As the world continues to experience the effects of SARS‐CoV‐2, there is evidence to suggest that the sequelae of viral infection (the post‐COVID‐19 condition; PCC) at both an individual and ...population level will be significant and long‐lasting. The history of pandemics or epidemics in the last 100 years caused by members of the RNA virus family, of which coronaviruses are a member, provides ample evidence of the acute neurological effects. However, except for the H1N1 influenza pandemic of 1918/1919 (the Spanish flu) with its associated encephalitis lethargica, there is little information on long‐term neurological sequelae. COVID‐19 is the first pandemic that has occurred in a setting of an aging population, especially in several high‐income countries. Its survivors are at the greatest risk for developing neurodegenerative conditions as they age, rendering the current pandemic a unique paradigm not previously witnessed. The SARS‐CoV‐2 virus, among the largest of the RNA viruses, is a single‐stranded RNA that encodes for 29 proteins that include the spike protein that contains the key domains required for ACE2 binding, and a complex array of nonstructural proteins (NSPs) and accessory proteins that ensure the escape of the virus from the innate immune response, allowing for its efficient replication, translation, and exocytosis as a fully functional virion. Increasingly, these proteins are also recognized as potentially contributing to biochemical and molecular processes underlying neurodegeneration. In addition to directly being taken up by brain endothelium, the virus or key protein constituents can be transported to neurons, astrocytes, and microglia by extracellular vesicles and can accelerate pathological fibril formation. The SARS‐CoV‐2 nucleocapsid protein is intrinsically disordered and can participate in liquid condensate formation, including as pathological heteropolymers with neurodegenerative disease‐associated RNA‐binding proteins such as TDP‐43, FUS, and hnRNP1A. As the SARS‐CoV‐2 virus continues to mutate under the immune pressure exerted by highly efficacious vaccines, it is evolving into a virus with greater transmissibility but less severity compared with the original strain. The potential of its lingering impact on the nervous system thus has the potential to represent an ongoing legacy of an even greater global health challenge than acute infection.
The consequences of nervous system exposure by the SARS‐CoV‐2 virus in an aging population are discussed, including the potential acceleration or advancement of neurodegenerative processes. Pathophysiological mechanisms include the ongoing manifestations of acute immune‐mediated inflammation but also chronic immune dysregulation. While there is little evidence to suggest viral replication in the central nervous system, the presence of the ACE2 receptor and coreceptors such as Neuropilin‐1 suggest the ability for uptake. The evidence that the exosomal transport of components of the viral protein, and in particular, of the intrinsically disordered nucleocapsid protein, can lead to neuronal protein expression is discussed. Created with BioRender.com
IR spectroscopy is an excellent method for biological analyses. It enables the nonperturbative, label-free extraction of biochemical information and images toward diagnosis and the assessment of cell ...functionality. Although not strictly microscopy in the conventional sense, it allows the construction of images of tissue or cell architecture by the passing of spectral data through a variety of computational algorithms. Because such images are constructed from fingerprint spectra, the notion is that they can be an objective reflection of the underlying health status of the analyzed sample. One of the major difficulties in the field has been determining a consensus on spectral pre-processing and data analysis. This manuscript brings together as coauthors some of the leaders in this field to allow the standardization of methods and procedures for adapting a multistage approach to a methodology that can be applied to a variety of cell biological questions or used within a clinical setting for disease screening or diagnosis. We describe a protocol for collecting IR spectra and images from biological samples (e.g., fixed cytology and tissue sections, live cells or biofluids) that assesses the instrumental options available, appropriate sample preparation, different sampling modes as well as important advances in spectral data acquisition. After acquisition, data processing consists of a sequence of steps including quality control, spectral pre-processing, feature extraction and classification of the supervised or unsupervised type. A typical experiment can be completed and analyzed within hours. Example results are presented on the use of IR spectra combined with multivariate data processing.
