Multi-tract multi-symptom relationships in pediatric concussion.

Background: The heterogeneity of white matter damage and symptoms in concussion has been identified as a major obstacle to therapeutic innovation. In contrast, most diffusion MRI (dMRI) studies on concussion have traditionally relied on group-comparison approaches that average out heterogeneity. To leverage, rather than average out, concussion heterogeneity, we combined dMRI and multivariate statistics to characterize multi-tract multi-symptom relationships. Methods: Using cross-sectional data from 306 previously concussed children aged 9-10 from the Adolescent Brain Cognitive Development Study, we built connectomes weighted by classical and emerging diffusion measures. These measures were combined into two informative indices, the first representing microstructural complexity, the second representing axonal density. We deployed pattern-learning algorithms to jointly decompose these connectivity features and 19 symptom measures. Results: Early multi-tract multi-symptom pairs explained the most covariance and represented broad symptom categories, such as a general problems pair, or a pair representing all cognitive symptoms, and implicated more distributed networks of white matter tracts. Further pairs represented more specific symptom combinations, such as a pair representing attention problems exclusively, and were associated with more localized white matter abnormalities. Symptom representation was not systematically related to tract representation across pairs. Sleep problems were implicated across most pairs, but were related to different connections across these pairs. Expression of multi-tract features was not driven by sociodemographic and injury-related variables, as well as by clinical subgroups defined by the presence of ADHD. Analyses performed on a replication dataset showed consistent results. Conclusions: Using a double-multivariate approach, we identified clinically-informative, cross-demographic multi-tract multi-symptom relationships. These results suggest that rather than clear one-to-one symptom-connectivity disturbances, concussions may be characterized by subtypes of symptom/connectivity relationships. The symptom/connectivity relationships identified in multi-tract multi-symptom pairs were not apparent in single-tract/single-symptom analyses. Future studies aiming to better understand connectivity/symptom relationships should take into account multi-tract multi-symptom heterogeneity. Funding: Financial support for this work came from a Vanier Canada Graduate Scholarship from the Canadian Institutes of Health Research (G.I.G.), an Ontario Graduate Scholarship (S.S.), a Restracomp Research Fellowship provided by the Hospital for Sick Children (S.S.), an Institutional Research Chair in Neuroinformatics (M.D.), as well as a Natural Sciences and Engineering Research Council CREATE grant (M.D.).

Concussions can damage networks of connections in the brain. Scientists have spent decades and millions of dollars studying concussions and potential treatments. Yet, no new treatments are available or in the pipeline. A major reason for this stagnation is that no two concussions are exactly alike. People affected by concussions may have different genetic or socioeconomic backgrounds. The nature of the injury or how its effects change over time may also vary among people with concussions. One central question facing scientists is whether there are multiple types of concussions. If so, what distinguishes them and what characteristics do they share. Some studies have looked at differences among subgroups of patients with concussions. But questions remain about whether ­ beyond differences between the patients ­ the brain injury itself differs and what impact that has on symptoms or patient trajectory. To better characterize different types of concussion, Guberman et al. analyzed diffusion magnetic resonance imaging scans from 306 nine or ten-year-old children with a previous concussion. The children were participants in the Adolescent Brain Cognitive Development Study. Using specialized statistical techniques, the researchers outlined subgroups of concussions in terms of connections and symptoms and studied how many of these subgroups each patient had. Some types of injury were linked with a category of symptoms like cognitive, mood, or physical symptoms. Some types of damage were linked with specific symptoms. Guberman et al. also found that one symptom, sleep problems, was part of many different injury subtypes. Sleep problems may occur in different patients for different reasons. For example, one patient with sleep difficulties may have experienced damage in brain regions controlling sleep and wakefulness. Another person with sleep problems may have injured parts of the brain responsible for mood and may have depression, which causes excessive sleepiness and difficulties waking up. Guberman et al. suggest a new way of thinking about concussions. If more studies confirm these concussion subgroups, scientists might use them to explore which types of therapies might be beneficial for patients with specific subgroups. Developing subgroup-targeted treatments may help scientists overcome the challenges of trying to develop therapies that work across a range of injuries. Similar disease subgrouping strategies may also help researchers study other brain diseases that may vary from patient to patient.

