@article {pmid40113485,
year = {2025},
author = {Anzilotti, S and Franco, C and Valsecchi, V and Cuomo, O and Lombardi, G and Di Muraglia, N and De Iesu, N and Laudati, G and Annunziato, L and Canzoniero, LMT and Giuseppe, P},
title = {Modulation of ZnT-1 by Let7a unveils a therapeutic potential in amyotrophic lateral sclerosis.},
journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics},
volume = {},
number = {},
pages = {e00571},
doi = {10.1016/j.neurot.2025.e00571},
pmid = {40113485},
issn = {1878-7479},
abstract = {The imbalance in cellular ionic homeostasis represents a hallmark of several neurodegenerative diseases, including Amyotrophic Lateral Sclerosis (ALS). Zinc Transporter 1 (ZnT1), the first described member of the ZnT family, stands out as the sole member of the SLC30 family responsible for exporting cytosolic zinc to the extracellular space. While ZnT1 is expressed across all tissues and cell types studied, it exhibits the highest prominence within the central nervous system. In ALS SOD1[G93A] mice, a reduction in ZnT1 expression consistent with disease progression has been observed, prompting our investigation into its role in ALS pathophysiology. Remarkably, through the use of a sequence complementary to the microRNA let-7a (anti-Let-7a) able to modulate ZnT1 expression, we demonstrated in ALS mice its capability to: (1) prevent the reduction in ZnT1 levels in the spinal cord; (2) preserve motor neuron survival in the ventral spinal horn; (3) decrease astroglial and microglial activation while sparing resident microglial cells in the spinal cord; and (4) improve the lifespan and alleviate motor symptoms.},
}

@article {pmid40109661,
year = {2025},
author = {Hong, Y and Shi, JQ and Feng, S and Huang, SQ and Yuan, ZH and Liu, S and Zhang, XH and Zhou, JS and Jiang, T and Zhao, HD and Zhang, YD},
title = {The systemic inflammation markers as potential predictors of disease progression and survival time in amyotrophic lateral sclerosis.},
journal = {Frontiers in neuroscience},
volume = {19},
number = {},
pages = {1552949},
pmid = {40109661},
issn = {1662-4548},
abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a fatal and untreatable neurodegenerative disease with only 3-5 years' survival time after diagnosis. Inflammation has been proven to play important roles in ALS progression. However, the relationship between systemic inflammation markers and ALS has not been well established, especially in Chinese ALS patients. The present study aimed to assess the predictive value of systemic inflammation markers including neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), lymphocyte to monocyte ratio (LMR), and systemic immune-inflammation index (SII) for Chinese amyotrophic lateral sclerosis (ALS).

METHODS: Seventy-two Chinese ALS patients and 73 controls were included in this study. The rate of disease progression was calculated as the change of Revised ALS Functional Rating Scale (ALSFRS-R) score per month. Patients were classified into fast progressors if the progression rate > 1.0 point/month and slow progressors if progression rate ≤ 1.0 point/month. The value of NLR, PLR, LMR, and SII were measured based on blood cell counts. The association between systemic inflammation markers and disease progression rate was confirmed by logistic regression analysis. Kaplan-Meier curve and Cox regression models were used to evaluate factors affecting the survival outcome of ALS patients.

RESULTS: For Chinese ALS patients, NLR, PLR and SII were higher, LMR was lower when compared with controls. All these four markers were proved to be independent correlated with fast progression of ALS. Both Kaplan-Meier curve and Cox regression analysis indicated that higher NLR and lower LMR were associated with shorter survival time in the ALS patients.

DISCUSSION: In conclusion, the systemic inflammation markers, especially NLR and LMR might be independent markers for rapid progression and shorter survival time in Chinese ALS patients.},
}

@article {pmid40109277,
year = {2025},
author = {Ding, XY and Habimana, JD and Li, ZY},
title = {The role of DPP6 dysregulation in neuropathology: from synaptic regulation to disease mechanisms.},
journal = {Frontiers in cellular neuroscience},
volume = {19},
number = {},
pages = {1547495},
pmid = {40109277},
issn = {1662-5102},
abstract = {As a transmembrane protein, DPP6 modulates the function and properties of ion channels, playing a crucial role in various tissues, particularly in the brain. DPP6 interacts with potassium channel Kv4.2 (KCND2), enhancing its membrane expression and channel kinetics. Potassium ion channels are critical in progressing action potential formation and synaptic plasticity. Therefore, dysfunction of DPP6 can lead to significant health consequences. Abnormal DPP6 expression has been identified in several diseases, such as amyotrophic lateral sclerosis (ALS), autism spectrum disorder (ASD), spinal bulbar muscular atrophy (SBMA), and idiopathic ventricular fibrillation. Recent research has indicated a connection between DPP6 and Alzheimer's disease as well. The most common symptoms resulting from DPP6 dysregulation are mental deficiency and muscle wastage. Notably, these symptoms do not always occur at the same time. Besides genetic factors, environmental factors also undoubtedly play a role in diseases related to DPP6 dysregulation. However, it remains unclear how the expression of DPP6 gets regulated. This review aims to summarize the associations between DPP6 and neurological diseases, offering insights as well as proposing hypotheses to elucidate the underlying mechanisms of DPP6 dysregulation.},
}

@article {pmid40108302,
year = {2025},
author = {Ma, W and Polgár, E and Dickie, AC and Hajer, MA and Quillet, R and Gutierrez-Mecinas, M and Yadav, M and Hachisuka, J and Todd, AJ and Bell, AM},
title = {Anatomical characterisation of somatostatin-expressing neurons belonging to the anterolateral system.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {9549},
pmid = {40108302},
issn = {2045-2322},
support = {MR/S002987/1/MRC_/Medical Research Council/United Kingdom ; MR/S002987/1/MRC_/Medical Research Council/United Kingdom ; 219433/Z/19/Z/WT_/Wellcome Trust/United Kingdom ; 304005/Z/23/Z/WT_/Wellcome Trust/United Kingdom ; },
mesh = {Animals ; *Somatostatin/metabolism/genetics ; Mice ; *Neurons/metabolism ; *Spinal Cord/metabolism/cytology ; Axons/metabolism ; Male ; Pain/metabolism/genetics ; },
abstract = {Anterolateral system (ALS) spinal projection neurons are essential for pain perception. However, these cells are heterogeneous, and there has been extensive debate about the roles of ALS populations in the different pain dimensions. We recently performed single-nucleus RNA sequencing on a developmentally-defined subset of ALS neurons, and identified 5 transcriptomic populations. One of these, ALS4, consists of cells that express Sst, the gene coding for somatostatin, and we reported that these were located in the lateral part of lamina V. Here we use a Sst[Cre] mouse line to characterise these cells and define their axonal projections. We find that their axons ascend mainly on the ipsilateral side, giving off collaterals throughout their course in the spinal cord. They target various brainstem nuclei, including the parabrachial internal lateral nucleus, and the posterior triangular and medial dorsal thalamic nuclei. We also show that in the L4 segment Sst is expressed by ~ 75% of ALS neurons in lateral lamina V and that there are around 120 Sst-positive lateral lamina V cells on each side. Our findings indicate that this is a relatively large population, and based on projection targets we conclude that they are likely to contribute to the affective-motivational dimension of pain.},
}

Animals
*Somatostatin/metabolism/genetics
Mice
*Neurons/metabolism
*Spinal Cord/metabolism/cytology
Axons/metabolism
Male
Pain/metabolism/genetics

@article {pmid40106466,
year = {2025},
author = {Lemmers, SAM and Le Luyer, M and Stoll, SJ and Hoffnagle, AG and Ferrell, RJ and Gamble, JA and Guatelli-Steinberg, D and Gurian, KN and McGrath, K and O'Hara, MC and Smith, ADAC and Dunn, EC},
title = {Inter-rater reliability of stress signatures in exfoliated primary dentition - Improving scientific rigor and reproducibility in histological data collection.},
journal = {PloS one},
volume = {20},
number = {3},
pages = {e0318700},
pmid = {40106466},
issn = {1932-6203},
mesh = {Humans ; *Dental Enamel ; Reproducibility of Results ; *Tooth, Deciduous ; Stress, Physiological ; Observer Variation ; Female ; Child ; Male ; Stress, Psychological ; Data Collection/methods ; },
abstract = {Accentuated Lines (ALs) in tooth enamel can reflect metabolic disruptions from physiological or psychological stresses during development. They can therefore serve as a retrospective biomarker of generalized stress exposure in archaeological and clinical research. However, little consensus exists on when ALs are identified and inter-rater reliability is poorly quantified across studies. Here, we sought to address this gap by examining the reliability of accentuated (AL) markings across raters, in terms of both the presence versus absence of ALs and their intensity (HAL= Highly Accentuated, MAL= Mildly Accentuated, RL= Retzius Line). Ratings were made and compared across observers (with different levels of experience) and pairs of raters (who agreed on AL coding through consensus meetings) (N = 15 teeth, eight observers). Results indicated that more experience in AL assessment does not necessarily produce higher reliability between raters. Most disagreements in intensity ratings occurred in categories other than HAL. Furthermore, when AL assessment was performed by pairs of raters, reliability was significantly higher than individual assessments (Gwet's AC1 = 0.28 to 0.56 for line presence assessment; Gwet's AC1 = 0.48 to 0.64 for line intensity assessment). Based on these results, we recommend a workflow called IRRISS (Improving Reliability and Reporting In Scoring of Stress-markers) to increase rigor and reproducibility in histological analysis of dental collections. The introduction of IRRISS is well-timed, given the surge in studies of teeth occurring across anthropological, epidemiological, medical, forensic, and climate research fields.},
}

Humans
*Dental Enamel
Reproducibility of Results
*Tooth, Deciduous
Stress, Physiological
Observer Variation
Female
Child
Male
Stress, Psychological
Data Collection/methods

@article {pmid40105438,
year = {2025},
author = {Ueha, R and Dealino, MA and Koyama, M and Yamakawa, K and Matsumoto, N and Sato, T and Goto, T and Mizukami, A and Kondo, K},
title = {Improved Pharyngeal Contraction and Oral Intake Status After Modified Central-Part Laryngectomy for Late-Stage ALS.},
journal = {Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery},
volume = {},
number = {},
pages = {},
doi = {10.1002/ohn.1229},
pmid = {40105438},
issn = {1097-6817},
abstract = {OBJECTIVE: To investigate the effects of modified central-part laryngectomy with pharyngeal space reduction (CPL-PR) on patients with weak deglutitive pharyngeal contraction, as seen in late-stage amyotrophic lateral sclerosis (ALS).

STUDY DESIGN: Retrospective case series.

SETTING: Single-institution academic center.

METHODS: Patients with late-stage ALS confined at The University of Tokyo Hospital between 2019 and March 2024 in whom CPL-PR had been performed were identified. Patients who had undergone simultaneous pharyngeal flap surgery or had no preoperative high-resolution manofluorography done were excluded. Preoperatively, penetration-aspiration scale (PAS) scores were determined via videofluoroscopic swallowing study. Functional oral intake scale (FOIS) scores and high-resolution manometric parameters were measured and compared preoperatively and postoperatively.

RESULTS: Eighteen patients were identified with a median age of 66.5 (interquartile range [IQR]: 58.0-74.8). The median preoperative PAS score was 7.5 (IQR: 5.5-8.0), indicating severe dysphagia. There was significant improvement in oral intake status with FOIS scores increasing from 1 (IQR: 1-1) to 3 (IQR: 2-3) at 3 months postoperatively (P = .0002). Significant increases in velopharyngeal closure integral (P = .024) and mesohypopharyngeal contractile integral (P = .0001) were observed. Upper esophageal sphincter (UES) resting pressure was reduced (P = .0002), and UES relaxation time was prolonged during swallowing (P < .0001).

CONCLUSION: There were tangible improvements in pharyngeal contraction, UES bolus passage, and oral intake status following CPL-PR, which contribute to regaining oral intake in late-stage ALS. CPL-PR is an option for patients requiring tracheostomy who wish to prevent aspiration and regain their ability to take food orally.},
}

@article {pmid40105291,
year = {2025},
author = {Ozeki-Hayashi, R and Wilkinson, DJC},
title = {'An Unimaginable Challenge': A Cross-Cultural Qualitative Study of Ethics and Decision-Making Around Tracheostomy Ventilation in Patients with Amyotrophic Lateral Sclerosis.},
journal = {AJOB empirical bioethics},
volume = {},
number = {},
pages = {1-13},
doi = {10.1080/23294515.2025.2474928},
pmid = {40105291},
issn = {2329-4523},
abstract = {BACKGROUND: The rate of tracheostomy with invasive ventilation (TIV) for patients with Amyotrophic Lateral Sclerosis (ALS) varies widely. Previous studies have shown that doctors' values may affect decision-making. There have been no previous international qualitative comparisons of medical decision-making process for TIV or why practice varies.

METHODS: We conducted semi-structured in-depth interviews with 16 doctors actively involved in the management of ALS patients from Japan (n = 7), the UK (n = 5), and the US (n = 4). We used three hypothetical cases to explore decision-making. Conversations were transcribed and thematically analyzed.

RESULTS: Our data reveals similarities but also marked differences in views between the US, the UK and Japan. Almost all participants stated that they ought to respect patient autonomy. However, their approaches varied. British participants wanted to (and felt that they should) respect patient autonomy, but they also believed that TIV was not a realistic option. US participants were likely to prioritize patient autonomy over other ethical principles, and Japanese participants were likely to limit patient autonomy indirectly. The option of TIV appeared to be heavily influenced by the availability of healthcare resources in all three countries. The high cost, limited availability and difficulty of treatment meant that particularly in the UK and the US, it is challenging to receive TIV even if patients wanted this.

CONCLUSIONS: Our study illustrates how the emphasis on autonomy varies along with variations in the way care is organized in the setting of highly resource intensive treatment and progressive severe disabling illness. There is a need to review elements of the decision-making process in all three countries. This includes the need for transparent, ideally centralized, decision-making guidelines about the provision of TIV. Although we investigated a rare neuromuscular disease, our results will be relevant to other diseases requiring highly resource-intensive treatment toward the end of life.},
}

@article {pmid40105198,
year = {2025},
author = {Gotkine, M and Schoenfeld, DA and Cohen, I and Shefner, JM and Lerner, Y and Cohen, IR and Klein, C and Ovadia, E and Cudkowicz, ME and , },
title = {Akt Activation With IPL344 Treatment for Amyotrophic Lateral Sclerosis: First in Human, Open-Label Study.},
journal = {Muscle & nerve},
volume = {},
number = {},
pages = {},
doi = {10.1002/mus.28393},
pmid = {40105198},
issn = {1097-4598},
support = {//Immunity Pharma/ ; },
abstract = {INTRODUCTION/AIMS: Akt intracellular signal transduction pathway dysfunction has been reported in people with amyotrophic lateral sclerosis (ALS) providing a novel target for intervention in this devastating progressive disease. This first-in-human study evaluated the safety, tolerability, and preliminary efficacy of the Akt pathway activator, IPL344, in people with ALS.

METHODS: Nine participants with ALS and a progression rate > 0.55 points/month on the Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) received open-label IPL344 treatment (once-daily) for up to 36 months. Safety was assessed through adverse event (AE) reporting. Plasma neurofilament light chain (NfL) concentrations were measured before and after treatment. Clinical outcomes were compared to historical data.

RESULTS: The mean ± SD duration of IPL344 follow-up was 14.0 ± 12.5 months. One participant developed drug hypersensitivity, two had central venous catheter-related AEs, and two had serious pneumonia AEs. The unadjusted mean ± SE slope of decline in ALSFRS-R was -0.53 ± 0.15 (48% slower progression vs. historical controls, p = 0.028). Adjustment for disease stage and rate-indicating covariates indicated a 64% slower ALSFRS-R progression (p = 0.034), with increased rather than reduced body weight (p = 0.02). Eight of nine IPL344-treated participants had a significantly improved slope compared to the median slope of a matched control group (p = 0.04). Plasma NfL concentrations were lowered by 27% (n = 6). Unadjusted median survival for participants in the IPL344 group was 43.4 months [95% CI: 20.5, NA] compared with 19.1 months [17.4, 23.0] in the historical control group.

DISCUSSION: These preliminary data indicate that IPL344 was safe and well-tolerated, and possibly effective. Our findings may merit further investigation in a larger placebo-controlled clinical trial.},
}

@article {pmid40103545,
year = {2025},
author = {Sonaglioni, A and Torretta, P and Nicolosi, GL and Lombardo, M},
title = {Left ventricular mechanics assessment in amyloidosis patients: a systematic review and meta-analysis.},
journal = {Minerva cardiology and angiology},
volume = {},
number = {},
pages = {},
doi = {10.23736/S2724-5683.24.06683-3},
pmid = {40103545},
issn = {2724-5772},
abstract = {BACKGROUND: Over the last decade, a small number of studies have used speckle tracking echocardiography (STE) or cardiac magnetic resonance (CMR) for measuring left ventricular (LV) mechanics in patients with amyloidosis. This systematic review and meta-analysis aimed at assessing the overall influence of amyloidosis on LV global longitudinal strain (GLS) and regional longitudinal strain at basal (BLS), mid (MLS) and apical (ALS) level, respectively.

METHODS: All imaging studies assessing LV-GLS, LV-BLS, LV-MLS and LV-ALS in amyloidosis patients versus healthy controls, selected from PubMed and EMBASE databases, were included. The risk of bias was assessed by using the National Institutes of Health (NIH) Quality Assessment of Case-Control Studies. Continuous data (LV-GLS, LV-BLS, LV-MLS and LV-ALS) were pooled as a standardized mean differences (SMDs) comparing amyloidosis group with healthy controls. The overall SMDs of LV-GLS, LV-BLS, LV-MLS and LV-ALS were calculated using the random-effect model.

RESULTS: The full-texts of 13 studies with 553 amyloidosis patients and 575 healthy controls were analyzed. STE (53.8%) and CMR (46.2%) studies were separately analyzed. Average LV-GLS magnitude was significantly impaired in amyloidosis patients vs. controls in both STE (13.8±3.9 vs. 19.8±2.7%) and CMR (12.3±4 vs. 17.9±3.5%) studies. The impairment of segmental strain detected in amyloidosis patients was prevalent at basal and mid level, with relative "apical sparing." SMDs obtained for LV-GLS (SMD -1.80, 95% CI: -2.35, -1.24, P <0.001), LV-BLS (-1.98; 95% CI: -2.51, -1.45, P <0.001) and LV-MLS (-1.84; 95% CI: -2.46, -1.23, P <0.001) assessment were significantly larger than that obtained for LV-ALS (-0.72; 95% CI: -1.31, -0.13, P=0.02) measurement. Substantial heterogeneity was found among the studies assessing LV-GLS (I[2]=92.5%), LV-BLS (I[2]=91.4%), LV-MLS (I[2]=94.3%) and LV-ALS (I[2]=94.6%). Egger's test yielded a P value of 0.10, 0.20, 0.09 and 0.55 for LV-GLS, LV-BLS, LV-MLS and LV-ALS assessment respectively, indicating no publication bias. On meta-regression analysis, none of the moderators was significantly associated with effect modification for LV-GLS, LV-BLS, LV-MLS and LV-ALS (all P<0.05).

CONCLUSIONS: Amyloidosis has a large negative effect on LV-GLS, primarily related to the deterioration of segmental longitudinal strain at the basal and mid level, with relative apical sparing.},
}

@article {pmid40102416,
year = {2025},
author = {Rivas-Fernández, JP and Vuillemin, M and Pilgaard, B and Klau, LJ and Fredslund, F and Lund-Hanssen, C and Welner, DH and Meyer, AS and Morth, JP and Meilleur, F and Aachmann, FL and Rovira, C and Wilkens, C},
title = {Unraveling the molecular mechanism of polysaccharide lyases for efficient alginate degradation.},
journal = {Nature communications},
volume = {16},
number = {1},
pages = {2670},
pmid = {40102416},
issn = {2041-1723},
support = {315385//Norges Forskningsråd (Research Council of Norway)/ ; 226244//Norges Forskningsråd (Research Council of Norway)/ ; 294946//Norges Forskningsråd (Research Council of Norway)/ ; DFF170746//Det Frie Forskningsråd (Danish Council for Independent Research)/ ; 2021-SGR-00680//Government of Catalonia | Agència de Gestió d'Ajuts Universitaris i de Recerca (Agency for Management of University and Research Grants)/ ; NNF10CC1016517//Novo Nordisk Fonden (Novo Nordisk Foundation)/ ; },
mesh = {*Polysaccharide-Lyases/metabolism/chemistry ; *Alginates/chemistry/metabolism ; *Catalytic Domain ; Crystallography, X-Ray ; Kinetics ; Magnetic Resonance Spectroscopy ; Models, Molecular ; },
abstract = {Alginate lyases (ALs) catalyze the depolymerization of brown macroalgae alginates, widely used naturally occurring polysaccharides. Their molecular reaction mechanism remains elusive due to the lack of catalytically competent Michaelis-Menten-like complex structures. Here, we provide structural snapshots and dissect the mechanism of mannuronan-specific ALs from family 7 polysaccharide lyases (PL7), employing time-resolved NMR, X-ray, neutron crystallography, and QM/MM simulations. We reveal the protonation state of critical active site residues, enabling atomic-level analysis of the reaction coordinate. Our approach reveals an endolytic and asynchronous syn β-elimination reaction, with Tyr serving as both Brønsted base and acid, involving a carbanion-type transition state. This study not only reconciles previous structural and kinetic discrepancies, but also establishes a comprehensive PL reaction mechanism which is most likely applicable across all enzymes of the PL7 family as well as other PL families.},
}

*Polysaccharide-Lyases/metabolism/chemistry
*Alginates/chemistry/metabolism
*Catalytic Domain
Crystallography, X-Ray
Kinetics
Magnetic Resonance Spectroscopy
Models, Molecular

@article {pmid40102061,
year = {2025},
author = {Tran, K and Hayes, HA and Bromberg, M},
title = {A prospective observational study of decision-making by patients with amyotrophic lateral sclerosis upon recommendation for PEG enteral feeding tubes.},
journal = {Nutrition in clinical practice : official publication of the American Society for Parenteral and Enteral Nutrition},
volume = {},
number = {},
pages = {},
doi = {10.1002/ncp.11290},
pmid = {40102061},
issn = {1941-2452},
abstract = {OBJECTIVE: To understand challenges surrounding acceptance of a percutaneous endoscopic gastroscopic enteral feeding tube by patients with amyotrophic lateral sclerosis: a prospective observational study.

METHODS: This was a prospective observational study of 41 patients and care partners attending a multidisciplinary Motor Neuron Disease clinic. Surveys were administered pregastrostomy tube placement (N = 23) and postplacement (N = 41). Some were not available both pre- and postplacement). For preplacement, we queried barriers affecting their decision for receiving a gastrostomy tube at the time of recommendation. For postplacement, we queried factors that influenced their decision as well as perceived benefit and satisfaction with use.

RESULTS: Patient concerns about receiving a gastrostomy tube centered on the procedure, possible pain/infection (48%), limitations on activities (44%), impact on body image, and possible extension of life. For patients who received a gastrostomy tube, satisfaction was very high (93%), and there was reduced patient (59%) and care partners (54%) stress. The average BMI was 28.6 kg/m[2] at diagnosis, and there was no net gain in weight. The average time until placement of a gastrostomy tube following recommendation was 145 days (range 13-824 days).

