Adult patients with inherited metabolic diseases are often overlooked. Limited data on this population hinder adequate planning of their clinical and social care. In this retrospective, observational, cross-sectional service evaluation study, we reviewed the electronic medical records of adult patients with inherited neurometabolic diseases (NIMD) managed at Skåne University Hospital between 2020 and 2024. Skåne University Hospital, located in Region Skåne in Southern Sweden, is one of three specialized tertiary centers for inherited metabolic diseases in Sweden. The aim of this study was to characterize these patients demographically and clinically and to describe their treatment profiles, functional status, and social support. We identified 59 patients. Most patients had disorders of intermediary energy metabolism (21/59; 35.6%) or lipid metabolism (14/59; 23.7%), including 10 patients (16.9%) with adrenoleukodystrophy. Disease-specific treatments were provided to 65.4% of patients, and 83.6% were under continuous follow-up. Sixteen patients (27.1%) were fully independent, lived in their own homes, did not require societal support nor mobility aid, and worked/studied full time/retired due to old age. More than half of the patients (50.8%) received no disability or social support. In conclusion, adult patients with NIMD represent a heterogeneous group with variable clinical and social needs. Despite the rarity of individual NIMDs, disease-specific treatments were commonly used in our center. Further studies, particularly long-term follow-up studies, are required to better understand NIMD clinical trajectories and to optimize both medical management and social support for adults with NIMD.
Bevacizumab is a humanized monoclonal antibody against vascular endothelial growth factor A. Its long half-life and low volume of distribution allow circulating drug to persist in the body for weeks, which becomes clinically relevant when urgent or emergent surgery is needed. Because bevacizumab is largely intravascular, therapeutic plasma exchange (TPE) is attractive, though published experience is limited. We describe four adults who underwent TPE to facilitate surgery or postoperative wound healing after bevacizumab exposure: two with glioblastoma multiforme (GBM) before craniotomy, one with GBM after bowel resection with primary anastomosis, and one with metastatic rectal adenocarcinoma before craniotomy for a hemorrhagic brain mass. Patients received one to three sessions with albumin replacement, with fresh frozen plasma added in one case. No postoperative hemorrhage or delayed wound healing occurred. These cases support a practical role for TPE when residual bevacizumab exposure remains relevant and awaiting spontaneous clearance is not feasible.
The link between the risk of developing Multiple Sclerosis (MS) and Epstein-Barr Virus (EBV) infection has been confirmed. However, the mechanisms by which EBV influences MS remain unclear, likely due to the complex interplay among the EBV subtype, the host's immune response, and viral and environmental exposures. In this review, we explore some of those complexities and the evidence on how EBV may contribute, at the molecular level, to MS pathogenesis across the spectrum of MS disease, both relapsing-remitting and progressive. For this review, we searched PubMed and Medline entries using a combination of terms related to 'Epstein-Barr Virus,' 'Multiple Sclerosis,' 'disease-modifying therapies,' and 'EBV activity.' Those search results were then used to address how EBV relates to MS pathophysiology and how the effects of MS risk factors and the efficacy of disease-modifying therapies may be explained by their effects on EBV. We posit that addressing EBV infection and viral replication is vital to the discovery of a cure for MS. Given that multiple genetic factors are involved, targeting EBV within cellular reservoirs and suppressing EBV protein expression is likely to provide the greatest benefit in preventing MS disease activity, progression, and immune-mediated neurodegeneration.
A 29-year-old woman with a novel homozygous VPS13A frameshift variant presented with drug-resistant temporal-lobe epilepsy and severe sensory neuronopathy, but no acanthocytes on repeated blood smears-expanding the phenotypic spectrum of chorea-acanthocytosis beyond its defining haematological feature.