Tractostorm 2: Optimizing tractography dissection reproducibility with segmentation protocol dissemination.

The segmentation of brain structures is a key component of many neuroimaging studies. Consistent anatomical definitions are crucial to ensure consensus on the position and shape of brain structures, but segmentations are prone to variation in their interpretation and execution. White-matter (WM) pathways are global structures of the brain defined by local landmarks, which leads to anatomical definitions being difficult to convey, learn, or teach. Moreover, the complex shape of WM pathways and their representation using tractography (streamlines) make the design and evaluation of dissection protocols difficult and time-consuming. The first iteration of Tractostorm quantified the variability of a pyramidal tract dissection protocol and compared results between experts in neuroanatomy and nonexperts. Despite virtual dissection being used for decades, in-depth investigations of how learning or practicing such protocols impact dissection results are nonexistent. To begin to fill the gap, we evaluate an online educational tractography course and investigate the impact learning and practicing a dissection protocol has on interrater (groupwise) reproducibility. To generate the required data to quantify reproducibility across raters and time, 20 independent raters performed dissections of three bundles of interest on five Human Connectome Project subjects, each with four timepoints. Our investigation shows that the dissection protocol in conjunction with an online course achieves a high level of reproducibility (between 0.85 and 0.90 for the voxel-based Dice score) for the three bundles of interest and remains stable over time (repetition of the protocol). Suggesting that once raters are familiar with the software and tasks at hand, their interpretation and execution at the group level do not drastically vary. When compared to previous work that used a different method of communication for the protocol, our results show that incorporating a virtual educational session increased reproducibility. Insights from this work may be used to improve the future design of WM pathway dissection protocols and to further inform neuroanatomical definitions.

Caution ahead: reassessing the functional morphology of the respiratory organs in amphibious snails.

After a long hiatus, interest in the morphology of the respiratory organs in apple snails (Ampullariidae, Caenogastropoda) and its functional and evolutionary bearings is making a comeback. The variability in the morphology of the gill and lung and its link to different lifestyles and patterns of air dependency within the Ampullariidae make research on the morphology of the respiratory organs particularly suitable for approaching the evolution of terrestriality in animals. Additionally, morphology is a valuable source of hypotheses regarding the several functions the ampullariid respiratory organs have besides respiration. However, this is an underexplored field that only recently has incorporated ultrastructural and three-dimension visualization tools and in which more research is much needed, particularly, comparisons between species representing the diversity within the Ampullariidae. In this paper, I examine Mueck, Deaton & Lee's (2020a) assessment of the morphology of the gill and lung of Pomacea maculata and compare it with earlier and contemporary studies on other ampullariid species. I show that Mueck, Deaton & Lee's paper combines significant morphological misinterpretations, conceptual and terminological mistakes, and crucial literature omissions. I also reinterpret their results and point to the similarities and differences between them and available data on other ampullariids.

The systemized exploitation of temporary migrant agricultural workers in Canada: Exacerbation of health vulnerabilities during the COVID-19 pandemic and recommendations for the future.

In 2018, 55,734 jobs in Canadian agriculture were filled by temporary migrant workers, accounting for nearly 20 percent of total employment in this sector. Though referred to as temporary, those migrant workers often fill long-term positions and provide crucial support to the Canadian agricultural industry, which has seen an increasing disengagement from the domestic workforce in the last fifteen years. Health vulnerabilities faced by temporary migrant workers are already well documented. In addition, there are multiple systemic factors inherent within the structure and implementation of the Temporary Foreign Worker Program that contribute to the perpetuation of health inequities within this population. The COVID-19 pandemic has both exacerbated many of these disparities and further increased the risk of labour rights violations and vulnerability to exploitation for these workers. As Canada's 2020 growing season comes to an end, thousands of temporary migrant agricultural workers are returning to their native countries. With planning for next year's growing season already commencing, this timely analysis aims to examine health vulnerabilities faced by TMAWs during the COVID-19 pandemic. Five key areas are examined: occupational injuries, substandard living conditions, psychological difficulties, lack of access to healthcare and barriers in exercising labour rights. Building on this analysis, recommendations for policy and practice aimed at improving migrant workers' health are discussed.