CONCLUSIONS: Despite counseling at multiple time points, the decision to obtain a feeding tube is often challenging for patients and care partners. Gastrostomy tube placement was perceived as a substantial benefit. Addressing these barriers may reduce concerns and promote earlier decision-making to maximize the benefits of placing a gastrostomy tube sooner.},
}

@article {pmid40101794,
year = {2025},
author = {Krüger, DR and Jeschke, E and Gehrke, T and Günster, C and Halder, AM and Leicht, H and Malzahn, J and Schräder, P and Wirtz, DC and Zacher, J and Heller, KD},
title = {Impact of Hospital Case Volume on the Complication Rate in Hip Arthroplasty: An Analysis of Nationwide AOK Data.},
journal = {Zeitschrift fur Orthopadie und Unfallchirurgie},
volume = {},
number = {},
pages = {},
doi = {10.1055/a-2538-6446},
pmid = {40101794},
issn = {1864-6743},
abstract = {Aufgrund des demografischen Wandels und damit verbundener erwarteter Steigerungen der Fallzahlen von primärer Hüftendoprothetik und Revisionseingriffen ist es wichtig, Faktoren zu identifizieren, die Komplikationen und Revisionen reduzieren können. Ein solcher Faktor ist die Fallzahl eines Krankenhauses. Studien haben gezeigt, dass Krankenhäuser mit höheren Fallzahlen niedrigere Morbiditäts- und Komplikationsraten aufweisen. Die meisten Studien basieren dabei auf Registerdaten, die oft unvollständig sind und keine patientenspezifischen Faktoren beinhalten.In dieser Studie wurden bundesweite pseudonymisierte stationäre Abrechnungsdaten und Versichertenstammdaten der Allgemeinen Ortskrankenkassen (AOK) im Zeitraum von 2017 bis 2019 bei Patienten mit primärer Hüftendoprothese analysiert. Zur Analyse des Einflusses der Fallzahl auf das Outcome wurden 5 Fallzahlkategorien gebildet (I: 1-49, II: 50-99, III: 100-199, IV: 200-399, V: ≥ 400 Operationen pro Jahr). Als Endpunkte wurden 90-Tage-Sterblichkeit, 1-Jahres-Revisionsoperationen, chirurgische Komplikationen (90 Tage bzw. 365 Tage), periprothetische Femurfrakturen (90 Tage) und schwere Allgemeinkomplikationen im Krankenhausaufenthalt betrachtet. Der Einfluss der Fallzahl auf das Outcome wurde mittels multipler logistischer Regression unter Berücksichtigung patientenspezifischer Faktoren bestimmt.Die Analyse von 137494 Fällen aus 993 Kliniken zeigt einen statistisch signifikanten Zusammenhang zwischen der Fallzahlgruppe und der Häufigkeit von Revisionsoperationen, chirurgischen Komplikationen, periprothetischen Femurfrakturen und allgemeinen Komplikationen. Bei Kliniken mit einer Fallzahl von weniger als 50 pro Jahr zeigte sich eine Risikoerhöhung um 65%-88% für diese Endpunkte gegenüber der fallzahlstärksten Gruppe. Für den Endpunkt Sterblichkeit ergibt eine dichotome Betrachtung der Fallkategorien ebenfalls einen signifikanten Einfluss der Fallzahlen.Die Studie zeigt, dass, auch unter Berücksichtigung patientenspezifischer Faktoren, höhere Fallzahlen bei primärer Hüftendoprothetik in Krankenhäusern mit niedrigeren Komplikationsraten verbunden sind. Diese Erkenntnisse unterstreichen die Bedeutung der Fallzahl als Faktor zur Verbesserung der Versorgungsqualität in der Hüftendoprothetik.},
}

@article {pmid40100917,
year = {2025},
author = {Thau-Habermann, N and Gschwendtberger, T and Bodemer, C and Petri, S},
title = {Parthenolide regulates microglial and astrocyte function in primary cultures from ALS mice and has neuroprotective effects on primary motor neurons.},
journal = {PloS one},
volume = {20},
number = {3},
pages = {e0319866},
pmid = {40100917},
issn = {1932-6203},
mesh = {Animals ; *Microglia/drug effects/metabolism/pathology ; *Amyotrophic Lateral Sclerosis/drug therapy/metabolism/pathology ; *Sesquiterpenes/pharmacology ; *Motor Neurons/drug effects/metabolism/pathology ; *Neuroprotective Agents/pharmacology ; Mice ; *Astrocytes/drug effects/metabolism ; Cells, Cultured ; Mice, Transgenic ; Superoxide Dismutase/metabolism ; },
abstract = {Over the last twenty years, the role of microgliosis and astrocytosis in the pathophysiology of neurodegenerative diseases has increasingly been recognized. Dysregulation of microglial and astrocyte properties and function has been described also in the fatal degenerative motor neuron disease amyotrophic lateral sclerosis (ALS). Microglia cells, the immune cells of the nervous system, can either have an immunonegative neurotoxic or immunopositive neuroprotective phenotype. The feverfew plant (Tanacetum parthenium) derived compound parthenolide has been found to be capable of interfering with microglial phenotype and properties. Positive treatment effects were shown in animal models of neurodegenerative diseases like Alzheimer's disease and Parkinson's disease. Now we were able to show that PTL has a modulating effect on primary mouse microglia cells, both wild type and SOD1, causing them to adopt a more neuroprotective potential. Furthermore, we were able to show that PTL, through its positive effect on microglia, also has an indirect positive impact on motor neurons, although PTL itself has no direct effect on these primary motor neurons. The results of our study give reason to consider PTL as a drug candidate for ALS.},
}

Animals
*Microglia/drug effects/metabolism/pathology
*Amyotrophic Lateral Sclerosis/drug therapy/metabolism/pathology
*Sesquiterpenes/pharmacology
*Motor Neurons/drug effects/metabolism/pathology
*Neuroprotective Agents/pharmacology
Mice
*Astrocytes/drug effects/metabolism
Cells, Cultured
Mice, Transgenic
Superoxide Dismutase/metabolism

@article {pmid40100796,
year = {2025},
author = {Giroud, M and Kuhn, B and Steiner, S and Westwood, P and Mendel, M and Mani, A and Pinard, E and Haap, W and Grether, U and Caramenti, P and Rombach, D and Zambaldo, C and Ritter, M and Schmid, P and Gasser, C and Aregger, N and Séchet, N and Topp, A and Bilyard, M and Malnight-Alvarez, A and Plitzko, I and Hilbert, M and Kalayil, S and Burger, D and Bonardi, C and Saal, W and Haider, A and Wittwer, MB and Brigo, A and Benz, J and Keaney, J},
title = {Discovery of a Potent SARM1 Base-Exchange Inhibitor with In Vivo Efficacy.},
journal = {Journal of medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.jmedchem.4c03127},
pmid = {40100796},
issn = {1520-4804},
abstract = {Sterile alpha and TIR Motif Containing 1 (SARM1) is a nicotinamide adenine dinucleotide (NAD[+]) hydrolase that plays a central role in programmed axonal degeneration. Axonal degeneration has been linked to neurodegenerative and neurological disorders such as multiple sclerosis, amyotrophic lateral sclerosis, Parkinson's disease, and peripheral neuropathies. Therefore, developing potent and selective SARM1 inhibitors could be an effective strategy to treat these disorders. We present herein the structure-guided discovery of two novel SARM1 inhibitors, 7 and 35. Compounds 7 and 35 are potent inhibitors across assays and possess favorable ADMET properties. When tested in vivo, compound 7 showed efficacy after oral dosing in a mouse model of peripheral nerve injury by decreasing plasma neurofilament light (NfL) levels at 50 mg/kg compared with vehicle-treated control mice, holding promise for the treatment of neurodegenerative and neurological disorders.},
}

@article {pmid40100285,
year = {2025},
author = {De Bertier, S and Lautrette, G and Amador, MD and Miki, T and Boillée, S and Lobsiger, CS and Bohl, D and Darios, F and Machat, S and Duchesne, M and Vourc'h, P and Fauret-Amsellem, AL and Corcia, P and Guy, N and Couratier, P and Seilhean, D and Millecamps, S},
title = {MAPT mutations in amyotrophic lateral sclerosis: clinical, neuropathological and functional insights.},
journal = {Journal of neurology},
volume = {272},
number = {4},
pages = {272},
pmid = {40100285},
issn = {1432-1459},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/pathology/physiopathology ; *tau Proteins/genetics ; Male ; Female ; Middle Aged ; Mutation ; Pedigree ; Adult ; Aged ; Brain/pathology ; Animals ; Mutation, Missense ; },
abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are part of a well-established disease continuum, underpinned by TDP43-pathology. In contrast, the clinical manifestations of Tau-linked disorders are typically limited to cognitive phenotypes or atypical parkinsonism, although few reports describe motor neuron involvement associated with MAPT (microtubule-associated protein Tau) mutations. This study aimed to investigate the contribution of MAPT to the ALS phenotype.

METHODS: We analyzed a whole-exome sequencing database comprising 470 ALS patients and explored the pathogenicity of the identified variants through familial, clinical, neuropathological, and cellular studies.

RESULTS: We identified two missense variants in the Tau repeat domains: the novel p.I308T variant, in a patient with early-onset ALS, and the p.P364S mutation in three families with spinal- or respiratory-onset ALS. Segregation of this mutation with disease could be confirmed in two affected cousins. The observation of p.P364S patient's tissue showed accumulations of hyperphosphorylated Tau in various brain regions, prominent in the motor cortex with Lewy body-like inclusions, along with a C-terminal cleaved form of Tau in muscle. In NSC-34 motor neuron cells expressing p.I308T or p.P364S mutants, Tau was discontinuous along the neurites, with clusters of mitochondria resulting from impaired mitochondrial motility.

CONCLUSION: These findings expand the molecular understanding of ALS to include MAPT mutations. MAPT analysis should be incorporated into ALS genetic screening, particularly in patients with a familial history of the disease. Recognizing the full spectrum of MAPT-linked neurodegenerative diseases is of considerable interest, given the ongoing efforts to develop MAPT-targeted therapies.},
}

Humans
*Amyotrophic Lateral Sclerosis/genetics/pathology/physiopathology
*tau Proteins/genetics
Male
Female
Middle Aged
Mutation
Pedigree
Adult
Aged
Brain/pathology
Animals
Mutation, Missense

@article {pmid40099869,
year = {2025},
author = {Kim, SB and Lee, JS and Lan, X and Huang, W and Taylor, DJ and Kwon, YT and Zhang, Y and Ji, CH},
title = {The structure-function relationship of ATE1 R-transferase of the autophagic Arg/N-degron pathway.},
journal = {Autophagy},
volume = {},
number = {},
pages = {1-3},
doi = {10.1080/15548627.2025.2473393},
pmid = {40099869},
issn = {1554-8635},
abstract = {ATE1 (arginyltransferase 1; EC 2.3.2) transfers the amino acid arginine (Arg) from Arg-tRNA[Arg] to the N-terminal (Nt) residues of proteins, such as aspartate (Asp), glutamate (Glu), and oxidized cysteine (Cys). The resulting Nt-Arg acts as an N-degron that regulates the degradation of various biomaterials via the ubiquitin/Ub-proteasome system (UPS) or the autophagy-lysosome system (ALS). In the UPS, Arg/N-degrons are recognized by cognate N-recognins, leading to substrate ubiquitination and proteasomal degradation. In the ALS, the same degrons bind the macroautophagy/autophagy receptor SQSTM1/p62 (sequestosome 1) to facilitate self-polymerization of SQSTM1 associated with cargoes and SQSTM1 interaction with LC3-II on phagophores. A key unresolved question is why only a small subset of proteins acquires Arg/N-degrons, given the rather weak binding affinity of ATE1 for Nt-substrates. In this study, we determined the cryo-EM structures of human ATE1 in complex with Arg-tRNA[Arg] and an Nt-Asp peptide. ATE1 harbors two adjacent pockets that each bind an Nt-substrate or Arg-tRNA[Arg], the latter being wrapped by a long, unstructured loop. In the apo state, two ATE1 monomers form a homodimer. ATE1 achieves the selectivity for its peptidyl-ligands through these multivalent interactions, with Kd values in the micro-molar range. These results reveal the structural principle of Nt-arginylation at the crossroads of the UPS and ALS.Abbreviations: ALS: autophagy-lysosome system; Arg: arginine; Asp: aspartate; ATE1: arginyltransferase 1; Cys: cysteine; CysO2(H): Cys sulfinic acid; Glu: glutamate; Nt: N-terminal; UBR: ubiquitin protein ligase E3 component n-recognin; UPS: ubiquitin-proteasome system; ZZ: ZZ-type zinc finger.},
}

@article {pmid40099804,
year = {2025},
author = {Zheng, W and Zhang, X and Chen, J and Luan, X and Wang, J and Zhang, L and Liu, K and Zhao, Y and Xu, Z},
title = {The Effect of Repetitive Transcranial Magnetic Stimulation of the Dorsolateral Prefrontal Cortex on the Amyotrophic Lateral Sclerosis Patients With Cognitive Impairment: A Double-Blinded, Randomized, and Sham Control Trial.},
journal = {CNS neuroscience & therapeutics},
volume = {31},
number = {3},
pages = {e70316},
pmid = {40099804},
issn = {1755-5949},
support = {20YF1436400//Shanghai Sailing program/ ; 23DZ2291500//Shanghai Science and Technology Innovation Action Plan/ ; },
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/complications/psychology ; *Transcranial Magnetic Stimulation/methods ; Double-Blind Method ; Male ; Female ; Middle Aged ; Aged ; *Cognitive Dysfunction/therapy/etiology/psychology ; *Dorsolateral Prefrontal Cortex/physiology ; Treatment Outcome ; Prefrontal Cortex ; Adult ; },
abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease. A large number of ALS patients have cognitive impairment. In this double-blinded, randomized, and sham-controlled study, we aimed to investigate the effect of repetitive transcranial magnetic stimulation (rTMS) on ALS patients with cognitive impairment.

METHODS: A total of 90 ALS patients with cognitive impairment were recruited from two cohorts; 80 participants were randomly assigned in a 1:1 ratio to receive 10 Hz rTMS or sham treatment on the bilateral dorsolateral prefrontal cortices (DLPFC) for 4 consecutive weeks. The patients were assessed by ECAS and ALSFRS-R scales. The Zarit care burden scale was administered to caregivers of ALS patients. The primary outcome measured was the rate of decline in the total ECAS score between pretreatment, 6 months post-treatment, and 12 months post-treatment. Secondary outcomes included the group difference in the slope of the Zarit score, ALSFRS-R total score, and the neurofilament light chain plasma levels.

RESULTS: The ECAS total score in the intention-to-treat population significantly changed from 79.74 ± 6.39 to 81.98 ± 6.51 and 79.22 ± 6.50 with rTMS intervention at the 6-month and 12-month follow-ups, respectively (p = 0.031, p = 0.042). The Zarit score also significantly decreased from 57.65 ± 3.42 to 52.24 ± 3.34 and 56.42 ± 3.41 at the 3-month and 6-month post-treatment time points, respectively (p = 0.003, p = 0.014). No significant differences were observed between the groups for other secondary endpoints. However, there was a trend of decreasing NF-L level rates in the treatment group over the first 6 months' follow-up.

CONCLUSIONS: rTMS could yield short-term positive effects on the ALS patients subgroup with cognitive impairment and alleviate caregivers' burden. No improvement was observed in the severity of ALS and ALS plasma biomarkers.},
}

Humans
*Amyotrophic Lateral Sclerosis/therapy/complications/psychology
*Transcranial Magnetic Stimulation/methods
Double-Blind Method
Male
Female
Middle Aged
Aged
*Cognitive Dysfunction/therapy/etiology/psychology
*Dorsolateral Prefrontal Cortex/physiology
Treatment Outcome
Prefrontal Cortex
Adult

@article {pmid40099353,
year = {2025},
author = {Giorgio, CM and Tancredi, V and Licata, G and Moscarella, E and Argenziano, G and Fulgione, E and Babino, G and Franzese, P and Di Brizzi, EV},
title = {Cutting-edge insights: LC-OCT and 5% cyclosporine for early lichen sclerosus treatment.},
journal = {Dermatology reports},
volume = {},
number = {},
pages = {},
doi = {10.4081/dr.2025.10279},
pmid = {40099353},
issn = {2036-7392},
abstract = {Dear Editor, Atrophic lichen sclerosus (ALS) is a chronic inflammatory dermatosis with significant morbidity, primarily affecting genital areas. The disease is often misdiagnosed or underdiagnosed, resulting in delayed treatment and progression to atrophic stages and permanent scars. While corticosteroids remain the first-line treatment, their long-term use may lead to adverse effects such as skin atrophy, prompting the need for alternative therapies. Cyclosporine, a calcineurin inhibitor, has shown efficacy in managing immune-mediated skin diseases and is delivered effectively through the Pentravan® vehicle. [...].},
}

@article {pmid32895997,
year = {2020},
author = {McElroy, KG and Stalter, AM and Smith, SD},
title = {Association of Community Health Nursing Educators 2020 Research Priorities and Research in Action Model.},
journal = {Public health nursing (Boston, Mass.)},
volume = {37},
number = {6},
pages = {909-924},
doi = {10.1111/phn.12790},
pmid = {32895997},
issn = {1525-1446},
mesh = {*Community Health Nursing/education ; *Education, Nursing, Baccalaureate/methods ; Humans ; Learning ; Public Health Nursing/education ; Research ; *Students, Nursing/psychology ; },
abstract = {OBJECTIVE: The Association of Community/Public Health Nurse Educators (ACHNE) Research Priorities Subcommittee presents a report on the state of the science of public health nursing education.

DESIGN: Whittemore and Knafl's (Journal of Advanced Nursing, 2005, 52, 546) five-step integrative review was used.

SAMPLE: Fifty-two articles were reviewed.

MEASUREMENTS: Braun et al's. (Handbook of research methods in health social sciences, 2019, 843) thematic analysis methods were used.

RESULTS: Four themes emerged: (a) Community/Public Health Nursing Education and teaching strategies/modalities; (b) Clinical teaching and learning partnerships; (c) Environmental health and emergency response; and, (d) Cultural competence and awareness.

CONCLUSIONS: Themes informed the following research priorities: (a) a need for rigorous scientific studies highlighting the impact and effectiveness of Community/Public Health Nursing Education; (b) a need for evidence on faculty development, support and training related to community/public health activities; (c) a need for evidence on impact of Community/Public Health Nursing teaching on communities and students, and (d) a need for evidence on impact of C/PHNE strategies on long-term student knowledge, attitudes or behavior (competencies). Finally, a Research in Action Model is proposed as a means for continued forward movement of the discipline, connecting the three fundamental driving mechanisms.},
}

*Community Health Nursing/education
*Education, Nursing, Baccalaureate/methods
Humans
Learning
Public Health Nursing/education
Research
*Students, Nursing/psychology

@article {pmid31497116,
year = {2019},
author = {Yamada, Y and Ansari, A and Sae-Ngow, T and Tanaka, R and Kawase, T and Kalyan, S and Kato, Y},
title = {Microsurgical Treatment of Paraclinoid Aneurysms by Extradural Anterior Clinoidectomy: The Fujita Experience.},
journal = {Asian journal of neurosurgery},
volume = {14},
number = {3},
pages = {868-872},
pmid = {31497116},
issn = {1793-5482},
abstract = {INTRODUCTION: Paraclinoid aneurysms pose technical difficulty in their approach, mainly because of their close proximity to neurovascular structures, deeper location, and a smaller corridor. Extradural anterior clinoidectomy is a highly beneficial technique in such cases, making more space to deal with these aneurysms. We describe our method of performing extradural anterior clinoidectomy in such patients.

MATERIALS AND METHODS: A total of 33 cases of paraclinoid internal carotid artery aneurysms presenting to Fujita Health University Banbuntane Hospital, Japan, were included. Females comprised the majority with 32 cases; the mean age was 54.8 years (range: 35-74 years). The mean size of the paraclinoid aneurysm was 5.3 mm (range: 3-12 mm).

RESULTS: Nine paraclinoid aneurysms were found projecting dorsally, 7 laterally, and 17 medially (Kazuhiko Kyoshim et al's. classification). An immediate complete occlusion rate of 100% was present. Visual disturbance was found in 6.2% of our patients. One of our patients developed permanent loss of vision.

CONCLUSION: Extradural anterior clinoidectomy enables a better exposure to paraclinoid aneurysms. Precise anatomical knowledge along with microsurgical tactics is required to prevent and manage potential complications to achieve good outcomes.},
}

@article {pmid31420835,
year = {2019},
author = {Prairie, TM and Wrye, B and Bowman, AS and Weatherby, N and Thareja, G},
title = {Does Location of Practice or Religiosity Predict Negative Physician Attitudes or Beliefs Toward LGB+ Individuals?.},
journal = {Journal of religion and health},
volume = {58},
number = {6},
pages = {2208-2218},
pmid = {31420835},
issn = {1573-6571},
mesh = {Adult ; *Attitude of Health Personnel ; *Bisexuality ; Female ; Health Personnel/*psychology ; Homophobia ; *Homosexuality ; Humans ; Male ; Middle Aged ; Prejudice ; *Professional Practice Location ; *Religion ; Sexual and Gender Minorities ; },
abstract = {The purpose of this study is to extend the Sabin et al's. (Am J Public Health 105(9):1831-1841, 2015. https://doi.org/10.2105/AJPH.2015.302631) findings to examine the extent to which religiosity and/or geographic region is predictive of negative attitudes or beliefs toward lesbian, gay, bisexual, and asexual (LGB+) individuals. Secondary data from the Sexuality Implicit Association Test were analyzed. Data included only participants from 2013 to 2015 who identified "Healthcare - Diagnosing and Treating Practitioners" as their occupation (n = 1376). The results of a factorial ANOVA revealed significant group differences accounting for 22.4% of the variance in attitudes toward LGB+ individuals. Religiosity was a significant factor in determining negative attitudes toward LGB+ individuals. However, the study was underpowered (5.8%) to detect an effect of geographic location in determining negative attitudes toward LGB+ individuals. It is important to validate a tool that can adequately measure the common assumptions associated with both religion and geographic region. Additionally, medical educators need to learn how to recognize and address negative attitudes among their students.},
}

Adult
*Attitude of Health Personnel
*Bisexuality
Female
Health Personnel/*psychology
Homophobia
*Homosexuality
Humans
Male
Middle Aged
Prejudice
*Professional Practice Location
*Religion
Sexual and Gender Minorities

@article {pmid28977145,
year = {2017},
author = {Fernandes, P and Meiga, C and Peres, AC and Taconeli, CA and Nickel, R and Silvado, C},
title = {Translation of social and occupational functioning scale for epilepsy into Portuguese - Brazil.},
journal = {Arquivos de neuro-psiquiatria},
volume = {75},
number = {9},
pages = {639-648},
doi = {10.1590/0004-282X20170099},
pmid = {28977145},
issn = {1678-4227},
mesh = {Adolescent ; Adult ; Brazil ; Cross-Cultural Comparison ; Epilepsy/*diagnosis/psychology ; Female ; Humans ; Male ; Middle Aged ; Social Behavior ; Socioeconomic Factors ; *Surveys and Questionnaires ; *Translations ; Young Adult ; },
abstract = {Epilepsy has important consequences on functionality and social activities. There are few evaluation tools for this purpose. This study aimed to translate the Social and Occupational Functioning Scale for Epilepsy. It is a translation study, for which Beaton et al's. guidelines were used. Sixty patients over 18 years of age, with a confirmed diagnosis of epilepsy, were evaluated. The analysis of internal consistency (Cronbach's alpha) showed values between 0.55 and 0.72 associated with the original dimensions of the instrument, while the five dimensions identified by the results of an exploratory factor analysis showed values between 0.60 and 0.68, with different grouping of the structures of the original scale. Respondents had no difficulty answering the translated version of the Social and Occupational Functioning Scale for Epilepsy, but the statistics show the need for cultural adaptation to the Brazilian population.},
}

Adolescent
Adult
Brazil
Cross-Cultural Comparison
Epilepsy/*diagnosis/psychology
Female
Humans
Male
Middle Aged
Social Behavior
Socioeconomic Factors
*Surveys and Questionnaires
*Translations
Young Adult

@article {pmid25436144,
year = {2014},
author = {de Figueiredo Ferreira, M and Detrano, F and Coelho, GM and Barros, ME and Serrão Lanzillotti, R and Firmino Nogueira Neto, J and Portella, ES and Serrão Lanzillotti, H and Soares, Ede A},
title = {Body composition and Basal metabolic rate in women with type 2 diabetes mellitus.},
journal = {Journal of nutrition and metabolism},
volume = {2014},
number = {},
pages = {574057},
pmid = {25436144},
issn = {2090-0724},
abstract = {Objective. The aim of this study was to determine which of the seven selected equations used to predict basal metabolic rate most accurately estimated the measured basal metabolic rate. Methods. Twenty-eight adult women with type 2 diabetes mellitus participated in this cross-sectional study. Anthropometric and biochemical variables were measured as well as body composition (by absorptiometry dual X-ray emission) and basal metabolic rate (by indirect calorimetry); basal metabolic rate was also estimated by prediction equations. Results. There was a significant difference between the measured and the estimated basal metabolic rate determined by the FAO/WHO/UNU (P value < 0.021) and Huang et al. (P value ≤ 0.005) equations. Conclusion. The calculations using Owen et al's. equation were the closest to the measured basal metabolic rate.},
}

@article {pmid17372624,
year = {2007},
author = {Kim, HK and Capaldi, DM and Crosby, L},
title = {Generalizability of Gottman and Colleagues' Affective Process Models of Couples' Relationship Outcomes.},
journal = {Journal of marriage and the family},
volume = {69},
number = {1},
pages = {55-72},
pmid = {17372624},
issn = {0022-2445},
support = {R01 HD046364-12/HD/NICHD NIH HHS/United States ; R01 DA015485/DA/NIDA NIH HHS/United States ; R01 HD046364/HD/NICHD NIH HHS/United States ; R01 MH037940-25/MH/NIMH NIH HHS/United States ; R01 DA015485-03/DA/NIDA NIH HHS/United States ; R01 MH037940/MH/NIMH NIH HHS/United States ; P30 MH046690/MH/NIMH NIH HHS/United States ; },
abstract = {The generalizability of Gottman et al's. (1998) affective process models was examined using a community-based sample of 85 married or cohabiting couples with at-risk backgrounds. Predictive associations between affective processes assessed at about age 21 years and relationship status and satisfaction approximately 2.5 years later were examined. The major findings of Gottman et al. failed to replicate. In particular, men's rejection of their partners' influence, the lack of men's deescalation of partners' negative affect, and women's negative start up were not predictive of relationship status. Further, differences in affective processes were found when comparing discussion sessions of the men's versus the women's chosen topics. The findings suggested that the validity and utility of the affective process models need further investigation.},
}

@article {pmid15742539,
year = {2004},
author = {Fisk, JE and Sharp, CA},
title = {Age-related impairment in executive functioning: updating, inhibition, shifting, and access.},
journal = {Journal of clinical and experimental neuropsychology},
volume = {26},
number = {7},
pages = {874-890},
doi = {10.1080/13803390490510680},
pmid = {15742539},
issn = {1380-3395},
mesh = {Adult ; Age Factors ; Aged ; Aged, 80 and over ; Aging/*physiology ; Aptitude/*physiology ; Cognition Disorders/*physiopathology ; Factor Analysis, Statistical ; Female ; Humans ; *Inhibition, Psychological ; Male ; Middle Aged ; Neuropsychological Tests/statistics & numerical data ; Problem Solving/*physiology ; Psychomotor Performance/physiology ; Reading ; },
abstract = {Miyake, Friedman, Emerson, Witzki, Howerter and Wager (2000) have argued that the central executive is fractionated consisting of at least three separable component processes: updating, shifting, and inhibition. The Wisconsin Card Sort Test, random letter generation, Brooks spatial sequences, reading and computation span, word fluency, and a measure of dual task performance were administered to 95 individuals aged between 20 and 81, average age 41.89. The executive measures were factor analyzed, using the oblique rotation method, yielding four factors. The factor structure obtained was broadly consistent with Miyake et al's. However, an additional factor, the only one not to show a significant performance decline with age, was also obtained and was believed to reflect the efficiency of access to long-term memory.},
}

