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Macrophages are fundamental cells of the innate immune system that support normal haematopoiesis and play roles in both anti-cancer immunity and tumour progression. Here we use a chimeric mouse model of chronic myeloid leukaemia (CML) and human bone marrow (BM) derived macrophages to study the impact of the dysregulated BM microenvironment on bystander macrophages. Utilising single-cell RNA sequencing (scRNA-seq) of Philadelphia chromosome (Ph) negative macrophages we reveal unique subpopulations of immature macrophages residing in the CML BM microenvironment. CML exposed macrophages separate from their normal counterparts by reduced expression of the surface marker CD36, which significantly reduces clearance of apoptotic cells. We uncover aberrant production of CML-secreted factors, including the immune modulatory protein lactotransferrin (LTF), that suppresses efferocytosis, phagocytosis, and CD36 surface expression in BM macrophages, indicating that the elevated secretion of LTF is, at least partially responsible for the supressed clearance function of Ph- macrophages., (© 2024. The Author(s).)

Amyotrophic lateral sclerosis (ALS) is a fatal multi-system neurodegenerative disorder with no effective treatment or cure. Although primarily characterized by motor degeneration, cognitive dysfunction is an important non-motor symptom that has a negative impact on patient and caregiver burden. Mild cognitive deficits are present in a subgroup of non-demented patients with ALS, often preceding motor symptoms. Detailed neuropsychological assessments reveal deficits in a variety of cognitive domains, including those of verbal fluency and retrieval, language, executive function, attention and verbal memory. Mild cognitive impairment (MCI), a risk factor for developing dementia, affects between 10% and over 50% of ALS patients. Neuroimaging revealed atrophy of frontal and temporal cortices, disordered white matter Integrity, volume reduction in amygdala and thalamus, hypometabolism in the frontal and superior temporal gyrus and anterior insula. Neuronal loss in non-motor brain areas, associated with TDP-43 deposition, one of the morphological hallmarks of ALS, is linked to functional disruption of frontostriatal and frontotemporo-limbic connectivities as markers for cognitive deficits in ALS, the pathogenesis of which is still poorly understood. Early diagnosis by increased cerebrospinal fluid or serum levels of neurofilament light/heavy chain or glial fibrillary acidic protein awaits confirmation for MCI in ALS. These fluid biomarkers and early detection of brain connectivity signatures before structural changes will be helpful not only in establishing early premature diagnosis but also in clarifying the pathophysiological mechanisms of MCI in ALS, which might serve as novel targets for prohibition/delay and future adequate treatment of this debilitating disorder., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)

Behavioral disorders, with an average prevalence of 30-60% are important non-motor symptoms in amyotrophic lateral sclerosis (ALS) that have a negative impact on prognosis, management and quality of life, yet the underlying neurobiology is poorly understood. Among people with ALS, apathy, fatigue, anxiety, irritability and other behavioral symptoms are the most prominent, although less frequent than cognitive impairment. The present review explores the current understanding of behavioral changes in ALS with particular emphasis on our current knowledge about their structural and functional brain correlates, substantiating a multisystem degeneration with particular dysfunction of frontal-subcortical circuits and dysfunction of fronto-striatal, frontotemporal and other essential brain systems. The natural history of behavioral dysfunctions in ALS and their relationship to frontotemporal lobe degeneration (FTLD) are not fully understood, although they form a clinical continuum, suggesting a differential vulnerability of non-motor brain networks, ALS being considered a brain network disorder. An assessment of risks or the early detection of brain connectivity signatures before structural changes may be helpful in investigating the pathophysiological mechanisms of behavioral impairment in ALS. Treatment of both ALS and co-morbid behavioral disorders is a multidisciplinary task, but whereas no causal or disease-modifying therapies for ALS are available, symptomatic treatment of a variety of behavioral symptoms plays a pivotal role in patient care, although the management of behavioral symptoms in clinical care still remains limited., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease. Syncytin-1 (Syn), an envelope glycoprotein encoded by the env gene of the human endogenous retrovirus-W family, has been resorted to be highly expressed in biopsies from the muscles from ALS patients; however, the specific regulatory role of Syn during ALS progression remains uncovered. In this study, C57BL/6 mice were injected with adeno-associated virus-overexpressing Syn, with or without Fasudil administration. The Syn expression was assessed by quantitative real-time polymerase chain reaction and immunohistochemistry analysis. The histological change of anterior tibial muscles was determined by hematoxylin-eosin staining. Qualitative ultrastructural analysis of electron micrographs obtained from lumbar spinal cords was carried out. Serum inflammatory cytokines were assessed by enzyme linked immunosorbent assay (ELISA) assay and motor function was recorded using Basso, Beattie, and Bresnahan (BBB) scoring, climbing test and treadmill running test. Immunofluorescence and western blot assays were conducted to examine microglial- and motor neurons-related proteins. Syn overexpression significantly caused systemic inflammatory response, muscle tissue lesions, and motor dysfunction in mice. Meanwhile, Syn overexpression promoted the impairment of motor neuron, evidenced by the damaged structure of the neurons and reduced expression of microtubule-associated protein 2, HB9, neuronal nuclei and neuron-specific enolase in Syn-induced mice. In addition, Syn overexpression greatly promoted the expression of CD16/CD32 and inducible nitric oxide synthase (M1 phenotype markers), and reduced the expression of CD206 and arginase 1 (M2 phenotype markers). Importantly, the above changes caused by Syn overexpression were partly abolished by Fasudil administration. This study provides evidence that Syn-activated microglia plays a pivotal role during the progression of ALS., (© 2024 Wiley Periodicals LLC.)

In the last few years, our understanding of disease molecular mechanisms underpinning ALS has advanced greatly, allowing the first steps in translating into clinical practice novel research findings, including gene therapy approaches. Similarly, the recent advent of assistive technologies has greatly improved the possibility of a more personalized approach to supportive and symptomatic care, in the context of an increasingly complex multidisciplinary line of actions, which remains the cornerstone of ALS management. Against this rapidly growing background, here we provide an comprehensive update on the most recent studies that have contributed towards our understanding of ALS pathogenesis, the latest results from clinical trials as well as the future directions for improving the clinical management of ALS patients., (© 2024. The Author(s).)

Amyotrophic lateral sclerosis (ALS) is a multi-system disorder that commonly affects cognition and behaviour. Verbal fluency impairments are consistently reported in ALS patients, and we aimed to investigate whether this deficit extends beyond the verbal domain. We further aimed to determine whether deficits are underpinned by a primary intrinsic response generation impairment (i.e., a global reduction across tasks), potentially related to apathy, or an inability to maintain responding over time (i.e., a 'drop off' pattern). Twenty-two ALS patients and 21 demographically-matched controls completed verbal and nonverbal fluency tasks (phonemic/semantic word fluency, design fluency, gesture fluency and ideational fluency), requiring the generation of responses over a specified time period. Fluency performance was analysed in terms of the overall number of novel items produced, as well as the number of items produced in the first 'initiation' and the remaining 'maintenance' time periods. ALS patients' overall performance was not globally reduced across tasks. Patients were impaired only on meaningful gesture fluency, which requires the generation of gestures that communicate meaning (e.g., waving). On phonemic fluency, ALS patients showed a 'drop off' pattern of performance, where they had difficulty maintaining responding over time, but this pattern was not evident on the other fluency tasks. Apathy did not appear to be related to fluency performance. The selective meaningful gesture fluency deficit, in the context of preserved meaningless gesture fluency, highlights that the retrieval of action knowledge may be weakened in early ALS., (© 2023 The Authors. Journal of Neuropsychology published by John Wiley & Sons Ltd on behalf of The British Psychological Society.)

