ranked as the least preferred model in 75.28% (CI: 70.78-79.78) of respondents. The most important factors driving respondent preferences were ALS expertise and team-based care. Overall, respondents are satisfied with their care teams. PLWALS utilizing non-triage MDC models reported more adherence to quality care measures compared with those utilizing triage and traditional models.

DISCUSSION: Respondent preference for non-triage models is consistent with the importance they place on the features of non-triage models. However, these findings should be understood in the context of our sample in which a large majority of respondents were receiving care via a non-triage model. To ensure ALS care delivery is patient-centered, practice parameters that aim to guide clinicians in managing ALS should provide more guidance to MDCs to deliver care aligned with patient preferences and values. Efforts should focus on sustainable financial models that can better facilitate non-triage models of care.},
}

@article {pmid41760955,
year = {2026},
author = {D'Amico, A and Cucunato, R and Schirò, G and Salemi, G and Ragonese, P and La Bella, V and Aridon, P and D'Amelio, M},
title = {KIF5A and ALS: a clinical and genetic description of a case series and review of literature.},
journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology},
volume = {47},
number = {3},
pages = {},
pmid = {41760955},
issn = {1590-3478},
abstract = {Approximately 10% of ALS (amyotrophic lateral sclerosis) cases show a family history, and the remaining 90% are sporadic. In 2018, through genome sequencing using two independent approaches, KIF5A was described as a novel ALS-associated gene. To describe clinical and genetic characteristics of a series of patients with motor neuron disease (MND), diagnosed at University Hospital of Palermo, carrying KIF5A variants. During 2019–2023, two hundred twenty-four patients with MND and healthy subjects with familial history of MND, underwent next-generation sequencing (NGS) for molecular analysis, including genetic testing for C9orf72 hexanucleotide-repeat expansion. The most mutated ALS genes, including KIF5A, were included in a NGS panel. Of the entire tested population, eight patients (including a brother and a sister) were found to carry KIF5A variants. Four patients had familial ALS, the other four were sporadic. Six patients were females (75%). Mean age at ALS onset was 59 years (33–75). Patients were evaluated according to the ALSFRS-revisited during follow-up visits. According to disease progression rate, five patients were defined as ∆FS ≤ 0.5 (slow-progressors), the remaining three patients showed a ∆FS > 1 (fast-progressors). Of the seven KIF5A variants, three are not already described in literature (respectively c.170 C > T, p.Thr57Met; c.2920T > G, p.Ser974Ala and c.2732 A > C, p.Lys911Thr). Two patients showed the association of variations in KIF5A with variations or mutations in other ALS genes, one of them carried a pathogenic variant of FUS (P525L). This study demonstrates phenotypic variability related to mutations in different regions of the same gene resulting in a susceptibility for the disease spectrum with different characteristics.},
}

@article {pmid41760732,
year = {2026},
author = {Sinderewicz, E and Dąbkowska, M and Sarnowska, A and Staszkiewicz-Chodor, J and Mystkowska, D and Holak, P and Drozd, I and Chodkowska-Michalowska, M and Rytel, M and Paczkowska, E and Mycko, MP and Machalinski, B and Jezierska-Wozniak, K},
title = {Safety and biodistribution of intrathecal administration of mesenchymal stem cells (MSCs) and neurotrophin-releasing nanoparticles in a porcine CSF-guided delivery model for amyotrophic lateral sclerosis (ALS) drug discovery.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-40196-0},
pmid = {41760732},
issn = {2045-2322},
support = {No: 2020/ABM/01/00014-00//Medical Research Agency, Poland/ ; No: 2020/ABM/01/00014-00//Medical Research Agency, Poland/ ; No: 2020/ABM/01/00014-00//Medical Research Agency, Poland/ ; No: 2020/ABM/01/00014-00//Medical Research Agency, Poland/ ; No: 2020/ABM/01/00014-00//Medical Research Agency, Poland/ ; No: 2020/ABM/01/00014-00//Medical Research Agency, Poland/ ; No: 2020/ABM/01/00014-00//Medical Research Agency, Poland/ ; No: 2020/ABM/01/00014-00//Medical Research Agency, Poland/ ; No: 2020/ABM/01/00014-00//Medical Research Agency, Poland/ ; No: 2020/ABM/01/00014-00//Medical Research Agency, Poland/ ; No: 2020/ABM/01/00014-00//Medical Research Agency, Poland/ ; No: 2020/ABM/01/00014-00//Medical Research Agency, Poland/ ; No: 2020/ABM/01/00014-00//Medical Research Agency, Poland/ ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a multifactorial neurodegenerative disorder that complicates the identification of effective therapeutic targets. The potential of stem cells and neurotrophins as promising candidates has become increasingly evident, owing to their neuroprotective and anti-inflammatory properties. In this study, a preclinical evaluation of the safety and biodistribution of mesenchymal stromal/stem cells (MSCs) combined with neurotrophin-releasing polyelectrolyte nanoparticles (NTs) was conducted in a porcine intrathecal delivery model relevant to ALS therapy development. Four groups of male pigs were administered saline with NTs, adipose-derived stem cells (ASCs) with NTs, Wharton's jelly-derived MSCs (WJ-MSCs) with NTs, or spinal puncture only. The safety of the treatment was assessed using magnetic resonance imaging (MRI), haematological and biochemical analyses, cerebrospinal fluid profiling, and histology. No adverse effects or significant systemic alterations were observed. It is noteworthy that C-reactive protein levels diminished following NT and NT-MSC administration, suggesting a systemic anti-inflammatory effect. The migration of MSCs was facilitated by cerebrospinal fluid, leading to their accumulation around the spinal cord and brain parenchyma. The present findings demonstrate short-term safety and biodistribution patterns following intrathecal administration of MSCs combined with neurotrophin-releasing nanoparticles in a large-animal model. These preliminary observations provide a pilot framework for future efficacy studies in disease-specific ALS models. This work establishes a translational platform for the development of future ALS therapies, with subsequent studies focused on efficacy testing in disease-specific models that more accurately reflect the slow, heterogeneous, multisystem nature of human ALS.},
}

@article {pmid41759589,
year = {2026},
author = {Cooper, M and Singh, S and Ferrer, E and Turner, S and Timko, CA},
title = {Calculating developmental weight suppression in practice: A commentary demonstrating the use and misuse of Singh and colleagues' new approach.},
journal = {Appetite},
volume = {},
number = {},
pages = {108513},
doi = {10.1016/j.appet.2026.108513},
pmid = {41759589},
issn = {1095-8304},
abstract = {Eating disorders (ED) typically onset during youth, a critical period of growth and development. Maintenance of appropriate body weight is a criterion in multiple ED diagnoses and informs weight restoration. Data suggest that weight suppression (WS), the difference between an individual's highest historical and current weights, may be linked to ED severity and prognosis. Singh et al. (2021) formulated a developmentally-adjusted measure of WS using BMI z-scores to account for developmental growth during adolescence. Studies since have established both the face and incremental validity of developmental WS with respect to eating concerns, binge eating behavior, and abnormal endocrine and metabolic markers of ED, suggesting its benefit over traditional estimates of WS. Unfortunately, however, many studies have misapplied Singh et al.'s method by using z-scores based on highest premorbid weight, rather than using highest premorbid BMI z-score. This error can lead to underestimation ofdevelopmental WS. In this commentary, we present several case examples to demonstrate the importance of using growth chart data to identify the highest BMI z-score for the purpose of developmental WS calculation, as opposed to self-report highest past weight and height. We discuss how this procedure influences target weight calculation, the need for weight restoration in treatment, and diagnostic and clinical care considerations.},
}

@article {pmid41759446,
year = {2026},
author = {Salmon, PM and King, B and Hall, D and McLean, S and Thompson, J and Cooke, N and Salas, E and Loft, S and Read, GJM},
title = {The big five model of teamwork and human autonomy teams: a scoping review.},
journal = {Applied ergonomics},
volume = {135},
number = {},
pages = {104761},
doi = {10.1016/j.apergo.2026.104761},
pmid = {41759446},
issn = {1872-9126},
abstract = {Teams play a critical role in society and represent a key area for Human Factors and Ergonomics. Salas et al.'s Big Five model is widely cited; however, the increasing use of Human-Autonomy Teams (HATs) has fuelled debate over its continued relevance. It is important to reflect on how the Big five model has been applied, in what contexts, and whether applications to contemporary teams are emerging. This article presents the findings from a scoping review undertaken to identify and synthesise the peer reviewed literature describing applications of the Big Five model. Articles were deemed eligible for inclusion if they were published in the peer reviewed literature and described an application of the Big Five model to study teamwork. 38 articles were included in the review and no applications of the Big Five model to study HATs were identified. Over half of the studies were undertaken in healthcare and a range of assessment methods have been used (e.g., questionnaires, surveys, interviews, observer-rating scales, communication transcript analysis). Just under a third of included studies evaluated all model components (i.e., the five processes and three coordinating mechanisms) and few considered the relationships between model components or between model components and team effectiveness. Research is required to explore the validity of the Big Five model for HATs, to gather evidence for the relationship between model components and team effectiveness, and to develop more precise Big five-based measures.},
}

@article {pmid41759417,
year = {2026},
author = {Zhang, M and Zhang, Y and Pu, Y and Bai, X},
title = {Ultra-high-dose methylcobalamin demonstrates safety in advanced ALS, but intramuscular administration poses practical burdens and its selected study cohort limits generalizability.},
journal = {Journal of the neurological sciences},
volume = {483},
number = {},
pages = {125838},
doi = {10.1016/j.jns.2026.125838},
pmid = {41759417},
issn = {1878-5883},
}

@article {pmid41757350,
year = {2026},
author = {Lee, JAK and Moutin, C and Granger, S and Roome, K and Shaw, A and Allen, SP and Ferraiuolo, L and Shaw, PJ and Mortiboys, H},
title = {C9orf72-ALS mutation drives basal mitophagy impairments in iNeurons.},
journal = {Frontiers in cellular neuroscience},
volume = {20},
number = {},
pages = {1731669},
pmid = {41757350},
issn = {1662-5102},
abstract = {INTRODUCTION: ALS is a neurodegenerative disorder characterized by progressive upper and lower motor neuron loss. A GGGGCC hexanucleotide repeat expansion (HRE) in the C9orf72 gene is the most common mutation found in populations of European descent. Mitochondrial dysfunction has been observed in C9orf72-ALS patients and models of the disease, however, reports on mitochondrial clearance via mitophagy in C9orf72-ALS are limited.

RESULTS: iNeurons from C9orf72-ALS patients displayed reduced mitochondrial membrane potential and reduced basal mitophagy, due to reductions in autophagosome production and reduced ULK1 recruitment to mitochondria. No consistent changes to PINK1/Parkin or BNIP3 mitophagy pathways were observed.

CONCLUSION: Our data show that certain aspects of mitochondrial function is impaired in C9orf72-ALS patient iNeurons. An in-depth characterization of mitophagy suggests that a deficit in autophagosome production is responsible and provides further evidence that toxic gain-of-function mechanisms in C9orf72-ALS are responsible for autophagy deficits.},
}

@article {pmid41757182,
year = {2026},
author = {Puerta, R and Garcia-Gonzalez, P and de Rojas, I and Capdevila-Bayo, M and Olive, C and Munoz-Morales, A and Bayon-Bujan, P and Valenzuela, A and Yang, C and Timsina, J and Liu, M and Chakkarai, S and Sotolongo-Grau, O and Calm, B and Miguel, A and Solivar, A and Montrreal, L and Martinez, M and Khan, A and Zhao, F and Tantinya, N and Rosende-Roca, M and Alegret, M and Moreno-Grau, S and Fernandez, MV and Marquie, M and Valero, S and Cavazos, JE and Sanz, P and Montalban, X and Tarraga, L and Smets, B and Boada, M and Seshadri, S and Sargurupremraj, M and Cruchaga, C and Cano, A and Cabrera-Socorro, A and Ruiz, A},
title = {Human CSF proteogenomics links genetic variation to neurodegenerative disease proteins.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.02.12.26345733},
pmid = {41757182},
abstract = {The cerebrospinal fluid (CSF) proteome offers a direct readout of central nervous system (CNS) biology but its genetic architecture remains incompletely defined. We conducted the largest single-site CSF genome-wide association study (GWAS) to date, analysing 7,092 SomaScan proteins in 1,259 individuals. Using a covariate-adjusted model including proteomic PCs and disease status, we identified 1,971 genome-wide significant pQTLs (954 cis, 971 trans), 1,409 of which replicated in an independent CSF dataset. We discovered 264 previously unreported loci, replicated 511 associations, refined 80 known loci, and 265 proxy-based associations. Using a previously published reproducibility framework, we show that robust discovery concentrates in reliable measurements, underscoring the importance of rigorous quality control. Enrichment analyses revealed immune/complement and extracellular matrix biology. Mendelian randomization prioritised causal proteins: PILRA, TREM2, IL34, CR2, SHARPIN and ERBB1 (Alzheimer's disease); BST1 and GPNMB (Parkinson's disease); STX6 (Creutzfeldt Jacobs disease); and ATXN3 and B4GALNT1 (Amyotrophic lateral sclerosis), providing a scalable framework for orthogonal target validation in neurodegeneration.},
}

@article {pmid41756973,
year = {2026},
author = {Plessis-Belair, J and Sher, RB},
title = {Neuronal Cell-Cycle Re-entry Defines Divergent Outcomes Through Replication-Dependent DNA Damage in ALS.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.02.13.705790},
pmid = {41756973},
issn = {2692-8205},
abstract = {Cell-cycle dysregulation has emerged as a shared mechanism of neuronal loss across neurodegenerative diseases (NDDs), including amyotrophic lateral sclerosis (ALS), Alzheimer's disease, and Parkinson's disease. In post-mitotic neurons, aberrant reactivation of cell-cycle signaling precedes degeneration, yet the upstream triggers and functional consequences of this process remain poorly defined. Nucleocytoplasmic transport (NCT) dysfunction, a hallmark of ALS and related disorders, disrupts the spatial distribution of key regulatory proteins and may contribute to maladaptive cell-cycle activation. Our recent evidence suggests that impaired nuclear import may initiate, rather than merely accompany, neuronal cell-cycle re-entry. Here, we show that cell-cycle activation in motor neurons distinguishes molecular subtypes and outcomes in ALS. We analyzed the AnswerALS transcriptomic cohort and identified a patient cluster characterized by robust upregulation of cyclins B and D. Clusters with lower levels of cell-cycle gene expression exhibited accelerated ALSFRS-R decline, whereas the highest cyclin-expressing cluster demonstrated comparatively improved functional trajectories over time. To test whether NCT disruption can mechanistically drive aberrant cell-cycle activation, we pharmacologically inhibited importin-β in human iPSC-derived spinal motor neurons. NCT disruption induced widespread proteomic mislocalization, including TDP-43 pathology, and triggered a transient wave of cell-cycle activity preceding neuronal death. Mechanistically, we identified DNA-replication initiation as a pathological event driving degeneration and demonstrated that selective inhibition of G1/S-associated CDK4/6 activity confers neuroprotection. Together, these findings link impaired nuclear import to maladaptive cell-cycle reactivation in neurons and highlight stage-specific engagement of the cell-cycle machinery as a determinant of neuronal vulnerability in ALS.},
}

@article {pmid41756852,
year = {2026},
author = {Malik, T and Jones, S and Ma, O and Mohan, S and Burger, RM and Babcock, DT},
title = {Autophagy induction mitigates FUS aggregate formation and early synaptic dysfunction at the NMJ in the FUS-ALS model.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.02.19.706635},
pmid = {41756852},
issn = {2692-8205},
abstract = {Mutations in Fused in Sarcoma (FUS), a RNA binding protein, cause Amyotrophic Lateral Sclerosis (ALS). ALS is an aggressive neurodegenerative disease resulting in motor neuron degeneration. Defects in synaptic integrity precede neuronal loss in ALS, but the mechanisms responsible for these early synaptic defects are unclear. To investigate early synaptic defects associated with ALS, we expressed an ALS-linked variant of human FUS in adult motor neurons and assessed synaptic pathology at the neuromuscular junction (NMJ). Here we highlight the accumulation of FUS-positive aggregates at synaptic terminals and subsequent reduction in microtubule stability. We show that inducing autophagy via expression of Rab1 or Fragile-X Mental Retardation Protein 1 (FMR1), or treatment with Rapamycin reduces aggregate formation and restores synaptic structure and function. These findings reveal the utility of inducing autophagy to address early synaptic dysfunction in an ALS model and demonstrate a potential therapeutic target to preventing later stages of disease progression.},
}

@article {pmid41756850,
year = {2026},
author = {Wake, N and Alcalde, J and Jutzi, D and Bajaj, A and Kour, S and Barai, M and Weng, SL and Cummings, S and Zheng, T and Anderson, EN and Wang, SH and Puterbaugh, R and Bosco, DA and Schuster, BS and Mittal, J and Pandey, UB and Ruepp, MD and Fawzi, NL},
title = {Breaking β-sheets in FUS prion-like domain preserves phase separation and function but prevents aggregation and toxicity.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.02.17.706410},
pmid = {41756850},
issn = {2692-8205},
abstract = {UNLABELLED: The RNA-binding protein Fused in Sarcoma (FUS) undergoes phase separation associated with RNA processing. However, the prion-like low complexity (LC) domain of FUS forms solid-like aggregates in neurodegenerative diseases. Whether the formation of β-sheet structure associated with pathology is also physiologically/functionally relevant is debated. Similarly, if mislocalization alone or concomitant aggregation is responsible for FUS gain-of-function toxicity remains to be probed. Here, we introduce β-sheet breaking proline residues into FUS LC with the goal of preventing cross-β-driven aggregation without disrupting essential functions and phase separation. β-sheet-deficient FUS variants maintain native-like global motions, disorder, and phase separation, but no longer show a liquid-to-solid transition (LST). Biochemical partitioning, cellular localization, and auto- and cross-regulatory functions of FUS all remain essentially unchanged. Conversely, FUS-induced neurodegeneration in several Drosophila models is drastically reduced. These findings suggest a strategy for mitigating disease-related toxicity through backbone structure modulation to prevent prion-like domain protein aggregation.

SUMMARY: The RNA-binding protein Fused in Sarcoma (FUS) undergoes phase separation as part of its physiological function but can aberrantly aggregate into solid-like assemblies in amyotrophic lateral sclerosis and frontotemporal dementia. To dissect the role of β-sheets in both function and pathological transition, we engineered β-sheet-preventing FUS variants via targeted proline residue insertions in the prion-like disordered region. These variants retained native structure, motions, and phase behavior yet showed dramatically reduced aggregation, both as an isolated prion-like domain and in full-length FUS. Crucially, these variants maintained a panel of FUS cellular functions that depend on FUS condensation but prevented FUS toxicity in fly models of neurodegeneration. Our findings implicate β-sheets as key drivers of FUS condensate maturation and neuronal toxicity, highlighting β-sheet modulation as a therapeutic strategy against FUS-related neurodegeneration.

HIGHLIGHTS: Targeted proline additions disrupt β-sheet formation in FUS without altering native conformations, dynamics, or phase separation behaviorβ-sheet-deficient FUS variants prevent aggregation and liquid-to-solid transitions while retaining key biological functions In vivo models reveal attenuated toxicity of β-sheet-deficient FUS in Drosophila β-sheets are identified as central drivers of condensate maturation and neuronal death, offering a therapeutic entry point for modulating prion-like domain pathology.},
}

@article {pmid41756461,
year = {2026},
author = {Petriti, B and Subramanian, S and Williams, P and Chau, KY and Licznerski, P and Lascaratos, G and Aguilar-Munoa, S and Kamal, D and Bae, H and Alavian, K and Garway-Heath, D and Jonas, E},
title = {Reversing Mitochondrial Dysfunction in Optineurin E50K Glaucoma: A Metabolic Approach to Neuroprotection.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-8380062/v1},
pmid = {41756461},
issn = {2693-5015},
abstract = {Mutations in optineurin (OPTN) are linked to neurodegenerative diseases such as normal tension glaucoma (NTG) and amyotrophic lateral sclerosis. The E50K-OPTN mutation is the most common genetic cause of NTG, where it disrupts mitophagy and leads to the accumulation of dysfunctional mitochondria. To understand how cellular metabolism is altered in these persistent mitochondria, and whether any pathological state can be reversed, we investigated NTG-patient-derived fibroblasts carrying the E50K-OPTN mutation. We identified a form of mitochondrial leak metabolism driven by elevated levels of the ATP synthase c-subunit leak channel (ACLC). These cells exhibit reversed F1FO ATP synthase activity, increased mitochondrial proton leak, and fragmented mitochondria, resulting in inefficient oxidative phosphorylation and a shift toward aerobic glycolysis and high protein synthesis rate. The ratio of ATP synthase c-subunit to β-subunit was markedly elevated, suggesting open ACLC pores. Treatment with dexpramipexole normalized ATP synthase function and cellular metabolism, promoted ATP synthesis rather than hydrolysis and reduced protein synthesis rates. Dexpramipexole reduced p62 levels in E50K fibroblasts, consistent with a reduced mitophagic burden from decreased accumulation of damaged mitochondrial cargo. These findings identify ACLC-mediated leak as a central driver of metabolic dysfunction in E50K-OPTN glaucoma and suggest ACLC closure as a viable therapeutic strategy.},
}

@article {pmid41754783,
year = {2026},
author = {González-Rivera, ML and Juárez-Vázquez, MDC and Melecio-Hernández, AA and Casique-Aguirre, D and López-González, GJ and Ramírez-Martínez, RM and Ayala-Torres, A and Quesada-Mendiola, Y and Zapata-Morales, JR and Alonso-Castro, AJ},
title = {Antidepressant-Like Effects of n-Butylidenephthalide Using In Vivo and In Silico Approaches.},
journal = {Pharmaceuticals (Basel, Switzerland)},
volume = {19},
number = {2},
pages = {},
doi = {10.3390/ph19020242},
pmid = {41754783},
issn = {1424-8247},
support = {CBF2023-2024-1888//Secretariat of Science, Humanities, Technology, and Innovation/ ; },
abstract = {Background: The plant-derived compound n-butylidenephthalide (BP) is an isobenzofuranone that has shown neuropharmacological effects on preclinical models of Parkinson's, Alzheimer's, and amyotrophic lateral sclerosis. Methods: This study evaluated the anti-inflammatory, antinociceptive, anxiolytic-like, hypnotic, anticonvulsant, and antidepressant-like effects of BP (50-200 mg/kg p.o.) using Balb/c mice in acute assays. This study also evaluated the antidepressant-like effects of BP in a mouse model of reserpine-induced depression-like behavior for 20 days. Inhibitors involved in the molecular process of depression and in silico studies were used to evaluate a possible mechanism of action for the antidepressant-like effects of BP. Results: BP induced low anti-inflammatory effects, showed low anticonvulsant effects, and lacked hypnotic effects or motor impairment in acute assays. The antidepressant-like effects of BP (100-200 mg/kg p.o.) were comparable to amitriptyline (25 mg/kg p.o.) in acute assays. The participation of serotonergic and adrenergic systems is involved in the acute antidepressant-like effects of BP. In the reserpine-induced depression model, BP (100 mg/kg p.o.) showed antidepressant-like effects in one of the two antidepressant tests, but with a lower effect than amitriptyline (20 mg/kg p.o.). Conclusions: BP (100 and 200 mg/kg) showed antidepressant-like effects in acute assays and, to a lesser extent, in a reserpine-induced chronic model of depression-like behavior.},
}

@article {pmid41754025,
year = {2026},
author = {Namkung, K and Lee, K},
title = {Acceptability and Implementation Considerations for 40 Hz Auditory Stimulation Using Nature-Based Soundscapes for Cognitive Health Applications: A Qualitative Exploratory Study.},
journal = {Healthcare (Basel, Switzerland)},
volume = {14},
number = {4},
pages = {},
doi = {10.3390/healthcare14040512},
pmid = {41754025},
issn = {2227-9032},
support = {NRF-2025S1A5B5A16006803//the Ministry of Education of the Republic of Korea and the National Research Foundation/ ; },
abstract = {BACKGROUND/OBJECTIVES: 40 Hz sensory stimulation is being explored for cognitive health applications, but sustained use may be constrained by the listenability of simple 40 Hz auditory stimuli. We examined user-perceived acceptability and implementation considerations for 40 Hz auditory stimulation delivered by embedding a pure 40 Hz sine wave within nature-based soundscapes.

