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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. While 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 two seemingly disparate syndromes are simply reflective of the co-occurrence of two distinct pathological processes or the clinical manifestations of a common pathophysiological 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 (TDP-43), marked by a shift in nucleocytoplasmic localization alongside a broad range of neuronal cytoplasmic inclusions consisting of pathological aggregates of RNA binding proteins. Similarly, several disease-associated or disease-modifying genetic mutations that are shared between the two disorders suggests 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 in 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.

OBJECTIVE In the era of modern medicine with an armamentarium full of state-of-the art technologies at our disposal, the incidence of wrong-level spinal surgery remains problematic. In particular, the thoracic spine presents a challenge for accurate localization due partly to body habitus, anatomical variations, and radiographic artifact from the ribs and scapula. The present review aims to assess and describe thoracic spine localization techniques. METHODS The authors performed a literature search using the PubMed database from 1990 to 2020, compliant with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). A total of 27 articles were included in this qualitative review. RESULTS A number of pre- and intraoperative strategies have been devised and employed to facilitate correct-level localization. Some of the more well-described approaches include fiducial metallic markers (screw or gold), metallic coils, polymethylmethacrylate, methylene blue, marking wire, use of intraoperative neuronavigation, intraoperative localization techniques (including using a needle, temperature probe, fluoroscopy, MRI, and ultrasonography), and skin marking. CONCLUSIONS While a number of techniques exist to accurately localize lesions in the thoracic spine, each has its advantages and disadvantages. Ultimately, the localization technique deployed by the spine surgeon will be patient-specific but often based on surgeon preference.

Understanding synergies between neurodegenerative and cerebrovascular pathologies that modify dementia presentation represents an important knowledge gap.This multi-site, longitudinal, observational cohort study recruited participants across prevalent neurodegenerative diseases and cerebrovascular disease and assessed participants comprehensively across modalities. We describe univariate and multivariate baseline features of the cohort and summarize recruitment, data collection, and curation processes.We enrolled 520 participants across five neurodegenerative and cerebrovascular diseases. Median age was 69 years, median Montreal Cognitive Assessment score was 25, median independence in activities of daily living was 100% for basic and 93% for instrumental activities. Spousal study partners predominated; participants were often male, White, and more educated. Milder disease stages predominated, yet cohorts reflect clinical presentation.Data will be shared with the global scientific community. Within-disease and disease-agnostic approaches are expected to identify markers of severity, progression, and therapy targets. Sampling characteristics also provide guidance for future study design.

Rationale Mycobacterium abscessus is a significant threat to individuals with cystic fibrosis (CF) due to innate drug resistance and potential transmission between patients. Recent studies describe...

Introduction The COVID‐19 pandemic has presented a major challenge to mental health and emotional wellbeing. The present study examined whether training in emotional intelligence (EI) skills, provided before the pandemic, would serve as a protective factor for sustaining mental health during the COVID‐19 crisis. Methods Data came from a longitudinal study (N = 89) that was initially designed to test the effectiveness of an EI training program versus a non‐emotion‐focused placebo program. The design and timing of the study were such that baseline and posttraining assessments of depression and anxiety had been completed before the pandemic, and planned 6‐month follow‐ups were serendipitously scheduled to occur after the onset of the COVID‐19 crisis. This provided us with an unexpected real‐world opportunity to investigate whether EI training would bolster emotional resilience to the challenges posed by the COVID‐19 pandemic. Results Although mental health concerns generally increased after the start of the pandemic, individuals who completed the EI training program scored lower on depression, suicidal ideation, and state anxiety relative to individuals who had been assigned to the placebo training program. Conclusion Online EI training appears to be effective at sustaining critical aspects of mental health during a subsequent real‐life crisis.