Phishing attacks are the biggest cybersecurity threats in the digital world. Attackers exploit users by impersonating real, authentic websites to obtain sensitive information such as passwords and bank statements. One common technique in these attacks is using malicious URLs. These malicious URLs mimic legitimate URLs, misleading users into interacting with malicious websites. This practice, URL phishing, presents a big threat to internet security, emphasizing the need for advanced detection methods. So we aim to enhance phishing URL detection by using machine learning and deep learning models, leveraging a set of low-level URL features derived from n-gram analysis. In this paper, we present a method for detecting malicious URLs using statistical features extracted from n-grams. These n-grams are extracted from the hexadecimal representation of URLs. We employed 4 experiments in our paper. The first 3 experiments used machine learning with the statistical features extracted from these n-grams, and the fourth experiment used these grams directly with deep learning models to evaluate their effectiveness. Also, we used Explainable AI (XAI) to explore the extracted features and evaluate their importance and role in phishing detection. A key advantage of our method is its ability to reduce the number of features required and reduce the training time by using fewer features after applying XAI techniques. This stands in contrast to the previous study, which relies on high-level URL features and needs pre-processing and a high number of features (87 high-level URL-based features). So our technique only uses statistical features extracted from n-grams and the n-gram itself, without the need for any high-level features. Our method is evaluated across different n-gram lengths (2, 4, 6, and 8), aiming to optimize detection accuracy. We conducted four experiments in our study. In the first experiment, we focused on extracting and using 12 common statistical features like mean, median, etc. In the first experiment, the XGBoost model achieved the highest accuracy using 8-gram features with 82.41%. In the second experiment, we expanded the feature set and extracted an additional 13 features, so our feature count became 25. XGBoost in the second experiment achieved the highest accuracy with 86.40%. Accuracy improvement continued in the third experiment, we extracted an additional 16 features (character count features), and these features increased XGBoost accuracy to 88.15% in the third experiment. In the fourth experiment, we directly fed n-gram representations into deep learning models. The Convolutional Neural Network (CNN) model achieved the highest accuracy of 94.09% in experiment four. Also, we applied XAI techniques, SHapley Additive exPlanations (SHAP), and Local Interpretable Model-agnostic Explanations (LIME). Through the explanation provided by XAI methods, we were able to determine the most important features in our feature set, enabling a reduction in feature count. Using fewer features (4, 7, 10, 13, 15), we got good accuracy compared to the 41 features used in experiment three and reduced the models' training times and complexity. This research aimed to enhance phishing URL detection by using machine learning and deep learning models, leveraging a set of low-level URL features derived from n-gram analysis. Our findings show the importance of using minimal statistical features to identify malicious URLs. Notably, the use of CNN had a great advancement, achieving an accuracy rate of 94.09% with using n-grams of URLs, surpassing traditional machine learning models. This achievement not only validates the efficacy of deep learning models in complex pattern recognition tasks but also highlights the efficiency of our feature selection approach, which relies on a lower number of features and is less complex compared to existing high-level feature-based studies. The research outcomes demonstrate a promising pathway toward developing more robust, efficient, and scalable phishing detection systems. [ABSTRACT FROM AUTHOR]

Oral squamous cell carcinoma (OSCC) often recurs aggressively and metastasizes despite surgery and adjuvant therapy, driven by postoperative residual cancer cells near the primary tumor site. An implantable in situ vaccine hydrogel was designed to target residual OSCC cells post‐tumor removal. This hydrogel serves as a reservoir for the sustained localized release of δ‐aminolevulinic acid (δ‐ALA), enhancing protoporphyrin IX‐mediated photodynamic therapy (PDT), and a polydopamine‐hyaluronic acid composite for photothermal therapy (PTT). Additionally, immune adjuvants, including anti‐CD47 antibodies (aCD47) and CaCO3 nanoparticles, are directly released into the resected tumor bed. This approach induces apoptosis of residual OSCC cells through sequential near‐infrared irradiation, promoting calcium interference therapy (CIT). The hydrogel further stimulates immunogenic cell death (ICD), facilitating the polarization of tumor‐associated macrophages from the M2 to the M1 phenotype. This facilitates phagocytosis, dendritic cell activation, robust antigen presentation, and cytotoxic T lymphocyte‐mediated cytotoxicity. In murine OSCC models, the in situ vaccine effectively prevents local recurrence, inhibits orthotopic OSCC growth and pulmonary metastases, and provides long‐term protective immunity against tumor rechalle nge. These findings support postoperative in situ vaccination with a biocompatible hydrogel implant as a promising strategy to minimize residual tumor burden and reduce recurrence risk after OSCC resection. [ABSTRACT FROM AUTHOR]

Background: Amyotrophic Lateral Sclerosis (ALS), an incurable motor neuron disease, primarily affects those between the ages of 60–79, and has an approximate post-diagnosis life-expectancy of only two to five years. The condition has an unpredictable but ultimately terminal trajectory that poses challenges for patients, caregivers and healthcare providers. While the diagnosis and disclosure are critical periods for intervention and support, knowledge regarding the relational, communicational and psychodynamic forces that occur within the process of diagnostic disclosure is relatively limited. Objectives: The purpose of this study was to explore the experiences of persons living with ALS in the diagnosis and disclosure of the condition, with the support of their caregivers. Methods: We conducted a focus group and in-depth individual interviews with people living with ALS (n = 9), and caregivers (n = 9). The interviews were transcribed, cleaned, and anonymized, and then entered into NVivo 11 for thematic analysis. Results: Participants discussed the diagnostic process, including inklings and subtle changes prior to diagnosis, attempts at self-diagnosis, and the lengthy assessment process. Time was also a consideration in the diagnostic disclosure process, in which participants shared how the disclosure was the product of longstanding conversations with their care providers. It was described as rarely a shock to finally have confirmation. Participants shared their information seeking strategies and needs for a diagnosis that, for them, typically came with insufficient information on the disease, prognosis, and next steps. Significance: This project serves as a step in bridging the relevant gaps in our knowledge and understanding towards improved person-centered care practices in the diagnosis and disclosure of ALS. [ABSTRACT FROM AUTHOR]

Uncontrolled and chronic inflammatory states in the Central Nervous System (CNS) are the hallmark of neurodegenerative pathology and every injury or stroke-related insult. The key mediators of these neuroinflammatory states are glial cells known as microglia, the resident immune cell at the core of the inflammatory event, and astroglia, which encapsulate inflammatory insults in proteoglycan-rich scar tissue. Since the majority of neuroinflammation is exclusively based on the responses of said glia, their phenotypes have been identified to be on an inflammatory spectrum encompassing developmental, homeostatic, and reparative behaviors as opposed to their ability to affect devastating cell death cascades and scar tissue formation. Recently, research groups have focused on peptide discovery to identify these phenotypes, find novel mechanisms, and mediate or re-engineer their actions. Peptides retain the diverse function of proteins but significantly reduce the activity dependence on delicate 3D structures. Several peptides targeting unique phenotypes of microglia and astroglia have been identified, along with several capable of mediating deleterious behaviors or promoting beneficial outcomes in the context of neuroinflammation. A comprehensive review of the peptides unique to microglia and astroglia will be provided along with their primary discovery methodologies, including top-down approaches using known biomolecules and naïve strategies using peptide and phage libraries. [ABSTRACT FROM AUTHOR]

Huntington's disease (HD) is caused by a CAG repeat expansion in exon1 of the HTT gene that encodes a polyglutamine tract in huntingtin protein. The formation of HTT exon1 fragments with an expanded polyglutamine repeat has been implicated as a key step in the pathogenesis of HD. It was reported that the CAG repeat length‐dependent aberrant splicing of exon1 HTT results in a short polyadenylated mRNA that is translated into an exon1 HTT protein. Under normal conditions, TDP‐43 is predominantly found in the nucleus, where it regulates gene expression. However, in various pathological conditions, TDP‐43 is mislocalized in the cytoplasm. By investigating HD knock‐in mice, we explore whether the pathogenic TDP‐43 in the cytoplasm contributes to HD pathogenesis, through expressing the cytoplasmic TDP‐43 without nuclear localization signal. We found that the cytoplasmic TDP‐43 is increased in the HD mouse brain and that its mislocalization could deteriorate the motor and gait behavior. Importantly, the cytoplasmic TDP‐43, via its binding to the intron1 sequence (GU/UG)n of the mouse Htt pre‐mRNA, promotes the transport of exon1‐intron1 Htt onto ribosome, resulting in the aberrant generation of exon1 Htt. Our findings suggest that cytoplasmic TDP‐43 contributes to HD pathogenesis via its binding to and transport of nuclear un‐spliced mRNA to the ribosome for the generation of a toxic protein product. [ABSTRACT FROM AUTHOR]