METHODS: Eleven adults aged ≥ 40 years in Seoul, Republic of Korea were assigned to waves or forest soundscapes (between-participants) and completed a within-session exposure to two conditions within the assigned set: 40 Hz-OFF (soundscape-only) and 40 Hz-ON (soundscape plus an additively layered 40 Hz sine wave). Each condition comprised seven cycles of 50 s playback and 10 s silence (~7 min) with a 10 min washout. After completing both listening blocks, participants provided brief comparative session-end ratings to aid recall and then completed a semi-structured interview focused on detectability and comparative impressions while blinded to condition identity. Following debriefing about the 40 Hz manipulation, participants completed a session-end 7-point Likert appraisal of the intended intervention stimulus (40 Hz-ON). Interview transcripts were analyzed using thematic analysis and interpreted using the Theoretical Framework of Acceptability and Proctor et al.'s implementation outcomes as sensitizing frameworks.

RESULTS: Session-end appraisals suggested that the 40 Hz-integrated soundscape (40 Hz-ON) was generally listenable, with mid-to-high comfort and immersion (medians = 5) and low unpleasantness (median = 2), while perceived artificiality spanned the full scale (range 1-7) and overall preference was moderate (median = 4). Interviews indicated that acceptability was governed by perceptual integration: natural blending supported "backgroundable" listening, whereas salient low-frequency rumble or a mechanical/artificial timbre contributed to negative reactions. Implementation-relevant themes highlighted context fit (bedtime vs. morning routines), low-friction automation (timers/scheduling), and conservative acoustic safeguards (gentle onset and default levels).

CONCLUSIONS: In a single-session evaluation among adults aged ≥ 40 years, embedding a 40 Hz sine wave within nature-based soundscapes was generally acceptable, with acceptability sensitive to perceptual integration and usage context. This qualitative study does not assess clinical or cognitive efficacy. These findings inform implementation considerations for cognitive health-oriented delivery, including space-oriented playback options, simplified automation, conservative acoustic safeguards, and coherence-supportive user guidance without overclaiming.},
}

@article {pmid41753201,
year = {2026},
author = {Hernández-Voth, A and Sayas-Catalán, J and Corral-Blanco, M and Jiménez-Gómez, M and Carvajal-Cuesta, G and Luján-Torné, M and Lalmolda-Puyol, C and Florez-Solarana, P and Villena-Garrido, V},
title = {Impact of Built-In Software Monitoring on Survival in Amyotrophic Lateral Sclerosis Patients Receiving Home Mechanical Ventilation: A Cohort Study.},
journal = {Journal of clinical medicine},
volume = {15},
number = {4},
pages = {},
doi = {10.3390/jcm15041513},
pmid = {41753201},
issn = {2077-0383},
abstract = {Background/Objectives: Amyotrophic lateral sclerosis is a progressive neurodegenerative disease in which respiratory failure is the leading cause of death. Mechanical ventilation improves both survival and quality of life; however, the prognostic implications of built-in ventilator software monitoring remain insufficiently characterized. The aim of the study was to determine whether built-in ventilator software-based monitoring is associated with enhanced survival in amyotrophic lateral sclerosis subjects. Methods: Cohort study of amyotrophic lateral sclerosis subjects, stratified into two groups: those monitored through detailed built-in ventilator software and those not monitored. Clinical and ventilatory data were systematically evaluated during a 24-month follow-up. Results: Among 120 ALS subjects (57 detailed built-in ventilator software, 63 non-detailed ventilator software), median survival from diagnosis was significantly longer in the detailed built-in ventilator software group (3.42 vs. 2.12 years; p < 0.001). Survival from mechanical ventilation initiation was also significantly longer in the built-in ventilator software group (2.79 years vs. 0.78 years). Greater daily mechanical ventilation usage was associated with shorter survival (p < 0.003). Paradoxically, subjects with the lowest proportion of spontaneous inspirations exhibited superior survival outcomes (p = 0.04). Neither persistent leaks nor asynchronies were independently predictive of survival. Conclusions: BVS-monitoring was associated with improved survival in amyotrophic lateral sclerosis subjects receiving home mechanical ventilation. Its integration into clinical practice may enable timely, data-driven ventilatory adjustments, ultimately contributing to more individualized and optimized patient management.},
}

@article {pmid41752224,
year = {2026},
author = {Oriol, NE and Lin, J and Bennet, J and DeLorenzo, D and Fallon, MK and Gracy, D and Hill, C and Vasquez, M and Vavasis, A and Williams, M and Honoré, P},
title = {Developing a Public Health Quality Tool for Mobile Health Clinics to Assess and Improve Care.},
journal = {International journal of environmental research and public health},
volume = {23},
number = {2},
pages = {},
doi = {10.3390/ijerph23020141},
pmid = {41752224},
issn = {1660-4601},
support = {unknown//Association of American Medical Colleges/ ; unknown/CC/CDC HHS/United States ; unknown//U.S. Department of Health and Human Services/ ; unknown//Family Health Council of Central Pennsylvania/ ; unknown//Aetna Foundation/ ; unknown//The Leon Lowenstein Foundation/ ; unknown//Northeastern University, Knox County Maine Mobile/ ; },
abstract = {This report describes the development and deployment of the Public Health Quality Tool (PHQTool), an online resource designed to help mobile health clinics (MHCs) assess and improve the quality of their public health services. MHCs provide essential clinical and public health services to underserved populations but have historically lacked tools to assess and improve the quality of their work. To address this gap, the PHQTool was developed as an online, evidence-based, self-assessment resource for MHCs, hosted on the Mobile Health Map (MHMap) platform. This report documents the collaborative development process of the PHQTool and presents preliminary evaluation findings related to usability and relevance among mobile health clinics. Drawing from national public health frameworks and Honore et al.'s established public health quality aims, the PHQTool focuses on six aims most relevant to mobile care: Equitable, Health Promoting, Proactive, Transparent, Effective, and Efficient. Selection of the six quality aims was guided by explicit criteria developed through pilot testing and stakeholder feedback. The six aims were those that could be directly implemented through mobile clinic practices and were feasible to assess within diverse mobile clinic contexts. The remaining three aims ("population-centered," "risk-reducing," and "vigilant") were determined to be less directly actionable at the program level or required system-wide or data infrastructure beyond the scope of individual mobile clinics. Development included expert consultation, pilot testing, and iterative refinement informed by user feedback. The tool allows clinics to evaluate practices, identify improvement goals, and track progress over time. Since implementation, 82 MHCs representing diverse organizational types have used the PHQTool, reporting high usability and identifying common improvement areas such as outreach, efficiency, and equity-driven service delivery. Across pilot and post-pilot implementation phases, a majority of respondents agreed or strongly agreed that the tool was user-friendly, relevant to their work, and appropriately scoped for mobile clinic practice. Usability and acceptance were assessed using descriptive statistics, including percentage agreement across Likert-scale items as well as qualitative feedback collected during structured debriefs. Reported findings reflect self-reported perceptions of feasibility, clarity, and relevance rather than inferential statistical comparisons. The PHQTool facilitates systematic quality assessment within the mobile clinic sector and supports consistent documentation of public health efforts. By providing a standardized, accessible framework for evaluation, it contributes to broader efforts to strengthen evidence-based quality improvement and promote accountability in MHCs.},
}

@article {pmid41752118,
year = {2026},
author = {Kurdi, MA and Alotaibi, H and Alkhuraymi, AT and Aldahery, LN and Alhawaj, AF and Aldali, HJ},
title = {Amyotrophic Lateral Sclerosis (ALS) Genetics and Microbiota: A Comprehensive Review.},
journal = {International journal of molecular sciences},
volume = {27},
number = {4},
pages = {},
doi = {10.3390/ijms27041978},
pmid = {41752118},
issn = {1422-0067},
abstract = {Amyotrophic Lateral Sclerosis (ALS) is a severe, progressive neurodegenerative disorder characterized by the loss of upper and lower motor neurons, affecting 0.5 to 2.6 per 100,000 people, with a median survival of 2 to 5 years. It is increasingly seen as a multisystem disorder, sharing essential clinicopathological features with Frontotemporal Dementia (FTD). This convergence arises from overlapping molecular processes, including severe oxidative stress, glutamate-mediated excitotoxicity, mitochondrial dysfunction, and widespread aggregated TDP-43 proteinopathy in both sporadic and familial cases. Several key genetic factors have been identified, particularly mutations in C9orf72, SOD1, TARDBP, and FUS, which serve as important targets for novel treatments, such as Tofersen, a recently approved SOD1-specific antisense oligonucleotide (ASO) gene therapy. Additionally, there is increasing evidence of the gut-brain connection. Dysbiosis, involving species such as Akkermansia muciniphila, and lower levels of neuroprotective metabolites, such as nicotinamide, may affect the course of the disease. As a result, treatment strategies are shifting toward a personalized approach. This includes using gene therapy, ranging from ASOs and RNA interference (RNAi) to new CRISPR-based genome editing. It also involves exploring microbiome-modulating treatments, such as specific probiotics and Fecal Microbiota Transplantation (FMT). While microbiome and gene therapies remain largely experimental, their potential is promising, as highlighted by the recent approval of Tofersen. These novel approaches could be further enhanced and guided by more robust diagnostic criteria and by investigating early multimodal treatment strategies to slow the progression of this complex disease.},
}

@article {pmid41752089,
year = {2026},
author = {Hall, B and Castelli, L and Higginbottom, A and He, J and Zou, LN and Walker, H and Yagüe-Capilla, M and Wong, KE and Burrows, DJ and George, J and Hamer, K and Tanner, JM and Kyrgiou-Balli, E and Ross, R and Garland, H and Tonkiss, E and George, R and Webster, CP and Smith, EF and Timmons, HO and Allsop, J and Stefanidis, N and Ward, BD and Lin, YH and Highley, JR and Azzouz, M and West, RJH and Rudd, SG and Vos, KJ and Shaw, PJ and Hautbergue, GM and Allen, SP},
title = {Antisense Dipeptide Repeat Proteins Drive Widescale Purine Metabolism Aberration in C9orf72 Amyotrophic Lateral Sclerosis via ADA.},
journal = {International journal of molecular sciences},
volume = {27},
number = {4},
pages = {},
doi = {10.3390/ijms27041953},
pmid = {41752089},
issn = {1422-0067},
support = {SBF005\1064/AMS_/Academy of Medical Sciences/United Kingdom ; Allen 887-791//MND Association/ ; Allen/Jun23/964-793//MND Association/ ; West/Oct22/909-792//MND Association/ ; BRC-203321//NIHR/ ; NF-SI-0617-10077//NIHR/ ; AMBRoSIA PJS 972-797//MND Association/ ; TJ2022-0063//Swedish Childhood Cancer Fund/ ; 19-0056-JIA//Swedish Cancer Society/ ; 23-2782-Pj//Swedish Cancer Society/ ; 260 (AS-PG-15-023)/ALZS_/Alzheimer's Society/United Kingdom ; MR/S025979/1/MRC_/Medical Research Council/United Kingdom ; MR/M013251/1/MRC_/Medical Research Council/United Kingdom ; MR/Z504701/1/MRC_/Medical Research Council/United Kingdom ; DEVOS/APR18/862-79//MND Association/ ; ARUK-PG2018B-005//Alzheimer's Research UK/ ; MR/W00416X/1/MRC_/Medical Research Council/United Kingdom ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterised by the death of motor neurons leading to paralysis and death, generally 3-5 years post-symptom onset. The most frequent genetic cause of ALS is a hexanucleotide repeat expansion (HRE) in the chromosome 9 open reading frame 72 (C9orf72) gene, that has three major hypothesised pathological mechanisms including the production of dipeptide repeat proteins (DPRs). Our laboratory has previously identified purine metabolism dysfunction in induced neural progenitor cell-derived astrocytes (iAstrocytes) from C9orf72 ALS (C9-ALS) cases (C9-iAstrocytes), driven by loss of the enzyme adenosine deaminase (ADA). Here, we have demonstrated that loss of ADA along with changes to ecto-5'-nucleotidase and hypoxanthine-guanine phosphoribosyl transferase led to disruption in purine metabolite levels including purine dNTP output. These changes were recapitulated in patient CSF, whilst loss of ADA was recapitulated in patient white matter. Immunofluorescence also demonstrated purinosome formation dysfunction in C9-iAstrocytes. These changes are likely driven by DPRs as ADA loss was recapitulated in in vitro and in vivo DPR models. Finally, ADA levels could be recovered by reducing DPR levels either by inhibiting serine/arginine-rich splicing factor 1 or overexpressing RuvB-like 2. Our data demonstrate that DPR production negatively affects purine function in C9-ALS suggesting a potentially pivotal role for purine metabolism dysfunction in C9-ALS pathology.},
}

@article {pmid41751955,
year = {2026},
author = {Luong, DT and Niu, C and Kim, E and Tanji, N and Duong, I and Galero, B and Zhang, YJ and Bennett, CL and La Spada, AR},
title = {PPAR-Delta Agonist Therapies Did Not Rescue Hallmark Disease Phenotypes in Two Sets of Preclinical Trials in ALS TDP-43 and C9orf72 Model Mice.},
journal = {International journal of molecular sciences},
volume = {27},
number = {4},
pages = {},
doi = {10.3390/ijms27041820},
pmid = {41751955},
issn = {1422-0067},
support = {W81XWH-20-1-0154//United States Department of Defense/ ; },
abstract = {Peroxisome-proliferator-activated receptor delta (PPARδ) regulates metabolic, mitochondrial, and inflammatory pathways implicated in neurodegeneration, making it an attractive therapeutic target for amyotrophic lateral sclerosis (ALS). In this study, we evaluated two PPARδ agonists, KD3010 and T3D-959, in two established ALS/FTD mouse models: an AAV-mediated C9orf72 G4C2-repeat expansion model (C9-149R) and the TDP-43[Q331K] transgenic model. Drug treatment was initiated prior to the emergence of key disease features and continued for 9-10 months. Comprehensive behavioral, neuropathological, and biomarker analyses revealed marked differences between the two models. C9-149R mice exhibited reduced body weight and subtle behavioral alterations without robust motor deficits, whereas TDP-43[Q331K] mice developed pronounced, progressive motor and cognitive impairments accompanied by a ~7-fold elevation in plasma neurofilament light chain (NfL). Despite effective target engagement-particularly for T3D-959-neither PPARδ agonist improved motor performance, cognitive behavior, neuroanatomical measures, plasma NfL levels, or disease-associated molecular phenotypes in either model. Prolonged KD3010 treatment resulted in loss of target engagement, consistent with drug tolerance, while T3D-959 sustained PPARδ activation without therapeutic benefit. Together, these findings demonstrate that PPARδ agonism is insufficient to modify disease progression in these ALS/FTD mouse models and underscore the importance of publishing well-powered negative preclinical studies to refine therapeutic strategies for ALS.},
}

@article {pmid41751793,
year = {2026},
author = {Ptáček, O and Musil, Z and Guarnieri, G and Vrbacká, A and Moudrá, P and Zlámalová, A and Röszlerová, P and Tonhajzer, M and Musil, V and Morelli, A and Zach, P},
title = {Amyotrophic Lateral Sclerosis: The State of the Art on Treatments and the Therapeutic Role of the Intestinal Microbiome in Human Studies.},
journal = {International journal of molecular sciences},
volume = {27},
number = {4},
pages = {},
doi = {10.3390/ijms27041655},
pmid = {41751793},
issn = {1422-0067},
support = {Cooperatio 39 - Oncology and Haematology//Charles University/ ; Cooperatio 33-Intensive Care Medicine//Charles University/ ; Cooperatio 36-Medical Diagnostics and Basic Medical Sciences//Charles University/ ; #NEXTGENERATIONEU//European Commission/ ; MNESYS (PE0000006) - A Multiscale integrated approach to the study of the nervous system in health and disease (DR. 1553 11.10.2022)//Ministry of University and Research (MUR), National Recovery and Resilience Plan (NRRP)/ ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a common neurodegenerative disorder; to date, there is no long-term effective treatment. Recently, a relationship has been discovered between the human intestinal microbiome and the pathogenesis of ALS, on which basis faecal microbiota transplantation (FMT) has been proposed as a potential treatment for ALS. In this review, we compare three existing case studies examining the effect of FMT on the course of ALS, highlighting differences in methodology and results. In two of the studies, a halt in the progression of ALS symptoms was observed following FMT, accompanied by improvement in patient health. However, in the third and largest study, no significant effect of FMT was observed. The possible explanation for this discrepancy may be the intentional depletion of intestinal microorganisms using antibiotics prior to FMT in the third study. Future studies and/or completion of the ongoing clinical studies will help clarify the therapeutic effectiveness of FMT in ALS patients.},
}

@article {pmid41751374,
year = {2026},
author = {Trabulo, A and Sousa, P and Alvites, R and Maurício, AC},
title = {Mesenchymal Stem Cell-Based Therapies Applied in Neurological Diseases: A Systematic Review.},
journal = {Biomedicines},
volume = {14},
number = {2},
pages = {},
doi = {10.3390/biomedicines14020475},
pmid = {41751374},
issn = {2227-9059},
abstract = {Background/Objectives: Neurodegenerative diseases (NDs) have a severe impact on patients' quality of life, and effective treatments remain limited. As the focus is on treating the symptoms, the root cause of the problem is commonly not addressed. Mesenchymal stem cells show an emerging potential due to the ability for self-renewal combined with their capability for differentiation into various cell lines, which makes them a strong candidate for regenerative therapies in general, and for application in neurological issues in particular. This article provides an overview of the safety, efficacy, and challenges associated with the use of mesenchymal stem cells (MSCs) and their derived secretome in clinical and preclinical models of Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD) and amyotrophic lateral sclerosis (ALS). Methods: A systematic search was conducted on PubMed to identify published studies providing clinical and preclinical evidence on the use of MSCs in neurodegenerative disorders. Results: Overall, the literature consistently indicates that MSCs and their derivatives exert disease-modifying effects across multiple NDs. Across AD, PD, HD and ALS, preclinical studies uniformly report improvements in behavioural outcomes, attenuation of neuroinflammation, and neuroprotective effects, largely mediated by MSCs' paracrine signalling rather than direct cell replacement. Clinical studies to date consistently support the safety and feasibility of MSC-based therapies, while efficacy signals remain modest, heterogeneous and predominantly short-term, highlighting the need for larger, well-controlled trials. Conclusions: Integration of genetic engineering, preconditioning, and EV technology may represent an emerging therapeutic approach that may complement existing neuroregeneration treatments, offering a scalable and minimally invasive frontier to improve long-term clinical outcomes in patients with AD, PD, HD, and ALS.},
}

@article {pmid41751343,
year = {2026},
author = {Iyer, MR and Zhao, B and He, X and Camacho, D and Wei, Z and Deng, J and Mitchell, CS},
title = {An Artificial Intelligence-Driven Multimorbidity Framework Reveals a Shared Metabolic and Immune Core Across Alzheimer's Disease, Amyotrophic Lateral Sclerosis, and Frontotemporal Dementia.},
journal = {Biomedicines},
volume = {14},
number = {2},
pages = {},
doi = {10.3390/biomedicines14020444},
pmid = {41751343},
issn = {2227-9059},
support = {1944247//National Science Foundation/ ; R35GM152245/NH/NIH HHS/United States ; U19AG056169/NH/NIH HHS/United States ; 253558//Chan Zuckerberg Initiative/ ; },
abstract = {Background/Objectives: Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD) share molecular features yet differ clinically, suggesting underlying systems-level commonalities. We aimed to characterize shared and disease-specific multimorbidity architectures across AD, ALS, and FTD using an artificial intelligence-driven literature-based semantic network. Methods: We applied SemNet 2.0, constructed from over 35 million PubMed abstracts, to analyze disease and syndrome (DSYN) and pharmacological substance (PHSU) nodes. Nodes were ranked using HeteSim and mapped to a harmonized 13-category mechanistic ontology. We quantified pairwise disease intersections, ontology-level enrichment, rank similarity, and intersection-disease alignment, and constructed an integrated multimorbidity priority landscape integrating disease-specific and intersection-level hierarchies. Results: Across AD, ALS, and FTD, a convergent multimorbidity architecture centered on a shared metabolic and immune core was identified, accompanied by prominent neurobehavioral processes and intermediate systems including gastrointestinal, endocrine, hematological, hepatic, and sensory pathways. Disease-specific signatures shaped distinct vulnerability profiles within this shared structure, including cardiovascular enrichment in AD, neuromuscular and toxin-related pathways in ALS, and coupled neurobehavioral-metabolic features in FTD. PHSU patterns reinforced these findings, with centrally positioned compounds predominantly targeting inflammatory, metabolic, or neuromodulatory processes. Conclusions: These findings position AD, ALS, and FTD within a unified, AI-derived multimorbidity framework. This ontology-guided approach provides a computational, hypothesis-generating foundation for multimorbidity-aware biomarker discovery, risk stratification, and cross-disease therapeutic exploration in neurodegenerative disease.},
}

@article {pmid41750455,
year = {2026},
author = {Bustos, C and Yuste, JR and Aguinaga, A and Parra, A and Carmona-Torre, F and Azanza, JR and Lacasa, C and Del Pozo, JL},
title = {Timing of Antimicrobial Lock Replacement for Gram-Positive Port Infections: Results of a Randomized Trial.},
journal = {Antibiotics (Basel, Switzerland)},
volume = {15},
number = {2},
pages = {},
doi = {10.3390/antibiotics15020157},
pmid = {41750455},
issn = {2079-6382},
support = {EC10-329//Instituto de Salud Carlos III/ ; },
abstract = {Background: Conservative management of port-related bacteremia often includes locally administered antimicrobials, known as antimicrobial lock therapy (ALT). Current guidelines recommend daily replacement of antimicrobial lock solutions (ALSs). We aimed to evaluate whether ALSs could remain effective with extended dwell times of up to 10 days. Methods: In this randomized clinical trial, patients with noninfected, recently implanted ports were assigned to one of five ALS dwell-time groups, ranging from 1 to 10 days. Each ALS contained heparin plus an antimicrobial at standard intraluminal concentrations: vancomycin 2 mg/mL, teicoplanin 10 mg/mL, linezolid 1.8 mg/mL, daptomycin 5 mg/mL, or tigecycline 4.5 mg/mL. The primary endpoint was the time at which intraluminal drug concentrations decreased below 1 mg/mL (ClinicalTrials.gov NCT01592032). Results: Vancomycin and linezolid concentrations fell significantly below 1 mg/mL after 3 days of dwell time. Daptomycin and tigecycline concentrations decreased significantly after 7 days but remained above 1 mg/mL. Teicoplanin concentrations did not decline significantly after 7 days. Conclusions: Optimal ALS dwell time depends on the antimicrobial agent. Vancomycin and linezolid locks require daily replacement, whereas daptomycin, tigecycline, and teicoplanin locks maintain therapeutic concentrations for up to 7 days. These findings support individualized ALS replacement strategies, potentially reducing the need for daily interventions.},
}