Structural Connectivity Alterations in Operculo-Insular Epilepsy.

Operculo-insular epilepsy (OIE) is an under-recognized condition that can mimic temporal and extratemporal epilepsies. Previous studies have revealed structural connectivity changes in the epileptic network of focal epilepsy. However, most reports use the debated streamline-count to quantify 'connectivity strength' and rely on standard tracking algorithms. We propose a sophisticated cutting-edge method that is robust to crossing fibers, optimizes cortical coverage, and assigns an accurate microstructure-reflecting quantitative conectivity marker, namely the COMMIT (Convex Optimization Modeling for Microstructure Informed Tractography)-weight. Using our pipeline, we report the connectivity alterations in OIE. COMMIT-weighted matrices were created in all participants (nine patients with OIE, eight patients with temporal lobe epilepsy (TLE), and 22 healthy controls (HC)). In the OIE group, widespread increases in 'connectivity strength' were observed bilaterally. In OIE patients, 'hyperconnections' were observed between the insula and the pregenual cingulate gyrus (OIE group vs. HC group) and between insular subregions (OIE vs. TLE). Graph theoretic analyses revealed higher connectivity within insular subregions of OIE patients (OIE vs. TLE). We reveal, for the first time, the structural connectivity distribution in OIE. The observed pattern of connectivity in OIE likely reflects a diffuse epileptic network incorporating insular-connected regions and may represent a structural signature and diagnostic biomarker.

Noninvasive magnetic resonance imaging techniques in mild traumatic brain injury research and diagnosis.

Mild traumatic brain injury (mTBI), frequently referred to as concussion, is one of the most common neurological disorders. The underlying neural mechanisms of functional disturbances in the brains of concussed individuals remain elusive. Novel forms of brain imaging have been developed to assess patients postconcussion, including functional magnetic resonance imaging (fMRI), susceptibility-weighted imaging (SWI), diffusion MRI (dMRI), and perfusion MRI [arterial spin labeling (ASL)], but results have been mixed with a more common utilization in the research environment and a slower integration into the clinical setting. In this review, the benefits and drawbacks of the methods are described: fMRI is an effective method in the diagnosis of concussion but it is expensive and time-consuming making it difficult for regular use in everyday practice; SWI allows detection of microhemorrhages in acute and chronic phases of concussion; dMRI is primarily used for the detection of white matter abnormalities, especially axonal injury, specific for mTBI; and ASL is an alternative to the BOLD method with its ability to track cerebral blood flow alterations. Thus, the absence of a universal diagnostic neuroimaging method suggests a need for the adoption of a multimodal approach to the neuroimaging of mTBI. Taken together, these methods, with their underlying functional and structural features, can contribute from different angles to a deeper understanding of mTBI mechanisms such that a comprehensive diagnosis of mTBI becomes feasible for the clinician.

Morphological grounds for the obligate aerial respiration of an aquatic snail: functional and evolutionary perspectives.

The freshwater caenogastropod family Ampullariidae is emerging as a model for a variety of studies, among them, the evolution of terrestriality. A common character of the family is that all its members bear a lung while retaining the ancestral gill. This ensures that many ampullariids are able to inhabit poorly oxygenated waters, to bury in the mud during estivation, and to temporarily leave the water, in some species for oviposition. To these characters Pomacea canaliculata (Caenogastropoda, Ampullariidae) adds that is an obligate air-breather. In a recent paper, we showed the gill epithelium of P. canaliculata has a set of characteristics that suggest its role for oxygen uptake may be less significant than its role in ionic/osmotic regulation and immunity. We complement here our morphological investigation on the respiratory organs of P. canaliculata by studying the lung of this species at the anatomical (3D reconstructions of the blood system and nerve supply), histological and ultrastructural levels. The circulation of the gill and the lung are interconnected so that the effluence of blood from the gill goes to the lung where it completes oxygenation. Besides that, we found the lung cavity is lined by a pavement epithelium that encloses an anastomosing network of small blood spaces resting over a fibromuscular layer, which altogether form the respiratory lamina. The pavement cells form a blood-gas barrier that is 80-150 nm thick and thus fulfils the requirements for an efficient gas exchanger. Tufts of ciliary cells, together with some microvillar and secretory cells, are interspersed in the respiratory lamina. Rhogocytes, which have been proposed to partake in metal depuration and in the synthesis of hemocyanin in other gastropods, were found below the respiratory lamina, in close association with the storage cell tissue. In light of these findings, we discuss the functional role of the lung in P. canaliculata and compare it with that of other gastropods. Finally, we point to some similarities in the pattern of the evolution of air dependence in this family.