TAR DNA binding protein 43 (TDP-43) is an RNA binding protein that accumulates as aggregates in the central nervous systems of some patients with neurodegenerative diseases. However, TDP-43 aggregation is also a sensitive and specific pathologic feature found in a family of degenerative muscle diseases termed inclusion body myopathy. TDP-43 aggregates from amyotrophic lateral sclerosis (ALS) and frontotemporal dementia brain lysates may serve as self-templating aggregate seeds in vitro and in vivo, supporting a prion-like spread from cell to cell. Whether a similar process occurs in patient muscle is not clear. We developed a mouse model of inducible, muscle-specific cytoplasmic localized TDP-43. These mice develop muscle weakness with robust accumulation of insoluble and phosphorylated sarcoplasmic TDP-43, leading to eosinophilic inclusions, altered proteostasis, and changes in TDP-43–related RNA processing that resolve with the removal of doxycycline. Skeletal muscle lysates from these mice also have seeding-competent TDP-43, as determined by a FRET-based biosensor, that persists for weeks upon resolution of TDP-43 aggregate pathology. Human muscle biopsies with TDP-43 pathology also contain TDP-43 aggregate seeds. Using lysates from muscle biopsies of patients with sporadic inclusion body myositis (IBM), immune-mediated necrotizing myopathy (IMNM), and ALS, we found that TDP-43 seeding capacity was specific to IBM. TDP-43 seeding capacity anticorrelated with TDP-43 aggregate and vacuole abundance. These data support that TDP-43 aggregate seeds are present in IBM skeletal muscle and represent a unique TDP-43 pathogenic species not previously appreciated in human muscle disease. Editor's summary: Aggregates of TAR DNA binding protein 43 (TDP-43) have been previously linked with neurodegenerative disease as well as inclusion body myopathy in skeletal muscle. Here, Lynch et al. demonstrate that residual aggregates termed "seeds" can persist in muscle after larger aggregates have been cleared and are no longer visible by traditional methods. Using a Förster resonance energy transfer (FRET) biosensor system, they show that both human and mouse TDP-43 seeds can be the initiators of new aggregates that contribute to disease pathology. These results highlight the importance of protein homeostasis and suggest that these seeds may be a potential therapeutic target for ameliorating disease. —Allison Williams [ABSTRACT FROM AUTHOR]

Background: Microglia play crucial roles in maintaining neuronal homeostasis but have been implicated in contributing to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). However, the role of microglia in ALS/FTD remains incompletely understood. Methods: Here, we generated highly enriched cultures of VCP mutant microglia derived from human induced pluripotent stem cells (hiPSCs) to investigate their cell autonomous and non-cell autonomous roles in ALS pathogenesis. We used RNA-sequencing, proteomics and functional assays to study hiPSC derived VCP mutant microglia and their effects on hiPSC derived motor neurons and astrocytes. Results: Transcriptomic, proteomic and functional analyses revealed immune and lysosomal dysfunction in VCP mutant microglia. Stimulating healthy microglia with the inflammatory inducer lipopolysaccharide (LPS) showed partial overlap with VCP mutant microglia in their reactive transformation. LPS-stimulated VCP mutant microglia displayed differential activation of inflammatory pathways compared with LPS-stimulated healthy microglia. Conserved gene expression changes were identified between VCP mutant microglia, SOD1 mutant mice microglia, and postmortem ALS spinal cord microglial signatures, including increased expression of the transmembrane glycoprotein GPNMB. While knockdown of GPNMB affected inflammatory and phagocytosis processes in microglia, this was not sufficient to ameliorate cell autonomous phenotypes in VCP mutant microglia. Secreted factors from VCP mutant microglia were sufficient to activate the JAK-STAT pathway in hiPSC derived motor neurons and astrocytes. Conclusions: VCP mutant microglia undergo cell autonomous reactive transformation involving immune and lysosomal dysfunction that partially recapitulate key phenotypes of microglia from other ALS models and post mortem tissue. These phenotypes occur independently of GPNMB. Additionally, VCP mutant microglia elicit non cell autonomous responses in motor neurons and astrocytes involving the JAK-STAT pathway. [ABSTRACT FROM AUTHOR]

Background: The nigrostriatal dopamine (DA) system plays a critical role in regulating the sleep–wake state. The relationship between baseline striatal DA transporter (DAT) specific binding ratios (SBR) and rapid eye movement sleep behavior disorder (RBD) has been established. This study aimed to investigate the association between the progression of striatal DA dysfunction and sleep disturbances, including excessive daytime sleepiness (EDS) and probable RBD (pRBD), in patients with Parkinson's disease (PD). Methods: Data were obtained from the Parkinson's Progression Markers Initiative (PPMI). Six hundred twenty-one newly diagnosed PD patients and followed up for 4 years were included in this longitudinal study. EDS and pRBD were defined using the Epworth Sleepiness Scale (ESS) and RBD Screening Questionnaire (RBDSQ). Striatal DAT SBR was evaluated by [123I] FP-CIT SPECT. Results: Using a linear mixed-effects model across all contemporaneous data points, we found a negative correlation between striatal DAT SBR and sleep disturbances (EDS/pRBD). The interaction between striatal DAT SBR and year was specific to RBDSQ score (β = − 0.102, 95% CI: − 0.187 to − 0.017, p = 0.019), with no evidence of a similar interaction for ESS score. Additionally, the association between the alpha-synuclein gene (SNCA) and sleep disturbances was mediated by the SBR (ESS score: total effect = − 2.717, p = 0.022; direct effect = − 3.222, p = 0.007; indirect effect = 0.505, p < 0.05; RBDSQ score: total effect = 1.402, p = 0.026; direct effect = 1.209, p = 0.057; indirect effect = 0.193, p < 0.05). Conclusions: Our findings support the role of striatal DA dysfunction in sleep disturbances in early PD patients. Furthermore, we demonstrated that genetic variations in causative genes of PD contribute to the development of sleep disturbances. Striatal DAT imaging may be a useful risk indicator for sleep disturbances, providing early intervention strategies. [ABSTRACT FROM AUTHOR]

The evolving landscape of cyber threats necessitates continuous advancements in defensive strategies. This paper explores the potential of artificial intelligence (AI) as an emerging tool to enhance cybersecurity. While AI holds widespread applications across information technology, its integration within cybersecurity remains a recent development. We offer a comprehensive review of current AI applications in this domain, focusing particularly on their preventative capabilities against prevalent threats like phishing, social engineering, ransomware, and malware. To illustrate these concepts, the paper presents a case study showcasing a specific AI application in a cybersecurity context. This case study addresses a critical gap in securing communication within resource-constrained Internet of Things (IoT) networks using the IEEE 802.15.4 standard. We discussed the advantages and limitations of employing PN sequence encryption for this purpose. [ABSTRACT FROM AUTHOR]

Phishing is one of the most widely observed types of internet cyber-attack, through which hundreds of clients using different internet services are targeted every day through different replicated websites. The phishing attacker spreads messages containing false URL links through emails, social media platforms, or messages, targeting people to steal sensitive data like credentials. Attackers generate phishing URLs that resemble those of legitimate websites to gain these confidential data. Hence, there is a need to prevent the siphoning of data through the duplication of trustworthy websites and raise public awareness of such practices. For this purpose, many machine learning and deep learning models have been employed to detect and prevent phishing attacks, but due to the ever-evolving nature of these attacks, many systems fail to provide accurate results. In this study, we propose a deep learning-based system using a 1D convolutional neural network to detect phishing URLs. The experimental work was performed using datasets from Phish-Tank, UNB, and Alexa, which successfully generated 200 thousand phishing URLs and 200 thousand legitimate URLs. The experimental results show that the proposed system achieved 99.7% accuracy, which was better than the traditional models proposed for URL-based phishing detection. [ABSTRACT FROM AUTHOR]

