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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]

Trans-activation response DNA binding protein of 43 kDa (TDP-43) regulates a great variety of cellular processes in the nucleus and cytosol. In addition, a defined subset of neurodegenerative diseases is characterized by nuclear depletion of TDP-43 as well as cytosolic mislocalization and aggregation. To perform its diverse functions TDP-43 can associate with different ribonucleoprotein complexes. Combined with transcriptomics, MS interactome studies have unveiled associations between TDP-43 and the spliceosome machinery, polysomes and RNA granules. Moreover, the highly dynamic, low-valency interactions regulated by its low-complexity domain calls for innovative proximity labeling methodologies. In addition to protein partners, the analysis of post-translational modifications showed that they may play a role in the nucleocytoplasmic shuttling, RNA binding, liquid-liquid phase separation and protein aggregation of TDP-43. Here we review the various TDP-43 ribonucleoprotein complexes characterized so far, how they contribute to the diverse functions of TDP-43, and roles of post-translational modifications. Further understanding of the fluid dynamic properties of TDP-43 in ribonucleoprotein complexes, RNA granules, and self-assemblies will advance the understanding of RNA processing in cells and perhaps help to develop novel therapeutic approaches for TDPopathies., (© 2023 The Authors. Proteomics published by Wiley-VCH GmbH.)

Purpose: Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease in adults. There are many patient-reported outcome measures (PROMs) for measuring quality of life (QoL) and health-related QoL (HRQoL) within this population; however, there is limited consensus regarding which are most valid, reliable, responsive, and interpretable. This systematic review assesses the psychometric properties and interpretability of QoL and HRQoL PROMs for individuals with ALS., Methods: This review was conducted following the Consensus-based Standards for the selection of health Measurement Instruments (COSMIN) methodology for systematic reviews of PROMs. MEDLINE, EMBASE, and CINAHL databases were searched. Studies were included if their aim was to evaluate one or more psychometric properties or the interpretability of QoL or HRQoL PROMs in individuals with ALS., Results: We screened 2713 abstracts, reviewed 60 full-text articles, and included 37 articles. Fifteen PROMs were evaluated including generic HRQoL (e.g., SF-36), ALS-specific HRQoL (e.g., ALSAQ-40), and individualized QoL (e.g., SEIQoL) measures. Evidence for internal consistency and test-retest reliability were acceptable. For convergent validity, 84% of hypotheses were met. For known-groups validity, outcomes were able to distinguish between healthy cohorts and other conditions. Responsiveness results ranged from low to high correlations with other measures over 3-24 months. Evidence for content validity, structural validity, measurement error, and divergent validity was limited., Conclusion: This review identified evidence in support of the ALSAQ-40 or ALSAQ-5 for individuals with ALS. These findings can guide healthcare practitioners when selecting evidence-based QoL and HRQoL PROMs for patients and provide researchers with insight into gaps in the literature., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Changes in synaptic function are an early hallmark of neuropathological conditions that often precede symptom onset, with mounting genetic, transcriptional, and epidemiological evidence implicating microglia in this process. The correlation between infection and neurocognitive sequelae further suggests that environmental exposures modulate neuroimmune interactions and contribute to synaptic alterations. Recent studies investigating functional roles of microglia across broad neuropathological contexts including neurodegeneration, aging, neuropsychiatric and neurodevelopmental disorders, and neurotropic infections reveal convergent mechanisms underlying microglial-mediated synaptic dysfunction. We propose that early microglial changes, driven by genetic alterations coupled with environmental neuroimmune modulation, may be a common denominator that contributes to early synaptic pathologies. Here we review the evidence and discuss how microglia respond, and contribute, to synaptopathies across diverse neurological conditions, spotlighting their importance as broadly relevant therapeutic targets within neurological diseases., (© 2023 New York Academy of Sciences.)

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]

This article examines the evolution in understanding of frontotemporal dementia (FTD) during the last four decades. A central theme is the recognition of heterogeneity. Originally construed as a disorder of behaviour and executive impairment, FTD is now known also to be associated with alterations in language, conceptual knowledge and praxis. An absence of neurological signs is the hallmark of many FTD patients, but there is also an established association with motor neurone disease (MND), progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). FTD is commonly defined as an early onset dementia, yet about a quarter of patients present after the age of 65. The underlying pathological protein is tau, TDP-43 or more rarely fused-in-sarcoma (FUS). Distinct genetic mutations have been identified in familial FTD. There are predictable relationships between clinical phenotype, pathological substrate and genetic mutation. For example, a circumscribed semantic disorder predicts TDP-43 pathology, and speech or limb apraxia tau pathology. The co-occurrence of MND predicts TDP-43 pathology, and PSP and CBD tau pathology. FUS pathology is associated with very youthful onset, stereotyped behaviours and caudate atrophy. Non-fluent aphasia is linked to progranulin (GRN) mutations and MND and psychosis to repeat expansions in the C9orf72 gene. Despite striking worldwide consensus in findings there remain some issues of contention, largely related to the classification of FTD and its sub-variants. Understanding the diverse nature of FTD is crucial for effective diagnosis, management and the development of targeted therapies., (© 2022 The Authors. Journal of Neuropsychology published by John Wiley & Sons Ltd on behalf of The British Psychological Society.)