Rationale Nontuberculous mycobacteria (NTM) are ubiquitous environmental bacteria that may cause chronic lung disease and are one of the most difficult-to-treat infections among persons with cystic fibrosis (pwCF). Environmental factors likely contribute to increased NTM densities, with higher potential for exposure and infection. Objective To identify water-quality constituents that influence odds of NTM infection among pwCF in Colorado. Methods We conducted a population-based nested case–control study using patient data from the Colorado CF Center NTM database. We associated data from pwCF and water-quality data extracted from the Water Quality Portal to estimate odds of NTM infection. Using Bayesian generalized linear models with binomial-distributed discrete responses, we modeled three separate outcomes; any NTM infection, infections due to Mycobacterium avium complex species, and infections due to M. abscessus group species. Results We observed a consistent association with molybdenum in the source water and M. abscessus group species infection among pwCF in all models. For every 1-unit increase in the log concentration of molybdenum in surface water, the odds of infection for those with M. abscessus group species compared to those who were NTM culture-negative increased by 79%. The odds of M. abscessus group infection varied by county; the counties with the highest probability of infection are located along the major rivers. Conclusions We have identified molybdenum in the source water as the most predictive factor of M. abscessus group infection among pwCF in Colorado. This finding will help inform patients at risk for NTM of their relative risks in residing within specific regions.

Recent studies have characterized a dominant clone (Clone 1) of Mycobacterium abscessus subspecies massiliense (M. massiliense) associated with high prevalence in cystic fibrosis (CF) patients, pulmonary outbreaks in the United States (US) and United Kingdom (UK), and a Brazilian epidemic of skin infections. The prevalence of Clone 1 in non-CF patients in the US and the relationship of sporadic US isolates to outbreak clones are not known. We surveyed a reference US Mycobacteria Laboratory and a US biorepository of CF-associated Mycobacteria isolates for Clone 1. We then compared genomic variation and antimicrobial resistance (AMR) mutations between sporadic non-CF, CF, and outbreak Clone 1 isolates. Among reference lab samples, 57/147 (39%) of patients with M. massiliense had Clone 1, including pulmonary and extrapulmonary infections, compared to 11/64 (17%) in the CF isolate biorepository. Core and pan genome analyses revealed that outbreak isolates had similar numbers of single nucleotide polymorphisms (SNPs) and accessory genes as sporadic US Clone 1 isolates. However, pulmonary outbreak isolates were more likely to have AMR mutations compared to sporadic isolates. Clone 1 isolates are present among non-CF and CF patients across the US, but additional studies will be needed to resolve potential routes of transmission and spread.

Spinal metastases are common in cancer. This preferential migration/growth in the spine is not fully understood. Dura has been shown to affect the surrounding microenvironment and promote cancer growth. Here, we investigate the role of dural cytokines in promoting the metastatic potential of prostate cancer (PCa) and the involvement of the CXCR2 signaling pathway. The role of dural conditioned media (DCM) in proliferation, migration and invasion of five PCa cell lines with various hormone sensitivities was assessed in the presence or absence of the CXCR2 inhibitor, SB225002. CXCR2 surface protein was examined by FACS. Cytokine levels were measured using a mouse cytokine array. We observed high levels of cytokines produced by dura and within the vertebral body bone marrow, namely CXCL1 and CXCL2, that act on the CXCR2 receptor. All prostate cell lines treated with DCM demonstrated significant increase in growth, migration and invasion regardless of androgen sensitivity, except PC3, which did not significantly increase in invasiveness. When treated with SB225002, the growth response to DCM by cells expressing the highest levels of CXCR2 as measured by FACS (LNCaP and 22Rv1) was blunted. The increase in migration was significantly decreased in all lines in the presence of SB225002. Interestingly, the invasion increase seen with DCM was unchanged when these cells were treated with the CXCR2 inhibitor, except PC3 did demonstrate a significant decrease in invasion. DCM enhances the metastatic potential of PCa with increased proliferation, migration and invasion. This phenomenon is partly mediated through the CXCR2 pathway.