This study examined the validity and reliability of the power slap test (PS) as an assessment for upper body pulling power to predict water polo functional performance and competitive experience of female water polo players. Seventeen female water polo players from the national and development squads were recruited. Subjects completed test-retest sessions of PS testing and 1 session of functional performance tests for the 15-m arms-only sprint (15 mAOS) and the 5-m maximum shooting velocity (5 mMSV). All PS, 15 mAOS and 5 mMSV results were compared for predictability. Power slap scores demonstrated high reliability for left PS (intraclass correlations [ICC]: 0.96, 90% confidence interval [CI]: 0.91-0.98), right PS (ICC: 0.96, 90% CI: 0.90-0.98), left and right center of mass (COM) displacement (ICC: 0.98, 90% CI: 0.96-0.99; ICC: 0.95, 90% CI: 0.88-0.98), and summed PS (ICC: 0.96, 90% CI: 0.92-0.99). All absolute PS scores and left COM displacement (COMdispL) demonstrated large correlations with the 15 mAOS times (r520.542 to 20.52, r2 5 0.27-0.29, p, 0.05). No performance parameters of the PS were correlated with the 5 mMSV performance (p. 0.05). This study validates the reliability of the PS as a dryland assessment tool for upper body pulling power. Only absolute PS scores and COMdisp were validated as weak predictors of the arms-only sprint times over 15 m. Its predictive power significantly improved when considered in combination with shooting performance. All absolute and normalized kinetic and kinematic PS parameters did not predict functional performance and competitive experience. [ABSTRACT FROM AUTHOR]

Recent literature suggests that markers of neuroaxonal damage, such as neurofilaments and tau protein, might serve as potential biomarkers for ALS. We conducted this systematic review and meta-analysis study to compare cerebrospinal fluid (CSF) and blood levels of total tau (t-tau), phosphorylated tau (p-tau), amyloid beta peptide 42 (Abeta-42), and neurofilaments in ALS patients and controls. A systematic search of Cochrane Library, PubMed, Embase, and ISI Web of Science was conducted on March 18, 2022, and updated on January 26, 2023. Observational studies that compared the concentrations of neurofilament light chain (NfL), neurofilament heavy chain (NFH), t-tau, p-tau, or Abeta-42 in CSF or peripheral blood of ALS patients and controls were included. Data from relevant studies were independently extracted and screened for quality using a standard tool, by at least two authors. Meta-analysis was conducted when a minimum of 3 studies reported the same biomarker within the same biofluid. A total of 100 studies were eligible for at least one meta-analysis. CSF and blood levels of NfL (standardized mean difference (SMD) [95% CI]; CSF: 1.46 [1.25–1.68]; blood: 1.35 [1.09–1.60]) and NFH (CSF: 1.32 [1.13–1.50], blood: 0.90 [0.58–1.22]) were significantly higher in ALS patients compared with controls. The pooled differences between ALS patients and controls were not significant for CSF t-tau, blood t-tau, and CSF Abeta-42, but CSF p-tau was lower in ALS patients (-0.27 [-0.47- -0.07]). Significantly decreased p-tau/t-tau ratios were found in ALS patients compared with controls (-0.84 [-1.16- -0.53]). Heterogeneity was considerable in most of our meta-analyses. CSF and blood neurofilament levels, as well as the CSF p-tau/t-tau ratio, might be potential candidates for improving ALS diagnosis. Further research is warranted to better understand the underlying mechanisms and the clinical implications of these biomarker alterations. [ABSTRACT FROM AUTHOR]

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive degeneration of upper and lower motor neurons. The heterogeneous nature of ALS at the clinical, genetic, and pathological levels makes it challenging to develop diagnostic and prognostic tools that fit all disease phenotypes. Limitations associated with the functional scales and the qualitative nature of mainstay electrophysiological testing prompt the investigation of more objective quantitative assessment. Biofluid biomarkers have the potential to fill that gap by providing evidence of a disease process potentially early in the disease, its progression, and its response to therapy. In contrast to other neurodegenerative diseases, no biomarker has yet been validated in clinical use for ALS. Several fluid biomarkers have been investigated in clinical studies in ALS. Biofluid biomarkers reflect the different pathophysiological processes, from protein aggregation to muscle denervation. This review takes a pathophysiologic approach to summarizing the findings of clinical studies utilizing quantitative biofluid biomarkers in ALS, discusses the utility and shortcomings of each biomarker, and highlights the superiority of neurofilaments as biomarkers of neurodegeneration over other candidate biomarkers. [ABSTRACT FROM AUTHOR]

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease that results in death within 2–5 years of diagnosis. Respiratory failure is the most common cause of death in ALS. Mutations in the transactive response DNA binding protein 43 (TDP-43) encoded by the TARDBP gene are associated with abnormal cellular aggregates in neurons of patients with both familial and sporadic ALS. The role of these abnormal aggregates on breathing is unclear. Since respiratory failure is a major cause of death in ALS, we sought to determine the role of TDP-43 mutations on the respiratory motor unit in the Prp-hTDP43A315T mouse model – a model that expresses human TDP-43 containing the A315T mutation. We assessed breathing using whole-body plethysmography, and investigated neuropathology in hypoglossal and phrenic respiratory motor units. Postmortem studies included quantification of hypoglossal and putative phrenic motor neurons, activated microglia and astrocytes in respiratory control centers, and assessment of hypoglossal and phrenic nerves of TDP43A315T mice. The male TDP43A315T mice display an early onset of rapid progression of disease, and premature death (less than 15 weeks) compared to control mice and compared to female TDP43A315T mice who die between 20 and 35 weeks of age. The TDP43A315T mice have progressive and profound breathing deficits at baseline and during a respiratory challenge. Histologically, hypoglossal and putative phrenic motor neurons of TDP43A315T mice are decreased and have increased microglial and astrocyte activation, indicating pronounced neurodegeneration and neuroinflammation. Further, there is axonopathy and demyelination in the hypoglossal and phrenic nerve of TDP43A315T mice. Thus, the TDP-43A315T mice have significant respiratory pathology and neuropathology, which makes them a useful translatable model for the study of novel therapies on breathing in ALS. [ABSTRACT FROM AUTHOR]

The care of a patient with neurologic disease at end-of-life requires expertise in addressing advance care planning, hospice, symptom management, and caregiver support. Neurologists caring for patients with advanced neurologic disease often identify changes in disease trajectory, functional status, or goals of care that prompt discussions of advance care planning and hospice. Patients nearing end-of-life may develop symptoms such as dyspnea, secretions, delirium, pain, and seizures. Neurologists may be the primary clinicians managing these symptoms, particularly in the hospitalized patient, though they may also lend their expertise to non-neurologists about expected disease trajectories and symptoms in advanced neurologic disease. This article aims to help neurologists guide patients and caregivers through the end-of-life process by focusing on general knowledge that can be applied across diseases as well as specific considerations in severe stroke and traumatic brain injury, amyotrophic lateral sclerosis, Parkinson's disease, and dementia. [ABSTRACT FROM AUTHOR]

The article discusses the use of CRISPR-based approaches to study inborn errors of immunity (IEI), focusing on human natural killer (NK) cells. The study identified a gene, MEF2C, associated with NK cell defects in patients with MEF2C haploinsufficiency syndrome (MCHS), a neurodevelopmental disorder. The research suggests a potential link between neurodevelopmental disorders and immune deficiencies, highlighting the importance of further study to better identify and care for potentially immunodeficient patients. The study's findings demonstrate the utility of CRISPR tools in identifying new IEIs and advancing our understanding of immune disorders. [Extracted from the article]