@article {pmid41750323,
year = {2026},
author = {Dong, L and Li, X and Li, A and Yi, J and Vockery, Y and Chang, Y and Pan, Z and Brotto, M and Zhou, J},
title = {Absence of Neuromuscular Dysfunction in Mice with Gut Epithelium-Restricted Expression of ALS Mutation hSOD1[G93A].},
journal = {Biomolecules},
volume = {16},
number = {2},
pages = {},
doi = {10.3390/biom16020253},
pmid = {41750323},
issn = {2218-273X},
support = {R01NS105621//National Institute of Health/ ; R01HL138570//National Institute of Health/ ; AL170061(W81XWH1810684)//United States Department of Defense/ ; 16-IIP-288//Bank of America/ ; },
abstract = {Amyotrophic Lateral Sclerosis (ALS) is a devastating neuromuscular disorder characterized by the progressive loss of motor neurons and skeletal muscle, ultimately leading to respiratory failure and death, typically within 3-5 years following diagnosis. While the death of motor neurons is the pathological hallmark, ALS is increasingly recognized as a systemic disorder involving non-motor systems. Gastrointestinal dysfunction has been widely observed in both ALS patients and animal models. However, because gut abnormalities and neuromuscular degeneration are intertwined during ALS disease progression, it remains unclear whether these gut abnormalities are merely a consequence of neuromuscular degeneration or whether they play a crucial role in initiating it. In this study, we investigated whether an ALS-associated mutation expressed exclusively in the gut can directly affect neuromuscular function. We generated a novel transgenic mouse model, Gut-hG93A, which overexpresses the human ALS mutation hSOD1[G93A] specifically in the epithelial cells of the intestine at a level comparable to the endogenous mouse SOD1. We found that the specific overexpression of hSOD1[G93A] in gut epithelial cells did not cause abnormalities in the structure of the tight junctions or in gut permeability. Furthermore, there were no significant differences between Gut-hG93A and control mice regarding lifespan, body weight, or neuromuscular activities, including grip strength, daily travel distance and in vivo muscle contractility. These findings suggest that the ALS-associated hSOD1[G93A] mutation, when expressed solely in the gut epithelium, is not sufficient to initiate neuromuscular degeneration of systemic ALS-like pathology.},
}

@article {pmid41750236,
year = {2026},
author = {Eisen, A},
title = {Exploring the ALS Multistep Model.},
journal = {Brain sciences},
volume = {16},
number = {2},
pages = {},
doi = {10.3390/brainsci16020236},
pmid = {41750236},
issn = {2076-3425},
abstract = {ALS is a multistep disease, in which (epi)genetic, environmental, and age-related processes, including senescence, converge over decades to reduce resilience resulting in self-sustaining symptomatic disease. The multistep model visualizes five to six impactful events in sporadic ALS, but fewer in those carrying high-penetrance mutations, such as SOD1, FUS, or C9orf72 expansions. The timing, duration, and cumulative effects of specific steps are presumed to have individual variability but, the steps themselves are inferred since they have not been observed and remain agnostic as to biological identity. Nevertheless, the model gives an opportunity to integrate genetics, aging, environmental exposures, and systems-level vulnerability into a single framework. Acting as step modifiers, environmental exposures including trauma lower the threshold for step acquisition, accelerate the accumulation of steps, influence the anatomical site of disease onset, and unmask preclinical disease. Because ALS emerges from the gradual collapse of multiple layers of biological robustness, tackling a single pathway will be insufficient and the multistep model forces a reconsideration of therapeutic timing and strategies. Protection against early-life insults, anti-aging, and anti-senescent therapies may curtail step accumulation preventing ALS from exceeding threshold and disease manifestation.},
}

@article {pmid41750189,
year = {2026},
author = {Ray, SK},
title = {'Molecular and Cellular Neuroscience': Impacts of Eight Highly Cited Articles Published in This Section of Brain Sciences in 2024.},
journal = {Brain sciences},
volume = {16},
number = {2},
pages = {},
doi = {10.3390/brainsci16020188},
pmid = {41750189},
issn = {2076-3425},
abstract = {This year, the selection criteria for highly cited articles in the 'Molecular and Cellular Neuroscience' section of Brain Sciences were focused on publications that achieved a citation count of 10 or more during 2024. Applying this metric, the Editorial Office, in collaboration with myself as Associate Editor of the 'Molecular and Cellular Neuroscience' section of the journal, identified eight articles that not only exemplified the mission of this section but also made significant scientific contributions by advancing our current understanding of the molecular and cellular mechanisms underlying major and rare neurological disorders. These articles encompass miscellaneous topics, including Alzheimer's disease (AD), chronic alcoholism, glioblastoma multiforme (GBM), amyotrophic lateral sclerosis (ALS), cognitive impairment, cerebrovascular disease, and Rett syndrome (RTT). Importantly, several contributions highlight experimental therapeutic strategies aimed at mitigating pathogenic mechanisms, offering promising avenues for translational research and future clinical applications.},
}

@article {pmid41750144,
year = {2026},
author = {Huang, X and Xia, K and Ye, S and Yang, Q and Fan, D},
title = {Enlarged Perivascular Spaces (EPVS) and the Risk of Amyotrophic Lateral Sclerosis (ALS): Evidence for Overlapping Genetic Signals in White Matter Without Causal Links.},
journal = {Brain sciences},
volume = {16},
number = {2},
pages = {},
doi = {10.3390/brainsci16020144},
pmid = {41750144},
issn = {2076-3425},
support = {81873784, 82071426, 82401670//National Natural Science Foundation of China/ ; BYSYDL2019002//Clinical Cohort Construction Program of Peking University Third Hospital/ ; there is no number of this funding.//the special fund of the National Clinical Key Specialty Construction Program, P. R.China(2024)/ ; },
abstract = {Background/Objectives: Emerging evidence suggests that enlarged perivascular spaces (EPVS), which play a significant role in brain fluid exchange and waste removal, may be involved in the pathogenesis of amyotrophic lateral sclerosis (ALS). In this study, we aimed to explore the shared genetic link and causal effect between EPVS and ALS. Methods: This study used publicly available summary data from the largest and most recent genome-wide association studies (GWAS) on EPVS (n = 40,095) and ALS (n = 138,086) in European populations. EPVS were assessed in the hippocampus (EPVS-HIP), basal ganglia (EPVS-BG), and white matter (EPVS-WM). We used linkage disequilibrium score regression (LDSC) to investigate the genetic correlation. Multi-trait analysis of GWAS (MTAG), Cross-Phenotype Association (CPASSOC) analysis, and genetic colocalization analysis were performed to identify shared risk loci. Bidirectional Mendelian randomization analysis was used to investigate the causal relationship. Results: A negative genetic correlation was observed between EPVS-WM and ALS after Bonferroni correction (rg = -0.24, p < 0.01). No significant correlations were observed between ALS and EPVS-HIP (rg = -0.03, p = 0.79) or EPVS-BG (rg = 0.01, p = 0.91). Four significant loci including rs113247976 in KIF5A and rs118082508 in SDR9C7 were identified as potential pleiotropic loci of the relationship. None of these loci demonstrated evidence of genetic colocalization. Furthermore, Mendelian randomization analysis revealed no causative effect in either direction. Conclusions: EPVS-WM and ALS may share part of their genetic architecture, but no evidence for a causal relationship was observed. Future research is needed to further refine these relationships.},
}

@article {pmid41749825,
year = {2026},
author = {De Simoni, O and Scarpa, M and Cavallin, F and Kotsafti, A and Marchegiani, F and Stepanyan, A and Tussardi, G and Rosato, A and Spolverato, G and Angriman, I and Urso, EDL and Ruffolo, C and Saadeh, LM and Maretto, I and Bao, QR and Negro, S and Vignotto, C and Facci, L and Rivella, G and D'Angelo, A and Matteazzi, A and Galuppini, F and Guzzardo, V and Salmaso, R and Pellegrini, V and Brignola, S and Ceccon, C and Stecca, T and Pozza, A and Massani, M and Pilati, P and Gruppo, M and Franzato, B and Cataldo, I and Portale, G and Cipollari, C and Zuin, M and Laurino, L and Dal Santo, L and Pirozzolo, G and Recordare, A and Ceccarini, L and Antoniutti, M and Marinelli, L and Brolese, A and Barbareschi, M and Bertalot, G and Ortenzi, M and Guerrieri, M and Zizzo, M and Dell'Atti, L and Guerriero, S and Piccioli, A and Pozza, G and Godina, M and Mondi, I and Verdi, D and Da Lio, C and Noaro, G and Cola, R and Bordignon, G and Merenda, R and Becherucci, G and Gavagna, L and Candioli, S and Tagliente, G and Tedeschi, U and Parini, D and Salmaso, B and Businello, G and Di Cristoforo, L and Bergamo, F and Porzionato, A and Scognamiglio, F and Bardini, R and Pucciarelli, S and Agostini, M and Chiminazzo, V and Gregori, D and Di Camillo, B and Castagliuolo, I and Dei Tos, AP and Fassan, M and Scarpa, M},
title = {IMMUNOREACT 4: Peritumoral Microenvironment Associated with Anastomotic Leaks After Surgery for Rectal Cancer.},
journal = {Cancers},
volume = {18},
number = {4},
pages = {},
doi = {10.3390/cancers18040571},
pmid = {41749825},
issn = {2072-6694},
support = {23381//AIRC IG 2019/ ; },
abstract = {Background: Anastomotic leaks (ALs) remain a critical complication after rectal cancer surgery. Emerging evidence suggests that local immune dysregulation may play a key role in anastomotic healing. We investigated the immune microenvironment of histologically normal, tumor-adjacent rectal mucosa-a tumor-conditioned field-as a potential substrate for AL predisposition. Methods: IMMUNOREACT 4 is a sub-analysis of the IMMUNOREACT project (clinicaltrials.gov NCT04915326 and NCT04915326), a multicenter translational study evaluating immune features of histologically normal, tumor-adjacent rectal mucosa of patients undergoing colorectal anastomosis. A prospective cohort (n = 121) was analyzed using flow cytometry, in addition to a retrospective cohort (n = 262) using immunohistochemistry. Immune markers of epithelial activation and lymphocyte subsets were compared between patients with and without postoperative ALs. Exploratory predictive models combining immune and clinical variables were developed and evaluated using discrimination, calibration and decision curve analyses. Results: At flow cytometry, the CK[+]HLAabc[+] MFI (AUC 0.66, 95% CI 0.52-0.80), CD8[+]CD38[+] cell rate (AUC 0.65, 95% CI 0.52-0.78) and CD3[+]CTLA4[+] cell rate (AUC 0.65, 95% CI 0.51-0.80) showed moderate predictive potential for ALs. In immunohistochemistry, CD3[+] (AUC 0.57, 95% CI 0.54-0.60), CD8[+] (AUC 0.57, 95% CI 0.52-0.62), CD8β[+] (AUC 0.59, 95% CI 0.53-0.65) and Tbet[+] (AUC 0.60, 95% CI 0.56-0.64) showed some predictive ability for ALs. The model including CD8β[+], the BMI, neutrophile/lymphocyte ratio and tumor location had an AUC of 0.67 (95% CI 0.62-0.72). Conclusions: Immune activation within histologically normal, tumor-adjacent rectal mucosa-characterized by epithelial HLA upregulation and cytotoxic or Th1 T cell infiltration-is associated with postoperative ALs. Although predictive accuracy is limited, these findings support the concept that a tumor-conditioned immune microenvironment may predispose patients to impaired anastomotic healing. Integration of mucosal immune profiling with clinical variables represents a promising exploratory approach that warrants further prospective validation.},
}

@article {pmid41749139,
year = {2026},
author = {Sun, Q and Wang, H and Deng, G and Du, Y and Ma, T and Ding, J and Xia, Z and Jiang, Y and Huang, Y and Huang, X},
title = {Nomogram prediction model for prognosis of patients with amyotrophic lateral sclerosis.},
journal = {BMC neurology},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12883-026-04741-8},
pmid = {41749139},
issn = {1471-2377},
support = {320.6750.18456//Wu Jieping Medical Foundation/ ; 320.6750.18456//Wu Jieping Medical Foundation/ ; 320.6750.18456//Wu Jieping Medical Foundation/ ; 320.6750.18456//Wu Jieping Medical Foundation/ ; 320.6750.18456//Wu Jieping Medical Foundation/ ; 320.6750.18456//Wu Jieping Medical Foundation/ ; 320.6750.18456//Wu Jieping Medical Foundation/ ; 320.6750.18456//Wu Jieping Medical Foundation/ ; },
}

@article {pmid41748409,
year = {2026},
author = {Anzilotti, S and Valente, V and Brancaccio, P and Franco, C and Casamassa, A and Lombardi, G and Palazzi, A and Conte, A and Paladino, S and Canzoniero, LMT and Annunziato, L and Pierantoni, GM and Pignataro, G},
title = {Corrigendum to "Chronic exposure to l-BMAA cyanotoxin induces cytoplasmic TDP-43 accumulation and glial activation, reproducing an amyotrophic lateral sclerosis-like phenotype in mice" [Biomed. Pharmacother. 167 (2023) 115503].},
journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie},
volume = {},
number = {},
pages = {119161},
doi = {10.1016/j.biopha.2026.119161},
pmid = {41748409},
issn = {1950-6007},
}

@article {pmid41748268,
year = {2026},
author = {Challa, S and Griffith, M and Jegede, A and Tijani, A and Himes, E and Idiodi, I and Okoli, C and Dimowo, S and Omoluabi, E and Liu, JX},
title = {Understanding clients' and providers' perspectives on the implementation of subcutaneous depot medroxyprogesterone acetate (DMPA-SC) for self-injection programming in Nigeria.},
journal = {BMJ global health},
volume = {10},
number = {Suppl 6},
pages = {},
doi = {10.1136/bmjgh-2024-018763},
pmid = {41748268},
issn = {2059-7908},
abstract = {Subcutaneous depot medroxyprogesterone acetate (DMPA-SC) is an injectable contraceptive method with a small needle and prefilled syringe system that has been approved for self-injection (SI) by clients. As DMPA-SC for SI programmes are being scaled, employing an implementation science lens is critical to understanding what works. This study explored providers' and clients' experiences with providing and receiving services, respectively, for DMPA-SC for SI in Nigeria, using an implementation science framework.Between 2021 and 2023, we conducted N=141 interviews with providers offering DMPA-SC for SI, and N=129 interviews with their clients using DMPA-SC for SI in Lagos, Enugu and Plateau States. Using Proctor et al's implementation science framework, we noted observations for each interview question, extracted related quotes, and coded observations and quotes by implementation outcome (acceptability, appropriateness, feasibility, fidelity, cost, efficiency, safety, client-centredness and adoption).Among clients, learning about DMPA-SC and SI from social network members facilitated acceptability and adoption of the method. Clients reported that provider outreach was appropriate for contraceptive information. However, providers desired support to mitigate their own out-of-pocket costs and enhance the feasibility of outreach. Occasionally, providers used clients' age or education to decide whether they could self-inject independently, rather than clients' ability to perform SI procedures, limiting client-centredness Many providers felt their fidelity to SI provision protocols could improve with refresher trainings on the latest guidelines around offering SI. Clients indicated that proactive follow-up support from providers for continued SI and side effect management was appropriate and desired; providers concurred with offering such support.Findings suggest that programme scale-up efforts should prioritise: (1) leveraging peer support or social networks to facilitate acceptability of DMPA-SC for SI among clients, (2) improving access to training aids to ensure fidelity to protocols and facilitate adoption among clients and providers, (3) emphasising shared decision-making in judgement-free client trainings to encourage client-centredness, and (4) investing in models for proactive follow-up support to improve feasibility of continuation for clients' desired length of time.},
}

@article {pmid41747658,
year = {2026},
author = {Fernandes, GL and Orssatto, LBR and Pinto, MD and Henkin, JS and Shandiz, E and McCombe, PA and Henderson, RD and Trajano, GS},
title = {Maximal motor unit firing rates decline with amyotrophic lateral sclerosis progression.},
journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology},
volume = {185},
number = {},
pages = {2111697},
doi = {10.1016/j.clinph.2026.2111697},
pmid = {41747658},
issn = {1872-8952},
abstract = {OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is characterised by progressive degeneration of upper and lower motor neurons and their motor units (MUs). MU loss is compensated by collateral sprouting and reinnervation of muscle fibres. There is limited information about the properties of these surviving MUs as these processes take place. High-density surface electromyography (HD-sEMG) decomposition enables non-invasive analysis of individual MU firing behaviour during maximal voluntary contractions and assess their changes with ALS progression.

METHODS: Thirty-nine individuals with ALS (24 men; mean age 63 ± 16 years) completed up to five visits (interval 20.0 ± 7.9 weeks). Tibialis anterior HD-sEMG recordings during maximal contractions were decomposed into individual MU spike trains, from which maximal firing rates were quantified. Muscle strength was assessed with the Medical Research Council (MRC) scale, and global function with the revised ALS Functional Rating Scale (ALSFRS-R).

RESULTS: Maximal MU firing rates declined significantly over time [-0.32 Hz/month, (95% CI -0.44; -0.19)], regardless of MRC scores. Across participants, maximal firing rates decreased by 2.38 Hz (1.78; 2.98) for each 1-point reduction in MRC and by 0.54 Hz for each ALSFRS-R point (-0.83; -0.26).

CONCLUSION: These findings demonstrate that maximal MU firing rates decline as ALS progresses, suggesting that the surviving motor unit undergo progressive pathophysiological changes as motor neurons degenerate. HD-sEMG MU firing-rates analysis appeared more sensitive than MRC in detecting early deterioration in muscle decline.

SIGNIFICANCE: Maximal firing rates analysis has the potential to serve as a quantitative clinical biomarker of neuromotor system degeneration, complementing global functional scales in clinical monitoring.},
}

@article {pmid41747520,
year = {2026},
author = {Ammari, F and Le Penglau, R and Bouhier, M and Neff, D},
title = {Characterization of long-term atmospheric corrosion of iron in indoor and outdoor conditions using Raman spectroscopy coupled to multivariate curve resolution-alternating least squares.},
journal = {Talanta},
volume = {305},
number = {},
pages = {129569},
doi = {10.1016/j.talanta.2026.129569},
pmid = {41747520},
issn = {1873-3573},
abstract = {This study presents a characterization of long-term atmospheric corrosion layers formed on historical iron samples from two cathedrals exposed to distinct environments: outdoor-exposed low-alloy steel clamps from Metz Cathedral and indoor-exposed iron reinforcements from Amiens Cathedral, both aged over 500 years. To address the complexity and heterogeneity of the corrosion products, Raman micro-spectroscopy was combined with multivariate curve resolution-alternating least squares (MCR-ALS) to extract pure spectral components and their spatial distribution, and estimate their relative contributions within the corrosion matrix. For the Amiens sample, MCR-ALS was first initialized using laboratory-acquired reference spectra of pure phases. The same dataset was then reprocessed using component spectra extracted from non-negative matrix factorization (NMF) as a blind initialization. The comparison of the results demonstrated that reliable and chemically consistent results can be obtained even without experimentally measured reference spectra, offering a robust solution for the analysis of complex mixtures. To further validate this approach in a more complex system, the Metz sample was analyzed using a fully blind NMF-based initialization, confirming the method's robustness across varying environmental contexts and over extended timescales. Finally, the identified corrosion phases and their spatial distributions were compared with previous studies, revealing strong agreement and thereby reinforcing the reliability of the approach.},
}

@article {pmid41747474,
year = {2026},
author = {Kaji, R and Ishida, T and Izumi, Y},
title = {Response to letter to the editor "Comment on: Clinical safety of ultra-high-dose methylcobalamin in patients with amyotrophic lateral sclerosis: Open-label extension of a phase 2/3 randomized controlled study".},
journal = {Journal of the neurological sciences},
volume = {483},
number = {},
pages = {125792},
doi = {10.1016/j.jns.2026.125792},
pmid = {41747474},
issn = {1878-5883},
}

@article {pmid41746412,
year = {2026},
author = {Tarazona-Santabalbina, FJ and Belenguer-Varea, A and Borrás-Blasco, J and García-Tercero, E and Martin, ML and Prior, NP and Mariscal, G and Valcuende-Rosique, A},
title = {Safety profile of tofersen in amyotrophic lateral sclerosis: a systematic review and meta-analysis.},
journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology},
volume = {47},
number = {3},
pages = {},
pmid = {41746412},
issn = {1590-3478},
}

@article {pmid41745965,
year = {2026},
author = {Haroun, M and Tratrat, C and Mathew, RT and Munir, M and Sattar, MN and Shawky, M and Kochkar, H and Aldakhilallah, ON and Ghafoor, A and Turk, KGB and Geronikaki, A and Ghazzawy, HS},
title = {Avian Candidiasis: A Comprehensive Review of Pathogenesis, Diagnosis, and Control.},
journal = {Veterinary sciences},
volume = {13},
number = {2},
pages = {},
pmid = {41745965},
issn = {2306-7381},
support = {Grant number: KFU260519//Deanship of Scientific Research, Vice Presidency for Graduate Studies and Scientific Research, King Faisal University, Saudi Arabia/ ; },
abstract = {This review is a comprehensive investigation of avian candidiasis, mainly caused by Candida albicans, although the prevalence of non-albicans Candida species has increased in domestic and wild birds. Avian candidiasis causes significant economic losses in poultry production through increased mortality, cost of treatments, and reduced growth rates, particularly in young birds and intensive farming operations. The pathogenesis section provides a description of the molecular virulence factors such as adhesin-mediated attachment (ALS, Agglutinin-Like Sequence family; HWP1, Hyphal Wall Protein 1), yeast-to-hypha morphogenesis, tissue damage by Candidalysin, biofilm formation on mucosal and abiotic surfaces, and secreted hydrolytic enzymes including secreted aspartyl proteinases (SAPs) and phospholipases. The identified predisposing factors include immunosuppression, malnutrition, abuse of antibiotics, bad husbandry, and crop stasis. The diagnostic methods discussed encompass cytological analysis and fungal culture on selective media to more sophisticated methods of molecular analysis (PCR, MALDI-TOF MS, and NGS). Antifungal susceptibility investigations indicate that nystatin and amphotericin B are still very effective against most avian isolates and that resistance to the azoles is on the rise, especially with respect to the non-albicans Candida species. Nystatin is still the first-line treatment of localized infections; azoles are still used for resistant or systemic infections despite their hepatotoxicity. Sanitation, proper nutrition, and proper use of antimicrobials are essential to prevent diseases. The knowledge gaps comprise the absence of avian-specific pharmacokinetic information, poor knowledge of species-species virulence phenotypes, and the lack of point-of-care diagnostics. The need to have integrated One Health surveillance systems is emphasized by the zoonotic potential of the avian Candida reservoirs.},
}

