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Aims We set out to explore associations between a ‘mitral-specific’ cardiac damage score (m-CDS) and survival outcomes in mitral regurgitation (MR) and compare the performance of the m-CDS and an ‘aortic-specific’ CDS (a-CDS) in patients with MR within the large National Echo Database of Australia.Methods Among 620 831 unique adults investigated with echocardiography, there were 17 658 individuals (3.1%) with moderate or greater functional MR (aged 76±13 years, 51% female) who met inclusion criteria. A randomly selected cohort of 5000 of these patients was used to test seven different CDS models for prediction of subsequent all-cause mortality during an average 3.8-year follow-up. The best-performing CDS model in the derivation cohort was then applied to a validation cohort of the remaining 12 658 individuals (aged 76±13 years, 51% female).Results The best-performing m-CDS model stratified the full cohort into Stage 0: control (1046 patients, 8%); Stage 1: left atrial damage (3416 patients, 27%); Stage 2: left ventricular damage (3352 patients, 26%); Stage 3: right ventricular damage (1551 patients, 12%) and Stage 4: pulmonary hypertension (3293 patients, 26%). Increasing m-CDS stage was consistently and incrementally associated with both all-cause and cardiovascular mortality at 1 year, 5 years and all-time and remained so after adjustment for increasing age and severity of MR, with a ~35% increase in mortality for each increase in CDS stage (p

Background: Understanding venous congestion is critical to the management of many illnesses, but assessing volume status can be challenging. The current gold standard for volume status assessment of right heart catheterization (RHC) is invasive, costly, and often unavailable. Venous Excess Ultrasound Score (VExUS) is a novel ultrasound protocol for to assessment of venous congestion using the inferior vena cava, hepatic, portal and renal veins. Though there is a much interest in the technique, the renal component of the exam is challenging to acquire. For this reason we aimed to see if a modified VExUS (mVExUS) excluding the kidney component performs similarly to traditional VExUS (tVExUS) for detecting elevated right atrial pressure (RAP) as measured by RHC., Methods: A consecutive cohort of 95 patients undergoing RHC had VExUS exams before the procedure. Researchers compared the performance of tVExUS, mVExUS, and inferior vena cava (IVC) diameter in predicting RAP > 12 mmHg., Results: The area under the curve (AUC) for detecting elevated RAP was similar for tVExUS (0.87) and mVExUS (0.85). Both methods achieved high sensitivity and specificity. Agreement between tVExUS and mVExUS scores was near-perfect (Cohen's Kappa = 0.85)., Conclusion: mVExUS may be as effective as tVExUS in identifying elevated RAP. This abbreviated version could improve efficiency and adoption of VExUS for assessing venous congestion. Further studies are needed in diverse patient populations., Competing Interests: Declarations. Ethics approval and consent to participate: This study had the approval of the local Institutional Review Board (COMIRB # 22-2024). All study participants provided informed consent for study procedures. Consent for publication: All study participants provided informed consent for publication. Competing interests: Authors have no conflicts of interest or competing interests to disclose., (© 2025. The Author(s).)

In healthy adults different language abilities-sentence processing versus emotional prosody-are supported by the left (LH) versus the right hemisphere (RH), respectively. However, after LH stroke in infancy, RH regions often support both abilities with normal outcomes. This finding raises an important question: How does the functional map of RH regions change to support both emotional prosody and also typically left-lateralized language functions after an early LH stroke? Does sentence processing simply become reflected into RH frontotemporal regions and overlap with emotional prosody processing? Or do these functions overlap less than would be expected with simple mirroring? In the current work we used task fMRI to examine precisely how sentence processing and emotional prosody processing are both organized in the intact RH of individuals who suffered a large LH perinatal arterial ischemic stroke (LHPS participants). We evaluated the activation of two fMRI tasks that probed auditory sentence processing and emotional prosody processing, comparing the overlap for these two functions in the RH of individuals with perinatal stroke with the symmetry of these functions in the LH and RH of their healthy siblings. We found less activation overlap in the RH of individuals with LH perinatal stroke than would be expected if both functions retained their typical spatial layout, suggesting that their spatial segregation may be an important feature of a functioning language system., Competing Interests: Declarations Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Competing Interests: Dr Yip reports compensation from AstraZeneca, Roche, Servier Pharmaceuticals LLC, Janssen Biotech, Bayer, Amgen, and Novartis for consultant services. The other authors report no conflicts.

Background:  Epilepsy surgery is recognized for its effectiveness in controlling seizures in a significant number of patients with drug-resistant epilepsy. Despite this, there remains a notable deficiency in referring these patients for video-electroencephalogram (EEG) monitoring and surgical evaluation. Addressing this gap, the Canadian Appropriateness of Epilepsy Surgery (CASES), an online tool for epilepsy surgery evaluation (www.epilepsycases.com), was developed to aid physicians in the referral process of patients with refractory epilepsy to surgical assessments., Objective:  The present study aimed to evaluate the utility of CASES in identifying candidates for epilepsy surgery, thereby facilitating clinical decision-making for patients with drug-resistant epilepsy., Methods:  A cross-sectional analysis was conducted using the CASES platform to assess surgical candidacy among individuals with epilepsy. Participants were selected among those receiving care at the Epilepsy Clinic of the Neurology Service, Hospital de Clínicas de Porto Alegre, Brazil, over a 3-month period. The study cohort included 211 patients. Data were systematically extracted from patient medical records or collected during clinical appointments., Results:  Of the evaluated cohort, 59.6% were identified as potential candidates for video-EEG monitoring and subsequent surgical evaluation. Factors significantly associated with recommendations for video-EEG and surgical assessment included seizure frequency, the number of antiseizure medications (ASMs) trialed, and the occurrence of drug-related adverse effects., Conclusion:  The CASES showed significant potential in guiding recommendations for video-EEG monitoring and facilitating referrals for epilepsy surgery. This tool may not only enhance patient treatments and outcomes but also contribute to cost savings in epilepsy management in both the short and long term., Competing Interests: The authors have no conflict of interest to declare., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution 4.0 International License, permitting copying and reproduction so long as the original work is given appropriate credit (https://creativecommons.org/licenses/by/4.0/).)