Adult
Age Factors
Aged
Aged, 80 and over
Aging/*physiology
Aptitude/*physiology
Cognition Disorders/*physiopathology
Factor Analysis, Statistical
Female
Humans
*Inhibition, Psychological
Male
Middle Aged
Neuropsychological Tests/statistics & numerical data
Problem Solving/*physiology
Psychomotor Performance/physiology
Reading

@article {pmid11859558,
year = {2002},
author = {Williams, T},
title = {Intercessory prayer and its effect on patients with rheumatoid arthritis.},
journal = {Kentucky nurse},
volume = {50},
number = {1},
pages = {16},
pmid = {11859558},
issn = {0742-8367},
mesh = {Aged ; Arthritis, Rheumatoid/nursing/*therapy ; Clinical Trials as Topic ; *Faith Healing ; Female ; Humans ; },
abstract = {Matthews et al's. (2000) study suggested that in person intercessory prayer was useful in the medical treatment of patients with RA, improving overall health. However, distant prayer showed no overall improvement. This study could be used to support a research utilization project to educate nurses on the potential benefits of prayer on the healthcare and health outcomes of patients with certain illnesses. An in-service could be made available for nurses to educate them on potential benefits of prayer. A feasibility issue would be cost. Religion and spiritual beliefs can influence a patient's level of health and self-care behaviors. It is essential for nurses to meet the spiritual needs of their patients. A nurse should also recognize that there are many different religions and not all patients have the same religion and beliefs.},
}

Aged
Arthritis, Rheumatoid/nursing/*therapy
Clinical Trials as Topic
*Faith Healing
Female
Humans

@article {pmid40099231,
year = {2025},
author = {Hwang, DW and Ser, J and Ziabrev, K and Park, GK and Jo, MJ and Yokomizo, S and Bao, K and Yamashita, A and Cho, H and Henary, M and Kashiwagi, S and Choi, HS},
title = {Image-Guided Monitoring of Mitochondria and Blood-Brain Barrier Dysfunction in Amyotrophic Lateral Sclerosis Mice.},
journal = {Biomaterials research},
volume = {29},
number = {},
pages = {0162},
pmid = {40099231},
issn = {1226-4601},
abstract = {Early detection of amyotrophic lateral sclerosis (ALS) progression is critical for improving disease management and therapeutic outcomes. However, the clinical heterogeneity and variability in ALS symptoms often lead to delayed diagnosis and suboptimal therapeutic interventions. Since mitochondrial dysfunction is a hallmark of ALS, we hypothesized that monitoring mitochondrial function could serve as a reliable strategy for early diagnosis and therapeutic monitoring of ALS. To address this, we synthesized and characterized 2 novel near-infrared fluorophores, ALS04 and ALS05, designed to target mitochondria and lysosomes. Their physicochemical properties, serum protein binding, fluorescence characteristics, photostability, and pharmacokinetics were systematically evaluated. We found that benzothiazole-based fluorophores exhibit excellent mitochondrial targeting, optimal optical properties, biocompatibility, and favorable biodistribution in vivo. Interestingly, ALS04 showed superior mitochondrial accumulation compared to ALS05, despite their similar physicochemical properties. This enhanced accumulation can be attributed to the lower molecular weight and higher lipophilicity of ALS04. Real-time fluorescence imaging revealed a substantial reduction in ALS04 signals in mitochondrial-rich tissues such as brown fat, highlighting its potential for monitoring mitochondrial dysfunction in early-stage ALS. Furthermore, the detection of ALS04 in the mouse brain suggests its ability to monitor blood-brain barrier hyperpermeability, another key feature of ALS pathology. These findings establish ALS04 as a promising noninvasive imaging tool for monitoring biomarkers associated with ALS progression. Its ability to detect early-stage pathophysiological changes in an ALS mouse model highlights its potential for advancing our understanding of ALS mechanisms and facilitating the identification of novel therapeutic targets.},
}

@article {pmid40097890,
year = {2025},
author = {Dezfouli, MA and Shalilahmadi, D and Shamsaei, G and Esmaeili, A and Majdinasab, N and Rashidi, SK},
title = {Circulating miR-223/NLRP3 axis and IL-1β level in functional disease progression of amyotrophic lateral sclerosis.},
journal = {Acta neurologica Belgica},
volume = {},
number = {},
pages = {},
pmid = {40097890},
issn = {2240-2993},
abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease identified by progressive motor neuron loss. NLRP3 inflammasomes induce inflammation and pyroptosis, which can lead to neurodegeneration, muscle atrophy, and respiratory decline. miR-223 targets NLRP3 and suppresses inflammasome formation. Here, miR-223, NLRP3 and IL-1β levels were evaluated as plasma biomarkers in the incidence and progression of ALS.

METHODS: 32 ALS patients and 32 healthy subjects were assessed. In all patients, the functional disability was determined by Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R), and the respiratory dysfunction was assessed by the percent predicted forced vital capacity (ppFVC) index in spirometry examination. Plasma levels of miR-223, NLRP3 and IL-1β were assessed in ALS and control groups.

RESULTS: Compared to the healthy controls, ALS patients showed decreased miR-223 expression (P < 0.0001), increased NLRP3 expression (P = 0.0002) and increased IL-1β level (P = 0.0003). The areas under the ROC curves for miR-223, NLRP3 and IL-1β were 0.82, 0.76 and 0.75 respectively. The ALSFRS-R and ppFVC values were positively correlated with miR-223 and negatively correlated with NLRP3 and IL-1β levels.

CONCLUSION: Our results indicated that changes in miR-223, NLRP3 and IL-1β levels may correlate with the occurrence and functional progression of ALS. Additionally, therapeutic approaches based on miR-223 and inflammatory mediators can be proposed as effective strategies against disease progression.},
}

@article {pmid40097762,
year = {2025},
author = {Nabakhteh, S and Lotfi, A and Afsartaha, A and Khodadadi, ES and Abdolghaderi, S and Mohammadpour, M and Shokri, Y and Kiani, P and Ehtiati, S and Khakshournia, S and Khatami, SH},
title = {Nutritional Interventions in Amyotrophic Lateral Sclerosis: From Ketogenic Diet and Neuroprotective Nutrients to the Microbiota-Gut-Brain Axis Regulation.},
journal = {Molecular neurobiology},
volume = {},
number = {},
pages = {},
pmid = {40097762},
issn = {1559-1182},
abstract = {Amyotrophic lateral sclerosis (ALS) is a complex neurodegenerative disease with significant challenges in diagnosis and treatment. Recent research has highlighted the complex nature of ALS, encompassing behavioral impairments in addition to its neurological manifestations. While several medications have been approved to slow disease progression, ongoing research is focused on identifying new therapeutic targets. The current review focuses on emerging therapeutic strategies and personalized approaches aimed at improving patient outcomes. Recent advancements highlight the importance of targeting additional pathways such as mitochondrial dysfunction and neuroinflammation to develop more effective treatments. Personalized medicine, including genetic testing and biomarkers, is proving valuable in stratifying patients and tailoring treatment options. Complementary therapies, such as nutritional interventions like the ketogenic diet and microbiome modulation, also show promise. This review emphasizes the need for a multidisciplinary approach that integrates early diagnosis, targeted treatments, and supportive care to address the multisystemic nature of ALS and improve the quality of life for patients.},
}

@article {pmid40097438,
year = {2025},
author = {Ayyadurai, VAS and Deonikar, P and Kamm, RD},
title = {A molecular systems architecture of neuromuscular junction in amyotrophic lateral sclerosis.},
journal = {NPJ systems biology and applications},
volume = {11},
number = {1},
pages = {27},
pmid = {40097438},
issn = {2056-7189},
mesh = {*Amyotrophic Lateral Sclerosis/genetics/pathology ; *Neuromuscular Junction/metabolism/pathology ; Humans ; *Motor Neurons/pathology/metabolism ; Animals ; Systems Biology/methods ; },
abstract = {A molecular systems architecture is presented for the neuromuscular junction (NMJ) in order to provide a framework for organizing complexity of biomolecular interactions in amyotrophic lateral sclerosis (ALS) using a systematic literature review process. ALS is a fatal motor neuron disease characterized by progressive degeneration of the upper and lower motor neurons that supply voluntary muscles. The neuromuscular junction contains cells such as upper and lower motor neurons, skeletal muscle cells, astrocytes, microglia, Schwann cells, and endothelial cells, which are implicated in pathogenesis of ALS. This molecular systems architecture provides a multi-layered understanding of the intra- and inter-cellular interactions in the ALS neuromuscular junction microenvironment, and may be utilized for target identification, discovery of single and combination therapeutics, and clinical strategies to treat ALS.},
}

*Amyotrophic Lateral Sclerosis/genetics/pathology
*Neuromuscular Junction/metabolism/pathology
Humans
*Motor Neurons/pathology/metabolism
Animals
Systems Biology/methods

@article {pmid40097075,
year = {2025},
author = {Cuevas, EP and Madruga, E and Martínez, IV and Ramírez, D and Gil, C and Nagaraj, S and Martin-Requero, A and Martinez, A},
title = {MicroRNA signature of lymphoblasts from amyotrophic lateral sclerosis patients as potential clinical biomarkers.},
journal = {Neurobiology of disease},
volume = {},
number = {},
pages = {106871},
doi = {10.1016/j.nbd.2025.106871},
pmid = {40097075},
issn = {1095-953X},
abstract = {MicroRNAs (miRNAs) are a class of small, non-coding RNAs involved in different cellular functions that have emerged as key regulators of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). ALS is a fatal disease that lacks of not only effective treatments, but also presents delays in its diagnosis, since reliable clinical biomarkers are unavailable. In recent years, advancements in high-throughput sequencing strategies have led to the identification of novel ALS biomarkers, facilitating earlier diagnosis and assessment of treatment efficacy. Since immortalized lymphocytes obtained from peripheral blood are a suitable model to study pathological features of ALS, we employed these samples with the aim of characterize the dysregulated miRNAs in ALS patients. Next-generation sequencing (NGS) was utilized in order to analyze the expression profiles of miRNAs in immortalized lymphocytes from healthy controls, sporadic ALS (sALS), and familial ALS with mutations in superoxide dismutase 1 (SOD1-ALS). The screening analysis of the NGS data identified a set of dysregulated miRNAs, of which nine candidates were selected for qRT-PCR validation, identifying for the first time the possible importance of hsa-miR-6821-5p as a potential ALS biomarker. Furthermore, the up-regulated miRNAs identified are predicted to have direct or indirect interactions with genes closely related to ALS, such as SIGMAR1, HNRNPA1 and TARDBP. Additionally, by Metascape enrichment analysis, we found the VEGFA/VEGFR2 signaling pathway, previously implicated in neuroprotective effects in ALS, as a candidate pathway for further analyses.},
}

@article {pmid40095345,
year = {2025},
author = {Dehghani, S and Ocakcı, O and Hatipoglu, PT and Özalp, VC and Tevlek, A},
title = {Exosomes as Biomarkers and Therapeutic Agents in Neurodegenerative Diseases: Current Insights and Future Directions.},
journal = {Molecular neurobiology},
volume = {},
number = {},
pages = {},
pmid = {40095345},
issn = {1559-1182},
abstract = {Neurodegenerative diseases (NDs) like Alzheimer's, Parkinson's, and ALS rank among the most challenging global health issues, marked by substantial obstacles in early diagnosis and effective treatment. Current diagnostic techniques frequently demonstrate inadequate sensitivity and specificity, whilst conventional treatment strategies encounter challenges related to restricted bioavailability and insufficient blood-brain barrier (BBB) permeability. Recently, exosomes-nanoscale vesicles packed with proteins, RNAs, and lipids-have emerged as promising agents with the potential to reshape diagnostic and therapeutic approaches to these diseases. Unlike conventional drug carriers, they naturally traverse the BBB and can deliver bioactive molecules to affected neural cells. Their molecular cargo can influence cell signaling, reduce neuroinflammation, and potentially slow neurodegenerative progression. Moreover, exosomes serve as non-invasive biomarkers, enabling early and precise diagnosis while allowing real-time disease monitoring. Additionally, engineered exosomes, loaded with therapeutic molecules, enhance this capability by targeting diseased neurons and overcoming conventional treatment barriers. By offering enhanced specificity, reduced immunogenicity, and an ability to bypass physiological limitations, exosome-based strategies present a transformative advantage over existing diagnostic and therapeutic approaches. This review examines the multifaceted role of exosomes in NDDs, emphasizing their diagnostic capabilities, intrinsic therapeutic functions, and transformative potential as advanced treatment vehicles.},
}

@article {pmid40094392,
year = {2025},
author = {Resch, M and Frickel, JS and Dischinger, K and Wen, RCS and Hell, K and Harner, ME},
title = {The Mia40 substrate Mix17 exposes its N-terminus to the cytosolic side of the mitochondrial outer membrane.},
journal = {Journal of cell science},
volume = {},
number = {},
pages = {},
doi = {10.1242/jcs.263661},
pmid = {40094392},
issn = {1477-9137},
support = {413985647//Deutsche Forschungsgemeinschaft/ ; },
abstract = {Mitochondrial architecture and the contacts between the outer and the inner mitochondrial membrane depend on the mitochondrial contact site and cristae organizing system (MICOS) that is highly conserved from yeast to human. Mutations in the mammalian MICOS subunit Mic14/CHCHD10 have been linked to amyotrophic lateral sclerosis and frontotemporal dementia, indicating the importance of this protein. Mic14/CHCHD10 has a yeast ortholog, Mix17, a protein of unknown function, which has not been shown to interact with MICOS so far. As a first step to elucidate the function of Mix17 and its orthologs, we analyzed its interactions, biogenesis and mitochondrial sublocation. We report that Mix17 is no stable MICOS subunit in yeast. Our data suggest that Mix17 is the first Mia40 substrate in the mitochondrial outer membrane. Unlike all other Mia40 substrates, Mix17 spans the outer membrane and exposes its N-terminus to the cytosol. The insertion of Mix17 is likely to be mediated by its interaction with Tom40, the pore of the TOM complex. Moreover, we show that the exposure of Mix17 to the cytosolic side of the membrane depends on its N-terminus.},
}

@article {pmid40093130,
year = {2025},
author = {Zhou, Z and Luquette, LJ and Dong, G and Kim, J and Ku, J and Kim, K and Bae, M and Shao, DD and Sahile, B and Miller, MB and Huang, AY and Nathan, WJ and Nussenzweig, A and Park, PJ and Lagier-Tourenne, C and Lee, EA and Walsh, CA},
title = {Recurrent patterns of widespread neuronal genomic damage shared by major neurodegenerative disorders.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.03.03.641186},
pmid = {40093130},
issn = {2692-8205},
abstract = {Amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Alzheimer's disease (AD) are common neurodegenerative disorders for which the mechanisms driving neuronal death remain unclear. Single-cell whole-genome sequencing of 429 neurons from three C9ORF72 ALS, six C9ORF72 FTD, seven AD, and twenty-three neurotypical control brains revealed significantly increased burdens in somatic single nucleotide variant (sSNV) and insertion/deletion (sIndel) in all three disease conditions. Mutational signature analysis identified a disease-associated sSNV signature suggestive of oxidative damage and an sIndel process, affecting 28% of ALS, 79% of FTD, and 65% of AD neurons but only 5% of control neurons (diseased vs. control: OR=31.20, p = 2.35×10 [-10]). Disease-associated sIndels were primarily two-basepair deletions resembling signature ID4, which was previously linked to topoisomerase 1 (TOP1)-mediated mutagenesis. Duplex sequencing confirmed the presence of sIndels and identified similar single-strand events as potential precursor lesions. TOP1-associated sIndel mutagenesis and resulting genome instability may thus represent a common mechanism of neurodegeneration.},
}

@article {pmid40092960,
year = {2025},
author = {Liu, Y and Li, XF},
title = {Characteristics and therapeutic strategies for familial gastrointestinal stromal tumors.},
journal = {World journal of gastrointestinal oncology},
volume = {17},
number = {3},
pages = {100463},
pmid = {40092960},
issn = {1948-5204},
abstract = {This editorial discusses Wang et al's article on familial gastrointestinal stromal tumors (GISTs). We read with great interest this article concerning the diagnosis, treatment, and post-treatment management of patients with familial GISTs. The actual incidence of GISTs may be underestimated due to diagnostic limitations and the long-term low-risk behavior of some GISTs. The molecular landscape of GISTs is primarily driven by mutations in the KIT and platelet-derived growth factor receptor alpha (PDGFRA) genes. A subset of GISTs without these mutations known as wild-type GISTs, may harbor other rare mutations, impacting their response to targeted therapies. Clinically, patients with GISTs present with non-specific symptoms, often leading to delayed diagnosis. Genetic predispositions in familial GISTs provide insights into the genetic architecture and extragastrointestinal manifestations of GISTs. Management has evolved from surgical interventions to molecular-based therapies using tyrosine kinase inhibitors. The management of GISTs, especially in familial cases, requires a multidisciplinary approach. Cases of different gene mutations were reported in the same family, suggesting that incorporating genetic testing into routine clinical practice is crucial for the early identification of high-risk individuals and the implementation of tailored surveillance programs.},
}

@article {pmid40092497,
year = {2025},
author = {Fujii, Y and Kanbayashi, T and Takahashi, K and Hamada, Y and Kobayashi, S and Sonoo, M},
title = {Correlation between decremental responses in repetitive nerve stimulation and disease progression rate in patients with amyotrophic lateral sclerosis.},
journal = {Clinical neurophysiology practice},
volume = {10},
number = {},
pages = {40-46},
pmid = {40092497},
issn = {2467-981X},
abstract = {OBJECTIVE: Decrement responses in repetitive nerve stimulation (RNS) are theoretically expected to correlate with the disease progression speed in amyotrophic lateral sclerosis (ALS). However, actual results have been controversial. We investigated this issue using ΔFS calculated from the ALS functional rating scale revised version (ALSFRS-R) and the duration of illness.

METHODS: RNS results of the abductor pollicis brevis, trapezius, and deltoid muscles in our previous study were reviewed. We investigated correlations and multiple regressions regarding decremental percentage (Decr%), the amplitude of the initial compound muscle action potential (Amp), and progression speed parameters, i.e. ΔFS or ΔUL-FS, the latter being the ΔFS for the upper-limb questions in ALSFRS-R.

RESULTS: Included subjects were 124 patients with ALS, 47 of whom were upper-limb onset. Multiple regression analyses revealed that Decr% is largely determined by Amp and that Δ FS or ΔUL-FS showed no or little contributions to Decr%.

CONCLUSIONS: Decremental responses in RNS does not predict the speed of progression of the functional impairment in patients with ALS.

SIGNIFICANCE: This study suggests that the decremental responses in RNS in ALS are contributed by the impaired neuromuscular transmission in chronic sprouts following extensive reinnervation, as well as by the immature sprouts.},
}

@article {pmid40092496,
year = {2025},
author = {Theuriet, J and Bohic, A and Bonjour, M and Bernard, E and Cluse, F and Svahn, J and Jomir, L and Vallet, AE and Demia, M and Roux, L and Bârsan, IC and Alves, L and Dion, M and Meens, L and Moussy, M and Bouhour, F and Péréon, Y and Pegat, A},
title = {Contralateral R1 response in blink reflex in patients with amyotrophic lateral sclerosis.},
journal = {Clinical neurophysiology practice},
volume = {10},
number = {},
pages = {47-51},
pmid = {40092496},
issn = {2467-981X},
abstract = {OBJECTIVE: This study aimed to compare the frequency of blink reflex's contralateral R1 responses (R1') between patients with amyotrophic lateral sclerosis (ALS), non-ALS motor deficit patients, and healthy volunteers.

METHODS: A total of 120 participants were prospectively recruited: 40 with ALS, 40 with a non-ALS motor deficit, and 40 healthy volunteers. Blink reflexes were recorded from orbicularis oculi muscles following supraorbital nerve stimulation.

RESULTS: R1' was more frequent in the ALS group (42.5 %) compared to healthy volunteers (12.5 %, p = 0.00588), and compared to non-ALS patients (7.5 %, p = 0.000789). Bilateral R1' was observed only in ALS patients (22.5 %). No clinically significant difference was found in the latencies or amplitudes of the R1, R2, or R1' responses among groups. R1' was more frequent in ALS patients with pseudobulbar affect (71.4 %) compared to those without (36.4 %).

CONCLUSIONS: The higher frequency of R1' in ALS highlights its potential role in distinguishing ALS from other motor disorders. Its sensitivity was low, but bilateral R1' was specific to ALS. The higher frequency of R1' among ALS patients with pseudobulbar affect potentially reflects corticobulbar neuron degeneration.

SIGNIFICANCE: The R1', especially when bilateral, could serve as an additional diagnostic biomarker for ALS, although its clinical relevance should be considered within the broader diagnostic context.},
}

@article {pmid40091916,
year = {2025},
author = {Ansari, U and Wen, J and Karabala, M and Syed, B and Abed, I and Razick, DI and Lui, F},
title = {Analysis of Respiratory Muscle Strength Training in Amyotrophic Lateral Sclerosis (ALS) Patients: A Systematic Review.},
journal = {Cureus},
volume = {17},
number = {2},
pages = {e78903},
pmid = {40091916},
issn = {2168-8184},
abstract = {Respiratory muscle weakness is a significant contributor to morbidity and mortality in amyotrophic lateral sclerosis (ALS) patients. Respiratory muscle strength training (RMST) has emerged as a potential therapeutic approach to mitigate respiratory muscle weakness in ALS. Still, its efficacy and safety remain unclear due to conflicting evidence and methodological heterogeneity in existing studies. A systematic review was conducted across three databases (PubMed (United States National Library of Medicine, Bethesda, MD, USA), Embase (Elsevier, Amsterdam, Netherlands), and Cochrane Library (Cochrane, Alberta, Canada)) following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines to assess the effectiveness of RMST in ALS patients. Eligible studies included comparative studies for RMST, focusing on outcomes such as maximum inspiratory pressure (MIP), maximum expiratory pressure (MEP), forced vital capacity (FVC), and ALS Functional Rating Scale (ALSFRS-R). Quality assessment was performed using the Cochrane Risk of Bias tool. This study included six studies, including 183 patients with a mean age of 58.0 years (49.6 to 63.2) and a mean follow-up time of 21.2 weeks (eight to 52). The average mean difference for ALSFRS-R (three studies), MIP (three studies), MEP (three studies), and FVC (two studies) were 2.062 (0.04 to 5.3), 2.285 (-8.145 to 10.8), 19.435 (10.86 to 21.7), and 7.23 (3.6 to 10.86), respectively. Complications related to RMST were poorly reported across studies. Secondary outcomes, such as depression scores, blood oxygen levels, and heart rate variability, showed promising trends but lacked consistency. Despite positive findings on respiratory muscle strength, RMST's efficacy in ALS management remains inconclusive. Challenges include methodological heterogeneity, limited sample sizes, and inadequate reporting of complications. Future research should focus on standardized protocols, larger sample sizes, longer follow-ups, and comprehensive assessment of adverse effects to clarify the role of RMST in ALS treatment.},
}

@article {pmid40098659,
year = {2023},
author = {Serrano-Giraldo, J and Becerra-Muñoz, MP and Tijaro-Santos, JA and Zarante, I},
title = {[Current situation of rare diseases in Bogotá: Notification to Sivigila from 2019 to 2022].},
journal = {Revista de salud publica (Bogota, Colombia)},
volume = {25},
number = {4},
pages = {107594},
pmid = {40098659},
issn = {2539-3596},
abstract = {OBJECTIVE: To analyze the reports of orphan diseases in Bogotá, in order to describe the epidemiological profile, based on the cases reported to the Public Health System (Sivigila), from January 2019 to March 2022.

METHODS: A descriptive and cross-sectional study was carried out in which the cases reported to Sivigila in Bogotá were analyzed in the period between January 2019 and March 2022. Absolute and relative frequencies, frequency distribution and prevalences and averages of different variables were calculated. notified in the notification sheets.

RESULTS: From January 2019 to March 2022, 10,399 patients with orphan diseases have been notified to Sivigila in Bogotá, of which 56.25% (5,849) are female and 43.75% (4,550) are female. male sex. 87.10% (9,060) of the cases belong to the contributory regime. The town with the highest number of reports was Suba with 15.85% (1,294). The most reported orphan diseases were: multiple sclerosis with 13.1% (1,363), amyotrophic lateral sclerosis with 4.04% (421) and Guillain-Barre syndrome with 3.6% (374). A patient with an orphan disease in Bogotá takes 61.3 months on average from the beginning of their symptoms to obtaining a diagnosis (SD 101.9).

CONCLUSIONS: From the notification to Sivigila in Bogotá, compared to the global prevalence, there is an under-registration of patients with orphan diseases and the delay in the diagnosis of these diseases is evident.},
}

@article {pmid9629709,
year = {1997},
author = {Forattini, OP and Kakitani, I and Sallum, MA and de Rezende, L},
title = {[Productivity of a breeding place of Aedes albopictus in an urban environment].},
journal = {Revista de saude publica},
volume = {31},
number = {6},
pages = {545-555},
doi = {10.1590/s0034-89101997000700002},
pmid = {9629709},
issn = {0034-8910},
mesh = {*Aedes ; Animals ; Brazil ; *Breeding ; Entomology/methods ; Female ; Humans ; *Insect Vectors ; Male ; Urban Population ; },
abstract = {INTRODUCTION: Aedes albopictus has been found at Cananeia city in the Southeastern State of S. Paulo, Brazil. A study was carried out to evaluate the productivity of its breeding place.