@article {pmid41744765,
year = {2026},
author = {Dellazizzo Toth, T and Bond, S and Saxena, S},
title = {The Calcium Connection: Explaining Motor Neuron Vulnerability in ALS.},
journal = {Cells},
volume = {15},
number = {4},
pages = {},
pmid = {41744765},
issn = {2073-4409},
abstract = {ALS is a severe neuromuscular disease classically characterized by the progressive loss of motor neurons, leading to incremental muscle weakness and eventually death. Current treatment options for ALS have proven to have limited effect, merely delaying the progression of symptoms and prolonging patient survival. This motor neuron subtype-related differential vulnerability has been linked to neuron excitability, metabolism, and protein aggregation. Calcium dysregulation, which serves as an important second messenger in neural signaling pathways, has been implicated in each of these mechanisms and represents a potential target for therapeutic intervention. Armed with cutting-edge tools for visualizing and recording calcium transients in vivo, ALS researchers have delved deeper into the role of calcium dysregulation in disease in recent years. Vulnerable motor neuron populations display an excess of calcium-permeable ion channels together with reduced expression of calcium-binding proteins, generating a cellular environment primed for excitotoxic stress. Loss of inhibitory synaptic input further heightens susceptibility to calcium overload. Paradoxically, some evidence suggests that elevated neuronal activity can exert neuroprotective effects, highlighting the complexity of activity-dependent calcium signaling in ALS. Additionally, ALS-related toxic protein accumulation disrupts calcium homeostasis, contributing to endoplasmic reticulum stress and mitochondrial dysfunction. Emerging data indicate that calcium dysregulation impairs neuron-glia communication, amplifying neuroinflammation and accelerating disease progression. This review aims to synthesize current evidence on how calcium imbalance contributes to motor neuron vulnerability and degeneration in ALS. By exploring the cellular, synaptic, and network-level mechanisms of calcium dysregulation in ALS, the review examines its interplay with mitochondrial and ER stress and explores its impact on neuron-glia interactions with the aim of synthesizing key mechanistic insights into the disease pathogenesis and therapeutic targets.},
}

@article {pmid41744314,
year = {2026},
author = {Gharib, M and Said, M and Lévy, R},
title = {Correspondence on "Carbon-Dot-Based Dual-Emission Nanohybrid Produces a Ratiometric Fluorescent Sensor for in Vivo Imaging of Cellular Copper Ions".},
journal = {Angewandte Chemie (International ed. in English)},
volume = {},
number = {},
pages = {e4904466},
doi = {10.1002/anie.4904466},
pmid = {41744314},
issn = {1521-3773},
support = {//European Research Council (ERC)/ ; 951393//European Union's Horizon 2020 research and innovation programme/ ; ANR-24-INBS-0005 FBI BIOGEN//French National Research Agency/ ; },
abstract = {The 2012 study by Zhu et al. (DOI: 10.1002/anie.201109089) reporting a hybrid nanosystem composed of carbon and CdSe/ZnS quantum dots functionalized with tris(pyridin-2-ylmethyl)ethane-1,2-diamine (CdSe@C-TPEA) as ratiometric fluorescent sensors for intracellular copper imaging remains highly influential, with 499 citations to date (Web of Science, December 4, 2025). As part of the NanoBubbles replication project, we attempted to reproduce key experimental findings following detailed pre-registered protocols. Despite strict adherence to the reported synthesis procedures, we failed to replicate the central claim of Cu[2+]-induced fluorescence quenching. Furthermore, our analysis reveals significant data anomalies in the original publication, including spectral overlaps with identical noise patterns inconsistent with independent measurements. These findings raise critical concerns regarding data integrity and reproducibility and cast significant doubt on the reliability of Zhu et al.'s reported results.},
}

@article {pmid41744269,
year = {2026},
author = {Nakamura, R and Steyn, FJ and Kobashi, S and Ogawa, N and Kitamura, A and Yamakawa, I and Henderson, RD and Ngo, ST and Urushitani, M},
title = {Blood Lactate as a Prognostic Biomarker for Survival and Weight Loss in Amyotrophic Lateral Sclerosis: An Exploratory-Validation Study.},
journal = {Annals of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1002/ana.78184},
pmid = {41744269},
issn = {1531-8249},
abstract = {OBJECTIVE: Lactate is increasingly recognized as an energy substrate, but its relevance to amyotrophic lateral sclerosis (ALS) remains unclear. We examined whether blood lactate is associated with survival and weight loss in ALS.

METHODS: This retrospective study included an Australian exploratory cohort and a Japanese validation cohort with clinical data matched to measures of blood lactate. The primary outcome was survival from onset to death or tracheostomy. In the exploratory cohort, survival was analyzed using Kaplan-Meier curves stratified by the first quartile (Q1) of lactate and multivariable Cox regression. This cutoff was applied for log-rank analysis in the validation cohort. The secondary outcome was 3-month body mass index (BMI) change (ΔBMI). Associations between baseline lactate and ΔBMI were assessed using multivariable regression in the exploratory cohort, whereas Q1-based stratification was used in the validation cohort.

RESULTS: The exploratory cohort included 110 patients with ALS (57 with ΔBMI data) and 86 healthy controls; the validation cohort included 36 patients (17 with ΔBMI data). In the exploratory cohort, lower lactate levels (below Q1; 1.05 mmol/L) were associated with shorter survival (p = 0.031) and remained independently predictive of higher risk for mortality (adjusted hazard ratio [HR] per 1 SD = 0.57, 95% confidence interval [CI] = 0.35-0.91). This association was confirmed in the validation cohort (p = 0.003). Lactate was independently associated with ΔBMI (β = 0.53, p = 0.032), and patients with lower lactate had a greater BMI decline (p = 0.010).

INTERPRETATION: Lower blood lactate is associated with increased risk for earlier death and greater weight loss in ALS, suggesting that lactate is a prognostic biomarker of nutritional status. ANN NEUROL 2026.},
}

@article {pmid41744255,
year = {2026},
author = {Labeit, B and Bach, J and Harborth, E and Dziewas, R and Meuth, SG and Grefkes, C and Willems, L and Lapa, S},
title = {Impact of a Neurogenic Dysphagia Outpatient Clinic on Diagnosis, Treatment, and Nutrition.},
journal = {European journal of neurology},
volume = {33},
number = {3},
pages = {e70544},
pmid = {41744255},
issn = {1468-1331},
support = {529859742//Deutsche Forschungsgemeinschaft/ ; },
abstract = {BACKGROUND: The aim was to evaluate the diagnostic, therapeutic, nutritional, and complication-related impact of a university-led neurogenic dysphagia outpatient clinic.

METHODS: We retrospectively analyzed all patients seen at the University Hospital Frankfurt Neurogenic Dysphagia Outpatient Clinic (January 2021-July 2023). Data included demographics, neurological diagnoses, Functional Oral Intake Scale (FOIS), Penetration-Aspiration Scale (PAS) from Flexible Endoscopic Evaluation of Swallowing (FEES), nutritional status, therapy adjustments, and pneumonia requiring hospitalization. We quantified diagnostic revisions, therapeutic/nutritional interventions, and modeled pneumonia risk using logistic regression.

RESULTS: Among 255 patients (mean age 65.9 years; 60.0% men), Parkinsonian syndromes (18.0%) and stroke (12.9%) were most frequent. Complications included weight loss (32.8%), choking (20.0%), and pneumonia (12.6%). Primary diagnosis changed in 38.8% of patients. Of 110 patients with initially unexplained dysphagia, 70.9% received a neurological diagnosis, most often ALS and Parkinsonian syndromes (each 19.5%). Therapy recommendations changed in 42.0% of patients, including symptomatic and disease-modifying treatments; nutritional management was dynamic (new PEG in 16.1%; removal in 50.0% of existing PEGs); 42.9% of tracheostomized patients were decannulated. Frailty (OR 1.49, p = 0.005) and PAS 8 (OR 3.67, p = 0.007) independently predicted pneumonia.

CONCLUSION: A dedicated outpatient dysphagia clinic enhances diagnostic precision, optimizes therapy, and supports individualized nutritional and airway management. FEES-based phenotyping strengthens differential diagnostics and enables the identification of previously unrecognized neurological syndromes. Silent aspiration and frailty identify patients at the highest pneumonia risk. Dysphagia should be regarded as an independent therapeutic target within disease-specific neurological treatment, and dysphagia outpatient clinics should be integrated into standard neurological care pathways.},
}

@article {pmid41744126,
year = {2026},
author = {Yang, Q and Wu, H and Huang, X and Xie, M and Shan, Y and Dou, Z and Li, Y and Wen, H and Li, C},
title = {Prevalence and Risk Factors of Dysphagia in Amyotrophic Lateral Sclerosis: A Retrospective Study Using the Nationwide Inpatient Sample Database.},
journal = {Muscle & nerve},
volume = {},
number = {},
pages = {},
doi = {10.1002/mus.70188},
pmid = {41744126},
issn = {1097-4598},
support = {2024FYQ001//Affiliated Hospital of Shandong Second Medical University/ ; 2023B110003//Guangdong Provincial Clinical Research Center for Rehabilitation Medicine/ ; },
abstract = {INTRODUCTION/AIMS: Dysphagia is a common but under-characterized complication in Amyotrophic lateral sclerosis (ALS), contributing to morbidity and healthcare burden. This study aimed to investigate the prevalence, pinpoint risk factors, and assess the adverse clinical outcomes linked to dysphagia in hospitalized patients with ALS.

METHODS: This retrospective cohort study analyzed 23,997 ALS cases derived from the Nationwide Inpatient Sample (NIS) database, covering the years 2010 to 2019. Data collection included patient demographics (age, sex, race/ethnicity), hospital characteristics (size, teaching status, location), clinical parameters (comorbidity profiles, complications), and healthcare utilization metrics (length of stay and hospitalization costs).

RESULTS: Among 23,997 ALS patients, 7419 (31.7%) were diagnosed with dysphagia. The annual prevalence of dysphagia in ALS patients varied substantially over the decade. Patients with dysphagia experienced a longer hospital stay (5 vs. 4 days; p < 0.001), incurred $6656 in additional hospitalization costs (p < 0.001), and faced heightened risks of complications such as cognitive impairment, cerebrovascular accidents, respiratory muscle paralysis, and tracheostomy. Multivariate analysis identified several independent risk factors for the development of dysphagia, including age ≥ 65 years, female sex, Hispanic ethnicity, treatment at large or medium-sized hospitals, care at urban teaching hospitals, and comorbidities such as depression, malnutrition, and weight loss.

DISCUSSION: Dysphagia affected approximately one-third of hospitalized ALS patients in this study, contributing to extended hospital stays and increased healthcare costs. Timely screening and tailored interventions are crucial for minimizing complications and maximizing the efficient use of resources.},
}

@article {pmid41744019,
year = {2026},
author = {Shi, Y and Xiao, S and He, D},
title = {Visualization analysis of the use of traditional Chinese medicine in the diagnosis and treatment of rare diseases in mainland China based on CiteSpace.},
journal = {Intractable & rare diseases research},
volume = {15},
number = {1},
pages = {71-84},
pmid = {41744019},
issn = {2186-3644},
abstract = {This study used CiteSpace (version 6.4.R1) to perform a visualization analysis of 3,058 articles on traditional Chinese medicine (TCM) diagnosis and treatment of rare diseases retrieved from the China National Knowledge Infrastructure (CNKI) database, the VIP Chinese Science and Technology Periodical Database (VIP), the Wanfang database (Wanfang), and the Chaoxing database (Chaoxing). The goal was to ascertain the current status of research, hotspots in research, and trends in the development of TCM for rare disease diagnosis and treatment in mainland China, providing insights for future TCM research in this field. Visual maps of annual publication volume, authors, institutions, keywords, and other content have revealed that TCM demonstrates prominent advantages in 5 out of 207 defined rare diseases: idiopathic pulmonary fibrosis, hepatolenticular degeneration (Wilson's disease), osteosarcoma, retinitis pigmentosa, and multiple sclerosis. Potential advantages are identified in treating melanoma, amyotrophic lateral sclerosis, homocysteinemia, primary biliary cholangitis, and lymphangioleiomyomatosis. TCM research on rare diseases focuses on etiology, pathogenesis, and syndrome differentiation-based treatment. Case-control studies and mechanism investigations have been initiated for some conditions, while clinical research is gradually incorporating integrated TCM-Western medicine approaches. However, enhanced team and institutional collaboration, development of multicenter networks, exploration of multidisciplinary research, and clinical studies yielding high-level evidence are still needed to provide quality evidence-based support for clinical decision-making in the TCM treatment of rare diseases.},
}

@article {pmid41743918,
year = {2026},
author = {Wang, X},
title = {Enhancing scientific discourse on penile girth augmentation: A critical appraisal of Chen et al.'s review.},
journal = {Current urology},
volume = {20},
number = {1},
pages = {58-59},
pmid = {41743918},
issn = {1661-7649},
}

@article {pmid41743427,
year = {2026},
author = {Luo, Y and Liu, X and Yang, M},
title = {Current status and future prospects of brain-computer interfaces in the field of neurological disease rehabilitation.},
journal = {Frontiers in rehabilitation sciences},
volume = {7},
number = {},
pages = {1666530},
pmid = {41743427},
issn = {2673-6861},
abstract = {Neurological disorders represent a significant category of diseases that profoundly affect human health, accounting for the second leading cause of global mortality. This group of conditions includes stroke, multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), spinal cord injury, Parkinson's disease, and cerebral palsy, among others. These disorders are highly susceptible to sequelae and profoundly impact individuals' daily lives. In this context, Brain-Computer Interface (BCI) technology has demonstrated considerable potential in the domain of neurorehabilitation, although numerous challenges remain. The manuscript provides a comprehensive review of recent advancements in research and clinical applications, highlighting current limitations and outlining future directions. It elucidates the applicability and constraints of Brain-Computer Interface (BCI) technology across various diseases and patient populations. To facilitate insights across different conditions, comparative tables are presented, aligning BCI strategies with therapeutic targets, outcomes, advantages, limitations, and existing evidence gaps. The scope extends beyond motor restoration to include under-explored domains, such as neuropathic pain, with a focus on real-world translation, including home and community feasibility and the distinction between assistive and rehabilitative applications. The review distills overarching limitations within the field, such as small sample sizes, protocol heterogeneity, and limited longitudinal evidence, while synthesizing the most recent studies. An actionable research and development roadmap is proposed to guide next-generation BCI rehabilitation, incorporating individualized cortical-network simulators, self-architecting decoders, adaptive therapy approaches akin to game seasons, and proprioceptive "write-back" mechanisms via peripheral interfaces. Moreover, the review reveals significant research focal points and critical issues that warrant further investigation in the context of neurological rehabilitation utilizing BCI technology.},
}

@article {pmid41742554,
year = {2026},
author = {Olby, NJ and Panek, W and Galifi, C and Faheem, K and Prasad, K and Goraczniak, R and Perrone, M and Tokarz, D and Sommer, S and Gunderson, SI},
title = {Development and pilot testing of U1 Adaptor therapy targeting SOD1 expression for dogs with degenerative myelopathy.},
journal = {Journal of veterinary internal medicine},
volume = {40},
number = {1},
pages = {},
doi = {10.1093/jvimsj/aalaf072},
pmid = {41742554},
issn = {1939-1676},
support = {//Finding the Cure for DM Foundation/ ; D19 CA033//Morris Animal Foundation/ ; },
abstract = {BACKGROUND: Degenerative myelopathy (DM) is a progressive neurodegenerative disease in dogs associated with a superoxide dismutase 1 (SOD1) gene mutation, resulting in SOD1 protein aggregation within neurons and astrocytes. Targeting SOD1 expression represents a viable therapeutic strategy.

HYPOTHESIS/OBJECTIVES: Assess the safety and potential efficacy of SOD1 silencing by intrathecal administration of a U1 Adaptor oligonucleotide targeting canine SOD1 (U1cSOD1) in healthy and DM-diseased dogs.

ANIMALS: Seven purpose-bred healthy adult dogs, 1 dog with stage III DM and 4 dogs with Stage I DM.

METHODS: Healthy dogs and the stage III DM dog received a single intrathecal dose of U1cSOD1 or a vehicle and were euthanized 5 or 30 days later. Four stage I DM-affected dogs received monthly intrathecal injections of U1cSOD1 for up to 10 months. Physical and neurologic examinations, blood tests, cerebrospinal fluid analysis, as well as pharmacokinetic, pharmacodynamic, and histopathologic analyses were performed in all dogs.

RESULTS: In dogs receiving U1cSOD1, spinal cord SOD1 RNA expression near the injection site was decreased to a median of 37% of normal (range, 21%-79%). Dogs tolerated the procedure and test agent well, exhibiting no adverse effects clinically or histopathologically. Two of 34 injections were aborted because of high intrathecal pressure.

Monthly intrathecal injections of U1cSOD1 in DM-affected dogs are safe and decrease spinal cord SOD1 expression by >50% but an alternative administration route would be preferred. This first test of U1 Adaptor technology in dogs with a naturally occurring disease shows potential for therapeutic intervention in a fatal disease without a current cure.},
}

@article {pmid41742309,
year = {2026},
author = {Xu, G and Dillon, K and Lopez, A and Brkic, S and Fromholt, S and Ostrow, LW and Glass, JD and Chakrabarty, P and Ayers, JI and Borchelt, DR},
title = {Fast and slow strains of misfolded mutant superoxide dismutase 1 in familial amyotrophic lateral sclerosis.},
journal = {Acta neuropathologica communications},
volume = {},
number = {},
pages = {},
doi = {10.1186/s40478-026-02262-6},
pmid = {41742309},
issn = {2051-5960},
support = {R01NS0927881/NH/NIH HHS/United States ; R01NS0927881/NH/NIH HHS/United States ; },
}

@article {pmid41742090,
year = {2026},
author = {Baierl, S and Öcek, Z and Jung-Sievers, C and Coenen, M},
title = {Towards the development of actionable recommendations for improving mental healthcare access for migrants: a qualitative study in Munich, Germany.},
journal = {BMC public health},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12889-026-26673-1},
pmid = {41742090},
issn = {1471-2458},
abstract = {BACKGROUND: The experience of migration is often associated with stressors affecting mental health. Furthermore, migrants face barriers to accessing mental healthcare. This study aims to explore the determinants influencing mental healthcare access for migrants in Munich, Germany, and to serve as a starting point for developing recommendations for action.

METHODS: The qualitative study examined the perspectives of migrants and health professionals. Former were derived from a secondary analysis of interview data collected in the SonarGlobal project in 2021. Semi-structured interviews with health professionals were conducted in 2023. Data from both groups were analysed iteratively using a shared coding structure for content analysis. Levesque et al.'s framework guided the analysis of healthcare access and was adapted by schematizing the results. The adapted framework served as the basis for developing action-oriented recommendations based on migrants' suggestions, refined and completed by health professionals' data. Recommendations for improving migrants' access to mental healthcare were organised thematically and then assigned to the levels of integrated care according to Valentijn et al.: micro, meso and macro.

RESULTS: The study included 24 migrants of SonarGlobal and seven health professionals. The dimensions of mental healthcare access encompassed: (1) perceiving mental health problems; (2) ability to seek mental healthcare, including knowledge about the new healthcare system and social support; (3) acceptability of mental health services, involving provider identity and gender; (4) availability and affordability of mental health services, including insurance coverage, bureaucratic processes, and capacity and geographical distribution of services; (5) appropriateness of mental health services with providers' and patients' understanding of mental healthcare, and providers' competence and capacity. Language exhibited a strong interplay across all dimensions. The analysis yielded 17 recommendations. Macro-level recommendations address discrimination and inequality. Meso-level recommendations included enhancing care capacity and coordination, training healthcare workers, and eliminating language barriers. Micro-level recommendations included activities to promote mental health.

CONCLUSIONS: The determinants of migrants' mental healthcare access are shaped by intersecting vulnerability mechanisms and systemic barriers. Improving access requires actions on micro, meso and macro level of care. This study's recommendations offer a starting point for developing comprehensive, evidence-based strategies to ensure equitable mental healthcare access for all.},
}

@article {pmid41741438,
year = {2026},
author = {Liu, T and Lin, Y and Liu, Q and Liao, W and Lin, Y and Zhang, Y and Zhang, J and Cao, W and Yang, L and Hong, Z and Lu, Z},
title = {Target-stabilized base editors enable robust high-fidelity RNA editing.},
journal = {Nature communications},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41467-026-69835-w},
pmid = {41741438},
issn = {2041-1723},
support = {82327805//National Natural Science Foundation of China (National Science Foundation of China)/ ; KQTD20210811090117032//Shenzhen Science and Technology Innovation Commission/ ; },
abstract = {RNA base editing using engineered deaminases represents a powerful tool to correct mutations at the RNA level. However, widespread off-target effects, primarily arising from dissociated free deaminases, remain a significant challenge. Here, we devise the RECODE (RNA editing with conditionally stable and enhanced ADAR1 deaminase variants) system, which employs designer degron-tagged ADAR1 deaminase (ADAR1d) with guide RNA (gRNA)-regulated stability. By promoting degradation of gRNA-unbound ADAR1d, RECODE markedly reduces transcriptome-wide edits while maintaining high on-target efficacy. Engineering gRNA for target RNA-induced conformational switching confines ADAR1d stabilization to intended editing sites, further enhancing editing precision. With structure-guided rational engineering of ADAR1d, RECODE efficiently corrects an Amyotrophic Lateral Sclerosis-relevant FUS mutation and installs a therapeutic mutation to Angptl3 in vivo, which mitigate FUS mislocalization to neuronal axons and lower plasma lipids, respectively. These findings establish RECODE as a highly stringent and efficient RNA editing technology and underscore a general principle for enhancing the specificity of RNA-guided protein effectors.},
}

@article {pmid41741312,
year = {2026},
author = {Herrero Babiloni, A and Dal Fabbro, C and Samin, F and Schmittbuhl, M and Blanchet, PJ and Lavigne, GJ and Rouleau, G},
title = {The role of dentists in the recognition of neurodegenerative and systemic conditions with neurological involvement.},
journal = {Oral surgery, oral medicine, oral pathology and oral radiology},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.oooo.2026.01.010},
pmid = {41741312},
issn = {2212-4411},
abstract = {Dentists are often the first healthcare providers to observe subtle orofacial and behavioral changes that may reflect underlying neurological diseases, including altered salivary flow, dysphagia, oral burning sensations, unusual orofacial movements, or tremors and pain, among others. These are symptoms of conditions such as Parkinson's disease, Alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis, and other systemic disorders with neurological involvement, which are frequently misattributed to local or functional causes, thereby delaying diagnosis and care. As the frequency of neurodegenerative and neuromuscular conditions rises with aging, the dental setting offers a critical opportunity for early recognition and referral. This clinical review summarizes orofacial manifestations, dental care challenges, and referral strategies across different neurological and systemic diseases. Organized by disease stage and functional impairment, the review provides practical tools for decision-making. Guidance on screening, behavioral adaptation, and care coordination is also provided, including multiple practical tables, figures, and chairside screening tools to support early recognition and referral. Finally, the review advocates for improved training, interdisciplinary collaboration, and progressive integration of artificial intelligence, machine learning, and other emerging technologies (e.g., biosensors, salivary biomarker platforms, or high-density electrophysiologic tools) to support clinicians in recognizing neurological diseases.},
}

@article {pmid41740899,
year = {2026},
author = {Al Tawil, A and Lauseker, M and Mansmann, U},
title = {Estimating Causal Effects on Quality of Life Under Treatment Discontinuation: The ALTA-1L Trial.},
journal = {Journal of clinical epidemiology},
volume = {},
number = {},
pages = {112189},
doi = {10.1016/j.jclinepi.2026.112189},
pmid = {41740899},
issn = {1878-5921},
abstract = {BACKGROUND: Time to worsening in health-related quality of life (HRQoL) is increasingly used in oncology trials. Treatment discontinuation poses a challenge: once discontinued, patients cease HRQoL assessments, precluding outcome observation. Standard survival analyses censor at discontinuation, assuming non-informative censoring-an assumption often violated when discontinuation relates to disease progression or toxicity. Bridging the ICH E9(R1) estimand framework with causal inference methods clarifies how to define and estimate treatment effects in such settings. We reanalyse time to worsening in global health status (GHS) from the ALTA-1L trial (brigatinib versus crizotinib in ALK+ non-small-cell lung cancer), integrating both frameworks.