OBJECTIVE Decompression with instrumented fusion is commonly employed for spinal metastatic disease. Arthrodesis is typically sought despite limited knowledge of fusion outcomes, high procedural morbidity, and poor prognosis. This study aimed to describe survival, fusion, and hardware failure after decompression and fusion for spinal metastatic disease. METHODS The authors retrospectively examined a prospectively collected, single-institution database of adult patients undergoing decompression and instrumented fusion for spinal metastases. Patients were followed clinically until death or loss to follow-up. Fusion was assessed using CT when performed for oncological surveillance at 6-month intervals through 24 months postoperatively. Estimated cumulative incidences for fusion and hardware failure accounted for the competing risk of death. Potential risk factors were analyzed with univariate Fine and Gray proportional subdistribution hazard models. RESULTS One hundred sixty-four patients were identified. The mean age ± SD was 62.2 ± 10.8 years, 61.6% of patients were male, 98.8% received allograft and/or autograft, and 89.6% received postoperative radiotherapy. The Kaplan-Meier estimate of median survival was 11.0 months (IQR 3.5–37.8 months). The estimated cumulative incidences of any fusion and of complete fusion were 28.8% (95% CI 21.3%–36.7%) and 8.2% (95% CI 4.1%–13.9%). Of patients surviving 6 and 12 months, complete fusion was observed in 12.5% and 16.1%, respectively. The estimated cumulative incidence of hardware failure was 4.2% (95% CI 1.5–9.3%). Increasing age predicted hardware failure (HR 1.2, p = 0.003). CONCLUSIONS Low rates of complete fusion and hardware failure were observed due to the high competing risk of death. Further prospective, case-control studies incorporating nonfusion instrumentation techniques may be warranted.

Mycobacterium abscessus, a multidrug-resistant nontuberculous mycobacterium, has emerged as a major pathogen affecting people with cystic fibrosis (CF). Although originally thought to be acquired independently from the environment, most individuals are infected with one of several dominant circulating clones (DCCs), indicating the presence of global transmission networks of M. abscessus. How and when these clones emerged and spread globally is unclear. Here, we use evolutionary analyses of isolates from individuals both with and without CF to reconstruct the population history, spatiotemporal spread and recent transmission networks of the DCCs. We demonstrate synchronous expansion of six unrelated DCCs in the 1960s, a period associated with major changes in CF care and survival. Each of these clones has spread globally as a result of rare intercontinental transmission events. We show that the DCCs, but not environmentally acquired isolates, exhibit a specific smoking-associated mutational signature and that current transmission networks include individuals both with and without CF. We therefore propose that the DCCs initially emerged in non-CF populations but were then amplified and spread through the CF community. While individuals with CF are probably the most permissive host, non-CF individuals continue to play a key role in transmission networks and may facilitate long-distance transmission., In this Article, the authors perform evolutionary analyses of M. abscessus clinical isolates and report the emergence of dominant circulating clones (DCCs) in non-cystic fibrosis (CF) individuals followed by amplification in the CF community.

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.

The ABO histo-blood group, the critical determinant of transfusion incompatibility, was the first genetic polymorphism discovered in humans. Remarkably, ABO antigens are also polymorphic in many other primates, with the same two amino acid changes responsible for A and B specificity in all species sequenced to date. Whether this recurrence of A and B antigens is the result of an ancient polymorphism maintained across species or due to numerous, more recent instances of convergent evolution has been debated for decades, with a current consensus in support of convergent evolution. We show instead that genetic variation data in humans and gibbons as well as in Old World monkeys are inconsistent with a model of convergent evolution and support the hypothesis of an ancient, multiallelic polymorphism of which some alleles are shared by descent among species. These results demonstrate that the A and B blood groups result from a trans-species polymorphism among distantly related species and has remained under balancing selection for tens of millions of years—to date, the only such example in hominoids and Old World monkeys outside of the major histocompatibility complex.