MATERIAL AND METHOD: A container classified as large and permanent was chosen. Water had accumulated at the bottom and was rich in organic matter, mainly of vegetal origin. From November 1996 until May 1997, fortnightly observations were performed, sampling immature stages found in a seventh part of the container's total water volume (nearly 70 litres). Pupae were collected, identified and sexed. The productivity of the breeding place was estimated using Focks et al's. (1981) formula adapted for a single large container. At the same time adults were caught by using human bait and the aspiration of resting places. The first catch was performed at six meters from the breeding place studied. Williams' mean was calculated for the human bait and mean hourly density for the aspiration results of the resting places (Subbarao et al., 1988).

RESULTS: Immature stages of Ae. albopictus represented 44.9% of the total collected through fifteen fortnightly regular samplings (November 1996 to May 1997). The pupae mean was 31.13 and so the emergence index was 2.1. Multiplied by seven the result was 14.7 as the estimated mean number of females per day produced in that container. Adult females caught on human bait gave a general Williams' mean of 30.7, while the mean hour by density was 9.2. According to the accumulated calculated adult number, 22.8 females per day were available to seek human bait, under the conditions of the observations performed.

DISCUSSION: Counting pupae is an efficient method of estimating the productivity of the breeding place of Ae. albopictus. The richness of the organic matter in the water in the container made it quite inappropriate to establish comparisons with water reservoirs for domestic use. Nevertheless, a lack of or deficient maintenance approximate these containers to the one here studied. So cleaning is an important factor and it must be emphasized as necessary to prevent the installation of mosquito breeding. Though it is a distinct species it is reasonable to expect that the application of these study methods to Ae. aegypti would be useful in the attempt being made to eradicate this latter species from our country.},
}

*Aedes
Animals
Brazil
*Breeding
Entomology/methods
Female
Humans
*Insect Vectors
Male
Urban Population

@article {pmid40091372,
year = {2025},
author = {Jaspers Focks, RJ and Helleman, J and van den Berg, LH and Visser-Meily, JM and Gaytant, MA and Wijkstra, PJ and Beelen, A},
title = {Initiating non-invasive ventilation in patients with Amyotrophic Lateral Sclerosis in The Netherlands: A centralised approach to respiratory care.},
journal = {Journal of neuromuscular diseases},
volume = {},
number = {},
pages = {22143602251319167},
doi = {10.1177/22143602251319167},
pmid = {40091372},
issn = {2214-3602},
abstract = {BACKGROUND: In the Netherlands a centralised approach to respiratory care for patients with Amyotrophic Lateral Sclerosis is used based on national guidelines. Patients with Amyotrophic Lateral Sclerosis are referred to one of 4 centres for Home Mechanical Ventilation.

OBJECTIVE: Our aim was to evaluate the respiratory care according to the Dutch guideline by evaluation of reasons for starting non-invasive ventilation, timing of initiating and survival in patients with Amyotrophic Lateral Sclerosis using non-invasive ventilation.

METHOD: A retrospective chart-review was performed of 323 patients, who had been referred to centres for Home Mechanical Ventilation in 2016-2018. Data collected included symptoms of hypoventilation, forced vital capacity, blood gasses, criteria for (not) initiating non-invasive ventilation, and survival. Kaplan-Meyer curves and Multivariate Cox proportional hazard regression were used in the analysis.

RESULTS: The main criteria used for initiating non-invasive ventilation were hypercapnia (77%) and the presence of orthopnea and/or dyspnoea (25%). Median survival after starting non-invasive ventilation was 11 months, and was shorter for patients with bulbar disease onset and older age. The proportion of the total disease duration that was spent on non-invasive ventilation was not significantly affected by age, sex or site of disease. Seventy nine percent of the patients who didn't start non-invasive ventilation had reached a joint decision with their caregivers and/or physicians.

CONCLUSION: Key outcomes of the Dutch centralised respiratory care approach have shown that most patients were initiated on non-invasive ventilation due to presence of hypercapnia and/or dyspnoea/orthopnea, which is according to the Dutch guidelines. Half of patients spent at least 33% of their disease duration on non-invasive ventilation. To help find the optimal criteria and timing for non-invasive ventilation it would be useful for other countries to share their key outcomes as well.},
}

@article {pmid40090808,
year = {2025},
author = {Rosina, M and Scaricamazza, S and Fenili, G and Nesci, V and Valle, C and Ferri, A and Paronetto, MP},
title = {Hidden players in the metabolic vulnerabilities of amyotrophic lateral sclerosis.},
journal = {Trends in endocrinology and metabolism: TEM},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.tem.2025.02.004},
pmid = {40090808},
issn = {1879-3061},
abstract = {Amyotrophic lateral sclerosis (ALS) is a complex and rapidly progressive motor neuron disorder with a fatal outcome. Despite the remarkable progress in understanding ALS pathophysiology, which has significantly contributed to clinical trial design, ALS remains a rapidly disabling and life-shortening condition. The non-motor neuron features of ALS, including nutritional status, energy expenditure, and metabolic imbalance, are increasingly gaining attention. Indeed, the bioenergetic failure and mitochondrial dysfunction of patients with ALS impact not only the high energy-demanding motor neurons but also organs and brain areas long considered irrelevant to the disease. As such, here we discuss how considering energy balance in ALS is reshaping research on this disease, opening the path to novel targetable opportunities for its treatment.},
}

@article {pmid40089090,
year = {2025},
author = {Men, J and Wang, X and Zhou, Y and Huang, Y and Zheng, Y and Wang, Y and Yang, S and Chen, N and Yan, N and Duan, X},
title = {Neurodegenerative diseases: Epigenetic regulatory mechanisms and therapeutic potential.},
journal = {Cellular signalling},
volume = {131},
number = {},
pages = {111715},
doi = {10.1016/j.cellsig.2025.111715},
pmid = {40089090},
issn = {1873-3913},
abstract = {Neurodegenerative diseases (NDDs) are a class of diseases in which the progressive loss of subtype-specific neurons leads to dysfunction. NDDs include Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS), among others. Previous studies have demonstrated that the pathogenesis of NDDs involves various mechanisms, including genetic factors, oxidative stress, apoptosis, and the immune response. Recent studies have shown that epigenetic regulation mediates the interactions between DNA methylation, chromatin remodeling, histone modification, and non-coding RNAs, thus affecting gene transcription. A growing body of research links epigenetic modifications to crucial pathways involved in the occurrence and development of NDDs. Epigenetics has also been found to regulate and maintain nervous system function, and its imbalance is closely related to the occurrence and development of NDDs. The present review summarizes focuses on the role of epigenetic modifications in the pathogenesis of NDDs and provides an overview of the key genes regulated by DNA methylation, histone modification, and non-coding RNAs in NDDs. Further, the current research status of epigenetics in NDDs is summarized and the potential application of epigenetics in the clinical diagnosis and treatment of NDDs is discussed.},
}

@article {pmid40087396,
year = {2025},
author = {Omar, OMF and Kimble, AL and Cheemala, A and Tyburski, JD and Pandey, S and Wu, Q and Reese, B and Jellison, ER and Hao, B and Li, Y and Yan, R and Murphy, PA},
title = {Endothelial TDP-43 depletion disrupts core blood-brain barrier pathways in neurodegeneration.},
journal = {Nature neuroscience},
volume = {},
number = {},
pages = {},
pmid = {40087396},
issn = {1546-1726},
support = {19IPLOI34770151//American Heart Association (American Heart Association, Inc.)/ ; 23PRE1027078//American Heart Association (American Heart Association, Inc.)/ ; R00-HL125727//U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; RF1-NS117449//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; NS074256//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; GM135592//U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS)/ ; AG046929//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; },
abstract = {Endothelial cells (ECs) help maintain the blood-brain barrier but deteriorate in many neurodegenerative disorders. Here we show, using a specialized method to isolate EC and microglial nuclei from postmortem human cortex (92 donors, 50 male and 42 female, aged 20-98 years), that intranuclear cellular indexing of transcriptomes and epitopes enables simultaneous profiling of nuclear proteins and RNA transcripts at a single-nucleus resolution. We identify a disease-associated subset of capillary ECs in Alzheimer's disease, amyotrophic lateral sclerosis and frontotemporal degeneration. These capillaries exhibit reduced nuclear β-catenin and β-catenin-downstream genes, along with elevated TNF/NF-κB markers. Notably, these transcriptional changes correlate with the loss of nuclear TDP-43, an RNA-binding protein also depleted in neuronal nuclei. TDP-43 disruption in human and mouse ECs replicates these alterations, suggesting that TDP-43 deficiency in ECs is an important factor contributing to blood-brain barrier breakdown in neurodegenerative diseases.},
}

@article {pmid40086112,
year = {2025},
author = {Liampas, I and Veltsista, D and Germeni, A and Batzikosta, P and Michou, E and Kefalopoulou, Z and Chroni, E},
title = {F waves in amyotrophic lateral sclerosis: A systematic review and meta-analysis.},
journal = {Neurophysiologie clinique = Clinical neurophysiology},
volume = {55},
number = {4},
pages = {103061},
doi = {10.1016/j.neucli.2025.103061},
pmid = {40086112},
issn = {1769-7131},
abstract = {OBJECTIVE: This systematic review and meta-analysis aimed to determine the pattern of F-wave abnormalities and their potential utility in the early diagnosis of amyotrophic lateral sclerosis (ALS).

METHODS: Medline and Embase were thoroughly searched. We primarily emphasized F-wave recordings from the abductor digiti minimi, following stimulation of the ulnar nerve at the wrist. Data from case-control studies involving individuals with ALS versus healthy controls (HC) or other well-defined patient groups were reviewed and -if appropriate- quantitatively synthesized.

RESULTS: Twenty-nine studies were included in this systematic review and 17 of them in the analytic part. The pattern of F-abnormalities in ALS compared to HC was as follows: decreased persistence (MD=20.25 %,15.67-24.84 %), mildly prolonged minimum latency (MD=1.59msec,1.11-2.06msec), increased maximum amplitude (MD=196μV,106-287μV) and elevated Index total Freps (MD=33.9 %,26.0-41.8 %). Affected limbs (with substantial weakness in clinical examination and/or muscle wasting and/or abnormal nerve conduction studies) exhibited more marked abnormalities in persistence, minimum latency, and Index total Freps, whereas abnormalities in these parameters were very mild in clinically unaffected limbs. More prominent increases in maximum amplitude accompanied pyramidal dysfunction. Of note, isolated upper motor neuron (UMN) disorders exhibited a comparable increase in Index total Freps without a decrease in persistence.

CONCLUSIONS: The pattern of F wave abnormalities may raise suspicion of involvement of the under-study lower motor neuron (LMN) pool in ALS. These findings may identify LMN dysfunction even at a preclinical stage and prompt extensive electromyographic investigations. UMN involvement may to some extent differentiate the profile of F wave abnormalities in ALS.},
}

@article {pmid40085521,
year = {2025},
author = {Mercan, M and Seyhan, S and Yayla, V},
title = {The phenotyping dilemma in VRK1-related motor neuron disease: a Turkish family with young-onset amyotrophic lateral sclerosis caused by a novel mutation.},
journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration},
volume = {},
number = {},
pages = {1-18},
doi = {10.1080/21678421.2025.2477732},
pmid = {40085521},
issn = {2167-9223},
abstract = {Objective: Vaccinia-related kinase 1 (VRK1)-related disease is an extremely rare autosomal recessive disorder primarily affecting the peripheral and/or central nervous system. In this report, we describe the genetic and clinical features of two siblings from a Turkish family presenting with an amyotrophic lateral sclerosis (ALS) phenotype due to a novel homozygous VRK1 mutation, and discuss the broad phenotypic spectrum associated with pathogenic variants in this gene. Methods: We analyzed the demographic data, clinical histories, neurological examinations, laboratory findings, and genetic results of 53 patients, including our cases, derived from 27 different reports. Results: Whole-exome sequencing identified a novel homozygous missense mutation, c.700A > G (p.Asn234Asp), in the VRK1 gene in two affected siblings. The characteristic features of the ALS phenotype included a recessive inheritance pattern, motor deficits with onset in the lower limbs, pyramidal tract signs, and a muscle magnetic resonance imaging (MRI) pattern demonstrating preferential involvement of the posterior compartments of the leg and thigh. The most common phenotypes associated with VRK1 mutations were ALS (18/53, 34%) and distal hereditary motor neuropathy (dHMN) (14/53, 26.4%), followed by pontocerebellar hypoplasia type 1 (7/53, 13.2%), hereditary motor and sensory neuropathy (5/53, 9.4%), autosomal recessive primary microcephaly with brain malformations (4/53, 7.5%), and spastic paraplegia (2/53, 3.8%). The ALS phenotype exhibited a significantly earlier mean age of onset compared to the dHMN phenotype (p = 0.015; 15.3 ± 11.5 and 27 ± 15.5 years, respectively). Conclusion: Our findings highlight the importance of investigating VRK1 mutations in patients with young-onset familial ALS. Furthermore, this report provides a systematic classification of the phenotype definitions associated with VRK1 mutations.},
}

@article {pmid40084393,
year = {2025},
author = {Helmold, B and Nathaniel, G and Barkhaus, P and Bertorini, T and Bromberg, M and Brown, A and Carter, GT and Chang, V and Crayle, J and Denson, K and Glass, J and Heiman-Patterson, T and Hobson, E and Jackson, C and Jhooty, S and Mallon, E and Maragakis, N and Cadavid, JM and Mcdermott, C and Pattee, G and Pierce, K and Wang, O and Wicks, P and Bedlack, R},
title = {ALSUntangled #78: Zinc.},
journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration},
volume = {},
number = {},
pages = {1-5},
doi = {10.1080/21678421.2025.2476688},
pmid = {40084393},
issn = {2167-9223},
abstract = {ALSUntangled reviews alternative and off-label treatments for people living with amyotrophic lateral sclerosis (PALS). In this review, we assess the utilization of dietary zinc supplements for modulating ALS pathology and progression. Studies in mouse models of ALS have demonstrated that high-dose zinc supplementation may be harmful, but moderate doses could potentially be beneficial. Clinical data is limited, and only one trial has explored zinc supplementation within PALS. This study reported potential benefits in slowing ALS progression but lacked statistical analyses and failed to report quantitative evidence. Numerous case reports from individual patients at varying doses have demonstrated no benefit. Zinc supplements at moderate doses are generally low cost and not associated with severe complications, but further research is required to determine the safety and efficacy of zinc supplementation within PALS. Therefore, we cannot at this time, endorse zinc supplementation to slow ALS progression.},
}

@article {pmid40080233,
year = {2025},
author = {Aydın, Ş and Özdemir, S and Adıgüzel, A},
title = {The Potential of cfDNA as Biomarker: Opportunities and Challenges for Neurodegenerative Diseases.},
journal = {Journal of molecular neuroscience : MN},
volume = {75},
number = {1},
pages = {34},
pmid = {40080233},
issn = {1559-1166},
mesh = {Humans ; *Biomarkers/blood ; *Cell-Free Nucleic Acids/blood ; *Neurodegenerative Diseases/blood/diagnosis/genetics ; Animals ; },
abstract = {Neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS), are characterized by the progressive and gradual degeneration of neurons. The prevalence and rates of these disorders rise significantly with age. As life spans continue to increase in many countries, the number of cases is expected to grow in the foreseeable future. Early and precise diagnosis, along with appropriate surveillance, continues to pose a challenge. The high heterogeneity of neurodegenerative diseases calls for more accurate and definitive biomarkers to improve clinical therapy. Cell-free DNA (cfDNA), including fragmented DNA released into bodily fluids via apoptosis, necrosis, or active secretion, has emerged as a promising non-invasive diagnostic tool for various disorders including neurodegenerative diseases. cfDNA can serve as an indicator of ongoing cellular damage and mortality, including neuronal loss, and may provide valuable insights into disease processes, progression, and therapeutic responses. This review will first cover the key aspects of cfDNA and then examine recent advances in its potential use as a biomarker for neurodegenerative disorders.},
}

Humans
*Biomarkers/blood
*Cell-Free Nucleic Acids/blood
*Neurodegenerative Diseases/blood/diagnosis/genetics
Animals

@article {pmid40077653,
year = {2025},
author = {de Carvalho Vilar, MD and Coutinho, KMD and de Lima Vale, SH and Dourado Junior, MET and de Medeiros, GCBS and Piuvezam, G and Brandao-Neto, J and Leite-Lais, L},
title = {Evidence-Based Nutritional Recommendations for Maintaining or Restoring Nutritional Status in Patients with Amyotrophic Lateral Sclerosis: A Systematic Review.},
journal = {Nutrients},
volume = {17},
number = {5},
pages = {},
pmid = {40077653},
issn = {2072-6643},
support = {grant number 302298/2017-7 (Jose Brandao-Neto)//National Council for Scientific and Technological Development/ ; TED 132/2018//Ministry of Health (Brazil) - Laboratory of Technological Innovation in Health from the Federal University of Rio Grande do Norte - LAIS/UFRN/ ; },
mesh = {*Amyotrophic Lateral Sclerosis/diet therapy/therapy/complications ; Humans ; *Nutritional Status ; *Nutrition Assessment ; Evidence-Based Medicine ; Quality of Life ; Nutritional Support/methods ; Dietary Supplements ; Deglutition Disorders/diet therapy/therapy ; Gastrostomy ; Nutrition Therapy/methods ; },
abstract = {Background/Objectives: This study is a systematic review of guidelines that aims to synthesize evidence-based recommendations to support appropriate nutritional management for patients with amyotrophic lateral sclerosis (ALS). Methods: PubMed/MEDLINE, Embase, Scopus, SciELO, Web of Science, LILACS, ScienceDirect, and Google Scholar were searched for records published up to July 2024. Clinical practice guidelines addressing any aspect of nutritional intervention in ALS were included. No language or country of publication restrictions were applied. Data extraction was performed by two independent reviewers. The methodological quality of the reports was assessed using the AGREE II instrument. Discrepancies were resolved by consensus. Results: The findings and main recommendations were summarized narratively. A total of 837 records were identified, and 11 were included in this review. The overall AGREE II scores for the included studies ranged from 3 to 7. The summary of nutritional recommendations was organized into topics: (1) dysphagia, (2) nutritional assessment, (3) energy, (4) protein, (5) supplementation, and (6) percutaneous endoscopic gastrostomy (PEG). This review summarizes relevant and updated nutritional recommendations to maintain or restore the nutritional status of patients with ALS, contributing to their quality of life and survival time. Conclusions: These nutritional recommendations will help health professionals and caregivers to implement and standardize nutritional care according to evidence-based practice in ALS. PROSPERO registration number CRD42021233088.},
}

*Amyotrophic Lateral Sclerosis/diet therapy/therapy/complications
Humans
*Nutritional Status
*Nutrition Assessment
Evidence-Based Medicine
Quality of Life
Nutritional Support/methods
Dietary Supplements
Deglutition Disorders/diet therapy/therapy
Gastrostomy
Nutrition Therapy/methods

@article {pmid40076771,
year = {2025},
author = {Aguiar, B and Alfenim, AR and Machado, CS and Moreira, J and Pinto, M and Otero-Espinar, FJ and Borges, F and Fernandes, C},
title = {Exploring Nano-Delivery Systems to Enhance the Edaravone Performance in Amyotrophic Lateral Sclerosis Treatment.},
journal = {International journal of molecular sciences},
volume = {26},
number = {5},
pages = {},
pmid = {40076771},
issn = {1422-0067},
support = {2023.13291.PEX//Foundation for Science and tecnhology/ ; UIDB/00081/2020 (CIQUP)//Foundation for Science and Technology/ ; LA/P/0056/2020(IMS)//Foundation for Science and Technology/ ; 2021.04016.CEECIND/CP1655/CT0004//Foundation for Science and Technology/ ; IMPULSE: IMproving User experience, Long-term sustainability, and Services//EU-OPENSCREEN HORIZON-INFRA-2023-DEV-0/ ; 2020.08731.BD//Foundation for Science and Technology/ ; 2023.01250.BD//Foundation for Science and Technology/ ; 2024.00809.BD//Foundation for Science and Technology/ ; SFRH/BD/145637/2019//Foundation for Science and Technology/ ; },
mesh = {*Edaravone/pharmacology/chemistry/administration & dosage ; *Amyotrophic Lateral Sclerosis/drug therapy ; Humans ; *Nanoparticles/chemistry ; Drug Delivery Systems/methods ; Free Radical Scavengers/chemistry/pharmacology ; Drug Carriers/chemistry ; Nanoparticle Drug Delivery System/chemistry ; Polyethylene Glycols/chemistry ; },
abstract = {Edaravone is one of the treatment options for Amyotrophic Lateral Sclerosis, but its therapeutic efficacy is limited due to the incapacity to cross the blood-brain barrier, as well as its short life span and poor stability, which is ultimately caused by its tautomerism in physiological condions. This work presents an overview about the use of several nanoformulations based on polymeric, protein, lipidic, or hybrid structure as suitable and stable drug delivery systems for encapsulating edaravone. We also evaluated the functionalization of nanoparticles with pegylated chains using the polyethylene glycol or tocopherol polyethylene glycol succinate and the possibility of preparing polymeric nanoparticles at different pH (7.4, 9, and 11). Edaravone was sucessfully encapsulated in polymeric, lipid-polymer hybrid, and lipidic nanoparticles. The use of higher pH values in the synthesis of polymeric nanoparticles has led to a decrease in nanoparticle size and an increase in the percentage of encapsulation efficiency. However, the resulting nanoformulations are not stable. Only polymeric and hybrid nanoparticles showed good stability over 80 days of storage, mainly at 4 °C. Overall, the nanoformulations tested did not show cytotoxicity in the SH-SY5Y cell line except the nanostructured lipid carrier formulations that showed some cytotoxicity possibly due to lipidic peroxidation. In conclusion, this work shows that edaravone can be encapsulated in different nanocarriers that could act as an interesting alternative for the treatment of Amyotrophic Lateral Sclerosis.},
}

*Edaravone/pharmacology/chemistry/administration & dosage
*Amyotrophic Lateral Sclerosis/drug therapy
Humans
*Nanoparticles/chemistry
Drug Delivery Systems/methods
Free Radical Scavengers/chemistry/pharmacology
Drug Carriers/chemistry
Nanoparticle Drug Delivery System/chemistry
Polyethylene Glycols/chemistry

@article {pmid40075757,
year = {2025},
author = {Rizzo, GEM and Coluccio, C and Forti, E and Fugazza, A and Binda, C and Vanella, G and Di Matteo, FM and Crinò, SF and Lisotti, A and Maida, MF and Aragona, G and Mauro, A and Repici, A and Anderloni, A and Fabbri, C and Tarantino, I and On Behalf Of The I-Eus Group, },
title = {Endoscopic Ultrasound-Guided Anastomoses of the Gastrointestinal Tract: A Multicentric Experience.},
journal = {Cancers},
volume = {17},
number = {5},
pages = {},
pmid = {40075757},
issn = {2072-6694},
support = {N/A//I-EUS working group/ ; },
abstract = {This multicenter retrospective study included patients undergoing EUS-guided GI anastomoses from 2016 to 2023. Indications for EUS-guided anastomosis were GOO, ALS or patients with altered anatomy needing endoscopic interventions. The primary outcome was technical success, while secondary outcomes included clinical success, safety, lumen-apposing metal stent (LAMS) patency, and the need for reinterventions. A total of 216 patients (mean age 64.5 [±13.94] years; 49.1% males) were included. In total, 149 cases (69%) were GOO, 44 (20.4%) cases were bilioenteric anastomotic strictures or lithiasis in altered anatomy, 14 cases (6.5%) were ALS, and 9 patients (4.2%) were for ERCP in altered anatomy after EUS-GG. Overall, EUS-GE was performed in 181 patients (83.8%), EUS-JJ in 44 cases (20.4%), and EUS-GG in 10 (4.6%). Technical success was 94.91%, and clinical success was 93.66%. The adverse event (AE) rate was 11.1%. The reintervention rate was 7.69%. The median follow-up was 85 days. In conclusions, EUS-guided GI anastomoses are technically feasible and safe in both malignant and benign diseases.},
}

@article {pmid40075315,
year = {2025},
author = {Soliman, R and Fahmy, N and Swelam, MS},
title = {Headache types and characteristics in patients with Amyotrophic Lateral Sclerosis.},
journal = {The journal of headache and pain},
volume = {26},
number = {1},
pages = {53},
pmid = {40075315},
issn = {1129-2377},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/diagnosis/physiopathology ; Female ; Male ; Middle Aged ; Cross-Sectional Studies ; Adult ; Headache/etiology/epidemiology/diagnosis ; Aged ; Tension-Type Headache/diagnosis ; Severity of Illness Index ; },
abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder associated with progressive loss of motor neurons, this result in muscle denervation, atrophy and consequently death takes place due to respiratory failure within 3-5 years of onset of symptoms.

OUR AIM: Was to investigate types and frequency of headache in ALS patients.