METHODS: Following Young et al.'s (2020) causal framework for competing events, we defined two estimands structured according to ICH E9(R1): (1) a controlled direct effect under a hypothetical strategy, envisioning a scenario where treatment discontinuation would not occur, estimated using inverse probability of censoring weighted Kaplan-Meier to adjust for informative censoring; and (2) a total effect under a while-on-treatment strategy, with discontinuation as a competing event, estimated using the Aalen-Johansen estimator. Risk ratios (RRs) were estimated at 36 months with bootstrap confidence intervals.

RESULTS: The original ALTA-1L analysis reported HR = 0.69 (95% CI: 0.49, 0.98), censoring at discontinuation and assuming non-informative censoring. Deriving the RR at 36 months from Kaplan-Meier curves yields 0.75 (95% CI: 0.59, 0.97). After adjusting for informative censoring, the controlled direct effect was RR = 0.89 (95% CI: 0.65, 1.26). The total effect was RR = 1.03 (95% CI: 0.76, 1.40), reflecting the competing risk structure: earlier discontinuation in the crizotinib arm (discontinuation RR = 0.54; 95% CI: 0.38, 0.72) reduced observed worsening events. These different estimates illustrate how different estimands address distinct clinical questions.

CONCLUSION: This study bridges the ICH E9(R1) estimand framework with causal inference methods for time-to-event HRQoL analysis when discontinuation precludes observation. By quantifying bias from standard approaches, we provide methodological clarity for applied researchers. To facilitate practical implementation, we translate these insights into a decision flowchart for estimand specification and method selection when intercurrent events (ICEs) act as competing events. Future trials should pre-specify ICE-handling strategies and consider data collection beyond ICEs to support treatment policy estimation.},
}

@article {pmid41740345,
year = {2026},
author = {Bai, J and Pang, X and Wang, H and Zhang, Y and Zhu, Y and Zhao, J and Li, Y and Li, M and Huang, X},
title = {Profiling mitochondrial DNA indices across whole blood, plasma, and CSF in amyotrophic lateral sclerosis.},
journal = {Journal of the neurological sciences},
volume = {483},
number = {},
pages = {125797},
doi = {10.1016/j.jns.2026.125797},
pmid = {41740345},
issn = {1878-5883},
abstract = {BACKGROUND: Recent studies increasingly implicate mitochondrial DNA (mtDNA) alterations in neurodegenerative diseases, but findings across studies remain inconsistent. We aimed to characterize mtDNA indices across whole blood, plasma and CSF compartments and evaluate their clinical relevance.

METHODS: We enrolled two study cohorts: (1) a whole blood cohort of 102 ALS patients; and (2) a plasma and cerebrospinal fluid (CSF) cohort including 132 ALS patients and 62 non-neurodegenerative controls. The D-loop and COX3 regions were selected as representative mtDNA fragments, while B2M was used as a nuclear reference. Quantification was performed using SYBR Green-based quantitative PCR.

RESULTS: In whole blood, higher D-loop/COX3 ratios were associated with better functional status and longer survival. In the cell-free compartments, CSF ccf-mtDNA markers (D-loop and COX3) were significantly higher in ALS than in controls, whereas plasma abundance showed no significant group difference. Within ALS, higher ccf-mtDNA indices tended to correlate with greater disease severity and more rapid functional decline. In addition, higher plasma and CSF D-loop/COX3 ratios showed marginal trends toward association with faster disease progression.

CONCLUSIONS: This study systematically characterizes mtDNA alterations in whole blood, plasma and CSF samples of ALS, offering new insights into mtDNA involvement in neurodegeneration.},
}

@article {pmid41739556,
year = {2026},
author = {Li, J and Iguchi, Y and Yoshida, K and Kato, D and Araki, K and Kobayashi, K and Yokoi, S and Yoshimoto, R and Iida, M and Amakusa, Y and Kawakami, Y and Yoshimura, T and Chikuchi, R and Tsujikawa, K and Riku, Y and Iwasaki, Y and Okada, Y and Ohno, N and Wake, H and Katsuno, M},
title = {Neuronal TDP-43 regulates myelin formation via neurexin 1 mRNA stabilization.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {123},
number = {9},
pages = {e2513642123},
doi = {10.1073/pnas.2513642123},
pmid = {41739556},
issn = {1091-6490},
support = {JP 24K02365//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; JP 24K22096//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; JP 23H00420//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; JP 20K16596//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; JP 22K15707//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; JP21wm0425013//Japan Agency for Medical Research and Development (AMED)/ ; JP24wm0625301//Japan Agency for Medical Research and Development (AMED)/ ; None//Hirose Foundation (å…¬çŠè²¡å£æ³•äººãƒ'ãƒã'»è²¡å£)/ ; None//Takeda Science Foundation (TSF)/ ; },
mesh = {Animals ; *DNA-Binding Proteins/metabolism/genetics ; Mice ; *Myelin Sheath/metabolism ; Mice, Knockout ; *Neurons/metabolism ; *RNA Stability ; RNA, Messenger/metabolism/genetics ; *Calcium-Binding Proteins/genetics/metabolism ; Humans ; *Cell Adhesion Molecules, Neuronal/genetics/metabolism ; Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology ; *Neural Cell Adhesion Molecules/genetics/metabolism ; Oligodendroglia/metabolism ; Frontotemporal Lobar Degeneration/genetics/metabolism/pathology ; },
abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) develop as spatial pathologies in which neurons and glial cells are interconnected. TAR DNA-binding protein 43 (TDP-43) is a major pathological protein that is inextricably associated with ALS and FTLD. In this study, we investigated the roles of neuronal TDP-43 in neuron-oligodendrocyte interactions using neuron-specific TDP-43 knockout (TDP-43cKO) mice. TDP-43 depletion in neurons induced hypomyelination, which was confirmed by immunohistochemistry and ultrastructural analysis. In addition, conduction disturbance was revealed by electrophysiological analysis. The hypomyelination of TDP-43cKO mouse was restored by cytoplasmic TDP-43 supplementation in neurons. Neuron-specific transcriptome analysis revealed that neurexin 1 (NRXN1) is the regulatory target of TDP-43, which promotes myelin formation. The hypomyelination of TDP-43cKO mice was also restored by NRXN1b supplementation in neurons. We further confirmed that TDP-43 stabilizes Nrxn1 mRNA by binding to the Nrxn1 3'untranslated region (3'UTR). Although TDP-43cKO exhibited impaired recognition memory, the supplementation of NRXN1 in the hippocampus recovered the memory disturbances. In conclusion, this study demonstrates the neuron-oligodendrocyte interaction mediated by neuronal TDP-43 via NRXN1 mRNA stabilization. These findings shed light on neuron-oligodendrocyte interaction in the disease mechanisms of ALS/FTLD.},
}

Animals
*DNA-Binding Proteins/metabolism/genetics
Mice
*Myelin Sheath/metabolism
Mice, Knockout
*Neurons/metabolism
*RNA Stability
RNA, Messenger/metabolism/genetics
*Calcium-Binding Proteins/genetics/metabolism
Humans
*Cell Adhesion Molecules, Neuronal/genetics/metabolism
Amyotrophic Lateral Sclerosis/metabolism/genetics/pathology
*Neural Cell Adhesion Molecules/genetics/metabolism
Oligodendroglia/metabolism
Frontotemporal Lobar Degeneration/genetics/metabolism/pathology

@article {pmid41739328,
year = {2026},
author = {Koulaouzidis, A and Marlicz, W and Toth, E},
title = {Methodological and Interpretative Considerations in Onishi et al.'s Study of Rebleeding Risk in Suspected Small Bowel Bleeding.},
journal = {Digestive diseases and sciences},
volume = {},
number = {},
pages = {},
pmid = {41739328},
issn = {1573-2568},
}

@article {pmid41739094,
year = {2026},
author = {Kashif, M and Keating, ME and Byrne, HJ},
title = {Raman spectroscopic monitoring of multiproduct chemical reaction kinetics; the case of ester hydrolysis.},
journal = {The Analyst},
volume = {},
number = {},
pages = {},
doi = {10.1039/d5an01055a},
pmid = {41739094},
issn = {1364-5528},
abstract = {Raman Spectroscopy (RS) is a powerful technique for the identification of molecules based on the characteristic fingerprint spectra of their vibrational modes. Although challenging, real time spectroscopic monitoring of reactions and processes has great potential value in multiple fields, including process analysis, bio reactors, cell therapies and in vitro metabolomics. Refined chemometrics methodologies are required to datamine the kinetic evolution of multivariate spectral mixtures to establish the constituent reactants and products, as well as the characteristic rates of the reaction. To explore the capabilities and challenges, RS was used to study the chemical kinetics of propyl acetate hydrolysis in an aqueous environment at room temperature, in situ, as a model reaction. The continuous conversion of propyl acetate to 1-propanol and acetic acid was monitored periodically over 250 min using RS with a 532 nm laser source. Simulated admixture solutions, mimicking the reaction from pure reactants to pure products conversion, were also recorded for comparison. Problem based nonlinear least squares (NLS) fitting was applied to both the actual reaction and simulated solution data sets using pure components spectra of both the reactants, propyl acetate, water and products, 1-propanol and acetic acid, in order to visualise and confirm the trends and kinetics of the reaction components. Multivariate Curve Resolution-Alternating Least Squares analysis (MCR-ALS) with kinetic constraints was applied to further resolve the concentration and spectral profiles and to quantify the rates of the reaction. It is demonstrated that MCR-ALS could not accurately resolve the evolving reaction species with respect to concentration, due to rank deficiency. To enhance the analysis, a data augmentation approach was used, seeding the measured datasets with the spectra of the pure components to bias the initial singular value decomposition and spectral unmixing process, resulting in an improved resolution of the systematic variation of concentration dependent data to monitor the kinetic evolution of the reaction mixture. The required seeding weights were optimized by visualizing the sum residual error (SUMR) in least squares fitting of the actual components with the identified pure components by MCR-ALS. Minimum SUMR values for admixtures were found at a seeding weight of 10 000X, while 100X was found to be optimum for the actual reaction. This proof of concept can further pave the way for better analysis and understanding of cascade reactions, and ultimately, potentially of metabolomic pathways.},
}

@article {pmid41738691,
year = {2026},
author = {Gonçalves, F and Machado, T and Viegas, P and Machado, A and Ribeiro, C},
title = {The burden of care: Health and wellbeing of informal caregivers of people with amyotrophic lateral sclerosis.},
journal = {Palliative & supportive care},
volume = {24},
number = {},
pages = {e65},
doi = {10.1017/S1478951526101825},
pmid = {41738691},
issn = {1478-9523},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/psychology/complications ; Female ; Male ; Cross-Sectional Studies ; Middle Aged ; Portugal ; *Caregivers/psychology/statistics & numerical data ; Adult ; Aged ; *Cost of Illness ; Surveys and Questionnaires ; Quality of Life/psychology ; Psychometrics/methods/instrumentation ; Health Status ; Caregiver Burden/psychology ; },
abstract = {OBJECTIVES: Amyotrophic lateral sclerosis (ALS) is a rare, progressive, and fatal disease that impacts the lives of affected individuals and their caregivers. Informal caregivers play a crucial role in supporting people with ALS (pwALS), yet they face major challenges. This study aims to analyze caregiver burden and health status among informal caregivers of pwALS in Portugal.

METHODS: A cross-sectional survey-based study was conducted with adult informal caregivers of pwALS in Portugal, recruited through the Portuguese ALS patient association and healthcare professionals. Data included sociodemographics, caregiving activities, caregiver health (SF-36), patient functional status (ALSFRS-R), and caregiver burden (ZBI).

RESULTS: The study included 113 caregivers. Most were female (61.9%) and the partner (65.5%) or offspring (23.9%) of the pwALS. A quarter of caregivers received no social benefits. Mean ZBI was 32 ± 14.8, with most reporting mild to moderate burden. On the SF-36, general health was 51.1 ± 19.8, with mental health (55 [40; 70]) and vitality (43.8 [31.3; 56.3]) particularly impaired. ZBI scores correlated positively with caregiving hours (r = 0.274, p = 0.003) and negatively with ALSFRS-R (r = -0.411, p < 0.001). High burden caregivers exhibited poorer sleep quality (p =  0.026).

SIGNIFICANCE OF RESULTS: Caregivers experienced mild to moderate burden, with impaired mental health and vitality, but preserved physical functioning. A higher burden was linked with lower quality of life, poorer sleep, and greater patient disability. These findings underline the need for targeted education and training to support caregivers of pwALS.},
}

Humans
*Amyotrophic Lateral Sclerosis/psychology/complications
Female
Male
Cross-Sectional Studies
Middle Aged
Portugal
*Caregivers/psychology/statistics & numerical data
Adult
Aged
*Cost of Illness
Surveys and Questionnaires
Quality of Life/psychology
Psychometrics/methods/instrumentation
Health Status
Caregiver Burden/psychology

@article {pmid41737544,
year = {2026},
author = {Xia, X and Chen, X and Sun, Y and Zhang, M and Qiao, K and Chen, Y and Zhao, C and Dong, Y and Zhu, W},
title = {Genetic Spectrum and Phenotypic Variability in Chinese Patients with Multisystem Proteinopathy and Related Disorders.},
journal = {Degenerative neurological and neuromuscular disease},
volume = {16},
number = {},
pages = {568971},
pmid = {41737544},
issn = {1179-9900},
abstract = {OBJECTIVE: Multisystem proteinopathy (MSP) is a pleiotropic group of disorders initially presenting as inclusion body myopathy (IBM), amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and/or Paget disease of bone (PDB). Additional genes including MATR3, OPTN, and ANXA11, have recently been implicated in MSP-like disorders, further expanding the genetic spectrum. This research aims to study the genetic and clinical characteristics of MSP and related disorders in a large Chinese cohort.

METHODS: Twenty-nine patients were identified in 953 patients diagnosed with ALS, IBM, or dementia at Huashan Hospital between 2000 and 2024. Variants in MSP-related genes were detected using next-generation sequencing and confirmed by Sanger sequencing. Clinical, pathological, imaging, and electromyography data were collected and analyzed.

RESULTS: A total of 29 patients (3.0%) were identified as carrying MSP-related gene variants. Most patients were male (72.4%), with disease onset predominantly in the third to fifth decades of life. The majority of patients (21/29) presented with a single clinical phenotype. ALS was the most common phenotype (20/29), followed by IBM (10/29), FTD (7/29), and PDB (1/29). The most frequent variants were in ANXA11 (34.5%) and VCP (20.7%), followed by OPTN (17.2%), SQSTM1 (10.3%), MATR3 (10.3%), and HNRNPA1 (6.9%). All patients with VCP variants presented with initial lower limb involvement, whereas those carrying ANXA11 or OPTN variants predominantly showed upper limb or bulbar onset. Patients harboring OPTN variants had a later age at onset compared with those carrying VCP or MATR3 variants. Patients with ALS-onset exhibited faster progression compared with those with myopathy-onset, even when harboring identical variants.

CONCLUSION: This study broadens the clinical and genetic landscape of MSP and related disorders in a Chinese cohort. These results emphasize the clinical utility of next-generation sequencing for improving diagnostic accuracy in patients with unexplained neuromuscular or cognitive presentations, especially in the presence of multisystem involvement.},
}

@article {pmid41737317,
year = {2026},
author = {Luo, R},
title = {Next questions of autophagy in neurodegenerative diseases: From mechanisms to therapeutics.},
journal = {Innovation (Cambridge (Mass.))},
volume = {7},
number = {1},
pages = {100989},
pmid = {41737317},
issn = {2666-6758},
abstract = {Autophagy, a key cellular degradation pathway, is central to the pathogenesis of neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Despite progress in understanding its role, critical questions remain. This perspective highlights pressing issues, including cell-type-specific autophagy regulation, interactions with other cellular pathways, and challenges in translating autophagy-modulating therapies to clinical practice. Addressing these questions will advance our understanding of neurodegenerative diseases and pave the way for novel therapeutics.},
}

@article {pmid41735713,
year = {2026},
author = {Elbadawi, M and Kafoor, NFA and Li, H and Protopapa, C and Vlachou, M and Gaisford, S},
title = {Active learning in pharmaceutical 3D printing: a multi-dataset comparison.},
journal = {Drug delivery and translational research},
volume = {},
number = {},
pages = {},
pmid = {41735713},
issn = {2190-3948},
abstract = {Machine learning (ML) is expected to accelerate the developments of three-dimensional (3D) printed medicines. Despite ML's potential, the need for large datasets can hinder progression, as 3D printing remains an emerging pharmaceutical manufacturing technology. This study explores an ML strategy called active learning (AL), which harnesses the benefits of ML whilst applicable with small datasets. AL was tested to predict the printability of three 3D printing datasets: 1437 fused deposition modelling (FDM), 650 vat polymerisation and 297 selective laser sintering (SLS) formulations. The analysis revealed that accuracies of 60% can be achieved when starting with 33 formulations, and subsequent increases in training data size enhances predictive performance. Furthermore, AL was found to achieve 100% predictive accuracy, which is the highest recorded to date for pharmaceutical 3D printing. These initial findings highlight AL's advantages over traditional ML modelling and showcase its potential to accelerate the development of 3D printing medicines. This research also demonstrates the potential of modelling with small datasets, thereby widening ML's application in pharmaceutical research.},
}

@article {pmid41734662,
year = {2026},
author = {Alam, P and Hasan, GM and Mohammad, T and Hassan, MI},
title = {Next-generation computational strategies for neurodegenerative biomarkers: Multi-omics integration, AI, and molecular modeling.},
journal = {Computational biology and chemistry},
volume = {123},
number = {},
pages = {108973},
doi = {10.1016/j.compbiolchem.2026.108973},
pmid = {41734662},
issn = {1476-928X},
abstract = {Neurodegenerative diseases (NDs) are progressively debilitating conditions driven by complex molecular perturbations and selective neuronal loss. Conventional approaches to discovering biomarkers, using single-omics or empirical screening, often fail to capture the multi-factorial nature of these disorders. It is now possible to integrate large-scale omics data with structural and molecular modeling methods to reveal mechanistically relevant biomarkers using integrative computational biology. Here, we review recent advances in integrative computational strategies that combine multi-omics, encompassing genomics, transcriptomics, proteomics, and metabolomics, with structural bioinformatics and molecular modeling to identify mechanistically informative biomarkers. We cover systems-level and network-based integration methods, machine learning (ML) and artificial intelligence (AI) frameworks, and structure-guided validation approaches, including homology/AI-based modeling, molecular docking, and molecular dynamics. We also discuss case studies illustrating how omics-based predictions are validated through protein structure modeling to identify key biomarkers and therapeutic targets. Finally, we discuss major challenges, such as data heterogeneity, reproducibility, and limitations of structural modeling, and emerging trends, such as AI-powered multi-omics, single-cell spatial profiling, and digital twin simulations. Together, the integrative computational strategies are likely to accelerate the discovery of reliable, mechanistically informative, and clinically translatable biomarkers for precision medicine in NDs.},
}

@article {pmid41733214,
year = {2026},
author = {Montalvo, A and Gromicho, M and Oliveira Santos, M and de Carvalho, M},
title = {Clinical characterization of the proximal lower-limb ALS phenotype: a retrospective cohort study.},
journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration},
volume = {},
number = {},
pages = {1-4},
doi = {10.1080/21678421.2026.2630882},
pmid = {41733214},
issn = {2167-9223},
abstract = {This study characterizes a rare phenotype of Amyotrophic Lateral Sclerosis (ALS) presenting with predominant proximal lower limb weakness at onset, a presentation often mimicking myopathy. We retrospectively reviewed 1980 patients, identifying 15 (0.75%) with this atypical onset. The majority were males (73%) with a median age of onset of 58.7 years. Approximately half presented with symmetric proximal lower limb weakness. Nine of the 11 tested patients had higher CK. Follow-up (median 53.7 months) revealed that 6 patients maintained isolated lower limb weakness for a median of 60.1 months, while others progressed to upper limbs or bulbar regions. NSG sequencing (in nine patients) identified mutations in three patients (SOD1, VAPB, and C9ORF72). This pattern poses a diagnostic challenge. While limitations include a small sample size and retrospective design, the findings highlight a heterogenous but often slow-spreading and benign course for this specific ALS subtype, offering valuable clinical information for differential diagnosis.},
}

@article {pmid41733022,
year = {2026},
author = {Destoop, M},
title = {[Heeft de e-sigaret een plaats als rookstopmiddel binnen de ggz?].},
journal = {Tijdschrift voor psychiatrie},
volume = {68},
number = {2},
pages = {57-59},
pmid = {41733022},
issn = {0303-7339},
}

@article {pmid41732281,
year = {2026},
author = {Maitra, S and Ham, DW and Baek, M and Choe, YJ and Kim, NC},
title = {FDA-approved PDE4 inhibitors alleviate the dominant toxicity of ALS-FTD-associated CHCHD10[S59L] in Drosophila and human cells.},
journal = {iScience},
volume = {29},
number = {3},
pages = {114879},
pmid = {41732281},
issn = {2589-0042},
abstract = {Mutations in CHCHD10 are a genetic cause of ALS-FTD. In our previous studies using Drosophila expressing C2C10H[S81L] and human cells expressing CHCHD10[S59L], we found that the aberrant activation of the PINK1/Parkin pathway drives cellular toxicity, and pseudo-substrate inhibitors of PINK1 or mitofusin-2 agonists can mitigate these effects. Evidence from in vitro, in vivo, and chemical approaches supports PINK1 inhibition as a promising strategy for CHCHD10[S59L]-associated disease. Here, we show that FDA-approved PDE4 inhibitors significantly reduce CHCHD10[S59L]-induced mitochondrial morphological and functional defects in both human cells and Drosophila. These protective effects occur through a cAMP/PKA-dependent mechanism, indicating that elevated cAMP signaling attenuates aberrant PINK1/Parkin activation. Moreover, forskolin combined with PDE4 inhibitors synergistically decreases mitochondrial toxicity at lower concentrations. Together, our findings suggest that clinically available PDE4 inhibitors could be repurposed for CHCHD10[S59L]-linked ALS-FTD, while emphasizing the need to carefully consider the effects of the PINK1/Parkin pathway, as it is generally recognized as a protective pathway.},
}

@article {pmid41731547,
year = {2026},
author = {Jammal, JK and Gomez, EA and Al-Chalabi, A and Iacoangeli, A},
title = {Classification of ALS molecular subtypes: a literature review on machine learning applications and their clinical value.},
journal = {BMC medicine},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12916-026-04725-y},
pmid = {41731547},
issn = {1741-7015},
support = {772376-EScORIAL/ERC_/European Research Council/International ; },
abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterised by considerable heterogeneity in both its underlying biological mechanisms and clinical presentation. High-dimensional transcriptomic datasets offer an opportunity to characterise this variation at the molecular level; however, traditional statistical methods struggle with their scale and complexity.