Alzheimer's disease (AD) is characterised by the intraneuronal aggregation of phosphorylated Tau (pTau) into neurofibrillary tangles and by the extracellular deposition of β-amyloid (Aβ). Tau pathology restricted to the hippocampal formation is frequently observed in the elderly brain in the absence of any Aβ deposition and considered as "primary age-related tauopathy" (PART). Here, we applied an unbiased proteomic approach to determine how concomitant Aβ pathology modifies the neurofibrillary tangle proteome. Neurofibrillary tangles were isolated by dissecting Tau pSer202/pThr205 "AT8" immunopositive neuronal profiles, combining chromogenic immunohistochemistry with laser capture microdissection, from hippocampal sections of 17 post-mortem brains spanning three groups: PART (n = 5; A0, B1-2, C0 scores), intermediate AD (n = 6; A1-2, B2-3, C1-2 scores) and advanced AD (n = 6; A3, B3, C3 scores). A label-free quantitative liquid chromatography-mass spectrometry based proteomic analysis, using data independent acquisition (DIA) on a Bruker timsTOF, was performed. A conserved core of 63 proteins was identified as enriched in tangles across all groups, mostly associated with "RNA binding" and "regulation of mRNA metabolic process", based on the Gene Ontology database. Group-specific signatures were also observed: 33 proteins were significantly enriched only in tangles collected from PART cases and were predominantly linked to "structural molecule activity", whereas Aβ-positive cases showed specific enrichment of "RNA binding" and "cytoplasmic translation" pathways-with intermediate AD cases displaying a transitional profile. Our findings are consistent with PART having distinct tangle proteomic features; however, the majority of its proteomic signature is in common with tangles within the AD continuum. By addressing how Aβ accumulation alters the tangle proteome, this study provides mechanistic insights into the expansion of Tau pathology, paving the way towards the identification of biomarkers and therapeutic strategies that would allow for stabilisation of Tau pathology in the elderly.
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In this article, the authors explore the topics of grief and loss through individual vignettes, sharing stories of grief ranging from the loss of identity, the loss of a parent or loved one, and the cultural divides that make nuanced care decisions more challenging, to working in systems that may fail us and our patients. They explore the idea of nested spheres of grief that span from the individual to societal and cultural realms. Each vignette reflects the depth and complexity of their personal experiences and emotions. These moments of grief may result in moral distress, but also present opportunities to rethink and reinvent flawed systems. The authors' individual experiences of grief have brought them together to form a community of like-minded practitioners across multiple disciplines. They seek to honor their losses and harness the power of grief to improve the care they provide patients and each other. The nested model of interconnecting spheres of grief they propose may prove useful as a framing device to help all of us name our often nuanced, challenging, and complex experiences with grief. The paper concludes with a call to action, which is voiced as a priority moving forward.
Blood glucose metabolism is a key process for maintaining normal physiological functions of the human body. The maintenance of its homeostasis relies on complex hormone regulation and the synergistic effect of tissues and organs. However, when insulin resistance occurs in skeletal muscles, insulin signalling is impaired, and glucose uptake decreases, leading to elevated blood sugar levels. This study investigates the SARS-CoV-2 spike protein's effect on insulin resistance in type 2 diabetes (T2DM) skeletal muscle in a specific demographic. In the cell experiment, we used human C2C12 skeletal muscle cells and co-cultured them with the spike protein to observe the effects of the spike protein on the proliferation, apoptosis, and glucose uptake. The research results show that the spike protein may reduce the expression and transport of GLUT4 by inhibiting the PI3K/AKT/mTOR signalling pathway, thereby decreasing glucose uptake, intensifying insulin resistance in skeletal muscle, and affecting blood glucose metabolism.
Despite high efficacy and favorable safety profile in adults, Onabotulinumtoxin A (ONA) injections have not been Food and Drug Administration approved for pediatric migraine due to a lack of consistent data in children with chronic headaches. We prospectively surveyed 45 patients between 12 and 22 years of age with chronic migraine receiving ONA treatments using the Phase II Research Evaluating Migraine Prophylaxis Therapy protocol in our pediatric headache clinic. Subgroup analysis was performed on patients with daily chronic migraine. Headache frequency, pain scores, and disability were assessed at baseline and 6 weeks after each treatment. Forty-five patients were included for analysis; median age was 17 years, and 36/45 (80%) were female. Twelve out of forty-five (27%) patients had a greater than 50% reduction in headache days after one treatment (P < 0.005). Of the patients with available data following two treatments, 8/24 (33%) patients had a greater than 50% decrease in headache days (P = 0.004). In the subset of patients with daily chronic migraine, 6/27 (22%) patients had a greater than 50% reduction in headache days after the first treatment (P = 0.016). Mean headache disability as measured by the Headache Impact Test decreased after the first four treatments in the entire cohort and after the second and third treatments in the subset of patients with chronic daily migraine. These results suggest that ONA is effective in decreasing headache frequency and disability in pediatric patients with both chronic migraine and daily chronic migraine, which may improve quality of life.