Background and Objectives: Despite general acceptance that corticosteroid therapy (CST) should be withheld before biopsy for suspected primary central nervous system lymphoma (PCNSL), there remains conflicting evidence surrounding the precise impact of preoperative CST on the histopathological diagnosis. The objective of this systematic review and meta-analysis was to describe and quantify the effects of preoperative CST on the diagnostic accuracy of biopsies for PCNSL., Methods: Primary articles were screened from Ovid MEDLINE, Embase, Web of Science, and Scopus databases. Meta-analysis was performed for immunocompetent patients with histologically confirmed PCNSL. Subgroup and regression analyses were performed to assess the effects of biopsy type, CST duration, dose, and preoperative taper on the diagnostic accuracy. In addition, the sensitivity of cerebrospinal fluid (CSF) analyses for PCNSL was assessed., Results: Nineteen studies, comprising 1226 patients (45% female; mean age: 60.3 years), were included. Preoperative CST increased the risk of nondiagnostic biopsy with a relative risk (RR) of 2.1 (95% CI: 1.1-4.1). In the stereotactic biopsy subgroup, the RR for nondiagnostic biopsy was 3.0 (95% CI: 1.2-7.5). CST taper, duration, and dose did not significantly influence diagnostic biopsy rates. The sensitivity of CSF cytology, including flow cytometry, for PCNSL was 8.0% (95% CI: 6.0%-10.7%)., Conclusion: Our results suggest that preoperative CST reduces the diagnostic yield of stereotactic biopsies for PCNSL. We found no evidence that tapering CST before biopsy improves diagnostic rates. CSF analysis currently has a poor sensitivity for the diagnosis of PCNSL., (Copyright © Congress of Neurological Surgeons 2024. All rights reserved.)

Vulvovaginal melanoma (VVM) is a rare but deadly disease, accounting for 5% of all vulvar malignancies, with a 5-yr survival rate of only 47% for all stages of the disease. VVM is a distinct subset of melanoma, with a unique genomic profile and underlying pathogenesis unassociated with sun exposure. Distinguishing these rare malignancies from very common pigmented lesions of the vulva and vagina is challenging as histologic features often overlap between entities. PReferentially expressed Antigen in MElanoma (PRAME) is a melanoma-associated protein, and immunohistochemistry (IHC) for PRAME distinguishes cutaneous, oral mucosal, and retinal melanoma from atypical nevi. Given the biological differences between VVM and cutaneous melanoma, the utility of PRAME IHC for the diagnosis of VVM is unknown. We accrued a cohort of 20 VVM and 21 benign vulvar melanocytic nevi. We found that nuclear PRAME IHC staining with 4+ intensity was present in 85% of the VVM and 0% of the nevi. With the assistance of PRAME IHC, we found evidence of close or positive margin involvement in 3 of 10 cases where margins were originally diagnosed as negative for melanoma in situ. Our study is the first to assess PRAME IHC in a cohort of VVM cases and provides confidence for using PRAME IHC to assist with diagnosis and margin assessment in this rare disease., Competing Interests: The authors declare no conflict of interest., (Copyright © 2023 by the International Society of Gynecological Pathologists.)

Though the novel venous excess ultrasound (VExUS) score is increasingly used as a noninvasive means of venous congestion measurement, the inter-rater reliability (IRR), inter-user reproducibility (IUR), and utility of concurrent ECG have not been evaluated. We conducted a multicenter study of the IRR, IUR, and utility of ECG for VExUS interpretation between four attending physicians of diverse specialties, reporting the Kappa statistic (KS) and Intraclass Correlation Coefficient (ICC) for IRR and IUR for scans with and without ECG. Eighty-four paired VExUS exams from 42 patients, 60 of which had a concurrent ECG tracing, were interpreted. They showed substantial IRR, with a KS of 0.71 and ICC of 0.83 for the overall VExUS grade (p < 0.001), and IUR, with a KS 0.63 and ICC of 0.8. There was greater agreement among images with an ECG tracing. These results suggest that ECG-augmented VExUS may be a reliable and reproducible measure interpretable by clinicians with diverse backgrounds., (© 2024. The Author(s).)

