Citations

Abstract Oxidative phosphorylation (OXPHOS) is a central function and a key indicator of mitochondrial fitness, yet studies in human tissue remain limited. Inclusion body myositis (IBM) is a progressive myopathy that lies at the intersection of aging, inflammation and mitochondrial dysfunction. We aimed to perform a comprehensive profiling of mitochondrial respiration in muscle tissue from patients with IBM. A wide battery of complementary approaches from RNA level to high-resolution respirometry on permeabilized muscle fibers was employed. The relationship between mitochondrial respiration, mitochondrial content, mitochondrial DNA (mtDNA) abnormalities and mitophagy was examined, along with the correlation with various clinical parameters to determine their clinical relevance. The study included a total of 67 patients with IBM and 45 controls. On high resolution respirometry of permeabilized muscle fibers, IBM samples exhibited reduced maximal mitochondrial respiration per tissue weight in State 3 (high substrates, high ADP) and uncoupled state with decreased coupling efficiency and higher leak control ratios. When adjusting for citrate synthase reflecting mitochondrial content, male patients had decreased State 3 intrinsic respiration, whereas female patients had greater intrinsic respiration under leak states. Complex I activity was decreased mainly in female patients, in whom complex II control ratio positively correlated with disease duration and severity. IBM was further associated with decreased RNA levels of all complexes, and lower protein expression of complex I, III, IV and V, likely related to the lower mtDNA content seen in IBM samples. Regarding the production of reactive oxygen species, IBM samples exhibited lower maximal H2O2 emission, accompanied by a higher total antioxidant capacity that positively correlated with disease duration in female patients. Lastly, correlation analyses suggested that impaired mitochondrial respiration, altered mitophagy, and reduced mtDNA content are interconnected in IBM and maybe of clinical significance. IBM is characterized by multifaceted, clinically relevant impairments in mitochondrial respiration. Future studies should further explore underlying pathomechanisms and the variation of mitochondrial respiration by disease stage.

MOGAD is a rare autoimmune encephalomyelitis that shares similar clinical manifestations with other central nervous system demyelinating diseases. However, they must be distinguished due to their distinct pathogenesis and treatment methods. Currently, the clinical diagnosis of MOGAD primarily relies on patients’ clinical manifestations and imaging features, with biomarker application being relatively limited. Meanwhile, research on MOGAD biomarkers has advanced rapidly, with findings mainly focusing on imaging features, antibody titers, nerve cell markers, cytokines, and inflammatory cell ratios. These biomarkers can distinguish among various autoimmune with similar clinical manifestations and exhibit certain specificity. If these biomarker findings are applied to the clinical diagnosis of MOGAD, they could enhance diagnostic accuracy and support earlier and more accurate diagnosis, while providing a scientific basis for evaluating disease progression and prognosis. We discuss the biomarkers and emerging biomarkers of MOGAD, emphasizing the specific changes and aspects that may be applicable to clinical diagnosis and treatment.

Abstract White matter bundles play a crucial role in cognitive functions by rapidly transmitting information between brain regions. Inter-areal conduction guides the integration of information and conduction velocity is a fundamental parameter in theories and models of brain function. However, distributions of conduction velocity remain difficult to characterize in vivo in humans. In this work, we integrated diffusion magnetic resonance imaging (dMRI) tractography with intracranial electrical stimulation during clinical stereo-electroencephalography (sEEG) monitoring in 17 subjects to measure conduction velocity within four major white matter bundles. Our findings reveal that human brain conduction is characterized by high variability both within and between bundles, reflecting a predominance of slow connections alongside rare high-speed connections. Because conduction velocity in myelinated fibers follows an approximately linear relationship with axon diameter, we derive underlying axon diameter distributions and show that these estimates are comparable to previous post-mortem studies. These findings demonstrate a heavily skewed distribution of human neural conduction velocities and show that structural heterogeneity shapes the timing and integration of information in large-scale networks.

Objective Systemic sclerosis (SSc) is an autoimmune disease marked by immune dysregulation, leading to progressive fibrosis and multiorgan dysfunction. Autologous hematopoietic cell transplantation (autoHCT) has demonstrated superiority over conventional immunosuppression in randomized trials yet remains underused in the United States. We report outcomes following implementation of autoHCT as a standard‐of‐care strategy at our institution. Methods We performed a retrospective analysis of consecutive patients with severe SSc undergoing autoHCT between April 1, 2020, and December 31, 2023. Eligibility required progressive disease despite standard immunosuppressive therapy. Primary endpoints were overall survival (OS) and event free survival (EFS). Secondary endpoints included cumulative incidence of relapse and nonrelapse mortality (NRM), organ‐specific outcomes, and transplant‐related complications. Results Twenty‐five patients underwent autoHCT. Median age was 46 years; 80% were female. At a median follow‐up of 23 (interquartile range 16.4–31.9) months, two‐year OS was 91.67% (95% confidence interval [CI] 81.25–100.0) and EFS was 74.51% (95% CI 58.78–94.45). Two‐year cumulative incidence of relapse was 23.93% (95% CI 4.27 –43.59), and NRM was 8.33% (95% CI 2.97–19.64). Significant improvement in Modified Rodnan Skin Score was observed at day +90 and +180 ( P < 0.05), whereas pulmonary function stabilized. Infectious complications occurred in 56% of patients, primarily viral reactivations. Conclusion Implementation of autoHCT for severe SSc in a multidisciplinary care model was associated with favorable survival and meaningful improvement in skin disease, with acceptable toxicity. Earlier referral and optimization of conditioning strategies may further reduce relapse and treatment‐related morbidity.

Despite major advances in cardiac care and decades of research, neurodevelopmental (ND) outcomes among children with congenital heart disease (CHD) have shown little improvement over time, substantial variability in outcomes remains unexplained, and prediction of individual developmental trajectories remains limited. This article argues that one contributor to these limitations is the field's reliance on descriptive but mechanistically underspecified models that catalog risk factors without clearly explaining how specific environmental experiences influence neurobehavioral development. To address this gap, this paper proposes an integrated dimensional model of neurodevelopment in CHD that conceptualizes ND outcomes as arising from the independent and interactive effects of CHD-related brain vulnerability and exposure to environmental medical adversity organized along the dimensions of deprivation and threat. Drawing from the Dimensional Model of Adversity and Psychopathology, the framework integrates prenatal dysmaturation, perioperative brain injury, and persistent alterations in brain structure and connectivity with adverse experiences occurring across prenatal, intensive care, caregiving, educational, and socioeconomic contexts. The model predicts that deprivation-related exposures will preferentially affect cognitive, language, and executive functioning systems, whereas threat-related exposures will more strongly influence emotional learning, stress regulation, and risk for psychopathology. By organizing CHD-related experiences according to developmentally meaningful dimensions of adversity, this framework provides a more mechanistic account of ND heterogeneity in CHD, generates testable hypotheses regarding developmental trajectories, and may support more precise developmental surveillance and targeted intervention strategies.