We quantified and determined for the first time the distribution pattern of the neuropeptide NPFF in the human cerebral cortex and subjacent white matter. To do so, we studied n = 9 cases without neurological disorders and n = 22 cases with neurodegenerative diseases, including sporadic amyotrophic lateral sclerosis (ALS, n = 8), Alzheimer's disease (AD, n = 8), Pick's disease (PiD, n = 3), and schizophrenia (n = 3). NPFF-immunopositive cells were located chiefly, but not exclusively, in the superficial white matter and constituted there a subpopulation of white matter interstitial cells (WMIC): Pyramidal-like and multipolar somata predominated in the gyral crowns, whereas bipolar and ovoid somata predominated in the cortex surrounding the sulci. Their sparsely ramified axons were unmyelinated and exhibited NPFF-positive bead-like varicosities. We found significantly fewer NPFF-immunopositive cells in the gray matter of the frontal, cingulate, and superior temporal gyri of both sporadic ALS and late-stage AD patients than in controls, and significantly fewer NPFF-positive cells in the subjacent as well as deep white matter of the frontal gyrus of these patients compared to controls. Notably, the number of NPFF-positive cells was also significantly lower in the hippocampal formation in AD compared to controls. In PiD, NPFF-positive cells were present in significantly lower numbers in the gray and white matter of the cingulate and frontal gyrii in comparison to controls. In schizophrenic patients, lower wNPFF cell counts in the neocortex were significant and global (cingulate, frontal, superior temporal gyrus, medial, and inferior gyri). The precise functions of NPFF-positive cells and their relationship to the superficial corticocortical white matter U-fibers are currently unknown. Here, NPFF immunohistochemistry and expression characterize a previously unrecognized population of cells in the human brain, thereby providing a new entry-point for investigating their physiological and pathophysiological roles. [ABSTRACT FROM AUTHOR]

There is a well-established link between physical activity and brain health. As such, the effectiveness of physical exercise as a therapeutic strategy has been explored in a variety of neurological contexts. To determine the extent to which physical exercise could be most beneficial under different circumstances, studies are needed to uncover the underlying mechanisms behind the benefits of physical activity. Interest has grown in understanding how physical activity can regulate microglia, the resident immune cells of the central nervous system. Microglia are key mediators of neuroinflammatory processes and play a role in maintaining brain homeostasis in healthy and pathological settings. Here, we explore the evidence suggesting that physical activity has the potential to regulate microglia activity in various animal models. We emphasize key areas where future research could contribute to uncovering the therapeutic benefits of engaging in physical exercise. [ABSTRACT FROM AUTHOR]

Background: Recent research has indicated the significance of immune activation in amyotrophic lateral sclerosis (ALS). However, the impact of peripheral immunity on cognitive impairment in sporadic ALS remains poorly characterized. Therefore, we aim to assess the relationship between peripheral immune parameters and cognitive impairment in patients with sporadic ALS. Methods: A case–control study involving 289 patients with sporadic ALS was conducted. All participants underwent cognitive assessment and measurements of blood immune parameters. The main outcomes included adjusted odds ratios (ORs) in multivariate logistic regression analysis and adjusted coefficients in a multivariate linear regression model. Sensitivity analysis was performed with stratification by the King’s clinical stage. Results: Cognitive impairment was observed in 98 (33.9%) patients. Higher counts of leukocyte (OR, 0.53; 95% CI, 0.29 to 0.95; p  =  0.03), neutrophil (OR, 0.48; 95% CI, 0.26 to 0.88; p  =  0.02), and monocyte (OR, 0.33; 95% CI, 0.18 to 0.60; p  <  0.001) were significantly associated with better cognitive preformence in sporadic ALS, particularly among patients in King’s clinical stages 1 and 2. Conversely, a higher percentage of CD4+ T cells was linked to an increased risk of cognitive impairment (OR, 2.79; 95% CI, 1.52 to 5.09; p  =  0.001), particularly evident in patients in King’s clinical stage 3. Conclusion: These results highlight the involvement of peripheral immunity in the cognitive impairment of sporadic ALS and suggest dynamic and intricate roles that vary across disease stages. Elucidating the links between immunity and ALS sheds light on the pathophysiological mechanisms underlying this fatal neurodegenerative disorder and informs potential immunotherapeutic strategies. [ABSTRACT FROM AUTHOR]