Purpose of Review: Venous pressure is an often-unrecognized cause of patient morbidity. However, bedside assessment of PV is challenging. We review the clinical significance of venous pressure measurement, existing techniques, and introduce the Venous Excess Ultrasound (VExUS) Score as a novel approach using doppler ultrasound to assess venous pressure., Recent Findings: Studies show clear associations between elevated venous pressure and adverse outcomes in critically ill patients. Current venous pressure measurement techniques include physical examination, right heart catheterization (RHC), two-dimensional ultrasound, and a variety of labor-intensive research-focused physiological maneuvers. Each of these techniques have specific shortcomings, limiting their clinical utility. To address these gaps, Beaubien-Souligny et al. introduced the VExUS Score, a novel doppler ultrasound-based method that integrates IVC diameter with doppler measurements of the hepatic, portal, and renal veins to generate a venous congestion assesment. Studies show strong correlations between VExUS score and RHC measurements, and well as an association between VExUS score and improvement in cardiorenal acute kidney injury, diuretic response, and fluid status shifts. However, studies in noncardiac populations have been small, heterogenous, and inconclusive., Summary: Early studies evaluating the use of doppler ultrasound to assess venous congestion show promise, but further research is needed in diverse patient populations and clinical settings., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

In the past few decades, neuropathology has experienced several paradigm shifts with the introduction of new technologies. Deep learning, a rapidly progressing subfield of machine learning, seems to be the next innovation to alter the diagnostic workflow. In this review, we will explore the recent changes in the field of neuropathology and how this has led to an increased focus on molecular features in diagnosis and prognosis. Then, we will examine the work carried out to train deep learning models for various diagnostic tasks in neuropathology, as well as the machine learning frameworks they used. Focus will be given to both the challenges and successes highlighted therein, as well as what these trends may tell us about future roadblocks in the widespread adoption of this new technology. Finally, we will touch on recent trends in deep learning, as applied to digital pathology more generally, and what this may tell us about the future of deep learning applications in neuropathology.

After initial bilateral acoustic processing of the speech signal, much of the subsequent language processing is left-lateralized. The reason for this lateralization remains an open question. Prevailing hypotheses describe a left hemisphere (LH) advantage for rapidly unfolding information-such as the segmental (e.g., phonetic and phonemic) components of speech. Here we investigated whether and where damage to the LH predicted impaired performance on judging the directionality of frequency modulated (FM) sweep stimuli that changed within short (25ms) or longer (250ms) temporal windows. Performance was significantly lower for stroke survivors (n = 50; 18 female) than controls (n = 61; 34 female) on FM Sweeps judgments, particularly on the short sweeps. Support vector regression lesion-symptom mapping (SVR-LSM) revealed that part of the left planum temporale (PT) was related to worse performance on judging the short FM sweeps, controlling for performance on the long sweeps. We then investigated whether damage to this particular area related to diminished performance on two levels of linguistic processing that theoretically depend on rapid auditory processing: stop consonant identification and pseudoword repetition. We separated stroke participants into subgroups based on whether their LH lesion included the part of the left PT that related to diminished short sweeps judgments. Participants with PT lesions (PT lesion+, n = 24) performed significantly worse than those without (PT lesion-, n = 26) on stop consonant identification and pseudoword repetition, controlling for lesion size and hearing ability. Interestingly, PT lesions impacted pseudoword repetition more than real word repetition (PT lesion-by-repetition trial type interaction), which is of interest because pseudowords rely solely on sound perception and sequencing, whereas words can also rely on lexical-semantic knowledge. We conclude that the left PT is a critical region for processing auditory information in short temporal windows, and it may also be an essential transfer point in auditory-to-linguistic processing., Competing Interests: Conflict of Interest Statement: The authors declare no competing financial interests.

Aging-related memory impairment and pathological memory disorders such as Alzheimer's disease differ between males and females, and yet little is known about how aging-related changes in the transcriptome and chromatin environment differ between sexes in the hippocampus. To investigate this question, we compared the chromatin accessibility landscape and gene expression/alternative splicing pattern of young adult and aged mouse hippocampus in both males and females using ATAC-seq and RNA-seq. We detected significant aging-dependent changes in the expression of genes involved in immune response and synaptic function and aging-dependent changes in the alternative splicing of myelin sheath genes. We found significant sex-bias in the expression and alternative splicing of hundreds of genes, including aging-dependent female-biased expression of myelin sheath genes and aging-dependent male-biased expression of genes involved in synaptic function. Aging was associated with increased chromatin accessibility in both male and female hippocampus, especially in repetitive elements, and with an increase in LINE-1 transcription. We detected significant sex-bias in chromatin accessibility in both autosomes and the X chromosome, with male-biased accessibility enriched at promoters and CpG-rich regions. Sex differences in gene expression and chromatin accessibility were amplified with aging, findings that may shed light on sex differences in aging-related and pathological memory loss., Competing Interests: DB has equity and serves on the board of directors for Panorama Medicine. GC is currently employed by Regeneron Pharmaceuticals. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Achiro, Tao, Gao, Lin, Watanabe, Neumann, Coppola, Black and Martin.)

Background: The World Health Organization 2021 classification introduces molecular grading criteria for anaplastic meningiomas, including TERT promoter ( TERTp ) mutations and CDKN2A/B homozygous deletion. Additional adverse prognostic factors include H3K27me3 and BAP1 loss. The aim of this study was to explore whether these molecular alterations stratified clinical outcomes in a single-center cohort of grade 3 meningiomas. Additionally, we examined whether p16 and MTAP immunohistochemistry can predict CDKN2A/B status., Methods: Clinical and histopathological information was obtained from the electronic medical records of grade 3 meningiomas resected at a tertiary center between 2007 and 2020. Molecular testing for TERTp mutations and CDKN2A/B copy-number status, methylation profiling, and immunohistochemistry for H3K27me3, BAP1, p16, and methylthioadenosine phosphorylase (MTAP) were performed. Predictors of survival were identified by Cox regression., Results: Eight of 15 cases demonstrated elevated mitotic index (≥20 mitoses per 10 consecutive high-power fields), 1 tumor exhibited BAP1 loss, 4 harbored TERTp mutations, and 3 demonstrated CDKN2A/B homozygous deletion. Meningiomas with TERTp mutations and/or CDKN2A/B homozygous deletion showed significantly reduced survival compared to anaplastic meningiomas with elevated mitotic index alone. Immunohistochemical loss of p16 and MTAP demonstrated high sensitivity (67% and 100%, respectively) and specificity (100% and 100%, respectively) for predicting CDKN2A/B status., Conclusions: Molecular alterations of grade 3 meningiomas stratify clinical outcomes more so than histologic features alone. Immunohistochemical loss of p16 and MTAP show promise in predicting CDKN2A/B status., Competing Interests: S.Y. is a member of advisory boards of Amgen, AstraZeneca, Bayer, Janssen, Pfizer, Roche, and Servier. G.Z. is the Editor-in-Chief of Neuro-Oncology Advances. The other authors have no conflicts to report., (© The Author(s) 2024. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