METHODS: This is cross sectional hospital based study. Clinically definite 100 ALS Patients (diagnosed according to El Escorial revised criteria) were recruited out of 137 ALS patients presented to the Neuromuscular Clinic in Ain Shams university Hospital from February 2022 to June 2024. Patients were screened for headache types and symptoms diagnosed according to International Headache Society criteria (IHS). Headache severity and impact were assessed using Arabic versions of Headache Impact Test (HIT) and Migraine Disability Assessment (MIDAS). Depression was also assessed via Arabic version of Beck's Depression Inventory (BDI). ALS symptoms severity was assessed via Arabic version of Amyotrophic Lateral Sclerosis Functional Rating Scale Revised (ALSFRS-R). Cognitive functions were assessed via the Egyptian version of the Edinburgh Cognitive and Behavioral Amyotrophic Lateral Sclerosis Screen (ECAS‑EG). Demographic data and ALS related parameters were collected.

RESULTS: Among 100 patients with clinically definite ALS, 79 patients reported headaches, 62 of them had primary headaches; with tension-type headache being the most commonly reported in 46 patients, Migraine in 16 patients. Fifteen ALS patients had secondary headaches; among them 12 had headache secondary to respiratory insufficiency and 3 patients developed headache after the initiation of Riluzole therapy. Two patients had non specific headache. Mean age for the patients at ALS presentation was 43.9 ± 13.8, Mean ALSFRS-R score 33.3 ± 9.04. The relationships between headache and clinical features of ALS were also investigated.

IN CONCLUSION: ALS patients should be evaluated for Headache; Not only headache secondary to respiratory compromise and hypercapnea, but also primary headaches which can be overlooked in patients with ALS.},
}

Humans
*Amyotrophic Lateral Sclerosis/complications/diagnosis/physiopathology
Female
Male
Middle Aged
Cross-Sectional Studies
Adult
Headache/etiology/epidemiology/diagnosis
Aged
Tension-Type Headache/diagnosis
Severity of Illness Index

@article {pmid40075110,
year = {2025},
author = {Raas, Q and Haouy, G and de Calbiac, H and Pasho, E and Marian, A and Guerrera, IC and Rosello, M and Oeckl, P and Del Bene, F and Catanese, A and Ciura, S and Kabashi, E},
title = {TBK1 is involved in programmed cell death and ALS-related pathways in novel zebrafish models.},
journal = {Cell death discovery},
volume = {11},
number = {1},
pages = {98},
pmid = {40075110},
issn = {2058-7716},
support = {682622//EC | EU Framework Programme for Research and Innovation H2020 | H2020 Priority Excellent Science | H2020 European Research Council (H2020 Excellent Science - European Research Council)/ ; },
abstract = {Pathogenic mutations within the TBK1 gene leading to haploinsufficiency are causative of amyotrophic lateral sclerosis (ALS). This gene is linked to autophagy and inflammation, two cellular mechanisms reported to be dysregulated in ALS patients, although its functional role in the pathogenesis could involve other players. We targeted the TBK1 ortholog in zebrafish, an optimal vertebrate model for investigating genetic defects in neurological disorders. We generated zebrafish models with invalidating tbk1 mutations using CRISPR-Cas9 or tbk1 knockdown models using antisense morpholino oligonucleotide (AMO). The early motor phenotype of zebrafish injected with tbk1 AMO beginning at 2 days post fertilization (dpf) is associated with the degeneration of motor neurons. In parallel, CRISPR-induced tbk1 mutants exhibit impaired motor function beginning at 5 dpf and increased lethality beginning at 9 dpf. A metabolomic analysis showed an association between tbk1 loss and severe dysregulation of nicotinamide metabolism, and incubation with nicotinamide riboside rescued the motor behavior of tbk1 mutant zebrafish. Furthermore, a proteomic analysis revealed increased levels of inflammatory markers and dysregulation of programmed cell death pathways. Necroptosis appeared to be strongly activated in TBK1 fish, and larvae treated with the necroptosis inhibitor necrosulfonamide exhibited improved survival. Finally, a combined analysis of mutant zebrafish and TBK1-mutant human motor neurons revealed dysregulation of the KEGG pathway "ALS", with disrupted nuclear-cytoplasmic transport and increased expression of STAT1. These findings point toward a major role for necroptosis in the degenerative features and premature lethality observed in tbk1 mutant zebrafish. Overall, the novel tbk1-deficient zebrafish models offer a great opportunity to better understand the cascade of events leading from the loss of tbk1 expression to the onset of motor deficits, with involvement of a metabolic defect and increased cell death, and for the development of novel therapeutic avenues for ALS and related neuromuscular diseases.},
}

@article {pmid40074931,
year = {2025},
author = {Michielsen, A and van Veenhuijzen, K and Hiemstra, F and Jansen, IM and Kalkhoven, B and Veldink, JH and Kruitwagen, ET and van Es, M and van Zandvoort, MJE and van den Berg, LH and Westeneng, HJ},
title = {Cognitive impairment within and beyond the FTD spectrum in ALS: development of a complementary cognitive screen.},
journal = {Journal of neurology},
volume = {272},
number = {4},
pages = {268},
pmid = {40074931},
issn = {1432-1459},
support = {grant agreement no 772376- EScORIAL//H2020 European Research Council/ ; },
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/complications/diagnosis/physiopathology ; Male ; Female ; *Frontotemporal Dementia/complications/diagnosis/physiopathology ; *Cognitive Dysfunction/etiology/diagnosis/physiopathology ; Middle Aged ; Aged ; *Neuropsychological Tests ; },
abstract = {OBJECTIVE: To investigate cognitive impairments in amyotrophic lateral sclerosis (ALS), extending both within and beyond the established frontotemporal dementia (FTD) spectrum, using the Complementary Cognitive ALS Screen (C-CAS).

METHODS: The C-CAS, designed to complement the Edinburgh cognitive and behavioural ALS screen (ECAS), explores cognitive (sub)domains not investigated by the ECAS. Normative data were collected, and models adjusted for age, sex, and education level were developed. Item scores below the 5th percentile in controls were considered abnormal. A sum score was constructed, and C-CAS impairments were compared between ALS patients and controls, and to ECAS impairments.

RESULTS: Data from 314 controls and 184 ALS patients were analyzed. The C-CAS is feasible, well-tolerated, and takes 15-20 min to complete. ALS patients performed worse across all 12 items. Within the FTD spectrum, impairments in social cognition, inhibition, and cognitive flexibility were identified in up to 16%, 14%, and 12% of ALS patients, respectively, with minimal overlap with ECAS impairments. Beyond the FTD spectrum, impairments were found in visuoconstruction, incidental non-verbal memory and body orientation (13% each), with minimal overlap with ECAS memory or visuospatial impairments. Overall, 24% of the ALS patients obtained an abnormal C-CAS sum score. Compared to the ECAS, the C-CAS detected additional impairments in 15% of ALS patients. Item-specific and sum score results based on normative data can be accessed at (https://apps4mnd.com/ccas/).

INTERPRETATION: We identified cognitive impairments in ALS within and beyond the FTD spectrum not captured by existing screening tools. The C-CAS complements the ECAS, improving personalized counseling and research stratification in ALS.},
}

Humans
*Amyotrophic Lateral Sclerosis/complications/diagnosis/physiopathology
Male
Female
*Frontotemporal Dementia/complications/diagnosis/physiopathology
*Cognitive Dysfunction/etiology/diagnosis/physiopathology
Middle Aged
Aged
*Neuropsychological Tests

@article {pmid40074537,
year = {2025},
author = {Mkhize, L and Marimani, M and Duze, ST},
title = {Characterization of Vibrio cholerae from the Jukskei River in Johannesburg South Africa.},
journal = {Letters in applied microbiology},
volume = {},
number = {},
pages = {},
doi = {10.1093/lambio/ovaf036},
pmid = {40074537},
issn = {1472-765X},
abstract = {The current study aimed to isolate and characterize Vibrio cholerae (V. cholerae) isolated from the Jukskei River, one of the largest Rivers in Johannesburg, South Africa. Water samples collected from the Jukskei River were subjected to culture-based methods for the detection and isolation of V. cholerae. Twenty-four V. cholerae were isolated, confirmed using real-time PCR, and sequenced using the MInION portable nanopore-sequencing device. Reference-based genome assemblies were constructed from the raw reads using the EPI2ME software followed by bioinformatics analysis using the Centre for Genomic Epidemiology website. All the V. cholerae isolates isolated from the Jukskei River were classified as non-O1/ non-O139 and none of the isolates harbored the cholera toxin gene, ctxA. All 24 V. cholerae isolates belonged to sequence type 741, virulent genes including toxR, vspD, als, hlyA, makA, and rtxA as well as the Vibrio pathogenicity island 2 were detected amongst the isolates. Antimicrobial resistance genes (parC, varG, and gyrA) were detected in 83% of isolates. Although V. cholerae non-O1/non-O139 are not associated with epidemic cholera they can still cause mild to life-threatening illnesses. Therefore, increased surveillance should be considered to better understand the public health risks to the local community.},
}

@article {pmid40074390,
year = {2025},
author = {Cappa, SF},
title = {Hemispheric asymmetry in neurodegenerative diseases.},
journal = {Handbook of clinical neurology},
volume = {208},
number = {},
pages = {101-112},
doi = {10.1016/B978-0-443-15646-5.00009-9},
pmid = {40074390},
issn = {0072-9752},
mesh = {Humans ; *Neurodegenerative Diseases/pathology/physiopathology ; *Functional Laterality/physiology ; Brain/pathology/physiopathology ; },
abstract = {Hemispheric asymmetry in pathologic involvement is frequently observed in neurodegenerative disorders (NDD) and is responsible for differences in cognitive and motor clinical manifestations in individual patients. While asymmetry is modest in typical Alzheimer disease (AD), atypical AD presentations with prominent language impairment [logopenic/phonologic variant of primary progressive aphasia (L/Phv-PPA)] are associated with prevalent involvement of the language-dominant hemisphere. Similarly, in the frontotemporal dementia-amyotrophic lateral sclerosis (FTD-ALS) spectrum, the semantic (Sv) and nonfluent/agrammatic (Nf/Av) variants of PPA are due to asymmetric pathology involving the language-dominant hemisphere. A reversed (typically right-sided) pattern of asymmetry is often found in conditions associated with prominent disorders of behavior and social cognition (i.e., behavioral variant of frontotemporal degeneration-Bv FTD). Asymmetry is generally modest and less consistent in NDD with prevalent motor manifestations, such as Parkinson disease (PD). Overall, the pattern of hemispheric involvement reflects the network-specific selectivity of NDD and is compatible with the spreading of pathology along connection pathways.},
}

Humans
*Neurodegenerative Diseases/pathology/physiopathology
*Functional Laterality/physiology
Brain/pathology/physiopathology

@article {pmid40073860,
year = {2025},
author = {Zhang, Z and Fu, X and Wright, N and Wang, W and Ye, Y and Asbury, J and Li, Y and Zhu, C and Wu, R and Wang, S and Sun, S},
title = {PTPσ-mediated PI3P regulation modulates neurodegeneration in C9ORF72-ALS/FTD.},
journal = {Neuron},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuron.2025.02.005},
pmid = {40073860},
issn = {1097-4199},
abstract = {The most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is the repeat expansion in C9ORF72. Dipeptide repeat (DPR) proteins translated from both sense and antisense repeats, especially arginine-rich DPRs (R-DPRs), contribute to neurodegeneration. Through CRISPR interference (CRISPRi) screening in human-derived neurons, we identified receptor-type tyrosine-protein phosphatase S (PTPσ) as a strong modifier of poly-GR-mediated toxicity. We showed that reducing PTPσ promotes the survival of both poly-GR- and poly-PR-expressing neurons by elevating phosphatidylinositol 3-phosphate (PI3P), accompanied by restored early endosomes and lysosomes. Remarkably, PTPσ knockdown or inhibition substantially rescues the PI3P-endolysosomal defects and improves the survival of C9ORF72-ALS/FTD patient-derived neurons. Furthermore, the PTPσ inhibitor diminishes GR toxicity and rescues pathological and behavioral phenotypes in mice. Overall, these findings emphasize the critical role of PI3P-mediated endolysosomal deficits induced by R-DPRs in disease pathogenesis and reveal the therapeutic potential of targeting PTPσ in C9ORF72-ALS/FTD.},
}

@article {pmid40073394,
year = {2025},
author = {Janes, WE and Marchal, N and Song, X and Popescu, M and Mosa, ASM and Earwood, JH and Jones, V and Skubic, M},
title = {Integrating Ambient In-Home Sensor Data and Electronic Health Record Data for the Prediction of Outcomes in Amyotrophic Lateral Sclerosis: Protocol for an Exploratory Feasibility Study.},
journal = {JMIR research protocols},
volume = {14},
number = {},
pages = {e60437},
doi = {10.2196/60437},
pmid = {40073394},
issn = {1929-0748},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/physiopathology/diagnosis ; *Electronic Health Records ; *Feasibility Studies ; Machine Learning ; Male ; Female ; },
abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) leads to rapid physiological and functional decline before causing untimely death. Current best-practice approaches to interdisciplinary care are unable to provide adequate monitoring of patients' health. Passive in-home sensor systems enable 24×7 health monitoring. Combining sensor data with outcomes extracted from the electronic health record (EHR) through a supervised machine learning algorithm may enable health care providers to predict and ultimately slow decline among people living with ALS.

OBJECTIVE: This study aims to describe a federated approach to assimilating sensor and EHR data in a machine learning algorithm to predict decline among people living with ALS.

METHODS: Sensor systems have been continuously deployed in the homes of 4 participants for up to 330 days. Sensors include bed, gait, and motion sensors. Sensor data are subjected to a multidimensional streaming clustering algorithm to detect changes in health status. Specific health outcomes are identified in the EHR and extracted via the REDCap (Research Electronic Data Capture; Vanderbilt University) Fast Healthcare Interoperability Resource directly into a secure database.

RESULTS: As of this writing (fall 2024), machine learning algorithms are currently in development to predict those health outcomes from sensor-detected changes in health status. This methodology paper presents preliminary results from one participant as a proof of concept. The participant experienced several notable changes in activity, fluctuations in heart rate and respiration rate, and reductions in gait speed. Data collection will continue through 2025 with a growing sample.

CONCLUSIONS: The system described in this paper enables tracking the health status of people living with ALS at unprecedented levels of granularity. Combined with tightly integrated EHR data, we anticipate building predictive models that can identify opportunities for health care services before adverse events occur. We anticipate that this system will improve and extend the lives of people living with ALS.

DERR1-10.2196/60437.},
}

Humans
*Amyotrophic Lateral Sclerosis/therapy/physiopathology/diagnosis
*Electronic Health Records
*Feasibility Studies
Machine Learning
Male
Female

@article {pmid40072375,
year = {2025},
author = {Gong, Z and Ba, L and Li, Z and Hou, H and Zhang, M},
title = {CD16[-]CD56[bright] NK Cells: A Protective NK Cell Subset for Progression and Prognosis in Amyotrophic Lateral Sclerosis.},
journal = {Aging and disease},
volume = {},
number = {},
pages = {},
doi = {10.14336/AD.2024.1597},
pmid = {40072375},
issn = {2152-5250},
abstract = {Amyotrophic lateral sclerosis (ALS) is a non-neuron-autonomous disease where peripheral immune dysregulation significantly impacts disease progression. However, the immunopathological mechanisms of natural killer (NK) cells in ALS remain largely unexplored. This study enrolled 241 ALS patients and 102 healthy controls (HC), analyzing lymphocyte subsets, including T cells, B cells, and NK cells. A sub-cohort of 81 ALS patients was followed up for one year at three-month intervals. Linear mixed and Cox proportional hazards models were used to evaluate the association between lymphocyte subsets and ALS progression and prognosis. Our results revealed significant reductions in total T cells, helper T cells (Th), and NK cells in ALS patients compared to HC (P &;lt 0.05). Slow-progressing ALS patients exhibited higher counts of total T cells, Th, CD16-CD56[bright] NK cells, and CD16[+]CD56[bright] NK cells, while showing lower counts of CD16[+]CD56[dim] NK cells compared to fast-progressing ALS patients (P &;lt 0.05). ALS patients with lower CD16[-]CD56[bright] NK cell counts experienced a faster decline in motor function than those with higher counts (P &;lt 0.05). Elevated CD16[-]CD56[bright] NK cell counts were associated with improved ALS prognosis (HR, 0.73; 95% CI: 0.60-0.90; P &;lt 0.05). This study suggests that CD16[-]CD56[bright] NK cells play a protective role in ALS progression and prognosis, offering a potential therapeutic target for ALS.},
}

@article {pmid40072076,
year = {2025},
author = {Calvo, B and Schembri-Wismayer, P and Durán-Alonso, MB},
title = {Age-Related Neurodegenerative Diseases: A Stem Cell's Perspective.},
journal = {Cells},
volume = {14},
number = {5},
pages = {},
doi = {10.3390/cells14050347},
pmid = {40072076},
issn = {2073-4409},
mesh = {Humans ; *Neurodegenerative Diseases/pathology ; *Aging/pathology ; Animals ; Stem Cells/metabolism ; Neurogenesis ; },
abstract = {Neurodegenerative diseases encompass a number of very heterogeneous disorders, primarily characterized by neuronal loss and a concomitant decline in neurological function. Examples of this type of clinical condition are Alzheimer's Disease, Parkinson's Disease, Huntington's Disease and Amyotrophic Lateral Sclerosis. Age has been identified as a major risk in the etiology of these disorders, which explains their increased incidence in developed countries. Unfortunately, despite continued and intensive efforts, no cure has yet been found for any of these diseases; reliable markers that allow for an early diagnosis of the disease and the identification of key molecular events leading to disease onset and progression are lacking. Altered adult neurogenesis appears to precede the appearance of severe symptoms. Given the scarcity of human samples and the considerable differences with model species, increasingly complex human stem-cell-based models are being developed. These are shedding light on the molecular alterations that contribute to disease development, facilitating the identification of new clinical targets and providing a screening platform for the testing of candidate drugs. Moreover, the secretome and other promising features of these cell types are being explored, to use them as replacement cells of high plasticity or as co-adjuvant therapy in combinatorial treatments.},
}

Humans
*Neurodegenerative Diseases/pathology
*Aging/pathology
Animals
Stem Cells/metabolism
Neurogenesis

@article {pmid40070688,
year = {2025},
author = {Hosseini Faradonbeh, SM and Seyedalipour, B and Keivan Behjou, N and Rezaei, K and Baziyar, P and Hosseinkhani, S},
title = {Structural insights into SOD1: from in silico and molecular dynamics to experimental analyses of ALS-associated E49K and R115G mutants.},
journal = {Frontiers in molecular biosciences},
volume = {12},
number = {},
pages = {1532375},
pmid = {40070688},
issn = {2296-889X},
abstract = {Protein stability is a crucial characteristic that influences both protein activity and structure and plays a significant role in several diseases. Cu/Zn superoxide dismutase 1 (SOD1) mutations serve as a model for elucidating the destabilizing effects on protein folding and misfolding linked to the lethal neurological disease, amyotrophic lateral sclerosis (ALS). In the present study, we have examined the structure and dynamics of the SOD1 protein upon two ALS-associated point mutations at the surface (namely, E49K and R115G), which are located in metal-binding loop IV and Greek key loop VI, respectively. Our analysis was performed through multiple algorithms on the structural characterization of the hSOD1 protein using computational predictions, molecular dynamics (MD) simulations, and experimental studies to understand the effects of amino acid substitutions. Predictive results of computational analysis predicted the deleterious and destabilizing effect of mutants on hSOD1 function and stability. MD outcomes also indicate that the mutations result in structural destabilization by affecting the increased content of β-sheet structures and loss of hydrogen bonds. Moreover, comparative intrinsic and extrinsic fluorescence results of WT-hSOD1 and mutants indicated structural alterations and increased hydrophobic surface pockets, respectively. As well, the existence of β-sheet-dominated structures was observed under amyloidogenic conditions using FTIR spectroscopy. Overall, our findings suggest that mutations in the metal-binding loop IV and Greek key loop VI lead to significant structural and conformational changes that could affect the structure and stability of the hSOD1 molecule, resulting in the formation of toxic intermediate species that cause ALS.},
}

@article {pmid40069959,
year = {2025},
author = {Chiò, A and Foucher, J and Gwathmey, KG and Ingre, C},
title = {Minimum clinically important difference for drug effectiveness in an area of patient-oriented therapeutic goals in amyotrophic lateral sclerosis.},
journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration},
volume = {},
number = {},
pages = {1-10},
doi = {10.1080/21678421.2025.2475893},
pmid = {40069959},
issn = {2167-9223},
abstract = {Objective: In this review, we will examine the more common endpoints incorporated in randomized controlled trials (RCTs) and their strength of evidence, focusing on the definition of what constitutes a clinically meaningful change. We will also reflect on the perspective of patients and their families regarding the design of RCTs in amyotrophic lateral sclerosis (ALS). Methods: Authors performed a scoping review of the literature around clinical meaningfulness in the ALS field and the minimum clinically important difference to deem a treatment effective. Results: The use of survival as an RCT endpoint, as well as the ALS functional rating scale-revised slope, has been criticized, and their relevance for patients remains debated. Biomarkers are promising alternatives as surrogate endpoints, but currently, only cerebrospinal fluid and plasma neurofilaments have emerged as reliable and sensitive biomarkers of disease progression. Incorporating patients' preferences and priorities for their care when treatments are selected is important to minimize the burden of care and limit the potential harms of overtreatment. Patients' interest in and acceptance of a new therapy is also determined by its impact on their quality of life. Discussion and conclusion: While scientifically sound trials must be conducted, this must be balanced with patient expectations of limiting trial burden, duration and placebo usage. An important approach in uniting these diverging needs is the inclusion of people with ALS and their organizations to advise in the design and execution of clinical trials, facilitating the design of RCTs more focused on patients' expectations while retaining a high scientific rigor.},
}

@article {pmid40069809,
year = {2025},
author = {Jonsdottir, G and Vilhjalmsson, R and Sigurdardottir, V and Hjaltason, H and Klinke, ME and Jonsdottir, H},
title = {Nursing contribution to end-of-life care decision-making in patients with neurological diseases on an acute hospital ward: documentation of signs and symptoms.},
journal = {BMC nursing},
volume = {24},
number = {1},
pages = {271},
pmid = {40069809},
issn = {1472-6955},
support = {71545//Icelandic Nurses Association/ ; },
abstract = {BACKGROUND: Recognizing impending death in patients with neurological diseases presents challenges for nurses and other healthcare professionals. This study aimed to identify nursing contribution to end-of-life (EOL) care decision-making for patients with neurological diseases in an acute hospital ward and to compare signs and symptoms among subgroups of patients.

METHODS: In this retrospective study, we analyzed data from 209 patient health records using the Neurological End-Of-Life Care Assessment Tool to evaluate the care in the last 3 to 7 days of life. Key aspects included the need for EOL care, EOL care decision-making, signs and symptoms of imminent death, and communication with relatives. The patient records pertain to patients who died in an acute neurological ward between January 2011 and August 2020; 123 with ischemic stroke, 48 with hemorrhagic stroke, 27 with amyotrophic lateral sclerosis [ALS], and 11 with Parkinson's disease or extrapyramidal and movement disorders [PDoed]. Both descriptive and inferential statistical analyses were performed to analyze the data.

RESULTS: Nurses identified the need for EOL care in 36% of cases and contributed to EOL decision-making as information brokers (15%), advocates (6%), and supporters (6%). They identified disease progression in 44% of the cases. The mean number of signs and symptoms in both the acute and progressive disease groups was 6.5 and ranged from 1 to 14. Patients with stroke without a documented EOL decision had more severe symptoms, including respiratory congestion (68%) and dyspnea (37%), than those with EOL decision. A higher frequency of no food intake was documented in patients with stroke receiving EOL care (p = 0.007) compared to those without. Among patients with ALS or PDoed, those with EOL decision showed a trend toward a higher frequency of unconsciousness or limited consciousness than those without EOL decision (p = 0.067). For all groups of patients, conversations with relatives occurred in 85% instances and family meetings in 93%.

CONCLUSIONS: Nurses made substantial contributions to EOL care decision-making for patients with neurological diseases. To improve early identification of imminent death in patients with neurological diseases in acute hospital wards, healthcare professionals must investigate barriers contributing to delayed recognition.