The etiology of the neurodegenerative disease amyotrophic lateral sclerosis (ALS) is complex and considered multifactorial. The majority of ALS cases are sporadic, but familial cases also exist. Estimates of heritability range from 8% to 61%, indicating that additional factors beyond genetics likely contribute to ALS. Numerous environmental factors are considered, which may add up and synergize throughout an individual's lifetime building its unique exposome. One level of integration between genetic and environmental factors is epigenetics, which results in alterations in gene expression without modification of the genome sequence. Methylation reactions, targeting DNA or histones, represent a large proportion of epigenetic regulations and strongly depend on the availability of methyl donors provided by the ubiquitous one-carbon (1C) metabolism. Thus, understanding the interplay between exposome, 1C metabolism, and epigenetic modifications will likely contribute to elucidating the mechanisms underlying altered gene expression related to ALS and to developing targeted therapeutic interventions. Here, we review evidence for 1C metabolism alterations and epigenetic methylation dysregulations in ALS, with a focus on the impairments reported in neural tissues, and discuss these environmentally driven mechanisms as the consequences of cumulative exposome or late environmental hits, but also as the possible result of early developmental defects. [ABSTRACT FROM AUTHOR]

Background: Caveolae are essential in regulating signal transduction mechanisms of ion channels in vascular tissue, including BKCa channels (maxi-K). The current study investigated the localization of maxi-K channels within caveolae. Methods: Sixteen rats were divided into two groups: A control group and a treated group, where arteries in the treated group were incubated with methyl-ß-cyclodextrin (MßCD) to disassemble caveolae from artery tissue. Immunohistochemistry (IHC), immunocytochemistry (ICC), transmission electron microscopy (TEM) and Western blot techniques were used in this study. Result: IHC of intact arteries showed colocalization of maxi-K channels with caveolin-1 in smooth muscle and endothelial cells and colocalized of maxi-K channels with caveolin-3 in smooth muscle cells only. These findings were also corroborated with ICC in a single smooth muscle cell. TEM revealed caveolae covering most plasma membranes of smooth muscle and endothelial cells and showed that caveolae sit close to the sarcoplasmic reticulum only in smooth muscle cells. TEM showed incubating arteries with MßCD led to the disassembly of caveolae from artery tissue. This study concluded that maxi-K channels localize to caveolae and that caveolae abolishment by MßCD led to the abolition of the coupling of caveolae and the sarcoplasmic reticulum. [ABSTRACT FROM AUTHOR]

Together, lower back and neck pain are among the leading causes of acquired disability worldwide and have experienced a marked increase over the past 25 years. Paralleled with the increasing aging population and the rise in chronic disease, this trend is only predicted to contribute to the growing global burden. In the context of cervical neck pain, this symptom is most often a manifestation of cervical degenerative disc disease (DDD). Traditionally, multilevel neck pain related to DDD that is recalcitrant to both physical and medical therapy can be treated with a procedure known as cervical corpectomy. Presently, there are many flavors of cervical corpectomy; however, the overarching goal is the removal of the pain-generating disc via the employment of the modern anterior approach. In this review, we will briefly detail the pathophysiological mechanism behind DDD, overview the development of the anterior approach, and discuss the current state of treatment options for said pathology. Furthermore, this review will also add to the current body of literature surrounding updated indications, surgical techniques, and patient outcomes related to cervical corpectomy. Finally, our discussion ends with highlighting the future direction of cervical corpectomy through the introduction of the "skip corpectomy" and distractable mesh cages. [ABSTRACT FROM AUTHOR]