When brain regions that are critical for a cognitive function in adulthood are irreversibly damaged at birth, what patterns of plasticity support the successful development of that function in an alternative location? Here we investigate the consistency of language organization in the right hemisphere (RH) after a left hemisphere (LH) perinatal stroke. We analyzed fMRI data collected during an auditory sentence comprehension task on 14 people with large cortical LH perinatal arterial ischemic strokes (left hemisphere perinatal stroke (LHPS) participants) and 11 healthy sibling controls using a "top voxel" approach that allowed us to compare the same number of active voxels across each participant and in each hemisphere for controls. We found (1) LHPS participants consistently recruited the same RH areas that were a mirror-image of typical LH areas, and (2) the RH areas recruited in LHPS participants aligned better with the strongly activated LH areas of the typically developed brains of control participants (when flipped images were compared) than the weakly activated RH areas. Our findings suggest that the successful development of language processing in the RH after a LH perinatal stroke may in part depend on recruiting an arrangement of frontotemporal areas reflective of the typical dominant LH., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

Neural activity is modulated over different timescales encompassing subseconds to hours, reflecting changes in external environment, internal state and behavior. Using Drosophila as a model, we developed a rapid and bidirectional reporter that provides a cellular readout of recent neural activity. This reporter uses nuclear versus cytoplasmic distribution of CREB-regulated transcriptional co-activator (CRTC). Subcellular distribution of GFP-tagged CRTC (CRTC::GFP) bidirectionally changes on the order of minutes and reflects both increases and decreases in neural activity. We established an automated machine-learning-based routine for efficient quantification of reporter signal. Using this reporter, we demonstrate mating-evoked activation and inactivation of modulatory neurons. We further investigated the functional role of the master courtship regulator gene fruitless (fru) and show that fru is necessary to ensure activation of male arousal neurons by female cues. Together, our results establish CRTC::GFP as a bidirectional reporter of recent neural activity suitable for examining neural correlates in behavioral contexts., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Diffuse gliomas are the most common type of primary central nervous system (CNS) neoplasm to affect the adult population. The diagnosis of adult diffuse gliomas is dependent upon the integration of morphological features of the tumour with its underlying molecular alterations, and the integrative diagnosis has become of increased importance in the fifth edition of the WHO classification of CNS neoplasms (WHO CNS5). The three major diagnostic entities of adult diffuse gliomas are as follows: (1) astrocytoma, IDH-mutant; (2) oligodendroglioma, IDH-mutant and 1p/19q-codeleted; and (3) glioblastoma, IDH-wildtype. The aim of this review is to summarize the pathophysiology, pathology, molecular characteristics, and major diagnostic updates encountered in WHO CNS5 of adult diffuse gliomas. Finally, the application of implementing the necessary molecular tests for diagnostic workup of these entities in the pathology laboratory setting is discussed.

During the last ice age, the Laurentide Ice Sheet exhibited extreme iceberg discharge events that are recorded in North Atlantic sediments 1 . These Heinrich events have far-reaching climate impacts, including widespread disruptions to hydrological and biogeochemical cycles 2-4 . They occurred during Heinrich stadials-cold periods with strongly weakened Atlantic overturning circulation 5-7 . Heinrich-type variability is not distinctive in Greenland water isotope ratios, a well-dated site temperature proxy 8 , complicating efforts to assess their regional climate impact and phasing against Antarctic climate change. Here we show that Heinrich events have no detectable temperature impact on Greenland and cooling occurs at the onset of several Heinrich stadials, and that both types of Heinrich variability have a distinct imprint on Antarctic climate. Antarctic ice cores show accelerated warming that is synchronous with increases in methane during Heinrich events, suggesting an atmospheric teleconnection 9 , despite the absence of a Greenland climate signal. Greenland ice-core nitrogen stable isotope ratios, a sensitive temperature proxy, indicate an abrupt cooling of about three degrees Celsius at the onset of Heinrich Stadial 1 (17.8 thousand years before present, where present is defined as 1950). Antarctic warming lags this cooling by 133 ± 93 years, consistent with an oceanic teleconnection. Paradoxically, proximal sites are less affected by Heinrich events than remote sites, suggesting spatially complex event dynamics., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: The Meningitis/Encephalitis FilmArray® Panel (ME panel) was approved by the U.S. Food and Drug Administration in 2015 and provides rapid results when assessing patients with suspected meningitis or encephalitis. These patients are evaluated by various subspecialties including pediatric hospital medicine (PHM), pediatric emergency medicine (PEM), pediatric infectious diseases, and pediatric intensive care unit (PICU) physicians. The objective of this study was to evaluate the current use of the ME panel and describe the provider and subspecialty practice variation., Methods: We conducted an online cross-sectional survey via the American Academy of Pediatrics Section of Hospital Medicine (AAP-SOHM) ListServe, Brown University PEM ListServe, and PICU Virtual pediatric system (VPS) Listserve., Results: A total of 335 participants out of an estimated 6998 ListServe subscribers responded to the survey. 68% reported currently using the ME panel at their institutions. Among test users, most reported not having institutional guidelines on test indications (75%) or interpretation (76%). 58% of providers self-reported lack of knowledge of the test's performance characteristics. Providers from institutions that have established guidelines reported higher knowledge compared to those that did not (51% vs. 38%; p = 0.01). More PHM providers reported awareness of ME panel performance characteristics compared to PEM physicians (48% vs. 27%; p = 0.004); confidence in test interpretation was similar between both groups (72 vs. 69%; p = 0.80)., Conclusion: Despite the widespread use of the ME panel, few providers report having institutional guidelines on test indications or interpretation. There is an opportunity to provide knowledge and guidance about the ME panel among various pediatric subspecialties., (© 2022. The Author(s).)