MAIN BODY: Machine learning approaches can reduce dimensionality and uncover latent patterns, enabling the identification of molecular subtypes that may refine prognosis and support patient stratification. Recent transcriptomic studies employing unsupervised machine learning have identified ALS subtypes with distinct molecular and clinical characteristics. Redefining ALS into more homogeneous molecular and clinical subtypes could transform all areas of ALS research by supporting novel experimental designs and precision medicine approaches.

CONCLUSIONS: In this review, we summarise and critically assess these studies, discussing their findings, strengths, and limitations, and highlighting research gaps and challenges that must be addressed to enable their translation into biomedical and clinical practice.},
}

@article {pmid41730762,
year = {2026},
author = {Min, MTP and Zhenyang, JH and Merchant, RA},
title = {When Dysphagia and Functional Decline Isn't Just Aging: A Case of Bulbar-Onset ALS in an Older Adult.},
journal = {Journal of the American Geriatrics Society},
volume = {},
number = {},
pages = {},
doi = {10.1111/jgs.70362},
pmid = {41730762},
issn = {1532-5415},
}

@article {pmid41730342,
year = {2026},
author = {Thomas, T and Jones, L and Dawson, S and Houghton, C and Hunter, A and O'Connell, N and Biesty, L},
title = {Existing Research Guidelines for Inclusive Trial Methodology. Working toward the integration of Qualitative Research, Equity, diversity, and inclusion (EDI) and Trial Methodology: a focused mapping review.},
journal = {Journal of clinical epidemiology},
volume = {},
number = {},
pages = {112202},
doi = {10.1016/j.jclinepi.2026.112202},
pmid = {41730342},
issn = {1878-5921},
abstract = {BACKGROUND: Equity, diversity, and inclusion (EDI) are increasingly emphasised in clinical research, yet practical guidance for applying inclusion principles across all clinical trial stages remain limited. Qualitative research can help address this gap by exploring participant experiences and identifying barriers to inclusive trial conduct.

OBJECTIVE: The aim of this review is to map guidelines and recommendations in relation to inclusive trial methodology, and to identify areas across these resources that can be potentially informed by qualitative research. This review presents Phases 1 and 2 of the QuAlitative reSearch Supporting IncluSive Trials (Q-ASSIST) Study.

METHODS: In Phase 1, we conducted a Focused Mapping Review and Synthesis (FMRS) of publicly available guidelines related to phase 3 and later clinical trials involving human participants. Eligible guidelines included those offering recommendations to enhance inclusive trial design and conduct. Each guideline was mapped to a priori data extraction framework informed by the SPIRIT and CONSORT 2025 guidelines. We then performed a narrative synthesis to examine the EDI focus of the selected guidelines and structured the findings according to the PRO-EDI Framework. In Phase 2, we juxtaposed the trial stages identified through our FMRS with O'Cathain et al.'s Framework of Qualitative Research in Trials.

RESULTS: We identified 15 guidelines through FMRS. Through conceptual mapping to SPIRIT and CONSORT headings, we developed a 12-stage trial lifecycle framework (the Q-ASSIST Trial Stages Model) to organise inclusion guidance. Most guidelines emphasised early stages of trials, with later stages less frequently addressed. Mapping to the PRO-EDI framework showed strong attention to race/ethnicity, gender, socioeconomic status, and disability, but limited focus on sexual identity, education, or intersectionality. Juxtaposition with O'Cathain et al.'s Framework highlighted similar gaps in how qualitative research has been used, especially in later trial stages.

CONCLUSION: Current inclusion guidance is concentrated in the early stages of trial design, with limited attention to later trial stages. Qualitative research offers a valuable way to address these gaps by capturing participant perspectives and supporting inclusive practices across the trial lifecycle. This review provides a foundation for developing practical tools to guide more inclusive trials, with the next phase involving co-production of guiding principles with interest holders.

PLAIN LANGUAGE SUMMARY: Including people from different backgrounds in clinical trials is important to make sure that the results apply to everyone and not just a few groups. While many organisations have developed guidelines to help researchers make clinical trials more inclusive, most of these focus on the early stages of a trial, like deciding who can take part or how to recruit participants. We wanted to understand what guidance exists for supporting inclusion throughout the entire trial process. This paper is part of the Q-ASSIST Study (QuAlitative reSearch Supporting IncluSive Trials), which explores how qualitative methods can support inclusivity across all stages of a clinical trial. Qualitative research focuses on people's experiences, views, and the context in which research happens. It can also help identify barriers to inclusion and ways to make trials more accessible and relevant. We examined 15 publicly available guidelines designed to improve inclusion in clinical trials. We organised their recommendations according to 12 key stages of a trial, based on well-known reporting frameworks. We found that most guidelines focus on the early stages of a trial, while later stages, such as training, oversight, and what happens after the trial ends, are often overlooked We then compared our findings to an existing framework (O'Cathain et al., 2013) that shows how qualitative research has been used in trials. This comparison helped us identify specific areas where both inclusion guidance and use of qualitative research are limited. This work lays the foundation for the next phase of our study, where we will work with interest holders to develop practical tools and guiding principles that help researchers use qualitative methods to design and run more inclusive trials. By addressing these gaps, we aim to help ensure that clinical trials better represent and serve all communities, ultimately leading to treatments that work effectively for everyone.},
}

@article {pmid41730149,
year = {2026},
author = {Nagel, G and Peter, RS and Uzelac, Z and Wernecke, D and Niehaus, L and Trottenberg, T and Jöbges, M and Dettmers, C and Bäzner, H and Börtlein, A and Althaus, K and Mayer-Freitag, K and Ratzka, P and Naumann, M and Lindner, A and Chatzikonstantinou, A and Andres, F and Arnold, G and Blickhan, M and Opherk, C and Knier, B and Ertl, M and Metrikat, J and Huber, R and Thomas, C and Kozian, R and Kimmig, H and Demuth, K and Hecht, M and Foerch, C and Kloetsch, C and Reinhard, M and Bengel, D and Neuhaus, O and Buttmann, M and Volkmann, J and Pinkhardt, E and Lichy, C and Laske, C and Beattie, J and Häckert, J and Jesse, S and Brenner, D and Weishaupt, J and Otto, M and Uttner, I and Anderl-Straub, S and Lulé, DE and Rothenbacher, D and Rosenbohm, A and Ludolph, AC and , },
title = {Incidence and Survival Rates of Frontotemporal Lobar Degeneration: Population-Based Registry Study.},
journal = {Neurology},
volume = {106},
number = {6},
pages = {e214482},
doi = {10.1212/WNL.0000000000214482},
pmid = {41730149},
issn = {1526-632X},
mesh = {Humans ; Male ; Female ; Registries ; Incidence ; Aged ; *Frontotemporal Lobar Degeneration/epidemiology/mortality/diagnosis ; Middle Aged ; Germany/epidemiology ; Survival Rate ; Aged, 80 and over ; },
abstract = {BACKGROUND AND OBJECTIVES: Frontotemporal lobar degeneration (FTLD) can present as a behavioral or language variant (bvFTLD or a primary progressive aphasia [PPA], or as a syndrome with parkinsonism, such as corticobasal syndrome [CBS] or progressive supranuclear palsy [PSP]). The incidence of FTLD varies in epidemiologic studies, reaching 3 per 100,000 person-years. Only few data exist regarding survival times. We evaluated incidence and survival rates in a population-based registry with high coverage in Southern Germany.

METHODS: The epidemiologic ALS-FTLD registry Swabia covers a population of 8.4 million inhabitants in south-west Germany. Raw and age-standardized incidence rates, as well as incidence rate ratios (IRR) with 95% CIs were calculated. Median survival time was estimated for different FTLD variants using the Kaplan-Meier method.

RESULTS: Between 2015 and 2022, 515 patients with FTLD (mean age at diagnosis 68.0 ± 9.5 years, 59.8% men) were registered. The median diagnostic delay was 24.8 months. The most common variant was bvFTLD (n = 185, 35.9%; 66.5% men), followed by PPA (n = 147, 28.5%; 51.0% men), PSP (n = 133, 25.8%; 62.9% men), and CBS (n = 22, 4.3%; 50% men). The overall FTLD incidence was 0.77 (95% CI 0.71-0.84), and the age-standardized incidence was 0.76 (95% CI 0.69-0.82) per 100.000 person-years. The age-standardized incidence was higher in men than in women, with an IRR of 1.73 (95% CI 1.44-2.00). In men, incidence increased from the age 50 years, primarily due to bvFTD, whereas in women this rise was primarily due to PSP. The median survival (N = 392) from diagnosis was 53.6 months (95% CI 50.9-62.0) overall, 73.1 months (95% CI 63.6-82.8) for patients with PPA, 42.8 months (95% CI 35.1-64.3) for patients with bvFTD, and 49.5 months (95% CI 39.2-53.7) for patients with PPS/CBS.

DISCUSSION: We observed a raw incidence rate of 0.77, thus considerably lower than in most previous reports. Incidence was substantially higher in men than in women. The prognosis from the time of diagnosis depended highly on the specific FTLD subtype. Our data are based on the large sample size and high capture rate of a central European population-based registry.},
}

Humans
Male
Female
Registries
Incidence
Aged
*Frontotemporal Lobar Degeneration/epidemiology/mortality/diagnosis
Middle Aged
Germany/epidemiology
Survival Rate
Aged, 80 and over

@article {pmid41729684,
year = {2026},
author = {Paulo-Ramos, A and Rhymes, ER and Villarroel-Campos, D and Sleigh, JN},
title = {Disruption of BDNF signalling in neuropathologies.},
journal = {Biochemical Society transactions},
volume = {54},
number = {2},
pages = {},
doi = {10.1042/BST20253079},
pmid = {41729684},
issn = {1470-8752},
support = {MR/Y010949/1/MRC_/Medical Research Council/United Kingdom ; 23GRO-PG36-0675-1//Muscular Dystrophy UK/ ; },
mesh = {*Brain-Derived Neurotrophic Factor/metabolism/genetics ; Humans ; *Signal Transduction ; Animals ; Receptor, trkB/metabolism ; Neuronal Plasticity ; Neurons/metabolism ; },
abstract = {The vital role of brain-derived neurotrophic factor (BDNF) in neuronal development, synaptic plasticity, and neuroprotection has been explored for decades. Therefore, the expression, processing, and signalling activities of this neurotrophin, which is reliant upon TrkB and p75NTR receptors, have been well characterised in both health and disease. This review summarises the latest findings on BDNF dysregulation in neuropathologies. Indeed, across diseases of both the central and peripheral nervous systems, BDNF signalling is frequently disrupted, contributing to neuronal dysfunction and degeneration. Consequently, through direct or indirect enhancement of its expression and/or function, BDNF has proved to be a promising therapeutic target across many neurological conditions. However, the complexity of its regulation and interaction with several different receptors underpins the need for further research to deepen our understanding of BDNF disruption in neuropathologies and to achieve its therapeutic potential.},
}

*Brain-Derived Neurotrophic Factor/metabolism/genetics
Humans
*Signal Transduction
Animals
Receptor, trkB/metabolism
Neuronal Plasticity
Neurons/metabolism

@article {pmid41729108,
year = {2026},
author = {Rozman, SI and Hamzaid, NA and Lim, E and Hamzah, N and Guan, JP and Sabirin, S and Hasnan, N and Shahrizaila, N},
title = {Standing up to neurodegeneration: evaluating autonomic stress and safety in sit-to-stand using heart rate variability analysis.},
journal = {Biomedizinische Technik. Biomedical engineering},
volume = {},
number = {},
pages = {},
pmid = {41729108},
issn = {1862-278X},
abstract = {OBJECTIVES: Sit-to-stand (STS) exercises are commonly incorporated in functional rehabilitation due to their simplicity, relevance to daily mobility and more recently, cardiac fitness. While generally considered safe for most clinical populations, its effect on autonomic stability remains underexplored - particularly in those with autonomic vulnerability such as individuals with amyotrophic lateral sclerosis (ALS). This study investigates the suitability of STS exercises for individuals with ALS, with specific focus on establishing baseline heart rate variability (HRV) data during rest and transient STS movement.

METHODS: Heart rate (HR) and HRV (RMSSD and HF) were assessed across three cohorts; healthy young adults (n=29), individuals living with ALS (n=8), and their age-matched controls (n=9), under resting condition and two STS protocols: Timed up and go (TUG) and five times sit-to-stand test (FTSST).

RESULTS: All groups exhibited significant increase in mean HR during STS compared to rest (p<0.05), whereas no statistically significant differences were observed in RMSSD and HF. These results indicate that STS exercises elicit measurable cardiovascular exertion without triggering acute autonomic dysfunction in ALS individuals, supporting its role in safe rehabilitation for early-mid stages ALS.

CONCLUSIONS: HRV serves as a potential tool for non-invasive monitoring and assessment of autonomic function during physical therapy.},
}

@article {pmid41728998,
year = {2026},
author = {Chiang, TS and Boisbouvier, J and Gandy, LA},
title = {Holding but not folding: How a single charge flip uncouples the DNAJC7-Hsp70 relay in amyotrophic lateral sclerosis.},
journal = {The FEBS journal},
volume = {},
number = {},
pages = {},
doi = {10.1111/febs.70472},
pmid = {41728998},
issn = {1742-4658},
support = {ERC-ADG #101097926/ERC_/European Research Council/International ; ANR-15-IDEX-02//Agence Nationale de la Recherche/ ; ANR-22-CE29-0024-01//Agence Nationale de la Recherche/ ; },
abstract = {Genetic mutations impact protein function through various routes: Some catalyze new oncogenic activities, while others trigger complete structural collapse. However, the E425K mutation in DNAJC7, associated with Amyotrophic Lateral Sclerosis (ALS), presents a far more subtle and intriguing case. In their recent study in The FEBS Journal, Elmaleh et al. (2026) FEBS Lett employed high-resolution NMR to demonstrate that this mutation leaves the protein's overall structure intact while selectively paralyzing its ability to communicate with the Hsp70 chaperone machinery. In this commentary, we show how their work complements in vivo studies that investigate ALS disease pathology at pathway complexity and defines a new target to rescue non-functioning Hsp70 chaperone systems.},
}

@article {pmid41673645,
year = {2026},
author = {Sterr, K and Bachner, J and Scheller, DA and Mess, F and Blaschke, S and Mühlberg, T and Butscher, F and Schmid-Ellinger, J},
title = {No healthy schools without healthy teachers: a scoping review on implementation determinants, strategies and outcomes of mental health-promoting interventions for school teachers.},
journal = {BMC public health},
volume = {26},
number = {},
pages = {},
pmid = {41673645},
issn = {1471-2458},
abstract = {BACKGROUND: The mental health and well-being of school teachers is critical not only for their individual health but also for the quality and stability of educational systems. Numerous interventions have been developed to address teachers’ mental health challenges, yet their implementation in everyday school settings remains limited. Understanding implementation determinants, strategies, and outcomes is essential for improving sustainable implementation, intervention effectiveness and broader public health impact. This scoping review explored how implementation is addressed in studies evaluating mental health-promoting interventions for teachers.

METHODS: Following Arksey and O’Malley’s (2005) and Levac et al.’s (2010) frameworks and PRISMA-ScR guidelines, we systematically searched Scopus and EBSCOhost up to April 2025. Studies were included if they evaluated an intervention targeting teachers’ mental health and reported at least one implementation aspect. Data extraction was guided by leading implementation science frameworks.

RESULTS: Of 4,062 identified records, 16 met the inclusion criteria. Most studies were primarily effectiveness-focused and assessed early-stage implementation rather than long-term implementation or sustainment. Implementation outcomes such as acceptability and feasibility were frequently reported but rarely grounded in implementation frameworks. Implementation determinants appeared in most studies, predominantly as post hoc barriers, with few studies assessing them a priori to guide implementation planning. Implementation strategies were commonly described but seldom explicitly labeled as such. Most studies examined implementation and intervention outcomes separately, limiting insights into how implementation processes influenced effectiveness. Nevertheless, several insights emerged, including the relevance of training and educating stakeholders, tailoring interventions to context, and strengthening relational dynamics, all examples of implementation strategies, as well as the importance of considering intervention content and implementation jointly.

CONCLUSION: Although implementation determinants, strategies, and outcomes were reported in studies on teachers’ mental health interventions, reporting was often fragmented, unsystematic and rarely guided by established frameworks or terminology. Future research should adopt comprehensive, theory-informed approaches that link implementation and intervention content. From a public health perspective, aligning evidence-based interventions, addressing both organizational and individual levels, with context-sensitive implementation strategies is key to sustainably improving teachers’ mental health and strengthening schools as healthy, supportive environments.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12889-026-26589-w.},
}

@article {pmid41728300,
year = {2026},
author = {Tsitkov, S and Raju, A and Wu, J and Li, J and Lim, RG and Wu, Z and Bistami, NA and , and Van Eyk, JE and Svendsen, CN and Rothstein, JD and Glass, JD and Finkbeiner, S and A Kaye, J and Thompson, LM and Fraenkel, E},
title = {Wild-type C9orf72 expression is a genetic modifier of C9-ALS survival.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.02.06.26345684},
pmid = {41728300},
abstract = {1 Amyotrophic lateral sclerosis (ALS) is highly heritable, yet the vast majority of cases lack an identifiable genetic cause and clinical progression remains largely unpredictable. To connect noncoding and rare genetic variation to disease phenotypes in a relevant cell type, we generated a multi-omic quantitative trait locus (QTL) atlas from 594 induced-pluripotent-stem-cell-derived human motor neuron lines (522 ALS patients, 72 controls). By mapping cis-QTLs for chromatin accessibility, splicing and gene expression from whole-genome sequencing, we identify common and rare variants on the wild-type C9orf72 allele that form regulatory haplotypes. These haplotypes influence C9orf72 expression levels in motor neurons and stratify C9-ALS patients into four subgroups; using clinical disease duration data and longitudinal ALSFRS-R scores, we show that these subgroups exhibit different survival trajectories, indicating that wild-type C9orf72 expression acts as a genetic modifier of disease duration. Beyond the C9orf72 locus, we detect ultra-rare intronic variants that create cryptic exons and structural and nonsense variants in established ALS genes, providing likely genetic explanations for disease in additional patients who previously lacked a molecular diagnosis. Our results show that QTL mapping in patient-derived motor neurons can reveal regulatory modifiers of progression and hidden pathogenic events in ALS, providing a framework for genetically informed risk attribution and patient stratification in complex neurological diseases.},
}

@article {pmid41728197,
year = {2026},
author = {Demaegd, KC and Koole, W and van Vugt, JJ and Dankbaar, JW and Hendrikse, J and Nazlı Başak, A and de Carvalho, M and Corcia, P and Codron, P and Bernard, E and Guissart, C and Couratier, P and Povedano Panades, M and van Doorn, PA and Warrenburg, BP and Cooper-Knock, J and , and Pasterkamp, RJ and van Rheenen, W and van Damme, P and van den Berg, LH and Veldink, JH and van Es, MA},
title = {Bi-allelic intermediate ATXN2 repeat expansions are associated with slow progressing, leg-onset familial ALS.},
journal = {BMJ neurology open},
volume = {8},
number = {1},
pages = {e001417},
pmid = {41728197},
issn = {2632-6140},
abstract = {OBJECTIVES: The identification of bi-allelic intermediate ATXN2 repeat expansions in a pedigree with amyotrophic lateral sclerosis (ALS) through clinical testing prompted us to investigate its relevance in the wider ALS population.

METHODS: ATXN2 repeat size was assessed in a large international cohort of ALS patients (n=6653 from Project MinE) and in neurologically intact control populations (n=13 515 controls from Project MinE and gnomad). For bi-allelic cases, we retrieved medical records, family history and MRI imaging. For familial cases, we obtained DNA samples from relatives for segregation analyses.

RESULTS: In total, we identified bi-allelic intermediate ATXN2 repeat expansions in five familial cases from three different pedigrees and five apparently sporadic cases. There is a relatively homogeneous phenotype characterised by lower limb onset and long survival (median 6 years) without significant cerebellar atrophy. Bi-allelic expansions were absent in controls (0 out of 13 515).