Arginine vasopressin (AVP) is used as an adjunct to catecholamine vasopressors, but its role as a sole agent in high-risk non-cardiac surgery remains poorly defined. To characterize the integrated hemodynamic effects of AVP when used as the primary intraoperative vasopressor. In a propensity-matched physiological analysis, high-risk patients receiving AVP as the sole intraoperative vasopressor were matched to contemporaneous controls managed with catecholamine-based vasopressors. Serial hemodynamic data were analyzed, including arterial pressure, cardiac index, central venous pressure (CVP), venous return determinants, efficiency measures, and intraoperative fluid administration. Fifteen AVP-treated patients were matched to 13 controls, with all covariates balanced (SMDs <0.10). Mean AVP infusion rate was 0.023 (0.005) IU min-1. AVP patients received lower intraoperative fluids (p = 0.03) and had reduced net positive fluid balance (p = 0.02). Mean arterial pressure targets were maintained in both groups (AVP: 72-78 mmHg; controls: 70-76 mmHg). Cardiac index remained preserved with AVP (2.2-2.5 L min-1 m-2), comparable to controls (2.1-2.4 L min-1 m-2), despite lower CVP (AVP: 6-7 mmHg vs. 8-10 mmHg), consistent with effective recruitment of stressed volume and preserved cardiac function. Resistance to venous return remained stable over time, with no between-group differences (p > 0.05). AVP-treated patients demonstrated patterns consistent with improved circulatory efficiency compared with controls. In high-risk non-cardiac surgery, AVP-based hemodynamic management was associated with stable circulatory dynamics, preserved venous return, and reduced fluid exposure. These findings provide a physiological rationale for considering AVP as an alternative hemodynamic strategy in selected surgical patients.
Intron retention (IR) is the molecular phenomenon by which introns, historically thought to represent non-coding 'junk', remain unspliced within pre-mRNA transcripts, resulting in their incorporation into the mature mRNA molecule. While the role of IR is well established in species of plant, fungi, insects and viruses, it remains relatively understudied in mammalian biology. It was previously assumed that IR only played a limited role in downregulating a transcript's translation potential through downstream initiation of nuclear detention or nonsense mediated decay (NMD). However, recent studies highlight IR's significantly more complex and dynamic contribution to cellular physiology and disease. In particular, a role for IR is emerging in both health and neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), a rapidly progressive and invariably fatal disease that renders patients paralysed and unable to eat, speak or breathe. Significant technological advances now permit a comprehensive interrogation of previously unrecognized aspects of RNA metabolism in clinically relevant human cell types. In this review, we focus on the differential role(s) of nuclear and cytoplasmic intron retaining transcripts (nIRTs and cIRTs, respectively), as well as how IRTs may influence subcellular localization of ribonucleoprotein (RNP) complexes, loss of function of bound RNA binding proteins (RBPs) and liquid-liquid phase separation (LLPS) in physiology and disease. Additionally, we discuss the potential of IRTs as independent regulatory elements beyond their protein-coding functions and highlight how artificial intelligence is poised to accelerate discoveries in this area. In the context of IR's increasing appreciation, we also highlight its potential as a therapeutic target and explore current and future challenges in this burgeoning field.
We aimed to investigate associations between menopausal characteristics, including age at menopause and cause (natural vs. artificial), with long-term outcomes in women with rheumatoid arthritis (RA), incident Alzheimer's disease and related dementias (ADRD), RA severity, and overall mortality. We hypothesized that atypical menopausal characteristics increase ADRD risk and disease severity. Women with incident RA in 1980-2014 who were ≥50 years of age at RA incidence were included. Menopause cause and age at menopause (categorized as <45, 45-54, ≥55 years) were abstracted from medical records. Associations between menopausal characteristics and ADRD, extra-articular manifestations (ExRA), erosions, cardiovascular events, and mortality were evaluated using Cox models. Associations with clinic visits for flares and remissions were assessed using mixed-effects models. Data were collected using the Rochester Epidemiology Project medical records-linkage system. Both early/premature and late menopause were associated with nonsignificant near two-fold increases in ADRD risk. In addition, early/premature (HR 2.40; 95% CI 1.15-5.01) and late menopause (HR 2.17; 95% CI 1.01-4.66) significantly increased severe ExRA risk. Menopausal characteristics were not associated with presence of erosions or mortality. Artificial menopause was associated with fewer cardiovascular events and fewer visits for RA remission. Early/premature menopause was associated with fewer remission visits (OR 0.50; 95% CI 0.29-0.87). Women with early/premature and late menopause had nonsignificant, increased risk of incident ADRD. Menopausal characteristics had significant associations with RA severity and cardiovascular events, and may be relevant contextual factors in long-term risk assessment for women with RA.