In contrast to other surgical fields, robotics is relatively new to spinal surgery. The initial focus for spinal robotics has been on accurate pedicle screw placement, which early studies have shown to be successful. Beyond pedicle screw placement, however, newer generation spinal robots have the capability of navigation, which can impact other aspects of a spinal procedure. In this study, pedicle screw placement with the recently introduced Excelsius GPS robot (Globus) was similarly found to be accurate in a cohort of patients undergoing both open and minimally invasive fusion. Potential applications of the spinal robot's navigation capability are demonstrated.

Despite the wide application of the magnetic resonance imaging (MRI) technique, there are no widely used standards on naming and describing MRI sequences. The absence of consistent naming conventions presents a major challenge in automating image processing since most MRI software require a priori knowledge of the type of the MRI sequences to be processed. This issue becomes increasingly critical with the current efforts toward open-sharing of MRI data in the neuroscience community. This manuscript reports an MRI sequence detection method using imaging metadata and a supervised machine learning technique. Three datasets from the Brain Center for Ontario Data Exploration (Brain-CODE) data platform, each involving MRI data from multiple research institutes, are used to build and test our model. The preliminary results show that a random forest model can be trained to accurately identify MRI sequence types, and to recognize MRI scans that do not belong to any of the known sequence types. Therefore the proposed approach can be used to automate processing of MRI data that involves a large number of variations in sequence names, and to help standardize sequence naming in ongoing data collections. This study highlights the potential of the machine learning approaches in helping manage health data.

With 2020 finally behind us, we can begin to think about how the historic events that took place will be understood in years to come. To do so, we asked young scientists this question: What new word or phrase would you add to the dictionary to help scientists explain the events of 2020 to future generations? Read a selection of the best responses below. Follow NextGen Voices on Twitter with hashtag #NextGenSci. Read previous NextGen Voices survey results at https://science.sciencemag.org/collection/nextgen-voices.

BACKGROUND Syringomyelia has a long-established association with pediatric scoliosis, but few data exist on the relationship of syringomyelia to pediatric kyphotic deformities. OBSERVATIONS This report reviewed a unique case of rapid and sustained regression of syringomyelia in a 13-year-old girl after surgical correction of iatrogenic kyphotic deformity. LESSONS In cases of syringomyelia associated with acquired spinal deformity, treatment of deformity to resolve an associated subarachnoid block should be considered because it may obviate the need for direct treatment of syrinx.

We asked young scientists to serve as peer mentors for “Seeking Career Clarity,” the author of the question below. By asking refl ective questions, sharing relevant personal experiences, and of ering advice, these scientists provide support and perspective. Follow NextGen Voices on Twitter with hashtag #NextGenSci.

One of the neuropathological hallmarks of the tauopathies is the formation of neuronal cytoplasmic inclusions and fibrils of microtubule-associated tau protein (tau). The phosphorylation of Thr175 of tau (pThr175 tau) appears to be sufficient for fibril formation in vitro and in vivo, but the mechanism by which this initiates fibril formation is unknown. Using transient transfections of tau mutants into HEK293T cells, we determined that the phosphorylation of Thr175 leads to exposure of the tau N-terminal phosphatase-activating domain (PAD). The exposed PAD is known to interact with protein phosphatase-1 (PP1) resulting in glycogen synthase kinase 3β (GSK3β) activation. In vivo, a single traumatic controlled cortical injury in rats also resulted in the phosphorylation of Thr175 and increased exposure of tau PAD followed by pathological tau fibril formation. Taken together, these data suggest that neurotoxicity may be precipitated by phosphorylation at Thr175 and subsequent tau PAD exposure, GSK3β activation and tau fibril formation. Cover Image for this issue: doi: 10.1111/jnc.14767.

A surgical heater-cooler unit has been implicated as the source for Mycobacterium chimaera infections among cardiac surgery patients in several countries. We isolated M. chimaera from heater-cooler units and patient infections in the United States. Whole-genome sequencing corroborated a risk for these units acting as a reservoir for this pathogen.