The fundamental origin of amyotrophic lateral sclerosis (ALS) has remained an enigma since its earliest description as a relentlessly progressive degeneration with prominent neuromuscular ...manifestations that are associated with upper and lower motor neuron dysfunction. Although this remains the hallmark of ALS, a significant proportion of patients will also demonstrate one or more features of frontotemporal dysfunction, including a frontotemporal dementia (FTD). Understanding whether these 2 seemingly disparate syndromes are simply reflective of the co-occurrence of 2 distinct pathologic processes or the clinical manifestations of a common pathophysiologic derangement involving the brain more widely has gripped contemporary ALS researchers. Supporting a commonality of causation, both ALS and FTD show an alteration in the metabolism of TAR DNA-binding protein 43, marked by a shift in nucleocytoplasmic localization alongside a broad range of neuronal cytoplasmic inclusions consisting of pathologic aggregates of RNA-binding proteins. Similarly, several disease-associated or disease-modifying genetic variants that are shared between the 2 disorders suggest shared underlying mechanisms. In both, a prominent glial response has been postulated to contribute to non-cell-autonomous spread. A more contemporary hypothesis, however, suggests that syndromes of cortical and subcortical dysfunction are driven by impairments in discrete neural networks. This postulates that such networks, including networks subserving motor or cognitive function, possess unique and selective vulnerabilities to either single molecular toxicities or combinations thereof. The co-occurrence of one or more network dysfunctions in ALS and FTD is thus a reflection not of unique neuroanatomic correlates but rather of shared molecular vulnerabilities. The basis of such shared vulnerabilities becomes the fulcrum around which the next advances in our understanding of ALS and its possible therapy will develop.
This article presents the revised consensus criteria for the diagnosis of frontotemporal dysfunction in amyotrophic lateral sclerosis (ALS) based on an international research workshop on ...frontotemporal dementia (FTD) and ALS held in London, Canada in June 2015. Since the publication of the Strong criteria, there have been considerable advances in the understanding of the neuropsychological profile of patients with ALS. Not only is the breadth and depth of neuropsychological findings broader than previously recognised -
- including deficits in social cognition and language - but mixed deficits may also occur. Evidence now shows that the neuropsychological deficits in ALS are extremely heterogeneous, affecting over 50% of persons with ALS. When present, these deficits significantly and adversely impact patient survival. It is the recognition of this clinical heterogeneity in association with neuroimaging, genetic and neuropathological advances that has led to the current re-conceptualisation that neuropsychological deficits in ALS fall along a spectrum. These revised consensus criteria expand upon those of 2009 and embrace the concept of the frontotemporal spectrum disorder of ALS (ALS-FTSD).
Epstein-Barr virus (EBV) is associated with roughly 10% of gastric carcinomas worldwide (EBVaGC). Although previous investigations provide a strong link between EBV and gastric carcinomas, these ...studies were performed using selected EBV gene probes. Using a cohort of gastric carcinoma RNA-seq data sets from The Cancer Genome Atlas (TCGA), we performed a quantitative and global assessment of EBV gene expression in gastric carcinomas and assessed EBV associated cellular pathway alterations. EBV transcripts were detected in 17% of samples but these samples varied significantly in EBV coverage depth. In four samples with the highest EBV coverage (hiEBVaGC - high EBV associated gastric carcinoma), transcripts from the BamHI A region comprised the majority of EBV reads. Expression of LMP2, and to a lesser extent, LMP1 were also observed as was evidence of abortive lytic replication. Analysis of cellular gene expression indicated significant immune cell infiltration and a predominant IFNG response in samples expressing high levels of EBV transcripts relative to samples expressing low or no EBV transcripts. Despite the apparent immune cell infiltration, high levels of the cytotoxic T-cell (CTL) and natural killer (NK) cell inhibitor, IDO1, was observed in the hiEBVaGCs samples suggesting an active tolerance inducing pathway in this subgroup. These results were confirmed in a separate cohort of 21 Vietnamese gastric carcinoma samples using qRT-PCR and on tissue samples using in situ hybridization and immunohistochemistry. Lastly, a panel of tumor suppressors and candidate oncogenes were expressed at lower levels in hiEBVaGC versus EBV-low and EBV-negative gastric cancers suggesting the direct regulation of tumor pathways by EBV.
The high level of accuracy and sensitivity of next generation sequencing for quantifying genetic material across organismal boundaries gives it tremendous potential for pathogen discovery and ...diagnosis in human disease. Despite this promise, substantial bacterial contamination is routinely found in existing human-derived RNA-seq datasets that likely arises from environmental sources. This raises the need for stringent sequencing and analysis protocols for studies investigating sequence-based microbial signatures in clinical samples.
The current review will examine the contemporary evidence that amyotrophic lateral sclerosis (ALS) is a syndrome in which the unifying feature is a progressive loss of upper and lower motor neuron ...function.