DISCUSSION: Here we report an apparently novel autosomal recessive form of familial ALS caused by bi-allelic intermediate ATXN2 repeat expansions, which is characterised by high penetrance, lower limb onset and slow progression. Although rare, testing for ATXN2 expansions should be performed in the clinical setting given its relevance to prognosis and genetic counselling.},
}

@article {pmid41727138,
year = {2026},
author = {He, Z and Zhou, J and Zhang, R and Meng, F and Nauen, DW and Troncoso, JC and Worley, PF and Zhang, W},
title = {TRIM32-UBQLN2-p62 axis promotes TDP-43 inclusion formation and amyloid aggregation through shuttle condensates.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.02.11.705390},
pmid = {41727138},
issn = {2692-8205},
abstract = {Aberrant protein aggregation is a hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD), which share overlapping genetic and pathological features. Similar aggregates are increasingly recognized in Alzheimer's disease (AD) and limbic-predominant age-related TDP-43 encephalopathy (LATE). However, it remains unclear whether a shared molecular pathway drives this pathological aggregation. Here, we report that the E3 ubiquitin ligase TRIM32, together with the shuttle factor UBQLN2 and the autophagy adaptor p62/SQSTM1, form condensates that depend on E3 ligase activity and a network of intermolecular interactions. These condensates act as scaffolds that capture UBQLN2 client proteins, including TDP-43 and ANXA11, and modulate their mobility. A unique hydrophobic loop within TRIM32's substrate-binding domain mimics low-complexity motifs in ANXA11 and TDP-43, enabling selective retention via competitive binding mediated by UBQLN2 STI1 domain. Moreover, TRIM32 condensates promote amyloid aggregation of TDP-43, an effect that is exacerbated by pathogenic UBQLN2 mutation. In brains from individuals with diverse neurodegenerative diseases, TRIM32 co-localizes with pathological phospho-TDP-43 (pTDP-43) inclusions, supporting a model in which TRIM32-driven condensates function as selective proteostasis sorting compartments that broadly contribute to TDP-43 proteinopathy.},
}

@article {pmid41727136,
year = {2026},
author = {Dubinski, A and Ferdi, A and Choughari, M and Spence, H and Adhikary, A and Fauchon, C and Touati, M and Gagné, M and Liu, M and Peyrard, S and Gregory, J and Vande Velde, C},
title = {TDP-43 pathology is linked to motor neuron loss but is independent of stress granules in vivo.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.02.11.705439},
pmid = {41727136},
issn = {2692-8205},
abstract = {Nuclear depletion and cytoplasmic aggregation of TDP-43 are pathological hallmarks of several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Alzheimer's disease, and the recently defined limbic-predominant age-related TDP-43 encephalopathy (LATE). Chronic activation of the integrated stress response (ISR) and persistence of stress granules, phase-separated assemblies proposed to function as a protective mechanism, have been hypothesized to initiate the formation of pathological TDP-43 inclusions observed in post-mortem neurons. However, recent clinical trials targeting the ISR and stress granule dissolution failed to demonstrate clinical benefit despite robust target engagement, calling this model into question. Here, we employ a recurrent hyperthermia paradigm to directly examine the relationship between stress granules and TDP-43 pathology in vivo . We find that RNA-binding proteins classically associated with stress granules persist as phase-separated cytoplasmic structures in spinal motor neurons of both non-transgenic and mutant TDP-43 mice. Importantly, these structures are reversible and spatially distinct from TDP-43 puncta. Moreover, in a mutant TDP-43 mouse model with an impaired acute stress granule response, stress exposure induces TDP-43 nuclear export and cytoplasmic accumulation. Recurrent stress in these mice leads to a selective loss of spinal α-motor neurons. Together, our findings demonstrate that TDP-43 nuclear clearance and cytoplasmic demixing occur independently of stress granules in vivo , challenging prevailing models of TDP-43 pathogenesis and highlighting important implications for therapeutic strategies targeting the ISR.},
}

@article {pmid41727111,
year = {2026},
author = {Ding, DY and Bot, VA and Chen, KL and Groves, J and Pálovics, R and Masuda, D and Farinas, A and Oh, HS and Wagner, V and Lu, N and , and Cruchaga, C and Isakova, A and Schott, JM and Wyss-Coray, T},
title = {Cellular Aging Signatures in the Plasma Proteome Record Human Health and Disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.02.10.704909},
pmid = {41727111},
issn = {2692-8205},
abstract = {Aging is asynchronous across cells and organs, but whether plasma proteins can capture cell type-specific aging and predict disease and mortality remains unknown. We developed machine learning models to estimate the biological age of more than 40 distinct cell types-spanning neuronal, immune, glial, endocrine, epithelial, and musculoskeletal origins-using over 7,000 plasma proteins measured in 60,000 individuals across three cohorts, comprising the largest human plasma proteomics aging study to date. Individuals showed heterogeneous aging profiles, with 20-25% exhibiting accelerated aging in a single cell type and 1-3% across ten or more cell types. APOE genotype showed antagonistic aging effects in different cell types: APOE4 carriers exhibited older astrocytes but younger macrophages, while APOE2 carriers showed the inverse. Cellular aging signatures were uniquely associated with disease status and predicted incident disease and mortality over 15 years of follow-up. Amyotrophic lateral sclerosis (ALS) showed the strongest association with skeletal myocyte aging (hazard ratio = 12.7 for extreme accelerated versus youthful aging). In Alzheimer's disease (AD), prevalent cases showed accelerated aging across multiple neural and peripheral cell types, with extreme astrocyte aging conferring AD risk comparable to APOE4 carrier status. Moreover, extreme astrocyte aging increased AD risk in APOE4/4 carriers threefold, while youthful astrocytes strikingly reduced risk. Beyond neurodegeneration, respiratory cell aging identified smokers at 58% higher lung cancer risk, and myeloid aging identified normoglycemic individuals at higher diabetes risk. Both specific cellular vulnerabilities and cumulative aging burden influenced survival, wherein youthful immune or neuronal profiles were protective. A polycellular aging risk score provided robust mortality risk stratification across platforms and cohorts. These findings establish a framework for quantifying biological aging at the cellular resolution using plasma proteomics, revealing heterogeneity in aging trajectories and their impact on disease susceptibility and resilience.},
}

@article {pmid41727102,
year = {2026},
author = {Russell, KA and Shahrabi, AA and Akerman, SC and Byrne, MD and Rothstein, JD and Trotti, D and Jensen, BK and Haeusler, AR},
title = {Intrathecal (G 4 C 2) 149 delivery in C9orf72-deficient mice yields mild motor dysfunction and ALS/FTD pathological hallmarks.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.02.09.704060},
pmid = {41727102},
issn = {2692-8205},
abstract = {A repeat expansion in C9orf72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), yet existing mouse models incompletely engage spinal regions implicated in disease. Here, an adeno-associated virus encoding (G 4 C 2) 149 repeats was delivered via neonatal intrathecal injection, achieving widespread CNS expression with robust spinal cord targeting. This approach was applied to mice with graded loss of endogenous C9orf72 to interrogate both gain- and loss-of-function mechanisms. Longitudinal motor, behavioral, and pathological analyses revealed that repeat expression primarily drives mild, progressive muscle weakness, whereas coordination deficits were largely genotype dependent. Subtle gait abnormalities and hyperactivity were also observed. Within spinal motor regions, repeat-expressing mice exhibited dipeptide repeat protein accumulation, reduced NeuN-positive area, glial activation, and sparse phosphorylated TDP-43 pathology. Cross-domain correlations further linked repeat expression, spinal pathology, and motor dysfunction. Collectively, these findings establish that CNS-wide repeat expression combined with reduced C9orf72 produces a coherent, mild ALS/FTD model.},
}

@article {pmid41692724,
year = {2026},
author = {Rönnholm, J and Weiner, S and Fuchs, J and Thorsell, A and Sihlbom, C and Dugom, L and Easton, A and Zetterberg, H and Gobom, J},
title = {Shake and bake: a robust and cost-effective proteomic sample preparation workflow for plasma and cerebrospinal fluid.},
journal = {Clinical proteomics},
volume = {23},
number = {1},
pages = {},
pmid = {41692724},
issn = {1542-6416},
abstract = {BACKGROUND: Plasma and cerebrospinal fluid are complementary sources of biomarkers for neurodegenerative diseases. The wide dynamic range of protein abundances, particularly in plasma, hampers detection of low-abundance proteins. Depletion of high-abundance proteins and efficient enzymatic digestion can improve proteome coverage but must be carefully optimized for reproducibility, throughput, and cost-efficiency for use in large-scale clinical proteomic studies.

METHODS: We developed a scalable sample preparation workflow for plasma and cerebrospinal fluid (CSF) that integrates depletion of high-abundance proteins, optimized digestion using Lys-C and trypsin, and compatibility with both label-free and tandem mass tag (TMTpro)-based quantification. Depletion was performed using a multi-affinity resin with immobilized antibodies targeting 14 high-abundance plasma proteins, which collectively constitute ≈ 95% of total plasma protein content. We systematically evaluated protein depletion and enzyme digestion conditions, and the effect of deoxycholate on digestion, monitoring the number of detectable proteins and the quantitation precision.

RESULTS: A resin-to-plasma ratio of ≥ 75 and a mixing speed of 900 rpm ensured complete and reproducible depletion. Depletion resulted in an increase in the number of identified proteins by ~ 65% in CSF, and ~ 80% in plasma, tripling the number of brain-enriched proteins, with maintained quantitative precision (median coefficient of variation (CV) for relative protein abundances < 11%). A two-step digestion protocol using Lys-C/trypsin followed by trypsin yielded the highest reproducibility and detectability in plasma. Adding the detergent deoxycholate to the samples had little effect in CSF and only marginally improved proteome coverage for plasma but decreased quantification precision and throughput. Technical replicates from a 528-sample clinical amyotrophic lateral sclerosis (ALS) cohort showed high reproducibility, with intra-sample CVs substantially lower than inter-individual variation.

CONCLUSIONS: The sample preparation workflow described here enabled deep and reproducible proteome profiling of plasma and CSF in high-throughput formats and was found to be suitable for biomarker discovery in large clinical studies.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12014-026-09589-1.},
}

@article {pmid41727032,
year = {2026},
author = {Kapsiani, S and Vora, S and Fernandez-Villegas, A and Kaminski, CF and Läubli, NF and Kaminski Schierle, GS},
title = {Discovery of TDP-43 aggregation inhibitors via a hybrid machine learning framework.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.02.12.705375},
pmid = {41727032},
issn = {2692-8205},
abstract = {TAR DNA-binding protein 43 (TDP-43) aggregation is a hallmark of several neurodegenerative diseases, including amyotrophic lateral sclerosis and frontotemporal dementia. Recent therapeutic efforts have highlighted the potential of small molecules capable of inhibiting TDP-43 aggregation; however, no effective treatments currently exist. Here, we developed a hybrid machine learning approach combining graph neural network (GNN) embeddings with traditional chemical descriptors and biological target annotations. Using XGBoost as the final classifier enabled model interpretability through SHAP analysis, allowing the identification of key chemical features and target annotations associated with TDP-43 anti-aggregation activity. Complementary Monte Carlo Tree Search analysis highlighted specific chemical substructures linked to predicted activity. By screening an external library of 3,853 small molecules, the model identified two compounds not previously evaluated against TDP-43 aggregation, namely berberrubine and PE859. Molecular docking analysis revealed that both compounds interact favourably with the TDP-43 RNA recognition motif (RRM) domain through distinct binding modes. Experimental validation showed that both compounds significantly reduced TDP-43 aggregation in HEK cells. Further testing in Caenorhabditis elegans expressing human TDP-43 demonstrated that PE859 significantly rescued locomotor defects, while berberrubine showed partial improvement. This work establishes a hybrid machine learning approach for accelerating small molecule drug discovery, yielding two promising therapeutic candidates for TDP-43 proteinopathies.},
}

@article {pmid41726972,
year = {2026},
author = {Natarajan, C and Budhwani, SM and Sreenivasamurthy, SGS and Katamoni, L and Thomson, B and Marcatti, M and Cuong, PP and Taglialatela, G and Krishnan, B},
title = {Exploring the PLD1-tau interaction in Frontotemporal Dementia.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.02.12.705569},
pmid = {41726972},
issn = {2692-8205},
abstract = {Frontotemporal dementia (FTD), a leading cause of young-onset dementia, is characterized by progressive behavioral and cognitive decline associated with frontotemporal cortical atrophy. Nearly 40% of cases exhibit tauopathy, yet the molecular drivers of tau aggregation leading to synaptic dysfunction remain poorly understood. Here, we investigated whether Phospholipase D1 (PLD1, a lipid signaling enzyme), implicated in Alzheimer's disease (AD), and amyotrophic lateral sclerosis (ALS), contributes to tau pathology dependent synaptic deficits in FTD. Postmortem temporal (BA38) and frontal (BA9) cortices from clinically diagnosed FTD and age-matched control subjects were analyzed using fluorescence-assisted single synaptosome long-term potentiation (FASS-LTP), immunofluorescence, proximity ligation assays (PLA), and PLD1-interactome proteomics. FASS-LTP revealed markedly reduced glutamatergic potentiation in BA38 and BA9 crude synaptoneurosomes from FTD brains compared to controls. Western blotting demonstrated elevated PLD1 expression in both crude synaptoneurosomal and cytosolic fractions from FTD subjects in BA38, but not BA9. Bielschowsky staining confirmed increased Pick body burden in FTD temporal cortex. Immunofluorescence and PLA showed robust PLD1 co-localization with total tau (HT7), hyperphosphorylated tau (AT8), and acetylated tau oligomers (TOMA2), indicating a strong spatial association between PLD1 and pathological tau species. PLD1 also exhibited enhanced co-localization with astrocytic GFAP and synaptic markers (PSD95, Nrx1β), suggesting compartmentalized involvement in glial and synaptic remodeling. Proteomic profiling of PLD1-associated complexes revealed compartment-specific alterations with cytosolic fractions enriched for metabolic enzymes, stress-response proteins, and GFAP, while crude synaptoneurosomal fractions showed depletion of presynaptic scaffolds, vesicle-trafficking regulators, and proteostasis components. Cross-compartment integration indicated that over one-third of proteins were redistributed from synapses to cytosol, consistent with trafficking and degradative impairments. Gene Ontology analysis highlighted lipid metabolism, astrocyte activation, and proteasome dysfunction as dominant pathways. Collectively, these findings identify PLD1 as a critical mediator of synaptic dysfunction and tau pathology in FTD, acting through astroglial activation and disrupting synaptic proteostasis. This study provides the human clinical relevance towards PLD1 attenuation as a therapeutic target for FTD and related tauopathies to mitigate tau-driven neurodegeneration and restore synaptic integrity.},
}

@article {pmid41726966,
year = {2026},
author = {Avila, TU and Wang, J and Adams, L and Hu, E and Beltran, AA and Kozlenkov, A and Urhekar, S and Gonzalez, ABM and Lee, HG and Calabrese, JM and Dracheva, S and Beltran, AS and Mah, W and Won, H},
title = {Repeat expansions in C9orf72 rewire the 3D chromatin landscape in ALS.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.02.09.704902},
pmid = {41726966},
issn = {2692-8205},
abstract = {Amyotrophic lateral sclerosis (ALS) is frequently driven by GGGGCC short tandem repeat (STR) expansions in C9orf72 , yet the mechanisms by which these expansions lead to neurodegeneration remain incompletely understood. Here, we propose a novel mechanism involving higher-order chromatin architecture where C9orf72 -STR expansions induce widespread, neuron-specific gains in chromatin loops that are closely linked to transcriptomic dysregulation in ALS. These ectopic loops colocalize with the genomic binding sites of C9orf72 -STR RNAs and the architectural protein CTCF, supporting a model in which RNA-DNA interactions promote aberrant loop formation. Together, our findings demonstrate how C9orf72 -STR expansions remodel the neuronal genome and disrupt gene expression, uncovering an RNA-driven mechanism of chromatin reorganization in C9-ALS that connects altered nuclear topology to gene dysregulation in neurodegeneration.},
}

@article {pmid41726352,
year = {2026},
author = {Angurana, SK and Gupta, S and Tiwari, L and Shamarao, S and Khera, D and Sarkar, M and Dhaliwal, M and Kumar, V and Chaudhary, A and Deb, S and Samprati, M and Mehta, A and Kapoor, R and Tago, N},
title = {Development and Validation of Indian Children Length-based Tape (InChiTape) for Use in Critically Sick Children.},
journal = {Indian journal of critical care medicine : peer-reviewed, official publication of Indian Society of Critical Care Medicine},
volume = {30},
number = {1},
pages = {35-39},
pmid = {41726352},
issn = {0972-5229},
abstract = {BACKGROUND AND AIM: Length-based tapes are extremely useful in critically sick children to estimate weight, emergency drug dosages, size of the equipment, and dose of defibrillation/cardioversion. The Indian Academy of Pediatrics (IAP), Advanced Life Support (ALS), and Basic Life Support (BLS) group felt the need to develop an indigenous tape for Indian children. A color-coded length-based tape [Indian Children Length-based Tape (InChiTape)] was planned to develop and later validate it.

PATIENTS AND METHODS: The population included children admitted to the emergency in the age range of 1 month-12 years and weight range of 2.5-40 kg. A color-coded length-based tape was developed using the World Health Organization (WHO) weight-for-length/height charts for boys (≤5 years) and the IAP weight-for-length/height charts for boys (>5 years). The median weights/lengths, corresponding +2SD and -2SD lengths, were marked on the charts for boys starting from 2.5 kg onward.

RESULTS: Fourteen centers from all zones of India pooled the data of 1,595 children. The majority of children were in the age range of 1-3.9 years (30%) and weight range of 5-9.9 and 10-14.9 kg (24.9 and 24.4%, respectively). The actual weight of children corresponded to the correct weight range/band on the InChiTape in 69.1% (n = 1,102) children, ranging from 56.6 to 78.4% in different age-groups and 55.5 to 76.3% in different weight ranges. There was a good correlation between actual weight and the average of respective weight range/band on the InChiTape (Pearson correlation of 0.95, p < 0.001).

CONCLUSION: The InChiTape is a rapid, reliable, and accurate method of estimating the weight of Indian children weighing 2.5-40 kg in an emergency.

HOW TO CITE THIS ARTICLE: Angurana SK, Gupta S, Tiwari L, Shamarao S, Khera D, Sarkar M, et al. Development and Validation of Indian Children Length-based Tape (InChiTape) for Use in Critically Sick Children. Indian J Crit Care Med 2026;30(1):35-39.},
}

@article {pmid41725371,
year = {2026},
author = {Carbó, J},
title = {Reviewer Comment on Dallaire et al. "Mortality and Complications of Percutaneous Gastrostomy in Amyotrophic Lateral Sclerosis Patients".},
journal = {The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques},
volume = {},
number = {},
pages = {1},
doi = {10.1017/cjn.2025.10512},
pmid = {41725371},
issn = {0317-1671},
}

@article {pmid41724566,
year = {2026},
author = {Caldero-Escudero, E and Romero-Sanz, S},
title = {Modeling stress-induced proteinopathies in Caenorhabditis elegans.},
journal = {Methods in cell biology},
volume = {203},
number = {},
pages = {201-231},
doi = {10.1016/bs.mcb.2025.12.007},
pmid = {41724566},
issn = {0091-679X},
mesh = {Animals ; *Caenorhabditis elegans/metabolism/genetics ; Disease Models, Animal ; Mitochondria/metabolism ; Proteostasis ; Reactive Oxygen Species/metabolism ; Endoplasmic Reticulum Stress ; *Proteostasis Deficiencies/metabolism/pathology ; *Caenorhabditis elegans Proteins/metabolism ; *Neurodegenerative Diseases/metabolism/pathology ; Humans ; *Stress, Physiological ; },
abstract = {Proteinopathies are a type of disorders characterized by the intracellular or extracellular accumulation of misfolded proteins that disrupt cellular proteostasis and exert toxic effects. These proteotoxic effects are a common hallmark of various age-related neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and polyglutamine disorders such as Huntington's disease (HD). Misfolded protein accumulation can impair numerous cellular processes, including mitochondrial function, protein degradation pathways, the endoplasmic reticulum stress response, and redox homeostasis, ultimately compromising cell viability. The nematode Caenorhabditis elegans (C. elegans) has emerged as a powerful model for studying proteotoxic stress due to its genetic tractability and the high degree of conservation of key cellular pathways when compared to mammals. These include mitochondrial dynamics and function, regulation of reactive oxygen species (ROS), and the cellular capacity to manage protein aggregates in terms of number, size, and clearance efficiency. The integration of these conserved stress response pathways together with C. elegans experimental versatility positioned this nematode as an ideal system to investigate the molecular mechanisms underlying proteinopathy-induced toxicity. In this chapter, we describe a set of complementary methodologies to evaluate proteotoxic stress in C. elegans models of protein misfolding. These include assays to measure mitochondrial reactive oxygen species (ROS) and membrane potential (Δψm), analyses of mitochondrial morphology and oxygen consumption, protein extraction protocols, and in vivo staining and semi-automated quantification of protein aggregates.},
}

Animals
*Caenorhabditis elegans/metabolism/genetics
Disease Models, Animal
Mitochondria/metabolism
Proteostasis
Reactive Oxygen Species/metabolism
Endoplasmic Reticulum Stress
*Proteostasis Deficiencies/metabolism/pathology
*Caenorhabditis elegans Proteins/metabolism
*Neurodegenerative Diseases/metabolism/pathology
Humans
*Stress, Physiological

@article {pmid41724277,
year = {2026},
author = {Zhao, X and Pu, L and Zeng, X and Nie, J},
title = {Role of nuclear import proteins in maintaining proteostasis and disease pathogenesis.},
journal = {Biochemical pharmacology},
volume = {},
number = {},
pages = {117831},
doi = {10.1016/j.bcp.2026.117831},
pmid = {41724277},
issn = {1873-2968},
abstract = {Nuclear import receptors (NIRs), particularly the importin α/β heterodimer system, function as essential gatekeepers of nucleocytoplasmic trafficking by decoding diverse nuclear localization signals (NLSs) to orchestrate cellular proteostasis. This review delineates the structural basis of NLS recognition and the coordinated mechanisms that facilitate the nuclear import of critical cargoes, including transcription factors, RNA-binding proteins, and DNA repair factors. Beyond their canonical transport role, we emphasize the emerging functions of NIRs as molecular chaperones that suppress aberrant phase separation and their co-translational regulatory roles in ensuring proper protein biogenesis and folding. The collapse of these regulatory functions underpins the pathogenesis of major human diseases. We examine in detail the pathological consequences of nuclear import dysfunction, highlighting its central role in specific neurodegenerative disorders such as Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD), oncogenic transformation, and viral pathogenesis. The discussion provides a critical appraisal of emerging therapeutic strategies that target the nuclear import machinery, including small-molecule inhibitors (e.g., importazole, ivermectin), peptide competitors, and advanced delivery platforms. We conclude by providing the associated challenges such as achieving tissue specificity, avoiding off-target effects and the significant opportunities that lie in pharmacologically modulating this fundamental pathway to restore proteostasis and develop disease modifying therapies.},
}

@article {pmid41723979,
year = {2026},
author = {Gao, Y and Lu, Y and Zhao, S and Chen, R and Liu, J and Zhang, S and Bai, X and Zhang, J},
title = {Allicin improves motor neuron survival in amyotrophic lateral sclerosis by reducing neuroinflammation and modulating gut microbiota.},
journal = {Biochemical and biophysical research communications},
volume = {809},
number = {},
pages = {153503},
doi = {10.1016/j.bbrc.2026.153503},
pmid = {41723979},
issn = {1090-2104},
abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive loss of motor neurons (MNs). Allicin, a defensive molecule in garlic with anti-inflammatory and gut microbiota-modulating properties, has shown therapeutic potential in animal models of various diseases including Alzheimer's disease (AD). However, its possible therapeutic role in ALS remains unclear. The purpose of this study is to investigate the therapeutic effect of allicin in ALS transgenic SOD1[G93A] mice. Starting at 60 days of age, SOD1[G93A] mice received oral gavage of allicin (10 mg/kg) on alternate days, while the control group received an equal volume of normal saline (NS) on the same schedule. Twelve mice per group were used for monitoring disease onset and survival. Nissl staining and choline acetyltransferase (ChAT) immunofluorescence were used to quantify MNs in the anterior horn. Microglial activation was analyzed by immunofluorescence staining for Iba1, ARG1, and CD86. The mRNA expression levels of IL-10, TGF-β, IL-1β, and TNF-α were examined using qPCR. Additionally, fecal samples were collected for 16S rDNA sequencing to evaluate changes in gut microbiota composition. We observed that allicin treatment failed to prolong the onset time and survival period of SOD1[G93A] mice, but it extended the disease duration. Nissl staining analysis revealed that allicin treatment delayed the loss of spinal MNs, a finding corroborated by ChAT immunofluorescence. Furthermore, allicin treatment significantly reduced neuroinflammation and improved gut microbiota. Taken together, although allicin may prolong disease duration in ALS, it did not improve overall survival or delay disease onset. Therefore, its potential disease-modifying effects require further validation.},
}

@article {pmid41723333,
year = {2026},
author = {Wang, Y and Zhang, H and Yang, T and Luo, J and Lin, T and Yan, X and Ding, J and Qiu, Y and Zhao, M and Yang, G},
title = {Imaging-derived neuromuscular ultrasound phenotypes are associated with functional status in amyotrophic lateral sclerosis.},
journal = {Journal of neurology},
volume = {273},
number = {2},
pages = {},
pmid = {41723333},
issn = {1432-1459},
support = {2025HZZD09//Construction Fund of Key Medical Disciplines of Hangzhou for Rare Disease (Motor Neuron Disease)/ ; },
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/physiopathology ; Male ; Female ; Middle Aged ; Ultrasonography/methods ; Aged ; *Muscle, Skeletal/diagnostic imaging/physiopathology ; Phenotype ; Adult ; *Peripheral Nerves/diagnostic imaging/physiopathology ; },
abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) presents with marked clinical heterogeneity, complicating diagnosis and management. Neuromuscular ultrasound (NMUS) provides a non-invasive means to visualize peripheral nerve and muscle integrity, but its potential to delineate ALS subtypes has not been systematically explored.