The mature human brain is lateralized for language, with the left hemisphere (LH) primarily responsible for sentence processing and the right hemisphere (RH) primarily responsible for processing suprasegmental aspects of language such as vocal emotion. However, it has long been hypothesized that in early life there is plasticity for language, allowing young children to acquire language in other cortical regions when LH areas are damaged. If true, what are the constraints on functional reorganization? Which areas of the brain can acquire language, and what happens to the functions these regions ordinarily perform? We address these questions by examining long-term outcomes in adolescents and young adults who, as infants, had a perinatal arterial ischemic stroke to the LH areas ordinarily subserving sentence processing. We compared them with their healthy age-matched siblings. All participants were tested on a battery of behavioral and functional imaging tasks. While stroke participants were impaired in some nonlinguistic cognitive abilities, their processing of sentences and of vocal emotion was normal and equal to that of their healthy siblings. In almost all, these abilities have both developed in the healthy RH. Our results provide insights into the remarkable ability of the young brain to reorganize language. Reorganization is highly constrained, with sentence processing almost always in the RH frontotemporal regions homotopic to their location in the healthy brain. This activation is somewhat segregated from RH emotion processing, suggesting that the two functions perform best when each has its own neural territory.

Studies of language organization show a striking change in cerebral dominance for language over development: We begin life with a left hemisphere (LH) bias for language processing, which is weaker than that in adults and which can be overcome if there is a LH injury. Over development this LH bias becomes stronger and can no longer be reversed. Prior work has shown that this change results from a significant reduction in the magnitude of language activation in right hemisphere (RH) regions in adults compared to children. Here we investigate whether the spatial distribution of language activation, albeit weaker in magnitude, still persists in homotopic RH regions of the mature brain. Children aged 4-13 ( n = 39) and young adults ( n = 14) completed an auditory sentence comprehension fMRI (functional magnetic resonance imaging) task. To equate neural activity across the hemispheres, we applied fixed cutoffs for the number of active voxels that would be included in each hemisphere for each participant. To evaluate homotopicity, we generated left-right flipped versions of each activation map, calculated spatial overlap between the LH and RH activity in frontal and temporal regions, and tested for mean differences in the spatial overlap values between the age groups. We found that, in children as well as in adults, there was indeed a spatially intact shadow of language activity in the right frontal and temporal regions homotopic to the LH language regions. After a LH stroke in adulthood, recovering early-life activation in these regions might assist in enhancing recovery of language abilities., (© 2022 Massachusetts Institute of Technology.)

Background: The FilmArray Meningitis/Encephalitis panel (MEP) has an 11% false-positive and 2.2% false-negative rate compared with conventional testing. We describe clinical characteristics, treatment decisions, and outcomes in children with discordant results between MEP and conventional testing., Methods: We conducted a multisite review of patients ≤ 18 years with suspected central nervous system infection and positive results by MEP or conventional testing (cerebrospinal fluid [CSF] culture, herpes simplex virus [HSV] polymerase chain reaction (PCR), and enterovirus [EV] PCR). Descriptive results are provided for patients with discordant results. Comparison between group 1 (MEP and CSF culture positive) and group 2 (MEP positive, CSF culture negative, or showing a different pathogen) was made by Mann-Whitney test for continuous and Fisher's test for categorical variables., Results: A total of 355 patients had at least one pathogen identified. More than half of patients with bacterial pathogens identified that are included in the MEP had discordant results (30/52; 58%). There were 28 samples with bacterial pathogen identified on MEP only, 1 with different bacterial pathogens on MEP and culture, and 1 with Escherichia coli identified on CSF culture only. Patients in group 1 were more likely to have CSF pleocytosis, elevated CSF protein, and decreased CSF glucose than group 2 (P < .05). Two patients were HSV positive by MEP while HSV negative by PCR. Ten patients had discordant results between MEP and EV PCR., Conclusions: Discordant results between MEP and conventional testing are common. Treatment decisions based on a positive MEP should be made in the appropriate clinical context., (© The Author(s) 2022. Published by Oxford University Press on behalf of The Journal of the Pediatric Infectious Diseases Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The language system is perhaps the most unique feature of the human brain's cognitive architecture. It has long been a quest of cognitive neuroscience to understand the neural components that contribute to the hierarchical pattern processing and advanced rule learning required for language. The most important goal of this research is to understand how language becomes impaired when these neural components malfunction or are lost to stroke, and ultimately how we might recover language abilities under these circumstances. Additionally, understanding how the language system develops and how it can reorganize in the face of brain injury or dysfunction could help us to understand brain plasticity in cognitive networks more broadly. In this chapter we will discuss the earliest features of language organization in infants, and how deviations in typical development can-but in some cases, do not-lead to disordered language. We will then survey findings from adult stroke and aphasia research on the potential for recovering language processing in both the remaining left hemisphere tissue and in the non-dominant right hemisphere. Altogether, we hope to present a clear picture of what is known about the capacity for plastic change in the neurobiology of the human language system., (Copyright © 2022 Elsevier B.V. All rights reserved.)