Rapid formation and recurrence of aneurysms accompanied by severe arterial stenosis following radiation therapy (RT) for nasopharyngeal carcinoma (NPC) is an uncommon clinical phenomenon. We present the case of a 51-year-old man who developed subarachnoid hemorrhage years after undergoing RT for NPC. Digital subtraction angiography revealed a ruptured, irregular, wide- neck aneurysm at the posterior communicating segment of the right internal carotid artery (ICA), along with significant stenosis (approximately 80%) at the cervical segment of the same artery. The cervical ICA stenosis was initially treated with stenting, followed by LVIS stent-assisted coil embolization of the aneurysm. Over the next four years, the patient developed three entirely new ICA aneurysms-one of which arose from within the middle portion of the previously placed LVIS stent (a finding not previously reported)-as well as one recurrent aneurysm. This rare case highlights the dynamic nature of RT-induced ICA aneurysm formation and recurrence. Lifelong monitoring and individualized endovascular management are crucial. Considering the fragility of irradiated tissues, extensive arterial involvement, and increased surgical risk from repeat procedures, endovascular treatment was favored over open surgery.
Objective measurement of tremors is important for assessing the severity and preventing misdiagnosis of Parkinson's disease (PD). To address this demand, this study presents a multichannel, wireless, patch-type tremor monitoring system that integrates a high-repeatable fibrous crack-based strain (FCBS) sensor with a flexible wireless communication circuit. The FCBS sensor, incorporating crack structures, random fiber orientation, junction melting, and polymer penetration within a 3D conductive fiber network, achieves high sensitivity (gauge factor up to 476.89), a fast response time (≈ 6.64 ms), a wide working range (>200% strain), low Young's modulus (≈45 kPa), and excellent repeatability (>100 000 cycles). In addition, this study demonstrates the first clinical application of a flexible strain sensor-based tremor monitoring system in patients with PD and ET for simultaneous multilocation tremor measurement. Through clinical trials, our system measured tremor indicators (peak amplitude and fundamental frequency), and tremor indicators obtained from multilocation showed improved correlation and statistical significance with tremor scoring in UPDRS III under specific conditions. These results demonstrate the applicability and potential of the flexible strain sensor-based system as a wearable platform for quantitative and objective tremor measurement.
Insufficient sleep syndrome (ISS) is characterized by excessive daytime sleepiness due to chronic sleep deprivation. We assessed the "real-word" experience of a tertiary sleep center with its diagnosis and management. We retrospectively studied patients with probable ISS referred to the University Sleep-Wake-Epilepsy Center, Bern, between 2000 and 2021. Diagnosis was based on the International Classification of Sleep Disorders, 3rd edition, and classified as probable (criteria 1-4 fulfilled) or definite (criteria 1-5 fulfilled). We analyzed the impact of comorbidities on demographic and baseline characteristics and the effect of sleep extension on Epworth sleepiness scale (ESS) score and actigraphy measures. Among >12,000 patients, 238 had probable ISS. Median age was 34 years (IQR ±22), 45% were female and 82% had comorbidities. Demographic, clinical, and sleep-wake test characteristics were broadly similar between patients with and without comorbidities. Of 95 patients with follow-up, 49 improved after sleep extension and were classified as definite ISS. Compared with patients remaining probable ISS, definite ISS patients had lower follow-up ESS scores (8.5 (7.0-11.2) vs. 10.0 (8.0-14.0), p = 0.03). In definite ISS, time in bed increased by 36 min (p ≤ 0.001). These patients had shorter baseline minimum time in bed, but otherwise similar actigraphy measures. In this sleep-disordered population, ISS was difficult to confirm and likely underreported. Comorbidities may be less decisive for diagnosis than previously assumed. Increasing TIB from the individual baseline and avoiding extremely short sleep periords may be clinically relevant. To improve ISS management, a critical reappraisal of current criteria and standardized approaches are needed.