OBJECTIVE: To identify clinically meaningful ALS subgroups through unsupervised clustering of NMUS features integrated with clinical and electrophysiological data.

METHODS: A total of 454 ALS patients (August 2024-December 2025) underwent standardized NMUS assessment, including muscle thickness, echogenicity, and nerve cross-sectional area, alongside ALSFRS-R, manual muscle testing (MMT), and compound muscle action potentials (CMAPs). K-means clustering was applied to standardized NMUS variables, with cluster stability assessed using silhouette coefficients, sensitivity analyses (k = 2-5), and resampling-based adjusted Rand indices. Multivariable regression examined associations between cluster membership and ALSFRS-R.

RESULTS: Two reproducible NMUS-based subgroups were identified: a Mild cluster (n = 288, 63.4%) and a Severe cluster (n = 166, 36.6%). The Severe cluster showed reduced muscle thickness and higher echogenicity across multiple sites, together with lower ALSFRS-R scores (adjusted β = - 3.84, 95% CI - 5.41 to - 2.27, P < 0.001). Cluster membership correlated negatively with MMT and CMAP amplitudes, supporting functional and electrophysiologic validity. Stability metrics confirmed robustness of the two-cluster solution.

CONCLUSION: Integrating NMUS with clinical data enables objective, imaging-derived stratification of ALS patients into biologically and functionally distinct subgroups. This approach offers a pragmatic framework for phenotypic characterization and may inform personalized monitoring and trial design in ALS.},
}

Humans
*Amyotrophic Lateral Sclerosis/diagnostic imaging/physiopathology
Male
Female
Middle Aged
Ultrasonography/methods
Aged
*Muscle, Skeletal/diagnostic imaging/physiopathology
Phenotype
Adult
*Peripheral Nerves/diagnostic imaging/physiopathology

@article {pmid41723070,
year = {2026},
author = {Togawa, N and Ayaki, T and Yoshii, D and Maki, T and Sawamoto, N and Takahashi, R},
title = {Corrigendum to "TMEM119-positive microglia were increased in the brains of patients with amyotrophic lateral sclerosis" [Neurosci. Lett. 833 (2024) 137829].},
journal = {Neuroscience letters},
volume = {},
number = {},
pages = {138544},
doi = {10.1016/j.neulet.2026.138544},
pmid = {41723070},
issn = {1872-7972},
}

@article {pmid41722586,
year = {2026},
author = {Jing Jing Yeo, C},
title = {The Tuesday lessons of ALS.},
journal = {The Lancet. Neurology},
volume = {25},
number = {3},
pages = {231},
doi = {10.1016/S1474-4422(26)00048-7},
pmid = {41722586},
issn = {1474-4465},
}

@article {pmid41722440,
year = {2026},
author = {Squintani, G and Muzio, MD and Rasera, A and Paio, F and Borin, GU and Humaidan, K and Orlando, D and Refatti, N and Romito, S and Tinazzi, M and Bonetti, B and Ermani, M},
title = {Corrigendum to "Sensory and motor cortical hyperexcitability in patients with amyotrophic lateral sclerosis: are they related? A prospective pilot study". [CLINPH 183 (2026) 2111485].},
journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology},
volume = {184},
number = {},
pages = {2111703},
doi = {10.1016/j.clinph.2026.2111703},
pmid = {41722440},
issn = {1872-8952},
}

@article {pmid41722224,
year = {2026},
author = {Ye, Y and Shen, B and Jiang, MY and Jong, MS},
title = {Beyond immersion: Investigating the impact of SVVR on FLCA in a Chinese EFL speaking class.},
journal = {Acta psychologica},
volume = {264},
number = {},
pages = {106504},
doi = {10.1016/j.actpsy.2026.106504},
pmid = {41722224},
issn = {1873-6297},
abstract = {Although spherical video-based virtual reality (SVVR) has demonstrated efficacy in enhancing English-as-a-foreign-language (EFL) learning outcomes, its impact on foreign language classroom anxiety (FLCA) within speaking contexts remains underexplored. This mixed methods study implemented a 16-week experiential learning (EL)-based SVVR intervention to examine its effects on FLCA that resides in four dimensions and on the speaking performance among Chinese EFL learners. Using a pre-post control-group design with 69 sophomores, quantitative data from Horwitz et al.'s (1986) FLCAS and speaking tests were analyzed with ANCOVA, and 12 post-intervention interviews were examined using reflexive thematic analysis. Relative to the control group, the SVVR group reported significantly lower overall FLCA, with moderate to large reductions in communication apprehension (partial η[2] = 0.160) and fear of negative evaluation (partial η[2] = 0.111) but no detectable changes in test anxiety (partial η[2] = 0.037) or other general anxiety (partial η[2] = 0.037), and achieved higher post-test speaking scores (partial η[2] = 0.078). Thematic analysis identified four underlying mechanisms that helped to explain the dimension-specific FLCA levels after intervention: (1) SVVR as a psychological "safety shield", (2) displaced social judgment, (3) pedagogy-test disconnect, and (4) task-based anxiety control. Theoretically, the study demonstrates that FLCA-CA and FLCA-FNE are most responsive to EL-based SVVR and shows that this approach primarily alleviates situational, interaction-related anxiety rather than all forms of FLCA. Practically, it indicates how SVVR can be used as a supplementary tool to design low-anxiety, high-engagement speaking activities that support EFL learners' emotional regulation and oral proficiency.},
}

@article {pmid41721173,
year = {2026},
author = {Bonin, P and Méot, A and Argon, S and Boucheix, JM and Thiebaut, G},
title = {The survival processing advantage in memory using virtual reality versus traditional desktop display: Does it make a difference?.},
journal = {Memory & cognition},
volume = {},
number = {},
pages = {},
pmid = {41721173},
issn = {1532-5946},
abstract = {The survival processing advantage refers to the fact that words processed in relation to survival (e.g., finding food) are memorized better than words processed in a context that is not evocative of survival (e.g., moving to a foreign country). This effect has been extensively studied in laboratory tasks in which participants have to imagine a survival situation rather than being placed in a "supporting perceptual context." In the present study, we aimed to investigate the survival effect using virtual reality and compare it with a traditional desktop display. Using virtual reality technology, we replicated the survival processing advantage found in Wang et al.'s (Survival processing advantage demonstrated with virtual reality-based survival environment: A promising tool for survival processing research. Memory & Cognition, 51[1], 129-142, 2023) study. More importantly, the survival effect obtained with virtual reality was no greater than that obtained using more conventional means (i.e., a desktop display). The findings are discussed in relation to the issue of the optimality of the survival effect and the way proximate mechanisms are involved.},
}

@article {pmid41720774,
year = {2026},
author = {Yang, M and Wang, Q and Yan, R and Kang, D and Luo, W and Zhang, L and Liu, R and Wu, L and Gu, J and Wang, X},
title = {A neurotoxic cryptic peptide arising from TDP-43-dependent cryptic splicing of PKN1.},
journal = {Nature communications},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41467-026-68916-0},
pmid = {41720774},
issn = {2041-1723},
abstract = {Dysfunction of transactive response DNA-binding protein 43 (TDP-43) drives neurodegeneration in amyotrophic lateral sclerosis (ALS) and Alzheimer's disease (AD), in part through inducing aberrant RNA splicing. However, whether such mis-splicing yields stable, pathogenic proteins remains unclear. Here, we identify a TDP-43-repressed cryptic exon in Protein kinase N1 (PKN1), designated PKN1-5a1, which is activated in ALS patient brains and introduces a premature termination codon. This aberrant transcript escapes nonsense-mediated decay and is translated into a truncated peptide, PKN1-N207 (PKN207), detectable in AD brains with TDP-43 pathology. In mice, PKN207 impairs cognition, memory, and synaptic plasticity. Our findings demonstrate that TDP-43 loss-induced cryptic splicing can generate stable neurotoxic polypeptides, revealing a peptide-mediated mechanism in TDP-43 proteinopathies.},
}

@article {pmid41720758,
year = {2026},
author = {Falahati, M and Orangi, K and Shaabanpoor Haghighi, A and Pouroushaninia, N and Niknam, N and Soltani, S and Radnia, P and Arab Bafrani, M and Shirdel, S and Aarabi, MH},
title = {Microstructural alterations of the amygdala in neurodegenerative and neuroinflammatory disorders: insights from diffusion tensor imaging.},
journal = {Reviews in the neurosciences},
volume = {},
number = {},
pages = {},
pmid = {41720758},
issn = {2191-0200},
abstract = {Diffusion tensor imaging (DTI) is a valuable method for evaluating microstructural changes in the amygdala associated with neurodegenerative and neuroinflammatory disorders. This systematic review examines amygdala microstructural alterations in Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), dementia with Lewy bodies (DLB), and multiple sclerosis (MS) using DTI metrics. Following PRISMA 2020 guidelines, we searched PubMed, Scopus, and Web of Science databases through August 2025, identifying 4,442 records. After screening and eligibility assessment, 13 studies were included, comprising 1,412 patients and 1,146 healthy controls. Due to sample heterogeneity and lack of standardized effect size measures, meta-analysis was not performed. Across disorders, elevated mean diffusivity (MD) emerged as the most consistent finding, present in 100 % of AD patients and observed in all examined conditions. Reduced fractional anisotropy (FA) was the second most frequent alteration, with 36.6 % of AD patients showing decreased FA. In MS, increased radial diffusivity (RD) was prominent, while longitudinal DLB studies revealed progressive free water (FW) increases. These DTI-based microstructural changes often preceded volumetric atrophy and correlated with clinical severity. Our findings demonstrate that DTI metrics, particularly MD and FA, serve as sensitive markers of amygdala pathology across neurodegenerative diseases and may facilitate early diagnosis, disease monitoring, and differential diagnosis of these conditions.},
}

@article {pmid41718986,
year = {2026},
author = {Shadfar, S and Assar Kashani, S and Gautam, S and Takalloo, Z and Farzana, F and Parakh, S and Atkin, JD},
title = {The Role of the Golgi Apparatus in Neurodegeneration.},
journal = {Sub-cellular biochemistry},
volume = {111},
number = {},
pages = {413-440},
pmid = {41718986},
issn = {0306-0225},
mesh = {*Golgi Apparatus/metabolism/pathology ; Humans ; *Neurodegenerative Diseases/metabolism/pathology ; Animals ; *Neurons/metabolism/pathology ; },
abstract = {The Golgi apparatus has important, well characterised functions in the trafficking, processing, and post-translational modification of proteins and lipids. However, roles in other cellular processes are increasingly reported, including autophagy, apoptosis, DNA repair, and cytoskeletal (microtubules and actin) function. The Golgi therefore serves as a regulatory hub for multiple signalling pathways that maintain essential cellular activities. The Golgi normally consists of flattened stacks of membrane (cisternae), but during normal physiology and pathological conditions it 'fragments', resulting in altered morphology and distribution. This is well described as an early pathological feature of many neurodegenerative diseases, including Alzheimer's (AD), Parkinson's (PD), Huntington's (HD) and prion diseases, and amyotrophic lateral sclerosis (ALS). These age-related conditions are characterised by the death of neurons: highly specialised, unique cells that form the foundation of the nervous system. Interestingly, many Golgi-related functions are also dysregulated in these diseases. However, this has received relatively little attention compared to other pathogenic mechanisms. The Golgi apparatus in neurons shares features common to other eukaryotic cells but it also has unique properties, such as the presence of distinctive assemblies: Golgi outposts and satellites, which remain poorly characterised. Here we discuss the increasing evidence describing dysfunction and fragmentation of the Golgi apparatus and its possible role in the pathogenesis of neurodegenerative diseases.},
}

*Golgi Apparatus/metabolism/pathology
Humans
*Neurodegenerative Diseases/metabolism/pathology
Animals
*Neurons/metabolism/pathology

@article {pmid41659424,
year = {2026},
author = {Chen, R and Stockwell, I and Pierce, JC and Peak-Chew, SY and Huang, M and Newell, K and Ghetti, B and Cousin, MA and Greger, IH and Ryskeldi-Falcon, B},
title = {Pathological TDP-43 filaments accumulate at synapses and cause synaptic dysfunction.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
pmid = {41659424},
issn = {2692-8205},
support = {R01 AG080001/AG/NIA NIH HHS/United States ; R01 NS137469/NS/NINDS NIH HHS/United States ; RF1 AG071177/AG/NIA NIH HHS/United States ; U01 NS110437/NS/NINDS NIH HHS/United States ; },
abstract = {The assembly of TAR DNA-binding protein 43 (TDP-43) into amyloid filaments within neurons is a hallmark of multiple neurodegenerative diseases, including motor neuron diseases (MND), frontotemporal dementias (FTD) and limbic-predominant age-related TDP-43 encephalopathy (LATE). These diseases result from the deterioration and loss of neurons, with synaptic dysfunction and neuronal hyperexcitability being prominent early events. Pathogenic mutations in the TDP-43 gene, TARDBP, that promote filament formation have established a causal role for TDP-43 assembly in neurodegenerative diseases. However, the molecular mechanisms underlying filament accumulation and their contribution to neurodegeneration are poorly understood. TDP-43 filaments can propagate between neurons in a prion-like manner, which may underlie the progressive spread and accumulation of TDP-43 pathology in disease. Here, we studied early stages of TDP-43 filament accumulation following internalisation of patient-derived TDP-43 filaments by mouse and human cortical neurons. Using proximity labelling, we identified molecular environments and putative interactions of TDP-43 filaments. We found that TDP-43 filaments accumulated at synapses, particularly in proximity to the presynaptic active zone, which we confirmed in FTD patient brain sections. Electron cryo-tomography (cryo-ET) directly visualised abundant TDP-43 filaments spanning the presynaptic cytoplasm in situ, which contacted synaptic vesicles and the plasma membrane. Functional measurements revealed that the accumulation of TDP-43 filaments led to presynaptic dysfunction and subsequent neuronal hyperexcitability. These findings suggest that synapses are a major early site of TDP-43 filament accumulation, relevant to their propagation, and directly link TDP-43 filament gain of function to synaptic dysfunction.},
}

@article {pmid41718496,
year = {2026},
author = {Judge, S and Ballesteros, K and McDermott, CJ and Bloch, S},
title = {Timing of communication and technology control support in ALS - a systematic review.},
journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration},
volume = {},
number = {},
pages = {1-9},
doi = {10.1080/21678421.2026.2627899},
pmid = {41718496},
issn = {2167-9223},
abstract = {Objective: To review evidence on the optimal timing of interventions that support communication and technology control for people living with Amyotrophic Lateral sclerosis (ALS). Methods: A systematic review was conducted following a pre-registered protocol. Databases were searched for studies involving people living with ALS that addressed timing of assistive technology interventions for communication or technology control. Screening and data extraction were completed in duplicate, findings were synthesized using a thematic analysis, and relevant findings presented as a descriptive summary. Results: Twenty-eight studies met the inclusion criteria. Evidence focused overwhelmingly on communication support rather than wider assistive technology interventions. Need for a communication aid typically occurs between one and five years from diagnosis and the timing of this varies significantly according to the site of onset of ALS. There are significant variations in the timing of changes for individuals within these groupings and there are likely a larger number of groupings that would be clinically useful. A significant correlation between changes in speaking rate and intelligibility has been shown. Once changes to speech do start to occur then the time to the loss of functional speech appears relatively consistent across the types of ALS. Conclusion: Current best practice guidelines are not reflective of the findings of this review and do not support professionals in identifying how to provide timely support. Monitoring speech changes systematically may support timely intervention. There is potential for individual level predictive modeling to help support people living with ALS to be proactive and prepared for changes.},
}

@article {pmid41718455,
year = {2026},
author = {Wan, Y and Yu, Z and Yang, J and Zhang, W and Yu, M and Meng, L and Wang, Z and Yuan, Y and Ruan, L and Deng, J and Wang, P},
title = {The Mislocalization of TDP-43 to Mitochondria Impairs Myotube Maturation.},
journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology},
volume = {40},
number = {4},
pages = {e71603},
doi = {10.1096/fj.202504624R},
pmid = {41718455},
issn = {1530-6860},
support = {2025ZD0217600//Brain Science and Brain-like Intelligence Technology/ ; 32460138//National Natural Science Foundation of China/ ; 82422025//National Natural Science Foundation of China/ ; 82401635//National Natural Science Foundation of China/ ; 82430059//National Natural Science Foundation of China/ ; 32571340//National Natural Science Foundation of China/ ; 2024YFA1803700//National Key Research and Development Program of China/ ; 2023HQ03//National High Level Hospital Clinical Research Funding/ ; PKU2025PKULCXQ016//Clinical Medicine Plus X/ ; },
mesh = {*DNA-Binding Proteins/metabolism/genetics ; Animals ; Mice ; Humans ; *Amyotrophic Lateral Sclerosis/metabolism/pathology ; *Muscle Fibers, Skeletal/metabolism/pathology ; *Mitochondria/metabolism ; Cell Differentiation ; Cell Line ; Protein Transport ; Myoblasts/metabolism ; },
abstract = {Aggregation of TDP-43 in neuronal cells is a defining neuropathological hallmark of amyotrophic lateral sclerosis (ALS). Emerging evidence suggests that TDP-43 pathology also occurs in skeletal muscle fibers, but its functional significance in myocytes remains poorly understood. In this study, we utilized the C2C12 myoblast cell to investigate the subcellular localization of TDP-43 during myogenic differentiation. Our findings demonstrate that TDP-43 progressively translocates to mitochondria in parallel with myotube maturation. Notably, increased mitochondrial localization of TDP-43 was also observed in skeletal muscle tissues from patients with ALS, corroborating the clinical relevance of this phenomenon. Functional assays revealed that inhibition of TDP-43 mitochondrial translocation significantly enhances myotube maturation. Collectively, these results support a pathophysiological role for aberrant mitochondrial mislocalization of TDP-43 in regulating myogenic differentiation and contributing to muscle degeneration in TDP-43 proteinopathies.},
}

*DNA-Binding Proteins/metabolism/genetics
Animals
Mice
Humans
*Amyotrophic Lateral Sclerosis/metabolism/pathology
*Muscle Fibers, Skeletal/metabolism/pathology
*Mitochondria/metabolism
Cell Differentiation
Cell Line
Protein Transport
Myoblasts/metabolism

@article {pmid41718290,
year = {2026},
author = {Messina, C},
title = {Silent Damage, Delayed Symptoms: A Case of Breast Cancer Radiation-Induced Lumbosacral Plexopathy.},
journal = {Reports (MDPI)},
volume = {9},
number = {1},
pages = {},
pmid = {41718290},
issn = {2571-841X},
abstract = {Background and Clinical Significance: Radiation-induced lumbosacral plexopathy (RILP) is a rare but potentially debilitating complication of radiotherapy, typically affecting patients treated for pelvic malignancies. We report the first documented case of asymmetric RILP following radiotherapy for breast cancer. Case Presentation: A 64-year-old woman developed progressive left lower limb weakness, foot drop, and sensory disturbances four years after receiving locoregional radiotherapy extending to the left thoracoabdominal and lumbar areas. Electrophysiological studies revealed an asymmetric sensorimotor axonal neuropathy predominantly involving the left lower limb, without conduction block and sparing the upper limbs, whereas needle electromyography of the lower limbs showed fibrillation potentials, positive sharp waves, and fasciculations in the vastus lateralis, tibialis anterior, and medial gastrocnemius muscles on the left. Magnetic resonance imaging demonstrated edema and contrast enhancement of bilateral L2-L4 nerve roots with paraspinal muscle atrophy. Cerebrospinal fluid analysis showed albuminocytologic dissociation and elevated neurofilament levels. After exclusion of alternative diagnoses, including amyotrophic lateral sclerosis and inflammatory neuropathies, a diagnosis of radiation-induced peripheral neuropathy and RILP was made. The patient's condition stabilized with physiotherapy and symptomatic treatment. Conclusions: This case highlights the need for heightened awareness of RILP as a late complication of breast cancer radiotherapy, underscoring the importance of accurate diagnosis to avoid misclassification and unnecessary treatments. Clinicians should carefully integrate all clinical elements-including a thorough remote medical history-since radiation-related neurological damage may manifest many years after the initial insult.},
}

@article {pmid41717003,
year = {2026},
author = {Inami, S and Jenny, BP and Akpoghiran, O and Gallagher, SI and Strich, AK and Tonoki, A and Trotti, D and Haeusler, AR and Koh, K},
title = {Increased neuronal activity restores circadian function in Drosophila models of C9orf72-ALS/FTD.},
journal = {iScience},
volume = {29},
number = {2},
pages = {114798},
pmid = {41717003},
issn = {2589-0042},
abstract = {Circadian rhythm disruptions are common across neurodegenerative diseases, but their link to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) remains unclear. The C9orf72 hexanucleotide repeat expansion is the most prevalent genetic cause of ALS/FTD. Here, we used Drosophila models expressing pathogenic arginine-rich dipeptides (PR or GR) or GGGGCC hexanucleotide repeats to investigate circadian deficits in C9orf72-ALS/FTD. We found that circadian rhythmicity and period length were altered in a repeat number-, dosage-, expression pattern-, and age-dependent manner. Additionally, we observed lower levels of the neuropeptide PDF, a key regulator of free-running circadian rhythms, as well as decreased projection complexity and reduced neuronal activity in PDF-expressing neurons. Importantly, increases in neuronal activity significantly rescued mild circadian dysfunction across ages and across PR, GR, and GGGGCC repeat models when appropriately tuned. These results implicate reduced neuronal activity in C9orf72-ALS/FTD circadian deficits, underscoring the importance of calibrated, and stage-specific interventions.},
}

@article {pmid41716354,
year = {2025},
author = {Moleón, VR and Ayoubi, R and Alende, C and Fothouhi, M and Ryan, J and Bolívar, SG and Worrall, D and Durcan, TM and Brown, CM and Francis, V and McPherson, PS and Laflamme, C},
title = {A guide to selecting high-performing antibodies for Optineurin (UniProt ID: Q96CV9) for use in western blot, immunoprecipitation, and immunofluorescence.},
journal = {F1000Research},
volume = {14},
number = {},
pages = {1137},
pmid = {41716354},
issn = {2046-1402},
mesh = {Humans ; Cell Cycle Proteins ; Membrane Transport Proteins ; *Transcription Factor TFIIIA/immunology ; *Immunoprecipitation/methods ; *Blotting, Western/methods ; *Antibodies/immunology ; *Fluorescent Antibody Technique/methods ; },
abstract = {Optineurin (OPTN) is a multifunctional cytoplasmic adaptor protein implicated in maintaining neuronal homeostasis through its roles in selective autophagy, vesicle trafficking, and regulation of inflammatory signaling. Mutations in the OPTN gene are causally linked to several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and primary open-angle glaucoma. Here we have eight optineurin commercial antibodies for western blot, immunoprecipitation, and immunofluorescence using a standardized experimental protocol based on comparing read-outs in knockout cell lines and isogenic parental controls. These studies are part of a larger, collaborative initiative seeking to address antibody reproducibility issues by characterizing commercially available antibodies for human proteins and publishing the results openly as a resource for the scientific community. While the use of antibodies and protocols vary between laboratories, we encourage readers to use this report as a guide to select the most appropriate antibodies for their specific needs.},
}

Humans
Cell Cycle Proteins
Membrane Transport Proteins
*Transcription Factor TFIIIA/immunology
*Immunoprecipitation/methods
*Blotting, Western/methods
*Antibodies/immunology
*Fluorescent Antibody Technique/methods