The TAR DNA Binding Protein 43 (TDP-43) has been implicated in the pathogenesis of human neurodegenerative diseases and exhibits hallmark neuropathology in amyotrophic lateral sclerosis (ALS). Here, we explore its tractability as a plasma biomarker of disease and describe its localization and possible functions in the cytosol of platelets. Novel TDP-43 immunoassays were developed on three different technical platforms and qualified for specificity, signal-to-noise ratio, detection range, variation, spike recovery and dilution linearity in human plasma samples. Surprisingly, implementation of these assays demonstrated that biobank-archived plasma samples yielded considerable heterogeneity in TDP-43 levels. Importantly, subsequent investigation attributed these differences to variable platelet recovery. Fractionations of fresh blood revealed that ≥ 95% of the TDP-43 in platelet-containing plasma was compartmentalized within the platelet cytosol. We reasoned that this highly concentrated source of TDP-43 comprised an interesting substrate for biochemical analyses. Additional characterization of platelets revealed the presence of the disease-associated phosphoserine 409/410 TDP-43 proteoform and many neuron- and astrocyte-expressed TDP-43 mRNA targets. Considering these striking similarities, we propose that TDP-43 may serve analogous functional roles in platelets and synapses, and that the study of platelet TDP-43 might provide a window into disease-related TDP-43 dyshomeostasis in the central nervous system. [ABSTRACT FROM AUTHOR]

Background: The aldehyde dehydrogenase 2 (ALDH2) rs671 (A) allele has been implicated in neurodegeneration, potentially through oxidative and inflammatory pathways. The study aims to investigate the effects of the ALDH2 rs671 (A) allele and high sensitivity C-reactive protein (hs-CRP) on the clinical phenotypes of amyotrophic lateral sclerosis (ALS) in male and female patients. Methods: Clinical data and ALDH2 rs671 genotype of 143 ALS patients, including 85 males and 58 females, were collected from January 2018 to December 2022. All patients underwent assessment using the Chinese version of the Edinburgh Cognitive and Behavioral ALS Screen (ECAS). Complete blood count and metabolic profiles were measured. Clinical and laboratory parameters were compared between carriers and non-carriers of the rs671 (A) allele in males and females, respectively. The significant parameters and rs671 (A) Allele were included in multivariate linear regression models to identify potential contributors to motor and cognitive impairment. Mediation analysis was employed to evaluate any mediation effects. Results: Male patients carrying rs671 (A) allele exhibited higher levels of hs-CRP than non-carriers (1.70 mg/L vs. 0.50 mg/L, p = 0.006). The rs671 (A) allele was identified as an independent risk factor for faster disease progression only in male patients (b = 0.274, 95% CI = 0.048-0.499, p = 0.018). The effect of the rs671 (A) allele on the executive function in male patients was fully mediated by hs-CRP (Indirect effect = -1.790, 95% CI = -4.555--0.225). No effects of the rs671 (A) allele or hs-CRP were observed in female ALS patients. The effects of the ALDH2 rs671 (A) allele and the mediating role of hs-CRP in male patients remained significant in the sensitivity analyses. Conclusion: The ALDH2 rs671 (A) allele contributed to faster disease progression and hs-CRP mediated cognitive impairment in male ALS patients. [ABSTRACT FROM AUTHOR]

Spine surgery has significantly progressed due to innovations in surgical techniques, technology, and a deeper understanding of spinal pathology. However, numerous challenges persist, complicating successful outcomes. Anatomical intricacies at transitional junctions demand precise surgical expertise to avoid complications. Technical challenges, such as underestimation of the density of fixed vertebrae, individual vertebral characteristics, and the angle of pedicle inclination, pose additional risks during surgery. Patient anatomical variability and prior surgeries add layers of difficulty, often necessitating thorough pre- and intraoperative planning. Technological challenges involve the integration of artificial intelligence (AI) and advanced visualization systems. AI offers predictive capabilities but is limited by the need for large, high-quality datasets and the "black box" nature of machine learning models, which complicates clinical decision making. Visualization technologies like augmented reality and robotic surgery enhance precision but come with operational and cost-related hurdles. Patient-specific challenges include managing postoperative complications such as adjacent segment disease, hardware failure, and neurological deficits. Effective patient outcome measurement is critical, yet existing metrics often fail to capture the full scope of patient experiences. Proper patient selection for procedures is essential to minimize risks and improve outcomes, but criteria can be inconsistent and complex. There is the need for continued technological innovation, improved patient-specific outcome measures, and enhanced surgical education through simulation-based training. Integrating AI in preoperative planning and developing comprehensive databases for spinal pathologies can aid in creating more accurate, generalizable models. A holistic approach that combines technological advancements with personalized patient care and ongoing education is essential for addressing these challenges and improving spine surgery outcomes. [ABSTRACT FROM AUTHOR]

Introduction: Despite the long-term use of intramuscular and intraosseous lidocaine trigger point injections (LTPI) in the treatment of patients with low back pain, there have been no studies examining their efficiency in treatment of residual pain after degenerative lumbar spinal stenosis (DLSS) decompression surgery. The purpose of our research is to examine the LTPI efficiency in the treatment of residual lumbar pain after DLSS decompression surgery and to compare the analgesic and recovery effects of intramuscular and intraosseous LTPI administered in the L4–S1 region and in the posterior superior iliac spine (PSIS) after treatment and during four months of follow-up. Materials and Methods: We observed 99 patients (F:50, M:49) aged 42 to 59 years with residual neurological disorders after DLSS decompression surgery. In all patients, the pain syndrome exceeded 6 points on the VAS and averaged 7.2 ± 0.11 points. The control group (n = 21) underwent only pharmacotherapy. In addition to pharmacotherapy, the LTPI group underwent intramuscular LTPI in L4–S1 (n = 20), intramuscular LTPI in the PSIS (n = 19), intraosseous LTPI in L5, S1 (n = 20), and intraosseous LTPI in the PSIS (n = 19). A neurological examination was carried out before treatment, 7 days after completion of treatment, and at the end of the second and fourth months of the follow-up period. Results: In the control group, intramuscular LTPI in L4–S1 subgroup, intramuscular LTPI in PSIS subgroup, intraosseous LTPI in L5, S1 subgroup, and intraosseous LTPI in PSIS subgroup, the severity of pain decreased after treatment by 27.1% (p ≤ 0.05), 41.7% (p ≤ 0.01), 50.7% (p ≤ 0.01), 69% (p ≤ 0.01), and 84.7% (p ≤ 0.01), respectively, and at the end of the second month of follow-up, by 14.3% (p > 1), 29.2% (p ≤ 0.05), 38% (p ≤ 0.01), 53.5% (p ≤ 0.01), and 72.2% (p ≤ 0.01), respectively. Reduction of neurogenic claudication, regression of sensory deficit, increase of daily step activity, and improvement of quality of life after treatment were noted in intramuscular LTPI subgroups by 19.6% (p ≤ 0.05), 36.4 (p ≤ 0.05), 40.3% (p ≤ 0.01), and 21.0% (p ≤ 0.05), respectively, and in interosseous LTPI subgroups by 48.6% (p ≤ 0.01), 67.4% (p ≤ 0.01), 68.3% (p ≤ 0.01), and 46% (p ≤ 0.01), respectively. Conclusions: LTPI is highly effective in the treatment of patients with residual pain after DLSS decompression surgery. High analgesic effect, significant regression of sensory deficits and gait disorders, and remarkable improvement of daily step activity and quality of life are noted not only after the end of LTPI treatment but also continue for at least 2 months after treatment. Intraosseous LTPI is more effective than intramuscular LTPI by 92%, and LTPI in PSIS is more effective than LTPI in L4–S1 by 28.6%. [ABSTRACT FROM AUTHOR]