The formation and plasticity of neuronal circuits relies on dynamic activity-dependent gene expression. Although recent work has revealed the identity of important transcriptional regulators and of genes that are transcribed and translated in response to activity, relatively little is known about the cell biological mechanisms by which activity alters the nuclear proteome of neurons to link neuronal stimulation to transcription. Using nucleus-specific proteomic mapping in silenced and stimulated neurons, we uncovered an understudied mechanism of nuclear proteome regulation: activity-dependent proteasome-mediated degradation. We found that the tumor suppressor protein PDCD4 undergoes rapid stimulus-induced degradation in the nucleus of neurons. We demonstrate that degradation of PDCD4 is required for normal activity-dependent transcription and that PDCD4 target genes include those encoding proteins critical for synapse formation, remodeling, and transmission. Our findings highlight the importance of the nuclear proteasome in regulating the activity-dependent nuclear proteome and point to a specific role for PDCD4 as a regulator of activity-dependent transcription in neurons., (© 2021 Herbst et al.)

The ability to custom-modify cell surface glycans holds great promise for treatment of a variety of diseases. We propose a glycomimetic of l-fucose that markedly inhibits the creation of sLe X by FTVI and FTVII, but has no effect on creation of Le X by FTIX. Our findings thus indicate that selective suppression of sLex display can be achieved, and STD-NMR studies surprisingly reveal that the mimetic does not compete with GDP-fucose at the enzymatic binding site.

Children in communities with concentrated socioeconomic and structural disadvantage tend to have elevated rates of nonurgent visits to emergency departments (EDs). Using a spatial regression model of 264 census block groups in Pittsburgh, Pennsylvania, we investigated sociodemographic and structural factors associated with lower-than-expected ("low utilization") versus higher-than-expected ("high utilization") nonurgent ED visit rates among children in block groups with concentrated disadvantage. Compared with high-utilization block groups, low-utilization block groups had higher percentages of households with two adults, high school graduates, access to vehicles, sound housing quality, and owner-occupied housing. Notably, low-utilization block groups did not differ significantly from high-utilization block groups either in the percentage of households located within very close proximity to public transit or primary care or in children's health insurance coverage rates. Stakeholders wishing to reduce pediatric nonurgent ED visits among families in communities of concentrated disadvantage should consider strategies to mitigate financial, time, transportation, and health literacy constraints that may affect families' access to primary care.

Background: Despite substantial progress, motor vehicle crashes remain a leading killer of US children. Previously, we documented significant positive impacts of Safe Routes to School interventions on school-age pedestrian and pedalcyclist crashes., Objective: To expand our analysis of US trends in motor vehicle crashes involving school-age pedestrians and pedalcyclists, exploring heterogeneity by age and geography., Methods: We obtained recent police-reported crash data from 26 states, calculating population rates of pedestrian and pedalcyclist crashes, crash fatality rates and pedestrian commuter-adjusted crash rates ('pedestrian danger index') for school-age children as compared with other age groups. We estimated national and statewide trends by age, injury status, day and travel hour using hierarchical linear modeling., Results: School-age children accounted for nearly one in three pedestrians and one in two pedalcyclists struck in motor vehicle crashes from 2000 to 2014. Yet, the rates of these crashes declined 40% and 53%, respectively, over that time, on average, even as adult rates rose. Average crash rates varied geographically from 24.4 to 100.8 pedestrians and 15.6 to 56.7 pedalcyclists struck per 100 000 youth. Crash rates and fatality rates were inversely correlated., Conclusions: Despite recent increases in adult pedestrian crashes, school-age and younger pedestrians experienced ongoing declines in motor vehicle crashes through 2014 across the USA. There was no evidence of displacement in crash severity; declines were observed in all outcomes. The growing body of state crash data resources can present analytic challenges but also provides unique insights into national and local pedestrian crash trends for all crash outcomes., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Sialyl Lewis X (sLeX) regulates T cell trafficking from the vasculature into skin and sites of inflammation, thereby playing a critical role in immunity. In healthy persons, only a small proportion of human blood T cells express sLeX, and their function is not fully defined. Using a combination of biochemical and functional studies, we find that human blood sLeX + CD4 + T cells comprise a subpopulation expressing high levels of Th2 and Th17 cytokines, chemokine receptors CCR4 and CCR6, and the transcription factors GATA-3 and RORγT. Additionally, sLeX + CD4 + T cells exclusively contain the regulatory T cell population (CD127 low CD25 high and FOXP3 + ) and characteristically display immune-suppressive molecules, including the coinhibitor receptors PD-1 and CTLA-4. Among CD8 + T cells, sLeX expression distinguishes a subset displaying low expression of cytotoxic effector molecules, perforin and granzyme β, with reduced degranulation and CD57 expression and, consistently, marginal cytolytic capacity after TCR engagement. Furthermore, sLeX + CD8 + T cells present a pattern of features consistent with Th cell-like phenotype, including release of pertinent Tc2 cytokines and elevated expression of CD40L. Together, these findings reveal that sLeX display is associated with unique functional specialization of both CD4 + and CD8 + T cells and indicate that circulating T cells that are primed to migrate to lesional sites at onset of inflammation are not poised for cytotoxic function., (Copyright © 2020 by The American Association of Immunologists, Inc.)