Distal transradial access (dTRA) is an alternative to proximal transradial access (pTRA) for neuroangiography, but comparative real-world data and evidence on its early learning curve remain limited. We compared procedural performance and access-site complications between dTRA and pTRA and evaluated the early learning curve of dTRA. We retrospectively analyzed 470 diagnostic cerebral angiography procedures, representing 421 unique patients, performed via radial access at a single center between January 2025 and February 2026, including 237 dTRA and 233 pTRA procedures. Baseline characteristics, including age, sex, body mass index (BMI) category, aortic arch type, and antiplatelet/anticoagulant use, procedural performance, and clinically assessed access-site events were compared between groups. Radial artery occlusion (RAO) was assessed by postoperative bedside pulse examination and confirmed with Doppler ultrasound when clinical findings were uncertain. Multivariable logistic regression was used to evaluate predictors of RAO, persistent bleeding or repeated compression, hand edema, and a composite access-site event endpoint. Because repeated procedures occurred in a subset of patients and event counts were limited, first-procedure sensitivity analysis and analyses of infrequent outcomes were interpreted cautiously. The dTRA learning process was assessed in the first 100 dTRA cases performed by a single operator using multivariable regression, cumulative sum (CUSUM) analysis, segmented trend analysis, and phase-based comparisons. Baseline characteristics were comparable between groups, including age, male sex, BMI category, aortic arch type, and antiplatelet/anticoagulant use. Compared with pTRA, dTRA was associated with more puncture attempts (3.0 [2.0-4.0] vs 2.0 [1.0-3.0], P < 0.001), longer puncture time (2.0 [1.0-5.0] vs 2.0 [1.0-3.0] min, P = 0.003), lower first-pass success (19.4% vs 35.2%, P < 0.001), and a higher crossover rate (11.4% vs 6.0%, P = 0.037). However, dTRA was associated with a lower clinically assessed RAO rate (2.5% vs 7.7%, P = 0.011). On multivariable analysis, pTRA was independently associated with higher odds of RAO (OR 3.27, 95% CI 1.26-8.49, P = 0.015) and the composite access-site event endpoint (OR 3.12, 95% CI 1.55-6.28, P = 0.001). Similar findings were observed in a sensitivity analysis restricted to the first procedure per patient. In the first 100 dTRA cases, cumulative dTRA experience was independently associated with shorter total procedure time (beta = -0.074 min/case, P = 0.009), while CUSUM and moving-average analyses suggested that the major learning effect occurred within approximately the first 10-15 cases. In this retrospective single-operator cohort, dTRA was associated with lower clinically assessed RAO than pTRA despite greater access difficulty. The early learning effect was mainly reflected in shorter total procedure time. These findings support the feasibility of dTRA but should be interpreted cautiously given the study's observational design and limited anatomical data.
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Mild malformation of cortical development with oligodendroglial hyperplasia in epilepsy (MOGHE) is a recently defined malformation of cortical development that is an important cause of childhood-onset drug-resistant epilepsy. Clinically, the epilepsies associated with MOGHE are heterogeneous, with infantile epileptic spasms syndrome (IESS) being the most common manifestation. Histopathologically, MOGHE demonstrates subtle cortical dyslamination, heterotopic neurons in the white matter, hypomyelination, and a distinctive increase in the density and clustering of oligodendroglial cells, features that distinguish it from other malformations of cortical development such as focal cortical dysplasia (FCD). Recent genetic analyses of epileptogenic tissue resected from individuals with MOGHE have identified somatic mosaic loss-of-function variants in SLC35A2. This gene encodes the Golgi transmembrane UDP-galactose transporter, suggesting disrupted N-glycosylation as a distinct pathogenic mechanism underlying epilepsy in this disorder. In this review, we present the current clinical, histopathological, and molecular understanding of MOGHE, with a particular focus on recent insights gained from experimental rodent and human cellular models of SLC35A2 deficiency. We contextualise these findings against established models of mTORopathies including FCD type 2, placing MOGHE within the broader malformation of cortical development spectrum. Synthesising this evidence, we observe that neuronal activity in models of both MOGHE and mTORopathies such as FCD type 2 converge on reduced action potential firing, despite their distinct genetic aetiologies. Finally, we discuss how these findings inform our understanding of epileptogenesis, especially the emergence of infantile epileptic spasms, and the development of future precision therapeutic strategies across malformations of cortical development.
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Microglia play a pivotal role in the pathophysiology of ischemic stroke, with substantial microglial demise occurring following cerebral ischemia. This study examined whether colony-stimulating factor 1 (CSF-1) and interleukin-34 (IL-34), ligands of the colony-stimulating factor 1 receptor (CSF1R) critical for microglial survival, promote microglial proliferation and ameliorate outcomes after ischemic stroke. In a mouse model of middle cerebral artery occlusion (MCAO), endogenous CSF-1 levels showed dynamic changes within the first 24 hours post-ischemia. Administration of CSF-1, but not IL-34, significantly improved neurological outcomes and reduced infarct volume. CSF-1 treatment was associated with a less reactive microglial morphology and an anti-inflammatory, homeostatic microglial phenotype. In vitro, CSF-1 enhanced Ki67 expression in oxygen-glucose deprivation (OGD)-exposed microglia, while decreasing pro-inflammatory cytokine production and excessive phagocytosis of neuronal debris. Conditioned medium from CSF-1-treated microglia and co-culture experiments further indicated that increased microglial numbers contribute to reduced OGD-induced neuronal apoptosis. Collectively, these findings suggest that CSF-1 fosters a neuroprotective microglial phenotype during acute ischemia, highlighting its potential as a therapeutic agent to mitigate ischemic brain injury through modulation of microglial proliferation and inflammatory responses.