Motor neuron loss is well recognized in amyotrophic lateral sclerosis (ALS), but research on retinal ganglion cells (RGCs) is limited. Ocular symptoms are generally not considered classic ALS symptoms, although RGCs and spinal motor neurons share certain cell pathologies, including hallmark signs of glutamate neurotoxicity, which may be triggered by activation of extrasynaptic NMDA receptors (NMDARs). To explore potential novel strategies to prevent ALS-associated death of RGCs, we utilized inhibition of the TwinF interface, a new pharmacological principle that detoxifies extrasynaptic NMDARs by disrupting the NMDAR/TRPM4 death signaling complex. Using the ALS mouse model SOD1G93A, we found that the small molecule TwinF interface inhibitor FP802 prevents the loss of RGCs, improves pattern electroretinogram (pERG) performance, increases the retinal expression of Bdnf, and restores the retinal expression of the immediate early genes, Inhibin beta A and Npas4. Thus, FP802 not only prevents, as recently described, death of spinal motor neurons in SOD1G93A mice, but it also mitigates ALS-associated retinal damage. TwinF interface inhibitors have great potential for alleviating neuro-ophthalmologic symptoms in ALS patients and offer a promising new avenue for therapeutic intervention. [ABSTRACT FROM AUTHOR]

Neurodegenerative disorders are typically "split" based on their hallmark clinical, anatomical, and pathological features, but they can also be "lumped" by a shared feature of impaired mitochondrial biology. This leads us to present a scientific framework that conceptualizes Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD) as "metabolic icebergs" comprised of a tip, a bulk, and a base. The visible tip conveys the hallmark neurological symptoms, neurodegenerative regions, and neuronal protein aggregates for each disorder. The hidden bulk depicts impaired mitochondrial biology throughout the body, which is multifaceted and may be subdivided into impaired cellular metabolism, cell-specific mitotypes, and mitochondrial behaviours, functions, activities, and features. The underlying base encompasses environmental factors, especially modern industrial toxins, dietary lifestyles, and cognitive, physical, and psychosocial behaviours, but also accommodates genetic factors specific to familial forms of AD, PD, and ALS, as well as HD. Over years or decades, chronic exposure to a particular suite of environmental and genetic factors at the base elicits a trajectory of impaired mitochondrial biology that maximally impacts particular subsets of mitotypes in the bulk, which eventually surfaces as the hallmark features of a particular neurodegenerative disorder at the tip. We propose that impaired mitochondrial biology can be repaired and recalibrated by activating "mitohormesis", which is optimally achieved using strategies that facilitate a balanced oscillation between mitochondrial stressor and recovery phases. Sustainably harnessing mitohormesis may constitute a potent preventative and therapeutic measure for people at risk of, or suffering with, neurodegenerative disorders. [ABSTRACT FROM AUTHOR]

Mucosal-associated invariant T (MAIT) cells are unconventional T cells that recognize microbial riboflavin pathway metabolites presented by evolutionarily conserved MR1 molecules. We explored the human MAIT cell compartment across organ donor–matched blood, barrier, and lymphoid tissues. MAIT cell population size was donor dependent with distinct tissue compartmentalization patterns and adaptations: Intestinal CD103+ resident MAIT cells presented an immunoregulatory CD39highCD27low profile, whereas MAIT cells expressing NCAM1/CD56 dominated in the liver and exhibited enhanced effector capacity with elevated response magnitude and polyfunctionality. Both intestinal CD39high and hepatic CD56+ adaptations accumulated with donor age. CD56+ MAIT cells displayed limited T cell receptor–repertoire breadth, elevated MR1 binding, and a transcriptional profile skewed toward innate activation pathways. Furthermore, CD56 was dynamically up-regulated to a persistent steady-state equilibrium after exposure to antigen or IL-7. In summary, we demonstrate functional heterogeneity and tissue site adaptation in resident MAIT cells across human barrier tissues with distinct regulatory and effector signatures. Editor's summary: Mucosal-associated invariant T (MAIT) cells are a subset of innate-like T cells that recognize microbial riboflavin pathway–derived metabolites. Our understanding of MAIT cell functions in tissue homeostasis and antimicrobial responses has primarily relied on studies of mice and human peripheral blood. Using paired samples from adult human blood and mucosal and lymphoid tissues, Kammann et al. performed a cross-tissue characterization of human MAIT cells. Tissue-specific adaptations included a population of intestinal CD39hi MAIT cells with an immunoregulatory phenotype and liver-enriched CD56+ MAIT cells bearing enhanced effector capacity and innate-like features. Together, these findings highlight the phenotypic and functional specialization of human MAIT cells within specific tissue sites. —Claire Olingy [ABSTRACT FROM AUTHOR]

This article discusses a study conducted on the pathology of the primary visual cortex in patients with C9ORF72-associated amyotrophic lateral sclerosis (C9ALS). The study found that dipeptide repeat (DPR) pathology was more prevalent in the visual cortex of C9ALS patients compared to phosphorylated TAR DNA-binding protein (pTDP) pathology. However, there was no significant difference in the density of calcium-binding proteins (CBPs) between C9ALS and non-C9ALS cases. The study suggests that calcium homeostasis may play a role in protecting the visual cortex from ALS-related pathologies. Further research is needed to fully understand the relationship between pTDP and DPR pathologies and their impact on cellular injury. [Extracted from the article]

Background: Hereditary Spastic Paraplegias (HSP) are genetic neurodegenerative disorders affecting the corticospinal tract. No established neuroimaging biomarker is associated with this condition. Methods: A total of 46 patients affected by HSP, genetically and clinically evaluated and tested with SPRS scores, and 46 healthy controls (HC) matched by age and gender underwent a single-voxel Magnetic Resonance Spectroscopy sampling (MRS) of bilateral pre-central and pre-frontal regions. MRS data were analyzed cross-sectionally (at T0 and T1) and longitudinally (T0 vs. T1). Results: Statistically significant data showed that T0 mI/Cr in the pre-central areas of HSP patients was higher than in HC. In the left (L) pre-central area, NAA/Cr was significantly lower in HSP than in HC. In the right (R) pre-frontal area, NAA/Cr was significantly lower in HSP patients than in HC. HSP SPG4 subjects had significantly lower Cho/Cr concentrations in the L pre-central area compared to HC. Among the HSP subjects, non-SPG4 patients had significantly higher mI/Cr in the L pre-central area compared to SPG4 patients. In the R pre-frontal area, NAA/Cr was reduced, and ml/Cr was higher in non-SPG4 patients compared to SPG4 patients. Comparing "pure" and "complex" forms, NAA/Cr was higher in pHSP than in cHSP in the R pre-central and R pre-frontal areas. The longitudinal analysis, which involved fewer patients (n = 30), showed an increase in mI/Cr concentration in the L pre-frontal area among HSP subjects with respect to baseline. The patients had significantly higher SPRS scores at follow-up, with a significant positive correlation between SPRS scores and mI/Cr in the L precentral area, while in bilateral pre-frontal areas, lower SPRS scores corresponded to higher NAA/Cr concentrations. To explore the discriminating power of MRS in correctly identifying HSP and controls, an inference tree methodology classified HSP subjects and controls with an overall accuracy of 73.9%, a sensitivity of 87.0%, and a specificity of 60.9%. Conclusion: This pilot study indicates that brain MRS is a valuable approach that could potentially serve as an objective biomarker in HSP. [ABSTRACT FROM AUTHOR]