CLINICAL TRIAL NUMBER: Not applicable.},
}

@article {pmid40069360,
year = {2025},
author = {Cheng, M and Lu, D and Li, K and Wang, Y and Tong, X and Qi, X and Yan, C and Ji, K and Wang, J and Wang, W and Lv, H and Zhang, X and Kong, W and Zhang, J and Ma, J and Li, K and Wang, Y and Feng, J and Wei, P and Li, Q and Shen, C and Fu, XD and Ma, Y and Zhang, X},
title = {Mitochondrial respiratory complex IV deficiency recapitulates amyotrophic lateral sclerosis.},
journal = {Nature neuroscience},
volume = {},
number = {},
pages = {},
pmid = {40069360},
issn = {1546-1726},
support = {2019YFA0508701//Ministry of Science and Technology of the People's Republic of China (Chinese Ministry of Science and Technology)/ ; 2022YFA1303300//Ministry of Science and Technology of the People's Republic of China (Chinese Ministry of Science and Technology)/ ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is categorized into ~10% familial and ~90% sporadic cases. While familial ALS is caused by mutations in many genes of diverse functions, the underlying pathogenic mechanisms of ALS, especially in sporadic ALS (sALS), are largely unknown. Notably, about half of the cases with sALS showed defects in mitochondrial respiratory complex IV (CIV). To determine the causal role of this defect in ALS, we used transcription activator-like effector-based mitochondrial genome editing to introduce mutations in CIV subunits in rat neurons. Our results demonstrate that neuronal CIV deficiency is sufficient to cause a number of ALS-like phenotypes, including cytosolic TAR DNA-binding protein 43 redistribution, selective motor neuron loss and paralysis. These results highlight CIV deficiency as a potential cause of sALS and shed light on the specific vulnerability of motor neurons, marking an important advance in understanding and therapeutic development of sALS.},
}

@article {pmid40067829,
year = {2025},
author = {O'Neill, K and Shaw, R and Bolger, I and , and Tam, OH and Phatnani, H and Gale Hammell, M},
title = {ALS molecular subtypes are a combination of cellular and pathological features learned by deep multiomics classifiers.},
journal = {Cell reports},
volume = {44},
number = {3},
pages = {115402},
doi = {10.1016/j.celrep.2025.115402},
pmid = {40067829},
issn = {2211-1247},
abstract = {Amyotrophic lateral sclerosis (ALS) is a complex syndrome with multiple genetic causes and wide variation in disease presentation. Despite this heterogeneity, large-scale genomics studies revealed that ALS postmortem samples can be grouped into a small number of subtypes, defined by transcriptomic signatures of mitochondrial dysfunction and oxidative stress (ALS-Ox), microglial activation and neuroinflammation (ALS-Glia), or TDP-43 pathology and associated transposable elements (ALS-TE). In this study, we present a deep ALS neural net classifier (DANCer) for ALS molecular subtypes. Applying DANCer to an expanded cohort from the NYGC ALS Consortium highlights two subtypes that strongly correlate with disease duration: ALS-TE in cortex and ALS-Glia in spinal cord. Finally, single-nucleus transcriptomes demonstrate that ALS subtypes are recapitulated in neurons and glia, with both ALS-wide and subtype-specific alterations in all cell types. In summary, ALS molecular subtypes represent a combination of cellular and pathological features that correlate with clinical features of ALS.},
}

@article {pmid40067821,
year = {2025},
author = {, and Berry, JD and Maragakis, NJ and Macklin, EA and Chibnik, LB and Quintana, M and Saville, BR and Detry, MA and Vestrucci, M and Marion, J and McGlothlin, A and Stommel, EW and Chase, M and Pothier, L and Harkey, BA and Yu, H and Sherman, A and Shefner, J and Hall, M and Kittle, G and Babu, S and Andrews, J and D'Agostino, D and Tustison, E and Scirocco, E and Giacomelli, E and Alameda, G and Locatelli, E and Ho, D and Quick, A and Ajroud-Driss, S and Katz, J and Heitzman, D and Appel, SH and Shroff, S and Felice, KJ and Simmons, Z and Miller, T and Olney, N and Weiss, MD and Goutman, SA and Fernandes, JA and Jawdat, O and Owegi, MA and Foster, L and Vu, T and Ilieva, H and Newman, DS and Arcila-Londono, X and Jackson, C and Ladha, S and Heiman-Patterson, T and Caress, J and Swenson, A and Peltier, A and Lewis, R and Fee, D and Elliott, M and Bedlack, R and Kasarskis, EJ and Elman, L and Rosenfeld, J and Walk, D and McIlduff, CE and Twydell, P and Young, E and Johnson, K and Rezania, K and Goyal, NA and Cohen, JA and Benatar, M and Jones, V and Glass, J and Shah, J and Beydoun, SR and Wymer, JP and Zilliox, L and Nayar, S and Pattee, GL and Martinez-Thompson, J and Rynders, A and Evan, J and Evan, J and Hartford, A and Sepassi, M and Ho, KS and Glanzman, R and Greenberg, B and Hotchkin, MT and Paganoni, S and Cudkowicz, ME and , },
title = {CNM-Au8 in Amyotrophic Lateral Sclerosis: The HEALEY ALS Platform Trial.},
journal = {JAMA},
volume = {},
number = {},
pages = {},
doi = {10.1001/jama.2024.27643},
pmid = {40067821},
issn = {1538-3598},
abstract = {IMPORTANCE: Bioenergetic failure has been proposed as a driver of amyotrophic lateral sclerosis (ALS). CNM-Au8 is a suspension of gold nanocrystals that catalyzes the conversion of nicotinamide adenine dinucleotide hydride into NAD+, resulting in an increase of cellular adenosine triphosphate production.

OBJECTIVE: To determine the effects of CNM-Au8 on ALS disease progression.

CNM-Au8 was tested as a regimen of the HEALEY ALS Platform Trial, a phase 2/3, multicenter, randomized, double-blind platform trial. The study was conducted at 54 sites in the US from July 2020 to March 2022 (final follow-up, March 17, 2022). A total of 161 participants with ALS were randomized to receive CNM-Au8 (n = 120) or regimen-specific placebo (n = 41). Data from 123 concurrently randomized placebo participants in other regimens were combined for analyses.

INTERVENTIONS: Eligible participants were randomized in a 3:3:2 ratio to receive CNM-Au8 60 mg daily (n = 61), CNM-Au8 30 mg daily (n = 59), or matching placebo (n = 41) for 24 weeks.

MAIN OUTCOMES AND MEASURES: The primary efficacy outcome was change from baseline through week 24 in ALS disease severity measured by a bayesian shared parameter model of function (based on the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale) and survival, which provided an estimate of the rate of disease progression measured by the disease rate ratio (DRR), with a DRR of less than 1 indicating treatment benefit. Secondary end points included a Combined Assessment of Function and Survival using a joint-rank test, rate of decline in slow vital capacity (percent predicted), and survival free of permanent assisted ventilation.

RESULTS: Among 161 participants who were randomized within the CNM-Au8 regimen (mean age, 58.4 years; 61 [37.9%] female), 145 (90%) completed the trial. In the primary analysis comparing the combined CNM-Au8 dosage groups vs the combined placebo groups, the primary end point (DRR, 0.97 [95% credible interval, 0.783-1.175]; posterior probability of DRR <1, 0.65) and the 3 secondary end points suggested no benefit or harm of CNM-Au8. In the active (n = 120) vs placebo (n = 163) groups, the most common adverse events were diarrhea (23 [19%] vs 12 [7%]), nausea (17 [14.2%] vs 14 [8.6%]), fatigue (12 [10.8%] vs 30 [18.4%]), and muscular weakness (24 [20%] vs 45 [27.6%]).

CONCLUSIONS AND RELEVANCE: No benefit of CNM-Au8 on ALS disease progression was observed at 24 weeks.

TRIAL REGISTRATION: ClinicalTrials.gov Identifiers: NCT04297683, NCT04414345.},
}

@article {pmid40067755,
year = {2025},
author = {, and Shefner, JM and Oskarsson, B and Macklin, EA and Chibnik, LB and Quintana, M and Saville, BR and Detry, MA and Vestrucci, M and Marion, J and McGlothlin, A and Heiman-Patterson, T and Chase, M and Pothier, L and Harkey, BA and Yu, H and Sherman, AV and Hall, M and Kittle, G and Berry, JD and Babu, S and Andrews, J and D'Agostino, D and Tustison, E and Scirocco, E and Giacomelli, E and Alameda, G and Locatelli, E and Ho, D and Quick, A and Ajroud-Driss, S and Katz, J and Heitzman, D and Appel, SH and Shroff, S and Felice, K and Maragakis, NJ and Simmons, Z and Miller, TM and Olney, N and Weiss, MD and Goutman, SA and Fernandes, JA and Jawdat, O and Owegi, MA and Foster, LA and Vu, T and Ilieva, H and Newman, DS and Arcila-Londono, X and Jackson, CE and Ladha, S and Caress, JB and Swenson, A and Peltier, A and Lewis, RA and Fee, D and Elliott, M and Bedlack, R and Kasarskis, EJ and Elman, L and Rosenfeld, J and Walk, D and McIlduff, C and Twydell, P and Young, E and Johnson, K and Rezania, K and Goyal, NA and Cohen, JA and Benatar, M and Jones, V and Shah, J and Beydoun, SR and Wymer, JP and Zilliox, L and Nayar, S and Pattee, GL and Martinez-Thompson, J and Leitner, ML and Chen, K and Goldberg, YP and Cohen, Y and Geva, M and Hayden, MR and Paganoni, S and Cudkowicz, ME and , },
title = {Pridopidine in Amyotrophic Lateral Sclerosis: The HEALEY ALS Platform Trial.},
journal = {JAMA},
volume = {},
number = {},
pages = {},
doi = {10.1001/jama.2024.26429},
pmid = {40067755},
issn = {1538-3598},
abstract = {IMPORTANCE: Amyotrophic lateral sclerosis (ALS) is a fatal disease. The sigma-1 (σ1) receptor emerged as a target for intervention.

OBJECTIVE: To determine the effects of pridopidine, a σ1-receptor agonist, in ALS.

Pridopidine was tested as a regimen of the HEALEY ALS Platform Trial, a phase 2/3, multicenter, randomized, double-blind, platform trial. The study was conducted at 54 sites in the US from January 2021 to July 2022 (final follow-up, July 14, 2022). A total of 163 participants with ALS were randomized to receive pridopidine or placebo. An additional 122 concurrently randomized participants were assigned to receive placebo in other regimens and included in the analyses.

INTERVENTIONS: Eligible participants were randomized 3:1 to receive oral pridopidine 45 mg twice daily (n = 121) or matching oral placebo (n = 42) for a planned duration of 24 weeks.

MAIN OUTCOMES AND MEASURES: The primary efficacy outcome was change from baseline through week 24 in ALS disease severity, analyzed using a bayesian shared parameter model, which has components for function (Revised Amyotrophic Lateral Sclerosis Functional Rating Scale [ALSFRS-R]) and survival that were linked through an integrated estimate of treatment-dependent disease slowing across these 2 components. This was denoted as the disease rate ratio (DRR), with DRR less than 1 indicating a slowing in disease progression on pridopidine relative to placebo. There were 5 key secondary end points: time to 2-point or greater reduction in ALSFRS-R total score among participants with bulbar dysfunction at baseline, rate of decline in slow vital capacity among participants with bulbar dysfunction at baseline, percentage of participants with no worsening in the ALSFRS-R bulbar domain score, time to 1-point or greater change in the ALSFRS-R bulbar domain score, and time to death or permanent assisted ventilation.

RESULTS: Among 162 patients (mean age, 57.5 years; 35% female) who were randomized to receive the pridopidine regimen and included in the primary efficacy analysis, 136 (84%) completed the trial. In the primary analysis comparing pridopidine vs the combined placebo groups, there was no significant difference between pridopidine and placebo in the primary end point (DRR, 0.99 [95% credible interval, 0.80-1.21]; probability of DRR <1, 0.55) and no differences were seen in the components of ALSFRS-R or survival. There was no benefit of pridopidine on the secondary end points. In the safety dataset (pridopidine, n = 121; placebo, n = 163), the most common adverse events were falls (28.1% vs 29.3%, respectively) and muscular weakness (24.0% vs 31.7%, respectively).

CONCLUSIONS AND RELEVANCE: In this 24-week study, pridopidine did not impact the progression of ALS.

TRIAL REGISTRATION: ClinicalTrials.gov Identifiers: NCT04297683, NCT04615923.},
}

@article {pmid40067754,
year = {2025},
author = {, and Andrews, J and Paganoni, S and Macklin, EA and Chibnik, LB and Quintana, M and Saville, BR and Detry, MA and Vestrucci, M and Marion, J and McGlothlin, A and Young, E and Chase, M and Pothier, L and Harkey, B and Yu, H and Sherman, A and Shefner, J and Hall, M and Kittle, G and Connolly, MR and Berry, JD and D'Agostino, D and Tustison, E and Giacomelli, E and Scirocco, E and Alameda, G and Locatelli, E and Ho, D and Quick, A and Heitzman, D and Ajroud-Driss, S and Appel, SH and Shroff, S and Katz, J and Felice, K and Maragakis, NJ and Simmons, Z and Goutman, SA and Olney, N and Miller, T and Fernandes, JA and Ilieva, H and Jawdat, O and Weiss, MD and Foster, L and Vu, T and Ladha, S and Owegi, MA and Newman, DS and Arcila-Londono, X and Jackson, CE and Swenson, A and Heiman-Patterson, T and Caress, J and Fee, D and Peltier, A and Lewis, R and Rosenfeld, J and Walk, D and Johnson, K and Elliott, M and Kasarskis, EJ and Rutkove, S and McIlduff, CE and Bedlack, R and Elman, L and Goyal, NA and Rezania, K and Twydell, P and Benatar, M and Glass, J and Cohen, JA and Jones, V and Zilliox, L and Wymer, JP and Beydoun, SR and Shah, J and Pattee, GL and Martinez-Thompson, J and Nayar, S and Granit, V and Donohue, M and Grossman, K and Campbell, DJ and Qureshi, IA and Cudkowicz, ME and Babu, S and , },
title = {Verdiperstat in Amyotrophic Lateral Sclerosis: Results From the Randomized HEALEY ALS Platform Trial.},
journal = {JAMA neurology},
volume = {},
number = {},
pages = {},
doi = {10.1001/jamaneurol.2024.5249},
pmid = {40067754},
issn = {2168-6157},
abstract = {IMPORTANCE: Myeloperoxidase is one of the most abundant peroxidase enzymes in activated myeloid cells. Myeloperoxidase inhibitors may have a clinical benefit in amyotrophic lateral sclerosis (ALS) by slowing neurodegeneration via reduced neuroinflammation and oxidative stress.

OBJECTIVE: To determine the safety, tolerability, and efficacy of verdiperstat, a selective myeloperoxidase inhibitor, in ALS.

Verdiperstat was tested as a regimen of the HEALEY ALS Platform Trial, a multicenter, double-blind, perpetual platform design, randomized clinical trial, with sharing of trial infrastructure and placebo data across multiple regimens. The study was conducted at 54 ALS referral centers across the US from July 2020 to April 2022. Adult participants with a diagnosis of clinically possible, probable, laboratory-supported probable, or definite ALS defined by the revised El Escorial criteria were randomized to verdiperstat or regimen-specific placebo. An additional group of participants concurrently randomized to placebo from other regimens was included in the analyses.

INTERVENTIONS: Eligible participants were randomized in a 3:1 ratio to receive oral verdiperstat, 600 mg, twice daily or matching placebo for a planned placebo-controlled duration of 24 weeks.

MAIN OUTCOMES AND MEASURES: The primary efficacy outcome was change from baseline through week 24 in disease severity, as measured by a joint model of ALS Functional Rating Scale-Revised and survival, with the treatment effect quantified by the disease rate ratio (DRR), with DRR less than 1 indicating a slowing in disease progression of verdiperstat relative to placebo.

RESULTS: A total of 167 participants (mean [SD] age, 58.5 [11.4] years; 59 [35.3%] female; 108 [64.6%] male) were randomized to either verdiperstat (126 [75.4%]) or to placebo (41 [25.6%]). Among the participants randomized to the verdiperstat regimen, 130 (78%) completed the trial. The estimated DRR was 0.98 (95% credible interval, 0.77-1.24; posterior probability = 0.57 for slowing of disease progression [DRR <1]). Verdiperstat was estimated to slow progression by 2% vs placebo (95% credible interval, -23% to 24%; posterior probability 0.57). Verdiperstat was overall safe and well tolerated. Common adverse events in the verdiperstat group were nausea, insomnia, and elevated thyrotropin levels.

CONCLUSIONS AND RELEVANCE: Results demonstrate that treatment with verdiperstat was unlikely to alter disease progression in ALS.

TRIAL REGISTRATION: Clinical Trial Identifiers: NCT04297683 and NCT04436510.},
}

@article {pmid40066150,
year = {2025},
author = {Stains, EL and Kennalley, AL and Tian, M and Boehnke, KF and Kraus, CK and Piper, BJ},
title = {Medical Cannabis in the United States: Comparing 2017 and 2024 State Qualifying Conditions to the 2017 National Academies of Sciences Report.},
journal = {Mayo Clinic proceedings. Innovations, quality & outcomes},
volume = {9},
number = {2},
pages = {100590},
pmid = {40066150},
issn = {2542-4548},
abstract = {OBJECTIVE: To compare the 2017 National Academies of Sciences, Engineering, and Medicine cannabis report to state medical cannabis (MC) laws defining approved qualifying conditions (QC) from 2017 and 2024 and to determine the evidence level of the QCs approved in each state.

PATIENTS AND METHODS: The 2017 National Academies of Sciences (NAS) report assessed therapeutic evidence for over 20 medical conditions treated with MC. We identified the QCs of 38 states (including Washington DC) where MC was legal in 2024 and compared them to the QCs listed by these states in 2017. The QCs were then categorized on the basis of NAS-established levels of evidence: limited, moderate, or substantial/conclusive evidence of effectiveness, limited evidence of ineffectiveness, or no/insufficient evidence to support or refute effectiveness. This study was completed from January 31, 2023 to June 20, 2024.

RESULTS: Most states listed at least one QC with substantial evidence-80.0% in 2017 and 97.0% in 2024. However, in 2024 only 8.3% of the QCs on states' QC lists met the standard of substantial/conclusive evidence. Of the 20 most popular QCs in the country in 2017 and 2024, one only (long-term pain) was categorized by the NAS as having substantial evidence for effectiveness. However, 7 were rated as either ineffective (eg, glaucoma) or insufficient evidence.

CONCLUSION: Most QCs lack evidence for use on the basis of the 2017 NAS report. Many states recommend QCs with little evidence (amyotrophic lateral sclerosis) or even those for which MC is ineffective (depression). These findings highlight a disparity between state-level MC recommendations and the evidence to support them.},
}

@article {pmid40065593,
year = {2025},
author = {Chen, S and Carter, D and Prier, J and Bingham, J and Patel, S and Kotay, M and Brockenbrough, PB and Gwathmey, K},
title = {Racial Disparities in ALS Progression: Time to Clinical Events Observed in a Single Center.},
journal = {Muscle & nerve},
volume = {},
number = {},
pages = {},
doi = {10.1002/mus.28390},
pmid = {40065593},
issn = {1097-4598},
abstract = {INTRODUCTION/AIMS: Studies examining racial differences in ALS have previously focused on diagnostic delay and disease severity. Time to critical clinical events has rarely been investigated, despite its importance in revealing differences in ALS patients' disease courses. This study explores racial disparities in time to specific clinical events in Black and non-Hispanic White ALS patients at a single center.

METHODS: We performed a retrospective analysis of 33 Black and 170 non-Hispanic White ALS patients examined at Virginia Commonwealth University between 2017 and 2023. Diagnosis dates, referral dates for wheelchair, noninvasive ventilation (NIV), augmentative and alternative communication (AAC) and hospice, along with demographic and clinical factors, were collected. We analyzed the racial difference for events occurring before or on the day of diagnosis using logistic regression models, and for events occurring after diagnosis using Cox proportional hazard models, adjusting for relevant demographic and clinical factors.

RESULTS: Black patients had significantly higher odds of acquiring a wheelchair (odds ratio = 4.06, p = 0.015) and NIV before diagnosis (odds ratio = 2.93, p = 0.017). Following diagnosis, Black patients had 1.72 times the hazards for wheelchair referral (p = 0.051), 2.17 times the hazard for NIV referral (p < 0.001), 1.84 times the hazard for AAC referral (p = 0.034), and 1.59 times the hazard for hospice referral (p = 0.24).

DISCUSSION: Our single-center findings demonstrate a large racial difference in time to clinical events for Black versus White ALS patients referred for NIV, AAC, hospice, and wheelchair, suggesting more advanced disease at the time of presentation or more rapid progression.},
}

@article {pmid40065553,
year = {2025},
author = {Boddy, SL and Simpson, RM and Walters, SJ and Walsh, T and McDermott, CJ and , and , },
title = {Further development of a patient-reported outcome measure to assess the impact of oral secretion problems in people living with MND.},
journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration},
volume = {},
number = {},
pages = {1-9},
doi = {10.1080/21678421.2025.2469721},
pmid = {40065553},
issn = {2167-9223},
abstract = {Objective: Oral secretion problems are common yet poorly managed in people living with MND (plwMND). A validated patient-reported outcome for measuring saliva symptoms in this patient group would facilitate better monitoring of individuals. This study aimed to assess the validity, reliability and sensitivity to change of a revised version of the clinical saliva score for MND (CSS-MNDr). Methods: Data were collected as part of a longitudinal, observational saliva management study. The CSS-MNDr, ALS Functional Rating Scale, a Global Rating of Change questionnaire and saliva-specific modified Likert scale were completed at each study visit, each of which probed the severity of saliva symptoms. Construct validity, test-retest reliability and sensitivity of the CSS-MNDr were assessed and the minimal important difference of the instrument was estimated. Results: The CSS-MNDr showed excellent test-retest reliability (intraclass correlation coefficient >0.9). Construct validity showed the CSS-MNDr performed as expected, with bulbar-onset participants scoring significantly higher than those who reported limb-onset across all visits (group mean scores). Strong correlation of total scores with the ALSFRS-R saliva question was demonstrated (-0.8), with the thick subscore correlating less well (-0.5). A minimal important difference in the range of -2.5 to -3.6 over 3 months was estimated for worsening symptoms. Conclusions: The CSS-MNDr has been validated as a reliable patient reported outcome for measuring saliva problems in plwMND. With separate scores for thick and thin secretion problems, the CSS-MNDr is the most comprehensive tool for assessing salivary problems in plwMND reported to date.},
}

@article {pmid40065552,
year = {2025},
author = {Shibata, N and Kataoka, I and Okamura, Y and Murakami, K and Kato, Y and Yamamoto, T and Masui, K},
title = {Implications for soluble iron accumulation, oxidative stress, and glial glutamate release in motor neuron death associated with sporadic amyotrophic lateral sclerosis.},
journal = {Neuropathology : official journal of the Japanese Society of Neuropathology},
volume = {},
number = {},
pages = {},
doi = {10.1111/neup.13033},
pmid = {40065552},
issn = {1440-1789},
abstract = {Oxidative stress in sporadic amyotrophic lateral sclerosis (ALS) has been evidenced by accumulation of oxidatively modified products of nucleic acids, lipids, sugars, and proteins in the motor neuron system of brains and spinal cords obtained at autopsy from the patients. We recently demonstrated soluble iron accumulation in activated microglia of sporadic ALS spinal cords. This finding could indicate that iron-mediated Fenton reaction is most likely to be responsible for oxidative stress associated with this disease. The excitatory amino acid neurotoxicity hypothesis for sporadic ALS has been proposed based on increased glutamate and aspartate concentrations in cerebrospinal fluid from the patients. Initially, the increase in extracellular excitatory amino acid levels was considered to reflect excessive release from the axon terminal of upper motor neurons. However, it is a question of whether the damaged upper motor neurons continue releasing glutamate even in advanced stage of this disease. To address this issue, we hypothesized that glial cells might be a glutamate release source. Our immunohistochemical analysis on autopsied human spinal cords revealed that ferritin, hepcidin, ferroportin, aconitase 1, tumor necrosis factor-α (TNF-α), TNF-α-converting enzyme (TACE), and glutaminase-C (GAC) were expressed mainly in microglia and that cystine/glutamate antiporter (xCT) was expressed mainly in astrocytes. We next performed cell culture experiments. Cultured microglia treated with soluble iron over-released glutamate and TNF-α via aconitase 1 and TACE, respectively. Cultured microglia treated with TNF-α over-released glutamate via GAC. Cultured microglia treated with hepcidin, of which expression is known to be upregulated by TNF-α, showed downregulated expression of ferroportin. Cultured astrocytes treated with hydrogen peroxide over-released glutamate via xCT. These observations provide in vivo and in vitro evidence that microglia and astrocytes are glutamate suppliers in response to soluble iron overload and oxidative stress, respectively, in sporadic ALS.},
}

@article {pmid40064496,
year = {2025},
author = {Su, Y and Yang, F and Xie, JC and Zhang, C and Luo, RX and Li, WS and Liu, BL and Su, MZ},
title = {Electroacupuncture Neural Stimulation Mitigates Bladder Dysfunction and Mechanical Allodynia in Cyclophosphamide Induced Cystitis through Downregulation of the BDNF-TrkB Signaling Pathway.},
journal = {eNeuro},
volume = {},
number = {},
pages = {},
doi = {10.1523/ENEURO.0329-24.2025},
pmid = {40064496},
issn = {2373-2822},
abstract = {Central sensitization plays a critical role in bladder pain syndrome/interstitial cystitis (BPS/IC). Electroacupuncture (EA) nerve stimulation therapy has been broadly acknowledged as an effective means of alleviating chronic pathological pain. However, it remains to be explored whether EA is effective in mitigating pain-sensitive symptoms of BPS/IC and the mechanisms involved. This study aims to investigate the analgesic effect and mechanism of EA therapy. To achieve this goal, we employed several techniques: mechanical pain threshold tests to assess pain sensitivity, urodynamic studies to evaluate bladder function, Western blotting (WB) for protein analysis, immunofluorescence for visualizing, and transcriptomics. A rat cystitis model was established through a systemic intraperitoneal injection with cyclophosphamide (CYP). EA therapy was executed by stimulating the deep part of the hypochondriac point, where the 2nd-4th sacral nerves traverse. EA treatment was observed to effectively reduce mechanical allodynia, enhance urinary function, suppress the activation of microglial cells, and alleviate neuroinflammation. Additionally, EA demonstrated the capability to downregulate BDNF-TrkB signal transduction in the spinal dorsal horn. Transcriptome sequencing has indicated that EA therapy potentially inhibits excitatory neural transmission and modulates several pathways related to longevity. Furthermore, EA therapy has shown efficacy in treating conditions such as Huntington's disease, amyotrophic lateral sclerosis, and prion diseases. In conclusion, by regulating the BDNF-TrkB signaling, EA nerve stimulation can effectively alleviate bladder dysfunction and mechanical allodynia in cyclophosphamide-induced cystitis model. Our research elucidates the underlying mechanisms of EA therapy in treating bladder dysfunction and offers new theoretical insights for addressing painful sensitization in BPS.Significance Statement Central sensitization is a major factor in bladder pain syndrome/interstitial cystitis (BPS/IC), making effective pain management crucial. This study explores the potential of electroacupuncture (EA) as a therapeutic approach to alleviate pain and improve bladder function in a rat model of BPS/IC induced by cyclophosphamide. Our findings demonstrate that EA therapy significantly reduces mechanical allodynia, enhances urinary function, and decreases neuroinflammation by modulating BDNF-TrkB signaling in the spinal dorsal horn. The research highlights EA's capability to inhibit excitatory neural transmission and provide relief in chronic pain conditions. These results offer new insights into the mechanisms of EA therapy, potentially improving treatment strategies for BPS/IC and similar pain syndromes.},
}