Background: The pineal gland, a small, pinecone-shaped organ deep within the brain, is responsible for producing melatonin. The gland consists of pineal parenchymal cells and glial cells that can form neoplasms. Pineal region neoplasms can also arise from germ cells and adjacent structures. This review focuses on detection of serum and cerebrospinal fluid (CSF) biomarkers of germ cell tumors and pineal parenchymal cell tumors, as these types comprise most neoplasms specific to the pineal region. Methods: For this review, we searched PubMed using the following keywords: biomarkers, germ cell tumor, germinoma, melatonin, pineal, pineal gland, pineal neoplasm, pinealoma, pineal parenchymal cell tumor, pineal region, and pineal tumor. We limited our search to full-text English articles and identified other relevant sources from the reference lists of identified articles. Results: Serum and CSF biomarker assays have a role in cases of suspected pineal germ cell or parenchymal neoplasms. Biomarkers including alpha-fetoprotein, beta-human chorionic gonadotropin, and placental alkaline phosphatase inform diagnosis and treatment and are important for monitoring germ cell tumor response to treatment. No biomarkers are currently available that inform diagnosis or treatment of pineal parenchymal tumors, although melatonin assays may have a role in monitoring response to treatment. Conclusion: Serum and CSF biomarkers in conjunction with clinical and radiographic evidence of a pineal region mass can inform the decision whether to undertake stereotactic biopsy or surgical excision or whether to proceed straight to medical treatment.

Retropleural, retrodiaphragmatic, and retroperitoneal approaches are utilized to access difficult thoracolumbar junction (T10–L2) pathology. The authors present a 58-year-old man with chronic low-back pain who failed years of conservative therapy. Preoperative radiographs demonstrated significant levoconvex scoliosis with coronal and sagittal imbalance. He underwent a retrodiaphragmatic/retroperitoneal approach for T12–L1, L1–2, L2–3, and L3–4 interbody release and fusion in conjunction with second-stage facet osteotomies, L4–5 TLIF, and T10–iliac posterior instrumented fusion. This video focuses on the retrodiaphragmatic approach assisted by 3D navigation. The video can be found here: https://stream.cadmore.media/r10.3171/2022.3.FOCVID2215

Background Viruses, including bacteriophages, are important components of environmental and human associated microbial communities. Viruses can act as extracellular reservoirs of bacterial genes, can mediate microbiome dynamics, and can influence the virulence of clinical pathogens. Various targeted metagenomic analysis techniques detect viral sequences, but these methods often exclude large and genome integrated viruses. In this study, we evaluate and compare the ability of nine state-of-the-art bioinformatic tools, including Vibrant, VirSorter, VirSorter2, VirFinder, DeepVirFinder, MetaPhinder, Kraken 2, Phybrid, and a BLAST search using identified proteins from the Earth Virome Pipeline to identify viral contiguous sequences (contigs) across simulated metagenomes with different read distributions, taxonomic compositions, and complexities. Results Of the tools tested in this study, VirSorter achieved the best F1 score while Vibrant had the highest average F1 score at predicting integrated prophages. Though less balanced in its precision and recall, Kraken2 had the highest average precision by a substantial margin. We introduced the machine learning tool, Phybrid, which demonstrated an improvement in average F1 score over tools such as MetaPhinder. The tool utilizes machine learning with both gene content and nucleotide features. The addition of nucleotide features improves the precision and recall compared to the gene content features alone.Viral identification by all tools was not impacted by underlying read distribution but did improve with contig length. Tool performance was inversely related to taxonomic complexity and varied by the phage host. For instance, Rhizobium and Enterococcus phages were identified consistently by the tools; whereas, Neisseria prophage sequences were commonly missed in this study. Conclusion This study benchmarked the performance of nine state-of-the-art bioinformatic tools to identify viral contigs across different simulation conditions. This study explored the ability of the tools to identify integrated prophage elements traditionally excluded from targeted sequencing approaches. Our comprehensive analysis of viral identification tools to assess their performance in a variety of situations provides valuable insights to viral researchers looking to mine viral elements from publicly available metagenomic data.