Background: Monitoring the recovery trajectory during and after hospitalization can be a valuable method to observe whether additional care is needed to optimize recovery. Hand grip strength tests are commonly used to measure an individual's physical condition. Eforto® is a system to monitor hand grip strength and grip work as measures of recovery. We examined the feasibility of daily repeated hand grip tests measured with Eforto® in geriatric inpatients, during hospitalization and at home after discharge. Methods: Geriatric inpatients (n = 191) were evaluated for grip strength and grip work with Eforto®, twice daily during their admission. We calculated attempt and success rates. Participants were divided into complete, high, moderate, and low attempt/success rate groups to study differences in patient characteristics. Reasons for non-attempt and unsuccessful tests were categorized and analyzed. Nine participants were interviewed about acceptability and user experience within the hospital setting. Four out of twenty participants accepted the invitation to continue the measurements after discharge at home for 4 weeks and were interviewed about acceptability and user experience. Results: Across the 191 participants, the attempt rate was 85% and 86% of the attempted tests was successful. The main reasons for non-attempt were that the patient felt physically unwell (41%), and that the patient was otherwise engaged, for example receiving care or undergoing medical tests (40%). Measurements were unsuccessful mostly because of the patient not having enough strength to reach the 80% threshold needed for the grip work test (60%). Participants in the complete and high attempt/success rate groups had a shorter length of stay (p<0.05) and a lower mortality (p<0.05) than participants in the moderate/low groups. The interview data showed good acceptability and user experience during hospitalization. The acceptability was strengthened by experienced usefulness. Self-monitoring at home resulted in low inclusion rate (20%) and low success rate (25%), with the uncertain time after discharge from the hospital as the main barrier. Conclusions: For most patients, the tests were feasible in the supervised hospital setting. At-home testing with Eforto® is challenging, primarily because of the uncertain time after discharge from the hospital. [ABSTRACT FROM AUTHOR]

Nowadays, phishing attacks have grown rapidly, and there is an urgent need to introduce a suitable detection method that has the ability to detect different types of phishing attacks. This paper investigates the capability to use bio-inspired meta-heuristic algorithms to improve the performance of the detection engine for phishing attacks by reducing the number of features. This improvement was practiced by investigating the effectiveness of five meta-heuristic algorithms: Particle Swarm Optimization (PSO), Firefly Optimization Algorithm (FFA), Multi-Verse Optimizer (MVO), Moth-Flame Optimization algorithm (MFO), and BAT optimization algorithm, to select the relevant features that could be affected directly by different types of phishing attacks. The suggested detection model was tested and evaluated using four benchmark phishing attack datasets, and the Apache Spark-based decision tree algorithm was selected as a detection engine. The conducted experiments have demonstrated that the Spark-based MVO algorithm achieved the highest detection rate for detecting different types of phishing attacks within four phishing attack datasets. Moreover, the suggested detection model was able to reduce effectively the feature space, which could enhance the computational efficiency. [ABSTRACT FROM AUTHOR]

It is known that the presence of CAA codons in the CAG tract affects the nature and time of disease onset caused by the expansion of trinucleotide repeats. The mechanisms leading to the occurrence of these diseases should be sought not only at the level of the physiological role of the ATXN2 protein, but also at the DNA level. These mechanisms are associated with non-canonical configurations (hairpins) that can form in the CAG tract. The tendency of hairpins to slide along the corresponding threads is usually considered important to explain the expansion of the CAG tract. At the same time, hairpins occur in areas of open states. Previous studies on the role of CAA interruptions have suggested that, under certain conditions, they can stabilize the dynamics of the hairpin, preventing the expansion of the CAG tract. We calculated the probability of additional open state zones occurrence in the CAG tract using an angular mathematical model of DNA. The calculations made it possible to establish that CAA interruptions affect the stability of the CAG tract, and this influence, depending on the localization of the interruption, can both increase and decrease the stability of the CAG tract. [ABSTRACT FROM AUTHOR]

Background: Upper motor neuron-dominant ALS (UMND ALS) is recognized to have early onset and good prognosis, but may have a rapid decline in motor function due to gait instability in the early stage. We investigated changes in lower extremity function in UMND ALS, particularly UMND ALS patients accompanied with postural instability or repeated falls (UMND ALS plus). Results: Among the 2,353 ALS patients reviewed, 211 (9.0%) had UMND ALS. UMND ALS had a longer diagnosis delay and restricted symptoms. Although UMND ALS patients had better lower extremity function and strength than matched classic ALS patients on first evaluation, there was no difference in the time of needing assistance or not being able to walk after disease onset. In contrast, UMND ALS plus has severe UMN symptoms and a more rapid decline in motor function. The lower extremity function was no better than that in the matched classic ALS. The prognosis of UMND ALS and UMND ALS plus were significantly better than those of overall ALS. Conclusion: UMND ALS has restricted symptoms but has a rapid decline in lower extremity function in the early stage of the disease. The motor function decline of UMND ALS plus is as fast as classic ALS. Whether these patients represent a distinct subgroup of ALS deserves further investigation. [ABSTRACT FROM AUTHOR]

Introduction: Older people living with frailty are at high risk of emergency hospital admission and often have complex care needs which may not be adequately met by conventional models of acute care. This has driven the introduction of adaptations to acute care pathways designed to improve outcomes in this patient group. The identification of differences in the organisational approach to frailty may highlight opportunities for quality improvement. Methods: The Society for Acute Medicine Benchmarking audit is a national service evaluation which uses a single day-of-care methodology to record patient and organisational level data. All acute hospitals in the United Kingdom are eligible to participate. Emergency admissions referred to acute medical services between 00:00 and 23:59 on Thursday 23rd June 2022 were recorded. Information on the structure and operational design of acute frailty services was collected. The use of a validated frailty assessment tool, clinical frailty scale within the first 24 h of admission, assessment by an acute frailty service and clinical outcomes were reported in patients aged 70 year and above. A mixed effect generalised linear model was used to determine factors associated same-day discharge without overnight stay in patients with frailty. Results: A total of 152 hospitals participated. There was significant heterogeneity in the operational design and staffing model of acute frailty services. The presence of an acute frailty unit was reported in 57 (42.2%) hospitals. The use of validated frailty assessment tools was reported in 117 (90.0%) hospitals, of which 107 (91.5%) used the clinical frailty scale. Patient-level data were recorded for 3604 patients aged 70 years and above. At the patient level, 1626 (45.1%) were assessed using a validated tool during the admission process. Assessment by acute frailty services was associated with an increased likelihood of same-day discharge (adjusted OR 1.55, 95%CI 1.03- 2.39). Conclusion: There is significant variation in the provision of acute frailty services. Frailty-related policies and services are common at the organisational level but implemented inconsistently at the patient level. Older people with frailty or geriatric syndromes assessed by acute frailty services were more likely to be discharged without the need for overnight bed-based admission. [ABSTRACT FROM AUTHOR]

Introduction: Cognitive dysfunction is commonplace in Motor Neurone Disease (MND). However, due to the prominent motor symptoms in MND, assessing patients' cognitive function through traditional cognitive assessments, which oftentimes require motoric responses, may become increasingly challenging as the disease progresses. Oculomotor pathways are apparently resistant to pathological degeneration in MND. As such, abnormalities in oculomotor functions, largely driven by cognitive processes such as saccades and smooth pursuit eye movement, may be reflective of frontotemporal cognitive deficits in MND. Thus, saccadic and smooth pursuit eye movements may prove to be ideal mechanistic markers of cognitive function in MND. Methods: To ascertain the utility of saccadic and smooth pursuit eye movements as markers of cognitive function in MND, this review summarizes the literature concerning saccadic and smooth pursuit eye movement task performance in people with MND. Results and discussion: Of the 22 studies identified, noticeable patterns suggest that people with MND can be differentiated from controls based on antisaccade and smooth pursuit task performance, and thus the antisaccade task and smooth pursuit task may be potential candidates for markers of cognition in MND. However, further studies which ascertain the concordance between eye tracking measures and traditional measures of cognition are required before this assumption is extrapolated, and clinical recommendations are made. [ABSTRACT FROM AUTHOR]