@article {pmid40064491,
year = {2025},
author = {Izumi, Y and Nakayama, Y},
title = {[Communicating the Diagnosis of Amyotrophic Lateral Sclerosis].},
journal = {Brain and nerve = Shinkei kenkyu no shinpo},
volume = {77},
number = {3},
pages = {259-263},
doi = {10.11477/mf.188160960770030259},
pmid = {40064491},
issn = {1881-6096},
mesh = {*Amyotrophic Lateral Sclerosis/diagnosis ; Humans ; *Communication ; Patient Care Team ; },
abstract = {When explaining amyotrophic lateral sclerosis, family members, caregivers, and other professionals are encouraged to be present with the patient's consent. Patients' perceptions vary considerably depending on their condition, personality, and home environment; therefore, the content of the explanation should be carefully considered. If the patient did not fully understand or provide consent to participate, the explanation was repeated. Depending on the patient's level of understanding and acceptance, we provided step-by-step explanations. The patients were informed that the decision could change later, even after the treatment plan had been decided. In explanations involving a multidisciplinary team, each professional explains; however, it is also important for the team leader to understand the patient's perceptions.},
}

*Amyotrophic Lateral Sclerosis/diagnosis
Humans
*Communication
Patient Care Team

@article {pmid40063887,
year = {2025},
author = {Hayden, CD and Murphy, BP and Gilsenan, D and Nasseroleslami, B and Hardiman, O and Murray, D},
title = {Clinical validation of a novel hand dexterity measurement device.},
journal = {PLOS digital health},
volume = {4},
number = {3},
pages = {e0000744},
pmid = {40063887},
issn = {2767-3170},
abstract = {The lack of sensitive objective outcome measures for hand dexterity is a barrier for clinical assessment of neurological conditions and has negatively affected clinical trials. Here, we clinically validate a new method for measuring hand dexterity, a novel hand worn sensor that digitises the Finger Tapping Test. The device was assessed in a cohort of 180 healthy controls and 51 people with Amyotrophic Lateral Sclerosis (ALS) and compared against rating scales and traditional measures (Nine Hole Peg test and grip dynamometry). 14 features were extracted from the device and using a logistic regression algorithm, a 0-100 dexterity performance score was generated for each participant, which accounted for age/sex differences. The device returned objective ratings of a participant's hand dexterity (dominant, non-dominant and overall score). The average overall dexterity performance score in all healthy participants was 88 ± 17 (mean ± standard deviation). The overall dexterity score was statistically significantly worse in participants with ALS (age/sex matched healthy subset: 80 ± 20, ALS: 45 ± 32, p-value < 0.0001). The device also had a higher completion rate, (94% dominant hand) compared to the traditional measures (82% dominant hand). This test and scoring system have been validated and the regression model was developed using a framework that is potentially applicable to any relevant condition. This device could act as an objective outcome measure in clinical trials and may be useful in improving patient care.},
}

@article {pmid40063831,
year = {2025},
author = {Kubinski, S and Claus, L and Schüning, T and Zeug, A and Kalmbach, N and Staege, S and Gschwendtberger, T and Petri, S and Wegner, F and Claus, P and Hensel, N},
title = {Aggregates associated with amyotrophic lateral sclerosis sequester the actin-binding protein profilin 2.},
journal = {Human molecular genetics},
volume = {},
number = {},
pages = {},
doi = {10.1093/hmg/ddaf020},
pmid = {40063831},
issn = {1460-2083},
support = {ZE994//Deutsche Forschungsgemeinschaft/ ; },
abstract = {Amyotrophic Lateral Sclerosis (ALS) is a devastating neurodegenerative disease characterized by the degeneration of upper and lower motoneurons. The four most frequently mutated genes causing familial ALS (fALS) are C9orf72, FUS, SOD1, and TARDBP. Some of the related wild-type proteins comprise intrinsically disordered regions (IDRs) which favor their assembly in liquid droplets-the biophysical mechanism behind the formation of physiological granules such as stress granules (SGs). SGs assemble and dissolve dependent on the cellular condition. However, it has been suggested that transition from reversible SGs to irreversible aggregates contributes to the toxic properties of ALS-related mutated proteins. Sequestration of additional proteins within these aggregates may then result in downstream toxicity. While the exact downstream mechanisms remain elusive, rare ALS-causing mutations in the actin binding protein profilin 1 suggest an involvement of the actin cytoskeleton. Here, we hypothesize that profilin isoforms become sequestered in aggregates of ALS-associated proteins which induce subsequent dysregulation of the actin cytoskeleton. Interestingly, localization of neuronal profilin 2 in SGs was more pronounced compared with the ubiquitously expressed profilin 1. Accordingly, FUS and C9orf72 aggregates prominently sequestered profilin 2 but not profilin 1. Moreover, we observed a distinct sequestration of profilin 2 and G-actin to C9orf72 aggregates in different cellular models. On the functional level, we identified dysregulated actin dynamics in cells with profilin 2-sequestering aggregates. In summary, our results suggest a more common involvement of profilins in ALS pathomechanisms than indicated from the rarely occurring profilin mutations.},
}

@article {pmid40061974,
year = {2025},
author = {Zhang, ZN and Hao, L and Han, S and Li, SS and Lin, SX and Miao, YD},
title = {Harnessing the prognostic power of preoperative systemic immune-inflammation index/albumin ratio in hepatocellular carcinoma resection.},
journal = {World journal of gastrointestinal surgery},
volume = {17},
number = {2},
pages = {102261},
pmid = {40061974},
issn = {1948-9366},
abstract = {The recent study by Chen et al, published in the World Journal of Gastroenterology, introduces a groundbreaking assessment tool-the preoperative systemic immune-inflammation index/albumin (SII/ALB) ratio-for patients with hepatocellular carcinoma (HCC) undergoing curative resection. This study not only establishes the independent prognostic significance of the SII/ALB ratio but also incorporates it into a predictive nomogram, enhancing its utility for clinical decision-making. The SII/ALB ratio, by integrating inflammatory and nutritional biomarkers, offers a novel lens through which the prognosis of HCC patients can be viewed, suggesting a more tailored approach to patient management. The development of the nomogram, validated for its accuracy in predicting patient outcomes, marks a pivotal advance, potentially guiding surgical decisions and postoperative care. However, the study's focus on a single-center cohort prompts the need for validation in a broader, more diverse patient population to ensure its applicability across various clinical settings. Moreover, longitudinal studies could elucidate the dynamic changes in SII/ALB post-surgery, offering insights into its potential as a continuous monitor for recurrence and long-term survival. This abstract aim to underscore the critical findings of Chen et al's study while calling for further research to explore the full potential of the SII/ALB ratio in the global management of hepatocellular carcinoma.},
}

@article {pmid40061972,
year = {2025},
author = {Yi, XM and Cai, HQ and Jiao, Y},
title = {Programmed cell death receptor 1 inhibitor Pembrolizumab in the treatment of advanced gastric cancer.},
journal = {World journal of gastrointestinal surgery},
volume = {17},
number = {2},
pages = {100257},
pmid = {40061972},
issn = {1948-9366},
abstract = {This editorial discusses Christodoulidis et al's article, which appeared in the most recent edition. The clinical trials have demonstrated the programmed cell death receptor 1 (PD-1) inhibitor Pembrolizumab involved combination therapy can improve the efficacy of advanced gastric cancer (AGC). Pembrolizumab combined with chemotherapy can enhance its sensitivity, and further eliminate tumor cells that develop resistance to chemotherapy. The combination of Pembrolizumab and Trastuzumab targeting human epidermal growth factor receptor 2 showed improved prognosis. The overall toxic effects of Pembrolizumab are significantly lower than traditional chemotherapy, and the safety is controllable. PD-1 inhibitor Pembrolizumab sheds a light on the treatment of AGC and brings new hope to the clinical practice.},
}

@article {pmid40061966,
year = {2025},
author = {Wang, H and Jiao, Y and Ma, Q and Liu, YH},
title = {Overview of endoscopic biliary stenting in malignant obstructive jaundice.},
journal = {World journal of gastrointestinal surgery},
volume = {17},
number = {2},
pages = {103378},
pmid = {40061966},
issn = {1948-9366},
abstract = {This article discusses Wang et al's essay. Endoscopic biliary stenting, a less invasive alternative to surgery, is effective for malignant obstructive jaundice. This article summarizes the pathophysiology of biliary obstruction, the technical aspects of stenting, and the clinical outcomes. By comparison of endoscopic stenting with percutaneous biliary drainage, improvements and complications are focused on. Additionally, patient selection for stenting and future advancements in stent technology are important. Overall, endoscopic biliary stenting is a valuable palliative option for patients with malignant jaundice, especially those ineligibles for surgery.},
}

@article {pmid40060668,
year = {2025},
author = {Axakova, A and Ding, M and Cote, AG and Subramaniam, R and Senguttuvan, V and Zhang, H and Weile, J and Douville, SV and Gebbia, M and Al-Chalabi, A and Wahl, A and Reuter, J and Hurt, J and Mitchell, A and Fradette, S and Andersen, PM and van Loggerenberg, W and Roth, FP},
title = {Landscapes of missense variant impact for human superoxide dismutase 1.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.02.25.640191},
pmid = {40060668},
issn = {2692-8205},
abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron disease for which important subtypes are caused by variation in the Superoxide Dismutase 1 gene SOD1 . Diagnosis based on SOD1 sequencing can not only be definitive but also indicate specific therapies available for SOD1 -associated ALS (SOD1-ALS). Unfortunately, SOD1-ALS diagnosis is limited by the fact that a substantial fraction (currently 26%) of ClinVar SOD1 missense variants are classified as "variants of uncertain significance" (VUS). Although functional assays can provide strong evidence for clinical variant interpretation, SOD1 assay validation is challenging, given the current incomplete and controversial understanding of SOD1-ALS disease mechanism. Using saturation mutagenesis and multiplexed cell-based assays, we measured the functional impact of over two thousand SOD1 amino acid substitutions on both enzymatic function and protein abundance. The resulting 'missense variant effect maps' not only reflect prior biochemical knowledge of SOD1 but also provide sequence-structure-function insights. Importantly, our variant abundance assay can discriminate pathogenic missense variation and provides new evidence for 41% of missense variants that had been previously reported as VUS, offering the potential to identify additional patients who would benefit from therapy approved for SOD1-ALS.},
}

@article {pmid40060539,
year = {2025},
author = {Petrescu, J and Roque, CG and Jackson, CA and Daly, A and Kang, K and Casel, O and Leung, M and Reilly, L and Eschbach, J and McDade, K and Gregory, JM and Smith, C and Phatnani, H},
title = {Differential Cellular Mechanisms Underlie Language and Executive Decline in Amyotrophic Lateral Sclerosis.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.02.26.640433},
pmid = {40060539},
issn = {2692-8205},
abstract = {Half of all amyotrophic lateral sclerosis (ALS) patients demonstrate a spectrum of cognitive and behavioral changes over the course of the disease, but the mechanisms underlying this heterogeneity remain unclear. We assemble a high-resolution cellular map of prefrontal cortex regions of the ALS brain by integrating spatial and single-nucleus transcriptomic profiles of a cognitively stratified ALS patient cohort that includes non-neuropathological controls. We find cellular programs characteristic of ALS, including a frequent gliotic response. We also find that executive and language cognitive impairments differ from ALS without cognitive impairment, and from each other, in the extent and pattern of neuronal dysregulation and neuron-glial interactions across different brain regions. These findings reveal a relationship between cognitive phenotype and prefrontal cortex dysfunction in ALS.},
}

@article {pmid40060442,
year = {2025},
author = {Deng, X and Bradshaw, G and Kalocsay, M and Mitchison, T},
title = {Tubulin Regulates the Stability and Localization of STMN2 by Binding Preferentially to Its Soluble Form.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.02.27.640326},
pmid = {40060442},
issn = {2692-8205},
abstract = {Loss of the tubulin-binding protein STMN2 is implicated in amyotrophic lateral sclerosis (ALS) but how it protects neurons is not known. STMN2 is known to turn over rapidly and accumulate at axotomy sites. We confirmed fast turnover of STMN2 in U2OS cells and iPSC-derived neurons and showed that degradation occurs mainly by the ubiquitin-proteasome system. The membrane targeting N-terminal domain of STMN2 promoted fast turnover, whereas its tubulin binding stathmin-like domain (SLD) promoted stabilization. Proximity labeling and imaging showed that STMN2 localizes to trans-Golgi network membranes and that tubulin binding reduces this localization. Pull-down assays showed that tubulin prefers to bind to soluble over membrane-bound STMN2. Our data suggest that STMN2 interconverts between a soluble form that is rapidly degraded unless bound to tubulin and a membrane-bound form that does not bind tubulin. We propose that STMN2 is sequestered and stabilized by tubulin binding, while its neuroprotective function depends on an unknown molecular activity of its membrane-bound form.},
}

@article {pmid40060160,
year = {2025},
author = {Mangalindan, KE and Wyatt, TR and Brown, KR and Shapiro, M and Maggio, LA},
title = {Investigating the Road to Equity: A Scoping Review of Solutions to Mitigate Implicit Bias in Assessment within Medical Education.},
journal = {Perspectives on medical education},
volume = {14},
number = {1},
pages = {92-106},
pmid = {40060160},
issn = {2212-277X},
mesh = {Humans ; *Education, Medical/methods ; Bias ; Educational Measurement/methods ; },
abstract = {INTRODUCTION: In medical education, assessments have high-stakes implications. Yet, assessments are rife with unconscious bias, which contributes to inequitable social structures. Implicit bias in assessment must be addressed because medical educators use assessments to guide learning and promote development of physicians' careers. In this scoping review, the authors map the literature on implicit bias in assessment, as it applies to: 1) the types of implicit bias addressed, 2) the targets and types of interventions studied or proposed, and 3) how publications describe intervention efficacy.

METHODS: The authors conducted a scoping review of the literature on interventions to mitigate implicit bias that was published between January 2010 and August 2023. Author pairs independently screened articles for inclusion and extracted data. Discrepancies were resolved with discussion and consensus. Qualitative and quantitative analysis was informed by Anderson et al's three assessment orientations: fairness, assessment for inclusion (AfI), and justice.

RESULTS: 7,831 articles were identified; 54 articles were included. The majority (n = 37; 69%) of articles focus on implicit bias toward those underrepresented in medicine. Interventions to mitigate implicit bias were targeted toward admissions and applications, faculty training, recruitment, summative assessments, and evaluation templates. Interventions had fairness (n = 43; 96%) and AfI (n = 22; 49%) orientations; no articles used a justice-orientation. For the sub-set of research studies (n = 40), almost all (n = 34; 85%) examined a single program/institution.

DISCUSSION: This scoping review showed that more work is necessary to address different types of implicit biases, move scholarship beyond single-institution studies, refine existing interventions, and evaluate how efficacy is defined.},
}

Humans
*Education, Medical/methods
Bias
Educational Measurement/methods

@article {pmid40059194,
year = {2025},
author = {Shang, Q and Zhou, J and Ye, J and Chen, M},
title = {Adverse events reporting of edaravone: a real-world analysis from FAERS database.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {8148},
pmid = {40059194},
issn = {2045-2322},
mesh = {*Edaravone/adverse effects/therapeutic use ; Humans ; *Adverse Drug Reaction Reporting Systems ; *Databases, Factual ; United States ; United States Food and Drug Administration ; Amyotrophic Lateral Sclerosis/drug therapy ; Bayes Theorem ; Drug-Related Side Effects and Adverse Reactions ; Female ; Male ; },
abstract = {For individuals with amyotrophic lateral sclerosis (ALS), intravenous edaravone is approved as a disease-modifying medication; yet, there have been many reports of adverse events (AEs). We examined the AEs associated with edaravone in this study using actual data from the FDA's (Food and Drug Administration) adverse event reporting system (FAERS). By extracting large-scale data from the FAERS database, this study used the signals of edaravone-associated AEs were quantified using the multiitem gamma Poisson shrinker (MGPS) method based on disproportionality, the Bayesian confidence propagation neural network (BCPNN), the reporting odds ratio (ROR), and the proportional reporting ratio (PRR). In the FAERS database, this study extracted data between April 2017 and March 2024, and edaravone was identified as the "primary suspect (PS)" in 2,986 AE reports. AEs associated with edaravone specifically targeted 27 system organ types (SOCs). Unexpectedly serious AEs that weren't mentioned in the drug insert, include abnormal hepatic function, catheter site thrombosis, pain, cerebral hemorrhage, infection, cerebral infarction, poor venous access, disseminated intravascular coagulation, vein collapse and cerebral venous sinus thrombosis. Our research found possible signals of new AEs that may offer substantial backing for clinical surveillance and edaravone risk assessment, but further research and validation are needed, especially for those AE that may occur in actual usage scenarios but are not yet explicitly described in the instruction.},
}

*Edaravone/adverse effects/therapeutic use
Humans
*Adverse Drug Reaction Reporting Systems
*Databases, Factual
United States
United States Food and Drug Administration
Amyotrophic Lateral Sclerosis/drug therapy
Bayes Theorem
Drug-Related Side Effects and Adverse Reactions
Female
Male

@article {pmid40057796,
year = {2025},
author = {Mitra, J and Kodavati, M and Dharmalingam, P and Guerrero, EN and Rao, KS and Garruto, RM and Hegde, ML},
title = {Endogenous TDP-43 mislocalization in a novel knock-in mouse model reveals DNA repair impairment, inflammation, and neuronal senescence.},
journal = {Acta neuropathologica communications},
volume = {13},
number = {1},
pages = {54},
pmid = {40057796},
issn = {2051-5960},
support = {R03AG064266/AG/NIA NIH HHS/United States ; R03AG064266/AG/NIA NIH HHS/United States ; RF1NS112719/NS/NINDS NIH HHS/United States ; },
mesh = {Animals ; *DNA-Binding Proteins/metabolism/genetics ; Mice ; *Disease Models, Animal ; *DNA Repair ; *Gene Knock-In Techniques ; *Cellular Senescence/physiology ; Motor Neurons/metabolism/pathology ; Mice, Transgenic ; Inflammation/metabolism/pathology/genetics ; DNA Ligase ATP/metabolism/genetics ; },
abstract = {TDP-43 mislocalization and aggregation are key pathological features of amyotrophic lateral sclerosis (ALS)- and frontotemporal dementia (FTD). However, existing transgenic hTDP-43 WT or ∆NLS-overexpression animal models primarily focus on late-stage TDP-43 proteinopathy. To complement these models and to study the early-stage motor neuron-specific pathology during pre-symptomatic phases of disease progression, we generated a new endogenous knock-in (KI) mouse model using a combination of CRISPR/Cas9 and FLEX Cre-switch strategy for the conditional expression of a mislocalized Tdp-43∆NLS variant of mouse Tdp-43. This variant is expressed either in the whole body (WB) or specifically in the motor neurons (MNs) in two distinct models. These mice exhibit loss of nuclear Tdp-43, with concomitant cytosolic accumulation and aggregation in targeted cells, leading to increased DNA double-strand breaks (DSBs), signs of inflammation, and associated cellular senescence. Notably, unlike WT Tdp-43, which functionally interacts with Xrcc4 and DNA Ligase 4, the key DSB repair proteins in the non-homologous end-joining (NHEJ) pathway, the Tdp-43∆NLS mutant sequesters them into cytosolic aggregates, exacerbating neuronal damage in mouse brain. The mutant mice also exhibit myogenic degeneration in hindlimb soleus muscles and distinct motor deficits, consistent with the characteristics of motor neuron disease (MND). Our findings reveal progressive degenerative mechanisms in motor neurons expressing endogenous Tdp-43∆NLS mutant, independent of Tdp-43 overexpression or other confounding factors. Thus, this unique Tdp-43 KI mouse model, which displays key molecular and phenotypic features of Tdp-43 proteinopathy, offers a significant opportunity to characterize the early-stage progression of MND further and also opens avenues for developing DNA repair-targeted approaches for treating TDP-43 pathology-linked neurodegenerative diseases.},
}

Animals
*DNA-Binding Proteins/metabolism/genetics
Mice
*Disease Models, Animal
*DNA Repair
*Gene Knock-In Techniques
*Cellular Senescence/physiology
Motor Neurons/metabolism/pathology
Mice, Transgenic
Inflammation/metabolism/pathology/genetics
DNA Ligase ATP/metabolism/genetics

@article {pmid40057753,
year = {2025},
author = {Sharbafshaaer, M and Siciliano, M and Passaniti, C and Sant'Elia, V and Silvestro, M and Russo, A and Esposito, S and Tedeschi, G and Trojano, L and Trojsi, F},
title = {Screening of visuospatial abilities in amyotrophic lateral sclerosis (ALS): a pilot study using the battery for visuospatial abilities (BVA).},
journal = {Orphanet journal of rare diseases},
volume = {20},
number = {1},
pages = {110},
pmid = {40057753},
issn = {1750-1172},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology ; Male ; Female ; Pilot Projects ; Middle Aged ; Aged ; *Neuropsychological Tests ; Visual Perception/physiology ; },
abstract = {BACKGROUND: Cognitive deficits related to frontotemporal dysfunction are common in Amyotrophic Lateral Sclerosis (ALS). Visuospatial deficits, related to posterior cerebral regions, are often underestimated in ALS, though they play a crucial role in attending daily living activities. Our pilot study aims at assessing visuospatial abilities using a domain-specific tool in ALS patients compared to healthy controls (HC).

METHODS: Twenty-three patients with early ALS and 23 age- and education-matched HC underwent the Battery for Visuospatial Abilities (BVA), including 4 visuo-perceptual and 4 visuo-representational subtests.

RESULTS: When compared to HC, ALS scored worse in 2 visuo-perceptual subtests (i.e., Line Length Judgment and Line Orientation Judgment) and 1 visuo-representational tasks (i.e., Hidden Figure Identification, HFI) (p < 0.01). No correlations arose between ALS clinical features and BVA performance. More than 80% of the ALS cohort obtained abnormal scores in the HFI subtest.

CONCLUSIONS: Our findings revealed that patients with ALS scored worse (compared to HC) on selective tests tapping "perceptual" and "representational" visuospatial abilities, since the early stages of disease. In clinical practice, our findings highlight the need for multi-domain neuropsychological assessment, for monitoring disease courses and properly organizing care management of patients with ALS.},
}

Humans
*Amyotrophic Lateral Sclerosis/physiopathology
Male
Female
Pilot Projects
Middle Aged
Aged
*Neuropsychological Tests
Visual Perception/physiology

@article {pmid40057669,
year = {2025},
author = {Hatcher, H and Stankeviciute, S and Learn, C and Qu, AX},
title = {Regulatory, Translational, and Operational Considerations for the Incorporation of Biomarkers in Drug Development.},
journal = {Therapeutic innovation & regulatory science},
volume = {},
number = {},
pages = {},
pmid = {40057669},
issn = {2168-4804},
abstract = {BACKGROUND: Biomarkers are an integral component in the drug development paradigm. According to the US Food and Drug Administration (FDA), a biomarker is "a defined characteristic that is measured as an indicator of normal biological processes, pathogenic processes, or biological responses to an exposure or intervention, including therapeutic intervention" (FDA-NIH Biomarker Working Group. BEST (Biomarkers, EndpointS, and other Tools) Resource [Internet]. Silver Spring (MD): Food and Drug Administration (US); 2016-. Glossary. 2016 [Updated 2021 Nov 29, cited 2024 Apr 14]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK338448/ Co-published by National Institutes of Health (US), Bethesda (MD)). The European Medicines Agency (EMA) defines a biomarker as "an objective and quantifiable measure of a physiological process, pathological process or response to a treatment (excluding measurements of how an individual feels or functions" European Medicines Agency (EMA). Biomaker. 2020a. Available from: https://www.ema.europa.eu/en/glossary-terms/biomarker#:~:text=Biomarker-,Biomarker,an%20individual%20feels%20or%20functions . Several clinical biomarkers are well-documented and have been used routinely for decades in health care settings and have long been accepted as valid endpoints for drug approval (for example, blood pressure measurement as a biomarker for cardiovascular health) (European Medicines Agency (EMA). Assessment report, TAGRISSO. 2016. Available from: https://www.ema.europa.eu/en/documents/assessment-report/tagrisso-epar-public-assessment-report_en.pdf . Accessed 15 Apr 2024). Recently, novel biomarkers have been identified and validated to accelerate developing innovative therapies indicated for serious human diseases, for example targeted/immune therapies of cancer (Chen in Med Drug Discov 21:100174, 2024). As indicators of the efficacy of new pharmacological treatments or therapeutic interventions, biomarkers can improve clinical trial efficacy and reduce uncertainty in regulatory decision making (Bakker et al. in Clin Pharmacol Ther 112:69-80, 2022; Califf in Exp Biol Med 243:213-221, 2018; Parker et al. in Cancer Med 10:1955-1963, 2021).

METHODOLOGY: This article describes case studies of recent drug approvals that successfully leveraged validated and non-validated biomarkers (i.e., tofersen for the neurodegenerative disease amyotrophic lateral sclerosis (ALS) in adults; and osimertinib for treatment of patients with metastatic epidermal growth factor receptor (EGFR) T790M mutation-positive non-small cell lung cancer (NSCLC)).