The 'maccullochi species group' of rainbowfishes are small and distinctly patterned freshwater fishes of streams and swamps, comprising around eight species. The species from which the group bears its name, Melanotaenia maccullochi Ogilby, 1915, has been thought to comprise three forms occurring in distinct geographic areas, and recent mitochondrial genetic data provides matching patterns of likely inter-specific divergence. Here we undertake a detailed investigation of the taxonomic status of M. maccullochi using a combined lines of evidence approach incorporating multiple nuclear genetic markers (55 allozyme loci), mitochondrial DNA sequence data (1141 bp cytochrome b) and morphology (examination of a suite of 38 morphometric and meristic characters). As all three datasets provide support for a three-way split, we accordingly describe two new species and redescribe M. maccullochi sensu stricto. McCulloch's Rainbowfish M. maccullochi, a species with brown body stripes and red fins occurs in northeast Queensland and is redescribed based on 338 specimens, 13.1-53.0 mm SL. This species was one of the first rainbowfishes to become known in the aquarium hobby. A second form with darker stripes on a contrasting light white-grey body and with distinct sub-marginal black bands in the dorsal and anal fins, distributed across northern and eastern Cape York Peninsula, Torres Strait and southern central New Guinea, is described as Sahul Rainbowfish M. sahulensis sp. nov. based on 267 specimens, 13.4-48.4 mm SL. A diminutive and well geographically isolated form occurring below the escarpment of the Tabletop Range in Litchfield National Park, Northern Territory possessing a more prominent and purplish mid-lateral stripe, is described as the Little Rainbowfish Melanotaenia wilsoni sp. nov. based on 50 specimens, 19.3-33.3 mm SL. A combination of morphological characters is useful for separating the respective taxa with M. wilsoni sp. nov. the most distinctive, typically having fewer vertebrae, lateral scales, cheek scales, procurrent caudal rays and anal rays and proportionally a shorter maxilla and snout than either of the other two species. Useful characters for further separating M. sahulensis sp. nov. from M. maccullochi include slightly higher counts of vertebrae, lateral scales and anal rays and proportionally greater body depth, body width and pre-dorsal distance. Information on the known distribution, habitats and conservation status of the three species is summarised, with the Northern Territory species being a narrow-range endemic with specific environmental requirements.

Neurons are among the most compartmentalized and interactive of all cell types. Like all cells, neurons use proteins as the main sensors and effectors. The modification of the proteome in axons and dendrites is used to guide the formation of synaptic connections and to store information. In this Review, we discuss the data indicating that an important source of protein for dendrites, axons and their associated elements is provided by the local synthesis of proteins. We review the data indicating the presence of the machinery required for protein synthesis, the direct visualization and demonstration of protein synthesis, and the established functional roles for local translation for many different neuronal functions. Finally, we consider the open questions and future directions in this field.

The success of dendritic cell (DC)-based immunotherapeutics critically hinges on the capacity of the vascularly administered cells to enter tissues. Transendothelial migration (TEM) is dictated by an ordered cascade of receptor/ligand interactions. In this study, we examined the key molecular effectors of TEM of human monocyte-derived DCs (mo-DCs) generated by clinically relevant methods: CD14 selection (CD14-S) and plastic adherence selection (PA-S). Without chemokine input, CD14-S cells undergo greater TEM than PA-S cells over TNF-α-stimulated HUVECs. TEM of CD14-S mo-DCs is E-selectin/very late Ag-4 (VLA-4) dependent, and engagement of E-selectin ligands activates VLA-4 on CD14-S mo-DCs but not on PA-S mo-DCs. E-selectin binding glycoforms of P-selectin glycoprotein ligand-1 (PSGL-1) (i.e., cutaneous lymphocyte Ag [CLA]) and CD44 (i.e., hematopoietic cell E-selectin/L-selectin ligand [HCELL]) are both expressed on CD14-S mo-DCs, but only CLA is expressed on PA-S mo-DCs. To elucidate the effect of CD44 or PSGL-1 engagement, mo-DCs were pretreated with their ligands. Ligation of CD44 on CD14-S mo-DCs triggers VLA-4 activation and TEM, whereas PSGL-1 ligation does not. HCELL expression on CD14-S mo-DC can be enforced by cell surface exofucosylation, yielding increased TEM in vitro and enhanced extravasation into bone marrow in vivo. These findings highlight structural and functional pleiotropism of CD44 in priming TEM of mo-DCs and suggest that strategies to enforce HCELL expression may boost TEM of systemically administered CD14-S mo-DCs., (Copyright © 2018 by The American Association of Immunologists, Inc.)

A localized transcriptome at the synapse facilitates synapse-, stimulus- and transcript-specific local protein synthesis in response to neuronal activity. While enzyme-mediated mRNA modifications are known to regulate cellular mRNA turnover, the role of these modifications in regulating synaptic RNA has not been studied. We established low-input m 6 A-sequencing of synaptosomal RNA to determine the chemically modified local transcriptome in healthy adult mouse forebrains and identified 4,469 selectively enriched m 6 A sites in 2,921 genes as the synaptic m 6 A epitranscriptome (SME). The SME is functionally enriched in synthesis and modulation of tripartite synapses and in pathways implicated in neurodevelopmental and neuropsychiatric diseases. Interrupting m 6 A-mediated regulation via knockdown of readers in hippocampal neurons altered expression of SME member Apc, resulting in synaptic dysfunction including immature spine morphology and dampened excitatory synaptic transmission concomitant with decreased clusters of postsynaptic density-95 (PSD-95) and decreased surface expression of AMPA receptor subunit GluA1. Our findings indicate that chemical modifications of synaptic mRNAs critically contribute to synaptic function.