Simple Summary: Amyotrophic lateral sclerosis (ALS) is the most common form of Motor Neuron Disease and is traditionally associated with motor cortex, brainstem and spinal cord degeneration. Neuropsychological deficits are also increasingly recognized in ALS and have considerable clinical ramifications, but existing studies of cognitive impairment in ALS have primarily focused on cortical frontotemporal disease burden. The aim of this study is the comprehensive assessment of the grey and white matter components of limbic networks in a large cohort of patients with ALS, stratified for the C9orf72 genotype. Our MRI analyses reveal that the cortical, subcortical and white matter components of limbic circuits are not only affected in C9orf72-positive patients, but also in those who test negative for this genetic variant. Our radiological findings are consistent with previous neuropsychological observations and highlight the importance of comprehensive neuropsychological testing in ALS, irrespective of the underlying genotype. Cognitive impairment in ALS has widespread practical implications, including compliance with assistive devices, participation in clinical trials, and it has been associated with increased caregiver burden and is widely regarded as an adverse prognostic indicator. Our data provide radiological evidence of widespread limbic degeneration in ALS, which is particularly severe in C9orf72 mutation carriers. Background: While frontotemporal involvement is increasingly recognized in Amyotrophic lateral sclerosis (ALS), the degeneration of limbic networks remains poorly characterized, despite growing evidence of amnestic deficits, impaired emotional processing and deficits in social cognition. Methods: A prospective neuroimaging study was conducted with 204 individuals with ALS and 111 healthy controls. Patients were stratified for hexanucleotide expansion status in C9orf72. A deep-learning-based segmentation approach was implemented to segment the nucleus accumbens, hypothalamus, fornix, mammillary body, basal forebrain and septal nuclei. The cortical, subcortical and white matter components of the Papez circuit were also systematically evaluated. Results: Hexanucleotide repeat expansion carriers exhibited bilateral amygdala, hypothalamus and nucleus accumbens atrophy, and C9orf72 negative patients showed bilateral basal forebrain volume reductions compared to controls. Both patient groups showed left rostral anterior cingulate atrophy, left entorhinal cortex thinning and cingulum and fornix alterations, irrespective of the genotype. Fornix, cingulum, posterior cingulate, nucleus accumbens, amygdala and hypothalamus degeneration was more marked in C9orf72-positive ALS patients. Conclusions: Our results highlighted that mesial temporal and parasagittal subcortical degeneration is not unique to C9orf72 carriers. Our radiological findings were consistent with neuropsychological observations and highlighted the importance of comprehensive neuropsychological testing in ALS, irrespective of the underlying genotype. [ABSTRACT FROM AUTHOR]

Aim: To investigate barriers to healthcare professionals recognizing and managing delirium in hospitalized older people. Design: A mixed‐methods systematic review. PROSPERO ID: CRD42020187932. Data Sources: MEDLINE, EMBASE, PsycINFO and CINAHL were searched (2007 to February 2023). Review Methods: Included studies focused on healthcare professionals' recognition and management of delirium for patients aged 65 years and over in a hospital ward or emergency department. Enhancing rigour, screening of results was conducted independently by two researchers. Qualitative and quantitative data were tabulated separately and grouped. Data were compared to identify similarities and differences. All studies were quality appraised. Results: 43 studies were included; 24 quantitative, 16 qualitative and three mixed‐methods. Data synthesis highlighted synergy between qualitative and quantitative findings. Barriers were reflected in six themes: (1) healthcare professionals' knowledge and understanding; (2) communication; (3) workforce development; (4) interprofessional working; (5) confounders; and (6) organizational constraints. Conclusions: Of significance, for older adults in hospital experiencing delirium, there is variability in whether and how well it is recognized and managed. To prevent adverse outcomes best practice guidance for screening, recognizing, diagnosing and managing delirium in older people needs to be agreed and disseminated widely. Supporting healthcare professionals to care for this patient population using an integrated approach is essential, how to involve and communicate with patients and their family and friends, how to recognize and manage delirium for patients with additional needs, e.g., those living with dementia and/or a learning disability. Hospitals need to have policy and guidance in place for the recognition and management of delirium in older adults presenting to a ward or to an emergency department. An IT infrastructure is needed that integrates assessments and care management plans in patient electronic records and makes them accessible within and across teams in hospital, primary and community care settings. Patient or Public Contribution: There was no patient or public contribution to this systematic review. Implications for the Profession and Patient Care: Healthcare professionals can be better supported to be able to recognize and manage delirium during an acute hospital stay for older adults. This includes maximizing best care for those patients living with dementia, involving families and friends to help understand patients' baseline status and changes and supporting families and friends during this process. Of significance, attention to hospital IT infrastructures is warranted, integrating screening, assessment and care management plans in patients' electronic records and making these accessible to healthcare professionals caring for this patient population across care settings. Impact: What problem did the study address? Delirium is a common condition experienced by older hospitalized patients, but it is consistently under‐recognized which has implications for patient and organization outcomes. To help address this, understanding barriers to healthcare professionals recognizing and managing delirium for this patient population is paramount. What were the main findings? Barriers to healthcare professionals recognizing and managing delirium for this patient population were synthesized in six themes: (1) healthcare professionals' knowledge and understanding, (2) communication; (3) workforce development; (4) interprofessional working; (5) confounders; and (6) organizational constraints. Where and on whom will the research have an impact? The findings of this original systematic review can contribute to hospital policy and protocol for the recognition and management of delirium in older patients. The findings can meaningfully contribute to workforce professional development for practitioners caring for older people during an acute hospital stay and for practitioners in primary and community settings involved in the follow‐up of patients post hospital discharge. For researchers, the findings indicate several research recommendations including investigating the impact of an education programme for nurses and other healthcare professionals on the recognition and management of the condition and understanding and investigating how best to support delirium‐related distress experienced by patients and their families and practitioners. Reporting Method: This systematic review was reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (Page et al., 2021). [ABSTRACT FROM AUTHOR]

Purpose: Speech fluency has important diagnostic implications for individuals with poststroke aphasia (PSA) as well as primary progressive aphasia (PPA), and quantitative assessment of connected speech has emerged as a widely used approach across both etiologies. The purpose of this review was to provide a clearer picture on the range, nature, and utility of individual quantitative speech/language measures and methods used to assess connected speech fluency in PSA and PPA, and to compare approaches across etiologies. Method: We conducted a scoping review of literature published between 2012 and 2022 following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews guidelines. Forty-five studies were included in the review. Literature was charted and summarized by etiology and characteristics of included patient populations and method(s) used for derivation and analysis of speech/language features. For a subset of included articles, we also charted the individual quantitative speech/language features reported and the level of significance of reported results. Results: Results showed that similar methodological approaches have been used to quantify connected speech fluency in both PSA and PPA. Two hundred nine individual speech-language features were analyzed in total, with low levels of convergence across etiology on specific features but greater agreement on the most salient features. The most useful features for differentiating fluent from nonfluent aphasia in both PSA and PPA were features related to overall speech quantity, speech rate, or grammatical competence. Conclusions: Data from this review demonstrate the feasibility and utility of quantitative approaches to index connected speech fluency in PSA and PPA. We identified emergent trends toward automated analysis methods and data-driven approaches, which offer promising avenues for clinical translation of quantitative approaches. There is a further need for improved consensus on which subset of individual features might be most clinically useful for assessment and monitoring of fluency. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) and Frontotemporal lobar degeneration (FTLD) represent the most common forms of neurodegenerative dementias with a highly phenotypic variability. Herein, we investigated the role of genetic variants related to the immune system and inflammation as genetic modulators in AD and related dementias. In patients with sporadic AD/FTLD (n = 300) and GRN/C9orf72 mutation carriers (n = 80), we performed a targeted sequencing of 50 genes belonging to the immune system and inflammation, selected based on their high expression in brain regions and low tolerance to genetic variation. The linear regression analyses revealed two genetic variants: (i) the rs1049296 in the transferrin (TF) gene, shown to be significantly associated with age at onset in the sporadic AD group, anticipating the disease onset of 4 years for each SNP allele with respect to the wild-type allele, and (ii) the rs7550295 in the calsyntenin-1 (CLSTN1) gene, which was significantly associated with age at onset in the C9orf72 group, delaying the disease onset of 17 years in patients carrying the SNP allele. In conclusion, our data support the role of genetic variants in iron metabolism (TF) and in the modulation of the calcium signalling/axonal anterograde transport of vesicles (CLSTN1) as genetic modulators in AD and FTLD due to C9orf72 expansions. [ABSTRACT FROM AUTHOR]