CONCLUSIONS: Best practices for biomarker selection and strategies for health authority biomarker qualification programs are presented along with an overview of current limitations and challenges to optimizing biomarker applications along the drug development continuum from regulatory, translational, and operational perspectives.},
}

@article {pmid40056296,
year = {2025},
author = {Li, Z and Fan, J and Gong, Z and Tang, J and Yang, Y and Liu, M and Zhang, M},
title = {Association between cardiac autonomic dysfunction, cognitive impairment, and survival in patients with amyotrophic lateral sclerosis.},
journal = {Clinical autonomic research : official journal of the Clinical Autonomic Research Society},
volume = {},
number = {},
pages = {},
pmid = {40056296},
issn = {1619-1560},
support = {82271478//the National Natural Science Foundation of China/ ; 2024AOXIANG05//the Research and Innovation Team Project for Scientific Breakthroughs at Shanxi Bethune Hospital/ ; },
abstract = {PURPOSE: The aim of this study was to investigate the relationship between cardiac autonomic dysfunction, cognitive impairment, and survival in patients with amyotrophic lateral sclerosis (ALS).

METHODS: The heart activity of 65 patients with ALS (28 with normal cognition [ALS-CN]; 37 with impaired cognition [ALS-CI]) and 38 healthy controls (HCs) was measured by 24-h Holter monitoring. Heart rate (HR) measures and heart rate variability (HRV) parameters were compared between the three study groups and, additionally, correlated with five Edinburgh Cognitive and Behavioral ALS Screen (ECAS) domains in the ALS subgroups. Age, gender, and educational level were adjusted. Factors associated with cognitive status were assessed using logistic regression. Survival predictors in patients with ALS were analyzed using the Kaplan-Meier estimator and Cox regression.

RESULTS: Compared to the HCs, patients with ALS-CI exhibited lower RRI (R-R-interval; P = 0.017), SDNN (standard deviation of all normal RR intervals; P = 0.013), SDNN Index (P = 0.044), and VLF power (very low-frequency power; P = 0.012). Total power was reduced in the ALS-CI group compared to the HCs (P = 0.036) and ALS-CN group (P = 0.048). In patients with ALS-CN, language negatively correlated with mean HR (P = 0.001) and positively with the RRI (P = 0.003), SDNN (P = 0.001), SDANN (standard deviation of the average NN intervals; P = 0.005), total power (P = 0.006), VLF power (P = 0.011), and low-frequency power (P = 0.026). Visuospatial function correlated positively with the SDNN Index (P = 0.041). In patients with ALS-CI, executive function (P = 0.015) and ECAS total score (P = 0.009) negatively correlated with the RMSSD (square root of mean sum-of-squares of differences between adjacent NN intervals), while visuospatial function correlated positively with normalized LF value (LFnu; P = 0.049). No associations were observed between the other cognitive domains and any of the 14 HRV/HR measures in patients with either ALS-CI or ALS-CN. SDNN ≤ 100 ms was linked to cognitive impairment (P = 0.039) and also showed a borderline association (P = 0.066) with poorer survival, while cognitive impairment (P = 0.010) was significantly linked to worse outcomes.

CONCLUSIONS: Patients with ALS with cognitive impairment demonstrated reduced cardiac autonomic modulations and altered cognitive autonomic associations. Cognitive impairment was linked to reduced survival, with baseline SDNN ≤ 100 ms identified as a potential marker.},
}

@article {pmid40056685,
year = {2025},
author = {Jakhar, M and Barone, V},
title = {Single atom catalysts adsorbed on reduced monolayers for enhanced kinetics in Al-S batteries.},
journal = {Journal of colloid and interface science},
volume = {689},
number = {},
pages = {137226},
doi = {10.1016/j.jcis.2025.03.015},
pmid = {40056685},
issn = {1095-7103},
abstract = {Rechargeable aluminum-sulfur (Al-S) batteries have attracted significant attention as potential next-generation energy storage devices due to their safety, the natural abundance of the elemental components, and high theoretical energy density. However, their utilization is hindered by sluggish reaction kinetics and poor reversibility. Introducing single-atom catalysts (SACs) can promote redox processes at the cathode and help in mitigating the shuttle effect of Al polysulfides (Al2Sx). While the electrochemical, thermodynamic, and thermal stabilities of SACs (Co, Fe, Ir, Ni, Pt, and Rh) have been explored in previous studies, this work focuses on their potential role in enhancing reaction kinetics in Al-S batteries. Our calculations indicate that SACs-based substrates exhibit more robust binding energies for capturing Al2Sx than the bare surfaces. Additionally, SACs lower the free energies associated with the rate-determining step during discharging and exhibit lower decomposition barriers during charging. Moreover, the interaction of soluble Al2Sx with the electrolyte reveals that SAC supported polysulfides are less likely to dissolve in the electrolyte than their pristine counterparts. The analysis of the underlying mechanisms of the interaction of molecules and the Co@ substrate reveals the ability of this substrate to accommodate large volume changes and support a sulfur loading up to 53.37 wt% during the charging and discharging cycles, without causing fractures. The mechanism driving this enhanced performance is extensively investigated through charge transfer, bond strength, and d-band center analyses. Our findings present an effective strategy for designing SACs substrates to improve the electrochemical performance of Al-S cathodes.},
}

@article {pmid40056552,
year = {2025},
author = {Newell, ME and Babbrah, A and Aravindan, A and Kulkarni, S and Ellershaw, A and Dupati, A and Rathnam, R and Shaffer, G and Estrada, L and Curtis, C and Leneaux, J and Driver, EM and Halden, RU},
title = {Wastewater-borne markers of neurodegenerative disease: β-methylamino-L-alanine and aminomethylphosphonic acid.},
journal = {The Science of the total environment},
volume = {970},
number = {},
pages = {179032},
doi = {10.1016/j.scitotenv.2025.179032},
pmid = {40056552},
issn = {1879-1026},
abstract = {Exposure to toxic organic chemicals such as β-methylamino-L-alanine (BMAA) and glyphosate has been associated with neurodegenerative diseases (NDDs), including amyotrophic lateral sclerosis (ALS), Parkinson's Disease (PD), and Alzheimer's Disease (AD). We explored the utility of BMAA and glyphosate's metabolite aminomethylphosphonic acid (AMPA) for serving as potential markers of NDDs by comparing levels of wastewater-borne BMAA and AMPA with regional U.S. rates of NDD prevalence. Newly developed liquid chromatography tandem mass spectrometry (LC-MS/MS) methods were applied to U.S. wastewater samples (n = 87) and resultant concentrations of putative biomarkers were statistically compared to NDD prevalence rates in conjunction with environmental data on algal blooms and agricultural glyphosate use. Locations of algal blooms were found to be significantly associated (p = 0.01) with ALS prevalence rates per 100,000 people. BMAA levels in wastewater were highly correlated (p < 0.0001) with ALS prevalence rates by region. BMAA in wastewater typically peaked in summer months. We conclude that NDD biomarker detection in wastewater holds potential value, with BMAA outperforming AMPA. Furthermore, prevalence data for NDDs may have to be reported to the Centers for Disease Control and Prevention at a higher geospatial resolution to further enhance the value for the present type of analysis. Further method development is needed for AMPA to be quantified using LC-MS/MS. Future method developments focusing on metabolites (e.g., AMPA) may enable epidemiologists to determine human exposure levels rather than the mere occurrence of toxic organic chemicals in the environment.},
}

@article {pmid40056503,
year = {2025},
author = {Zhan, A and Zhong, K and Zhang, K},
title = {Novel subcellular regulatory mechanisms of protein homeostasis and its implications in amyotrophic lateral sclerosis.},
journal = {Biochemical and biophysical research communications},
volume = {756},
number = {},
pages = {151582},
doi = {10.1016/j.bbrc.2025.151582},
pmid = {40056503},
issn = {1090-2104},
abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron degenerative disorder. Protein aggregates induce various forms of neuronal dysfunction and represent pathological hallmarks in ALS patients. Reducing protein aggregates could be a promising therapeutic strategy for ALS. While most studies have focused on cytoplasmic protein homeostasis, neurons adaptively reduce aggregates across subcellular compartments during stress through previously uncharacterized mechanisms. Here, we summarize novel compartment-specific proteostatic mechanisms: (1) the ERAD/RESET pathways, (2) HSPs-mediated nuclear sequestration, (3) mitochondrial aggregate import (MAGIC), (4) neurite-localized UPS/autophagosome and NMP, and (5) exopher-mediated extracellular disposal. These mechanisms collectively ensure cellular stress adaptation and provide novel therapeutic targets for ALS treatment.},
}

@article {pmid40056413,
year = {2025},
author = {Kahn, OI and Dominguez, SL and Glock, C and Hayne, M and Vito, S and Sengupta Ghosh, A and Adrian, M and Burgess, BL and Meilandt, WJ and Friedman, BA and Hoogenraad, CC},
title = {Secreted neurofilament light chain after neuronal damage induces myeloid cell activation and neuroinflammation.},
journal = {Cell reports},
volume = {44},
number = {3},
pages = {115382},
doi = {10.1016/j.celrep.2025.115382},
pmid = {40056413},
issn = {2211-1247},
abstract = {Neurofilament light chain (NfL) is a neuron-specific cytoskeletal protein that provides structural support for axons and is released into the extracellular space following neuronal injury. While NfL has been extensively studied as a disease biomarker, the underlying release mechanisms and role in neurodegeneration remain poorly understood. Here, we find that neurons secrete low baseline levels of NfL, while neuronal damage triggers calpain-driven proteolysis and release of fragmented NfL. Secreted NfL activates microglial cells, which can be blocked with anti-NfL antibodies. We utilize in vivo single-cell RNA sequencing to profile brain cells after injection of recombinant NfL into the mouse hippocampus and find robust macrophage and microglial responses. Consistently, NfL knockout mice ameliorate microgliosis and delay symptom onset in the SOD1 mouse model of amyotrophic lateral sclerosis (ALS). Our results show that released NfL can activate myeloid cells in the brain and is, thus, a potential therapeutic target for neurodegenerative diseases.},
}

@article {pmid40056187,
year = {2025},
author = {Wiesenfarth, M and Forouhideh-Wiesenfarth, Y and Elmas, Z and Parlak, Ö and Weiland, U and Herrmann, C and Schuster, J and Freischmidt, A and Müller, K and Siebert, R and Günther, K and Fröhlich, E and Knehr, A and Simak, T and Bachhuber, F and Regensburger, M and Petri, S and Klopstock, T and Reilich, P and Schöberl, F and Schumann, P and Körtvélyessy, P and Meyer, T and Ruf, WP and Witzel, S and Tumani, H and Brenner, D and Dorst, J and Ludolph, AC},
title = {Correction: Clinical characterization of common pathogenic variants of SOD1-ALS in Germany.},
journal = {Journal of neurology},
volume = {272},
number = {4},
pages = {259},
doi = {10.1007/s00415-025-12952-1},
pmid = {40056187},
issn = {1432-1459},
}

@article {pmid40055545,
year = {2025},
author = {Giblin, A and Cammack, AJ and Blomberg, N and Anoar, S and Mikheenko, A and Carcolé, M and Atilano, ML and Hull, A and Shen, D and Wei, X and Coneys, R and Zhou, L and Mohammed, Y and Olivier-Jimenez, D and Wang, LY and Kinghorn, KJ and Niccoli, T and Coyne, AN and van der Kant, R and Lashley, T and Giera, M and Partridge, L and Isaacs, AM},
title = {Author Correction: Neuronal polyunsaturated fatty acids are protective in ALS/FTD.},
journal = {Nature neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41593-025-01926-1},
pmid = {40055545},
issn = {1546-1726},
}

@article {pmid40054065,
year = {2025},
author = {Tserennadmid, B and Nam, MK and Park, JH and Rhim, H and Kang, S},
title = {HAP/ClpP-mediated disaggregation and degradation of Mutant SOD1 aggregates: A potential therapeutic strategy for Amyotrophic lateral sclerosis (ALS).},
journal = {Biochemical and biophysical research communications},
volume = {756},
number = {},
pages = {151533},
doi = {10.1016/j.bbrc.2025.151533},
pmid = {40054065},
issn = {1090-2104},
abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease marked by the accumulation of misfolded Cu/Zn superoxide dismutase (SOD1) protein aggregates in motor neurons, leading to progressive motor dysfunction and ultimately death. While the molecular chaperone heat shock protein 104 (Hsp104) has been shown to reduce protein misfolding by disaggregating protein aggregates, fully degrading these disaggregated proteins remains a significant challenge. In this study, we have investigated the effects of Hsp104 and its hyperactive variant, HAP, in combination with caseinolytic protease P (CIpP), on the disaggregation and degradation of SOD1 aggregates. Using laser confocal microscopy, fluorescence loss in photobleaching (FLIP), and biomolecular fluorescence complementation (BiFC)-fluorescence resonance energy transfer (FRET) assays, we demonstrate that Hsp104 effectively disaggregates SOD1 aggregates across 14 different G93 mutants, classified based on the properties of substituted amino acids, thus restoring protein mobility. Notably, the HAP/CIpP system not only disaggregates ALS-associated SOD1[G93A] aggregates but also promotes their proteolytic degradation, as evidenced by a significant reduction in high-order oligomers observed through BiFC and FRET assays. This dual mechanism of action presents. the HAP/CIpP system holds significant therapeutic potential for ALS and other neurodegenerative diseases characterized by protein aggregates, as it enables both effective disaggregation and degradation of toxic protein aggregates, thereby maintaining protein homeostasis.},
}

@article {pmid40053600,
year = {2025},
author = {Nie, Y and Szebényi, K and Wenger, LMD and Lakatos, A and Chinnery, PF},
title = {Origin and cell type specificity of mitochondrial DNA mutations in C9ORF72 ALS-FTLD human brain organoids.},
journal = {Science advances},
volume = {11},
number = {10},
pages = {eadr0690},
pmid = {40053600},
issn = {2375-2548},
mesh = {Humans ; *C9orf72 Protein/genetics/metabolism ; *Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; *DNA, Mitochondrial/genetics ; *Organoids/metabolism/pathology ; *Mutation ; *Brain/metabolism/pathology ; *Induced Pluripotent Stem Cells/metabolism ; Frontotemporal Lobar Degeneration/genetics/pathology/metabolism ; Astrocytes/metabolism/pathology ; Mitochondria/genetics/metabolism ; DNA Repeat Expansion/genetics ; },
abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are primarily genetic in ~20% of patients. Mutations in C9ORF72 are the most frequent cause, but it is not understood why there is notable regional pathology. An increased burden of mitochondrial DNA (mtDNA) mutations in ALS-FTLD brains implicates mitochondrial mechanisms; however, it remains unclear how and when these mutations arise. To address this, we generated cerebral organoids derived from human-induced pluripotent stem cells (hiPSCs) of patients with ALS-FTLD harboring the C9ORF72 hexanucleotide repeat expansion alongside CRISPR-corrected isogenic and healthy controls. Here, we show a higher mtDNA single-nucleotide variant (mtSNV) burden in astroglia derived from C9ORF72-mutant organoids, with some de novo mtSNVs likely due to the C9ORF72 repeat and others evading selection to reach higher heteroplasmy levels. Thus, the functional consequences of the regional accumulation of mtSNVs in C9ORF72 ALS-FTLD brains are likely to manifest through astroglial mitochondrial dysfunction.},
}

Humans
*C9orf72 Protein/genetics/metabolism
*Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism
*DNA, Mitochondrial/genetics
*Organoids/metabolism/pathology
*Mutation
*Brain/metabolism/pathology
*Induced Pluripotent Stem Cells/metabolism
Frontotemporal Lobar Degeneration/genetics/pathology/metabolism
Astrocytes/metabolism/pathology
Mitochondria/genetics/metabolism
DNA Repeat Expansion/genetics

@article {pmid40053462,
year = {2025},
author = {Fazzini, L and Martis, A and Pateri, MI and Maccabeo, A and Borghero, G and Puligheddu, M and Montisci, R and Marchetti, MF},
title = {Long-term outcomes and worse clinical course in Takotsubo syndrome patients with amyotrophic lateral sclerosis.},
journal = {Journal of cardiovascular medicine (Hagerstown, Md.)},
volume = {26},
number = {4},
pages = {184-190},
doi = {10.2459/JCM.0000000000001711},
pmid = {40053462},
issn = {1558-2035},
mesh = {Humans ; *Takotsubo Cardiomyopathy/mortality/epidemiology/complications/physiopathology/diagnosis/therapy ; *Amyotrophic Lateral Sclerosis/mortality/diagnosis/complications/epidemiology/therapy/physiopathology ; Female ; Male ; Aged ; Retrospective Studies ; Middle Aged ; Time Factors ; Prevalence ; Aged, 80 and over ; Hospital Mortality ; Risk Factors ; Prognosis ; Cause of Death ; Risk Assessment ; Respiration, Artificial/statistics & numerical data ; Shock, Cardiogenic/mortality/epidemiology/etiology/therapy/diagnosis ; },
abstract = {AIMS: Takotsubo syndrome (TTS) is usually triggered by either physical/psychological stressors or comorbidities, neurological among others. The prevalence of amyotrophic lateral sclerosis (ALS) among TTS and whether it has a worse clinical course is not known. We aim to describe ALS prevalence and its impact on clinical presentation, clinical course, and long-term mortality.

METHODS: We retrospectively screened the overall TTS population admitted and followed up at our institution between 2007 and 2020. Clinical, electrocardiographic, and echocardiographic data were collected. Kaplan-Meier method was applied for time-to-event analysis to assess the outcome of interest of all-cause death.

RESULTS: Eighty-five patients with TTS were included in our study. Overall, the mean age was 70 ± 12 years, 86% were females. Six patients (7% prevalence) were affected by ALS. At admission, patients with ALS were more likely to present left ventricular systolic dysfunction (P = 0.007). The clinical course of ALS patients was more likely complicated by cardiogenic shock (P = 0.003) which required catecholamines infusion (P = 0.001) and mechanical ventilation (P = 0.009). Despite similar in-hospital mortality rates, ALS patients exhibited significantly elevated all-cause mortality during a median 6-year follow-up (hazard ratio, 19.189, 95% confidence interval 5.639-65.296, log-rank test P < 0.001) with significantly shorter hospitalization to death time (P = 0.039).

CONCLUSIONS: Our findings highlight a notable prevalence of ALS among TTS patients, with worse clinical presentation and in-hospital course in ALS-affected individuals. While in-hospital mortality rates were comparable, highlighting the reversible nature of TTS in both groups, long-term follow-up revealed significantly heightened all-cause mortality in ALS patients, emphasizing the impact of ALS on patient prognosis.},
}

Humans
*Takotsubo Cardiomyopathy/mortality/epidemiology/complications/physiopathology/diagnosis/therapy
*Amyotrophic Lateral Sclerosis/mortality/diagnosis/complications/epidemiology/therapy/physiopathology
Female
Male
Aged
Retrospective Studies
Middle Aged
Time Factors
Prevalence
Aged, 80 and over
Hospital Mortality
Risk Factors
Prognosis
Cause of Death
Risk Assessment
Respiration, Artificial/statistics & numerical data
Shock, Cardiogenic/mortality/epidemiology/etiology/therapy/diagnosis

@article {pmid40051750,
year = {2025},
author = {Dib, A and Salem, J and Fares, M},
title = {Recurrent Spontaneous Pneumothorax in the Setting of Amyotrophic Lateral Sclerosis.},
journal = {European journal of case reports in internal medicine},
volume = {12},
number = {3},
pages = {005151},
pmid = {40051750},
issn = {2284-2594},
abstract = {UNLABELLED: Spontaneous pneumothorax (SP) occurrence in amyotrophic lateral sclerosis (ALS) patients is relatively rare and may thus be under-recognised. This latter is a progressive neurodegenerative disorder, leading to muscle weakness and such respiratory complications. This article reports a case manifesting such a rare association.

LEARNING POINTS: The presence of spontaneous pneumothorax in amyotrophic lateral sclerosis patients can exacerbate respiratory insufficiency, leading to acute respiratory failure.Given the under-recognition of this latter complication, clinicians should maintain a high index of suspicion, especially in patients with amyotrophic lateral sclerosis presenting with sudden onset of dyspnoea or chest pain.Early detection and appropriate management are crucial to prevent further respiratory compromise.},
}

@article {pmid40051509,
year = {2025},
author = {Syed, SA and Singh, J and Elkholy, H and Rojnić Palavra, I and Tomicevic, M and Eric, AP and Pinto da Costa, M and Guloksuz, S and Radhakrishnan, R},
title = {International perspectives on physician knowledge, attitudes, and practices related to medical cannabis.},
journal = {Frontiers in public health},
volume = {13},
number = {},
pages = {1463871},
pmid = {40051509},
issn = {2296-2565},
mesh = {Humans ; *Medical Marijuana/therapeutic use ; Female ; Cross-Sectional Studies ; Male ; Adult ; *Health Knowledge, Attitudes, Practice ; *Physicians/psychology/statistics & numerical data ; Surveys and Questionnaires ; *Attitude of Health Personnel ; Middle Aged ; Internationality ; Practice Patterns, Physicians'/statistics & numerical data ; },
abstract = {BACKGROUND: The trends of recreational use of cannabis and the use of cannabis for medical indications (i.e., "medical cannabis") have grown in recent years. Despite that, there is still limited scientific evidence to guide clinical decision-making, and the strength of evidence for the medical use of cannabis is currently considered to be low. In contrast, there is growing evidence of negative health outcomes related to the use of cannabis. In this rapidly shifting landscape, the role of physician attitudes regarding the therapeutic value of cannabis has become essential. This study aimed to characterize knowledge/experience, attitudes, and potential predictors of clinical practice regarding medical cannabis.

METHODS: We conducted a cross-sectional survey of physicians from 17 countries between 2016 and 2018. The survey consisted of questions designed to explore physician knowledge, attitude, and practices regarding the use of medical cannabis. Descriptive statistics were used to examine willingness to recommend medical cannabis for medical and psychiatric indications, followed by regression analysis to identify the predictors of physician willingness to recommend medical cannabis.

RESULTS: A total of 323 physicians responded to the survey, among which 53% were women. The mean age was 35.4 ± 9.5 years, with 10.04 ± 8.6 years of clinical experience. Clinical experience with medical cannabis was overall limited (51.4% noted never having recommended medical cannabis and 33% noted inadequate knowledge regarding medical cannabis). The majority of respondents (84%) recognized the risk of psychosis with cannabis use, while only 23% correctly identified the risk of addiction with daily cannabis use. Overall, willingness to recommend medical cannabis was the highest for chemotherapy-induced nausea (67%), refractory chronic neuropathic pain (52%), and spasticity in amyotrophic lateral sclerosis (ALS; 51%).

CONCLUSION: This international study examining physician knowledge, attitudes, and practices related to medical cannabis revealed that there are significant gaps in domain-specific knowledge related to medical cannabis. There is a wide variability in willingness to recommend medical cannabis, which is not consistent with the current strength of evidence. This study thus highlights the need for greater education related to domain-specific knowledge about medical cannabis.},
}

Humans
*Medical Marijuana/therapeutic use
Female
Cross-Sectional Studies
Male
Adult
*Health Knowledge, Attitudes, Practice
*Physicians/psychology/statistics & numerical data
Surveys and Questionnaires
*Attitude of Health Personnel
Middle Aged
Internationality
Practice Patterns, Physicians'/statistics & numerical data

@article {pmid40050936,
year = {2025},
author = {Jeejan, J and Rao, L and Sadasivan, S and Lopes, R and Dsouza, N},
title = {Impact of cysteine mutations on the structural dynamics and functional impairment of SOD1: insights into the pathogenicity of amyotrophic lateral sclerosis.},
journal = {Genomics & informatics},
volume = {23},
number = {1},
pages = {7},
pmid = {40050936},
issn = {1598-866X},
abstract = {Amyotrophic lateral sclerosis (ALS) is a rare neurodegenerative disease prevalent in American and European populations, with its onset and progression significantly influenced by mutations in the superoxide dismutase 1 (SOD1) protein. While previous studies have highlighted the effects of mutations in the metal-binding region and catalytic region and dimerisation of SOD1, the impact of mutations involving the Cysteine residue at the N-terminal end remains unexplored. This study investigates the effects of Cysteine-to-Trp, Phe, Ser, and Gly mutations at the 6th position of SOD1's N-terminal end on its structural dynamics and functional impairment. Our computational analysis using PolyPhen-2, PROVEAN, Meta-SNP, and PhD-SNP predicted mutations to be deleterious, with their negative impacts likely contributing to disease development. Furthermore, stability studies and bonding pattern changes due to the mutations, analysed by mCSM, SDM, DUET, Dynamut2, and PremPS revealed changes in free energy and disruption in intramolecular interactions. The molecular dynamics studies revealed distinct changes in stability patterns among the mutations, particularly in Cys6Trp and Cys6Phe. All the mutations primarily altered the catalytic region of the protein; additionally, Cys6Phe and Cys6Gly caused disruption in the metal-binding region. The impact of mutations on the dimerisation of SOD1, analysed using MM/PBSA showed destabilisation due to Cys6Phe mutation. These findings provide molecular insights into the clinical symptoms observed in patients, highlighting the critical impact of the Cys6Phe mutation on the metal-binding and catalytic loops of SOD1 along with destabilisation of dimer formation. Overall, our analysis offers valuable insights into the molecular mechanisms driving structural changes in SOD1 due to mutations, contributing to a deeper understanding of their role in ALS pathogenicity.},
}