Although ALS is traditionally viewed as a neurodegenerative disorder affecting the motor neurons, there is considerable phenotypic heterogeneity and widespread involvement of the central nervous system. A broad range of both causative and disease modifying genetic variants are associated with both sporadic and familial forms of ALS. A significant proportion of ALS patients have an associated frontotemporal dysfunction which can be a harbinger of a significantly shorter survival and for which there is increasing evidence of a fundamental disruption of tau metabolism in those affected individuals. Although the traditional neuropathology of the degenerating motor neurons in ALS is that of neuronal cytoplasmic inclusions composed neuronal intermediate filaments, the presence of neuronal cytoplasmic inclusions composed of RNA binding proteins suggests a key role for RNA dysmetabolism in the pathogenesis of ALS.
ALS is a complex multisystem neurodegenerative syndrome with marked heterogeneity at not only the level of clinical expression, but also etiologically.
Abstract In this review, the role of aberrant RNA metabolism in ALS is examined, including the evidence that a majority of the genetic mutations observed in familial ALS (including mutations in ...TDP-43, FUS/TLS, SOD1, angiogenin (ANG) and senataxin (SETX)) can impact directly on either gene transcription, pre-mRNA splicing, ribonucleoprotein complex formation, transport, RNA translation or degradation. The evidence that perturbed expression or function of RNA binding proteins is causally related to the selective suppression of the low molecular weight subunit protein (NFL) steady state mRNA levels in degenerating motor neurons in ALS is examined. The discovery that mtSOD1, TDP-43 and 14-3-3 proteins, all of which form cytosolic aggregates in ALS, can each modulate the stability of NFL mRNA, suggests that a fundamental alteration in the interaction of mRNA species with key trans -acting binding factors has occurred in ALS. These observations lead directly to the hypothesis that ALS can be viewed as a disorder of RNA metabolism, thus providing a novel pathway for the development of molecular pharmacotherapies.
The gap between the tremendous burden of neurological disease requiring surgical management and the limited capacity for neurosurgical care has fueled the growth of the global neurosurgical movement. ...It is estimated that an additional 23 300 neurosurgeons are needed to meet the burden posed by essential cases across the globe. Initiatives to increase neurosurgical capacity through systems strengthening and workforce development are key elements in correcting this deficit. Building on the growing interest in global health among neurosurgical trainees, we propose the integration of targeted public health education into neurosurgical training, in both high-income countries and low- and middle-income countries. This effort will ensure that graduates possess the fundamental skillsets and experience necessary to participate in and lead capacity-building efforts in the developing countries. This additional public health training can also help neurosurgical residents to achieve the core competencies outlined by accreditation boards, such as the Accreditation Committee on Graduate Medical Education in the United States. In this narrative review, we describe the global burden of neurosurgical disease, establish the need and role for the global neurosurgeon, and discuss pathways for implementing targeted global public health education in the field of neurosurgery.
Randomized trials support the use of transcatheter aortic valve replacement (TAVR) for the treatment of aortic stenosis in high- and intermediate-risk patients, but the generalizability of those ...results in clinical practice has been challenged.
The aim of this study was to determine the safety and effectiveness of TAVR versus surgical aortic valve replacement (SAVR), particularly in intermediate- and high-risk patients, in a nationally representative real-world cohort.
Using data from the Transcatheter Valve Therapy Registry and Society of Thoracic Surgeons National Database linked to Medicare administrative claims for follow-up, 9,464 propensity-matched intermediate- and high-risk (Society of Thoracic Surgeons Predicted Risk of Mortality score ≥3%) U.S. patients who underwent commercial TAVR or SAVR were examined. Death, stroke, and days alive and out of the hospital to 1 year were compared, as well as discharge home, with subgroup analyses by surgical risk, demographics, and comorbidities.
In a propensity-matched cohort (median age 82 years, 48% women, median Society of Thoracic Surgeons Predicted Risk of Mortality score 5.6%), TAVR and SAVR patients experienced no difference in 1-year rates of death (17.3% vs. 17.9%; hazard ratio: 0.93; 95% confidence interval CI: 0.83 to 1.04) and stroke (4.2% vs. 3.3%; hazard ratio: 1.18; 95% CI: 0.95 to 1.47), and no difference was observed in the proportion of days alive and out of the hospital to 1 year (rate ratio: 1.00; 95% CI: 0.98 to 1.02). However, TAVR patients were more likely to be discharged home after treatment (69.9% vs. 41.2%; odds ratio: 3.19; 95% CI: 2.84 to 3.58). Results were consistent across most subgroups, including among intermediate- and high-risk patients.
Among unselected intermediate- and high-risk patients, TAVR and SAVR resulted in similar rates of death, stroke, and DAOH to 1 year, but TAVR patients were more likely to be discharged home.
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