Background: Rare diseases, predominantly caused by genetic factors and often presenting neurological manifestations, are significantly underrepresented in research. This review addresses the urgent need for advanced research in rare neurological diseases (RNDs), which suffer from a data scarcity and diagnostic challenges. Bridging the gap in RND research is the integration of machine learning (ML) and omics technologies, offering potential insights into the genetic and molecular complexities of these conditions. Methods: We employed a structured search strategy, using a combination of machine learning and omics-related keywords, alongside the names and synonyms of 1840 RNDs as identified by Orphanet. Our inclusion criteria were limited to English language articles that utilized specific ML algorithms in the analysis of omics data related to RNDs. We excluded reviews and animal studies, focusing solely on studies with the clear application of ML in omics data to ensure the relevance and specificity of our research corpus. Results: The structured search revealed the growing use of machine learning algorithms for the discovery of biomarkers and diagnosis of rare neurological diseases (RNDs), with a primary focus on genomics and radiomics because genetic factors and imaging techniques play a crucial role in determining the severity of these diseases. With AI, we can improve diagnosis and mutation detection and develop personalized treatment plans. There are, however, several challenges, including small sample sizes, data heterogeneity, model interpretability, and the need for external validation studies. Conclusions: The sparse knowledge of valid biomarkers, disease pathogenesis, and treatments for rare diseases presents a significant challenge for RND research. The integration of omics and machine learning technologies, coupled with collaboration among stakeholders, is essential to develop personalized treatment plans and improve patient outcomes in this critical medical domain. [ABSTRACT FROM AUTHOR]

The connection between body weight alterations and Alzheimer's disease highlights the intricate relationship between the brain and adipose tissue in the context of neurological disorders. During midlife, weight gain increases the risk of cognitive decline and dementia, whereas in late life, weight gain becomes a protective factor. Despite their substantial impact on metabolism, the role of adipokines in the transition from healthy aging to neurological disorders remains largely unexplored. We aim to investigate how the adipose tissue milieu and the secreted adipokines are involved in the transition between biological and pathological aging, highlighting the bidirectional relationship between the brain and systemic metabolism. Understanding the function of these adipokines will allow us to identify biomarkers for early detection of Alzheimer's disease and uncover novel therapeutic options. [ABSTRACT FROM AUTHOR]

Purpose of Review: Atypical parkinsonism is a term usually used to describe three neurodegenerative parkinsonian disorders: progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and multiple system atrophy (MSA). In contrast to Parkinson's disease, these disorders have a poor prognosis and present with a multitude of diverse symptoms, including parkinsonism, dystonia, myoclonus, gait disorders, dysarthria, dysphagia, sleep, cognitive, and behavioral disorders. In the absence of an approved disease-modifying treatment, symptomatic treatment is the mainstay of management. The purpose of this review is to present an overview of the management of these complex disorders, with a particular focus on a holistic and multidisciplinary approach. Recent Findings: In addition to presenting the most significant pharmacological interventions for symptom management, data regarding non-pharmacological interventions are analyzed. Important non-pharmacological clinical practice questions such as breaking the news, palliative care, and end-of-life issues are discussed, in an effort to present an overview of the management of atypical parkinsonism from diagnosis to the most advanced stages of these diseases. Summary: Management of atypical parkinsonian disorders includes symptomatic pharmacological and non-pharmacological interventions, in addition to addressing issues such as informing the patient of the diagnosis, palliative care, and end-of-life issues, which require a multidisciplinary approach. [ABSTRACT FROM AUTHOR]

The disease-specific accumulation of pathological proteins has long been the major focus of research in neurodegenerative diseases (ND), including Alzheimer's disease (AD) and related dementias (RD), but the recent identification of a multitude of genetic risk factors for ND in immune-associated genes highlights the importance of immune processes in disease pathogenesis and progression. Studies in animal models have characterized the local immune response to disease-specific proteins in AD and ADRD, but due to the complexity of disease processes and the co-existence of multiple protein pathologies in human donor brains, the precise role of immune processes in ND is far from understood. To better characterize the interplay between different extracellular and intracellular protein pathologies and the brain's intrinsic immune system in ND, we set out to comprehensively profile the local immune response in postmortem brain samples of individuals with "pure" beta-Amyloid and tau pathology (AD), "pure" α-Synuclein pathology in Lewy body diseases (LBD), as well as cases with Alzheimer's disease neuropathological changes (ADNC) and Lewy body pathology (MIX). Combining immunohistochemical profiling of microglia and digital image analysis, along with deep immunophenotyping using gene expression profiling on the NanoString nCounter® platform and digital spatial profiling on the NanoString GeoMx® platform we identified a robust immune activation signature in AD brain samples. This signature is maintained in persons with mixed pathologies, irrespective of co-existence of AD pathology and Lewy body (LB) pathology, while LBD brain samples with "pure" LB pathology exhibit an attenuated and distinct immune signature. Our studies highlight disease- and brain region-specific immune response profiles to intracellular and extracellular protein pathologies and further underscore the complexity of neuroimmune interactions in ND. [ABSTRACT FROM AUTHOR]