The freshwater melanotaeniid genus Cairnsichthys is endemic to a relatively small area of specialised habitat within the Wet Tropics bioregion of north-eastern Queensland, Australia. It was previously considered as monotypic, including only a single species, C. rhombosomoides (Nichols Raven, 1928). The recent discovery of an apparently-isolated population in the Daintree rainforest, approximately 120 km north of the known range extent, prompted a detailed investigation of its taxonomic status using a combined lines of evidence approach. We provide compelling evidence from multiple nuclear genetic markers (52 allozyme loci), mitochondrial DNA sequence data (1141 bp cytochrome b) and morphology (examination of a suite of 38 morphometric and meristic characters) that supports north-south splitting of C. rhombosomoides. Accordingly, we describe the northern population as a distinct species, C. bitaeniatus sp. nov., on the basis of 25 specimens, 34.7-65.6 mm SL. The new species differs morphologically primarily by having a more slender and narrow shape, featuring a flatter, straighter predorsal profile and shorter second dorsal fin base; possession of slightly smaller scales, reflected in higher counts of lateral scales and predorsal scales; typically more vertebrae; and colour differences including a more robust, short black stripe across the upper operculum, a pronounced yellow patch on the anteroventral body and usually a more conspicuous second dark stripe on the lower body, with adult males generally having yellowish compared to reddish fins. We also provide a generic diagnosis for Cairnsichthys and a redescription of C. rhombosomoides. Information on the known distribution, habitats and conservation status of species in the genus is summarised, the new species being of particular concern as a narrow range endemic with specific environmental requirements.

Astrocytes are complex bushy cells that serve important functions through close contacts between their processes and synapses. However, the spatial interactions and dynamics of astrocyte processes relative to synapses have proven problematic to study in adult living brain tissue. Here, we report a genetically targeted neuron-astrocyte proximity assay (NAPA) to measure astrocyte-synapse spatial interactions within intact brain preparations and at synaptic distance scales. The method exploits resonance energy transfer between extracellularly displayed fluorescent proteins targeted to synapses and astrocyte processes. We validated the method in the striatal microcircuitry following in vivo expression. We determined the proximity of striatal astrocyte processes to distinct neuronal input pathways, to D1 and D2 medium spiny neuron synapses, and we evaluated how astrocyte-to-excitatory synapse proximity changed following cortical afferent stimulation, during ischemia and in a model of Huntington's disease. NAPA provides a simple approach to measure astrocyte-synapse spatial interactions in a variety of experimental scenarios. VIDEO ABSTRACT., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Dysfunction of the neuronal RNA binding protein RBFOX1 has been linked to epilepsy and autism spectrum disorders. Rbfox1 loss in mice leads to neuronal hyper-excitability and seizures, but the physiological basis for this is unknown. We identify the vSNARE protein Vamp1 as a major Rbfox1 target. Vamp1 is strongly downregulated in Rbfox1 Nes-cKO mice due to loss of 3' UTR binding by RBFOX1. Cytoplasmic Rbfox1 stimulates Vamp1 expression in part by blocking microRNA-9. We find that Vamp1 is specifically expressed in inhibitory neurons, and that both Vamp1 knockdown and Rbfox1 loss lead to decreased inhibitory synaptic transmission and E/I imbalance. Re-expression of Vamp1 selectively within interneurons rescues the electrophysiological changes in the Rbfox1 cKO, indicating that Vamp1 loss is a major contributor to the Rbfox1 Nes-cKO phenotype. The regulation of interneuron-specific Vamp1 by Rbfox1 provides a paradigm for broadly expressed RNA-binding proteins performing specialized functions in defined neuronal subtypes., (Published by Elsevier Inc.)

Objectives: Miscommunication has been implicated as a leading cause of medical errors, and standardized handover programs have been associated with improved patient outcomes. However, the role of structured handovers in pediatric emergencies remains unclear. We sought to determine if training with an airway, breathing, circulation, situation, background, assessment, recommendation handover tool could improve the transmission of essential patient information during multidisciplinary simulations of critically ill children., Methods: We conducted a prospective, randomized, intervention study with first-year pediatric residents at a quaternary academic children's hospital. Baseline and second handovers were recorded for residents in the intervention group ( n = 12) and residents in the control group ( n = 8) during multidisciplinary simulations throughout the academic year. The intervention group received handover education after baseline handover observation and a cognitive aid before second handover observation. Audio-recorded handovers were scored by using a Delphi-developed assessment tool by a blinded rater., Results: There was no difference in baseline handover scores between groups ( P = .69), but second handover scores were significantly higher in the intervention group (median 12.5 [interquartile range 12-13] versus median 7.5 [interquartile range 6-8] in the control group; P < .01). Trained residents were more likely to include a reason for the call ( P < .01), focused history ( P = .02), and summative assessment ( P = .03). Neither timing of the second observation in the academic year nor duration between first and second observation were associated with the second handover scores (both P > .5)., Conclusions: Structured handover training and provision of a cognitive aid may improve the inclusion of essential patient information in the handover of simulated critically ill children., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2018 by the American Academy of Pediatrics.)