Background: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that is now recognized to involve autonomic dysfunction. The burden of autonomic dysfunction is an important factor in the quality of life and prognosis of ALS patients. This article presents the clinical characteristics of a young female ALS patient with a fused in sarcoma (FUS) gene mutation and notable hyperhidrosis. Method: Detailed clinical characteristics of the patients were collected, and comprehensive examinations such as electrophysiological assessment, neuro-ultrasound, genetic testing, and relevant blood tests were conducted. Result: A 24-year-old female experienced progressive weakness in both lower limbs for over 5 months, along with excessive sweating on both palms and feet. A positive skin iodine-starch test was observed. Electromyography revealed extensive neurogenic damage and prolonged sympathetic skin response (SSR) latency in both lower limbs. Full exon gene sequencing showed a heterozygous mutation c.1574C>T (p.Pro525Leu) in the FUS gene. Conclusion: The pathogenesis of ALS remains unclear at present. This case underscores the presence of autonomic nervous symptoms in ALS associated with FUS mutation and highlights the importance of early diagnosis and timely treatment intervention to enhance patient prognosis. [ABSTRACT FROM AUTHOR]

The e4 allele of the apolipoprotein E gene is the strongest genetic risk factor for sporadic Alzheimer's disease. Nevertheless, how APOE is regulated is still elusive. In a trans-eQTL analysis, we found a genome-wide significant association between transmembrane protein 106B (TMEM106B) genetic variants and cortical APOE mRNA levels in human brains. The goal of this study is to determine whether TMEM106B is mis-regulated in Alzheimer's disease or in other neurodegenerative conditions. Available genomic, transcriptomic and proteomic data from human brains were downloaded from the Mayo Clinic Brain Bank and the Religious Orders Study and Memory and Aging Project. An in-house mouse model of the hippocampal deafferentation/reinnervation was achieved via a stereotaxic lesioning surgery to the entorhinal cortex, and mRNA levels were measured using RNAseq technology. In human temporal cortices, the mean TMEM106B expression was significantly higher in Alzheimer's disease compared to cognitively unimpaired individuals. In the mouse model, hippocampal Tmem106b reached maximum levels during the early phase of reinnervation. These results suggest an active response to tissue damage that is consistent with compensatory synaptic and terminal remodeling. [ABSTRACT FROM AUTHOR]

Phishing, a well-known cyberattack that cannot be completely eradicated from the Internet, has increased dramatically since the COVID-19 pandemic. Despite previous efforts to reduce this prevalent Internet threat, constantly changing attacks make phishing detection a difficult task. The lack of continuous learning support provided by existing solutions and the lack of a systematic knowledge acquisition process make its detection more difficult. SmartiPhish is introduced in this context as the first anti-phishing solution with integrated continuous learning support with an innovative knowledge acquisition process. SmartiPhish combines deep learning and reinforcement learning to have a successful phishing detection solution. The deep learning model predicts a phishing probability for a given web page based on the URL and HTML content, and the probability is then passed to a reinforcement learning environment to make a decision based on the popularity of the web page and prior knowledge of it. SmartiPhish has a detection accuracy of 96.40% and a detection time of 4.3 s. SmartiPhish performs well in an imbalanced environment, and zero-day attack detection is also interesting. Furthermore, SmartiPhish demonstrated a 5.65% performance improvement in just six weeks, in contrast to the existing anti-phishing tools' declining performance trend over time. [ABSTRACT FROM AUTHOR]

The recent surge in phishing incidents in the post-COVID era poses a serious threat towards the social and economic well-being of users. The escalation in dependency upon the internet for meeting daily chores has made them vulnerable to falling prey to the ever-evolving menace of phishing. The objective of this article is: to explore different tactics and motivational factors behind phishing, identify the communication mediums through which phishing is circulated and perform a detailed review along with a comparison of the various surveys in this domain. Another objective is to determine the open research challenges in this genre and to identify the scope of research in the future. An extensive literature survey is performed, which includes articles from eminent online research databases. Barring a few initial articles related to phishing, the articles published in Science Citation/Scopus-indexed journals and survey/review articles published in the last ten years are considered. Highly cited works are given preference. The search query returned numerous articles, which were narrowed by title screening. Further screening of articles was performed by reading the abstract and eliminating the articles related to user-oriented phishing interventions. Eventually, 25 survey articles were shortlisted to be surveyed. This article is an effort to provide a novel taxonomy of phishing to academia that would assist in identifying the sections where phishing countermeasures are inadequate. [ABSTRACT FROM AUTHOR]