Structural abnormalities in thalamo-prefrontal tracks revealed by high angular resolution diffusion imaging predict working memory scores in concussed children.

Because of their high prevalence, heterogeneous clinical presentation, and wide-ranging sequelae, concussions are a challenging neurological condition, especially in children. Shearing forces transmitted across the brain during concussions often result in white matter damage. The neuropathological impact of concussions has been discerned from animal studies and includes inflammation, demyelination, and axonal loss. These pathologies can overlap during the sub-acute stage of recovery. However, due to the challenges of accurately modeling complex white matter structure, these neuropathologies have not yet been differentiated in children in vivo. In the present study, we leveraged recent advances in diffusion imaging modeling, tractography, and tractometry to better understand the neuropathology underlying working memory problems in concussion. Studying a sample of 16 concussed and 46 healthy youths, we used novel tractography methods to isolate 11 working memory tracks. Along these tracks, we measured fractional anisotropy, diffusivities, track volume, apparent fiber density, and free water fraction. In three tracks connecting the right thalamus to the right dorsolateral prefrontal cortex (DLPFC), we found microstructural differences suggestive of myelin alterations. In another track connecting the left anterior-cingulate cortex with the left DLPFC, we found microstructural changes suggestive of axonal loss. Structural differences and tractography reconstructions were reproduced using test-retest analyses. White matter structure in the three thalamo-prefrontal tracks, but not the cingulo-prefrontal track, appeared to play a key role in working memory function. The present results improve understanding of working memory neuropathology in concussions, which constitutes an important step toward developing neuropathologically informed biomarkers of concussion in children.

A Prospective Study of Childhood Predictors of Traumatic Brain Injuries Sustained in Adolescence and Adulthood.

OBJECTIVE: Traumatic brain injuries (TBIs) are sustained by approximately 17% of males in the general population, many of whom subsequently present mental disorders, cognitive, and physical problems. Little is known about predictors of TBIs and how to prevent them. The present study aimed to determine whether inattention-hyperactivity and/or all externalizing problems presented by boys at age 10 predict subsequent TBIs to age 34 after taking account of previous TBIs and family social status (FSS). METHOD: 742 Canadian males were followed, prospectively, from age 6 to 34. Diagnoses of TBIs were extracted from health files, parents-reported sociodemographic and family characteristics at participants' age 6, and teachers-rated participants' behaviors at age 10. Separate logistic regression models predicted TBIs sustained from age 11 to 17 and from age 18 to 34. For each age period, two models were computed, one included previous TBIs, inattention-hyperactivity, FSS, and interaction terms, the second included previous TBIs, externalizing problems, FSS, and interaction terms. RESULTS: In models that included inattention-hyperactivity, TBIs sustained from age 11 to 17 were predicted by age 10 inattention-hyperactivity (odds ratio [OR] = 1.46, 1.05 to 2.05) and by TBIs prior to age 11 (OR = 3.50, 1.48 to 8.24); TBIs sustained from age 18 to 34 were predicted by age 10 inattention-hyperactivity (OR = 1.31, 1.01 to 170). In models that included all externalizing problems, TBIs from age 11 to 17 were predicted by prior TBIs (OR = 3.66, 1.51 to 8.39); TBIs sustained from age 18 to 34 were predicted by age 10 externalizing problems (OR = 1.45, 1.12 to 1.86). Neither FSS nor interaction terms predicted TBIs in any of the models. CONCLUSIONS: Among males, using evidence-based treatments to reduce inattention-hyperactivity and externalizing problems among boys could, potentially, decrease the risk of TBIs to age 34. Further, boys who sustain TBIs in childhood require monitoring to prevent recurrence in adolescence.

Functional and evolutionary perspectives on gill structures of an obligate air-breathing, aquatic snail.

Ampullariids are freshwater gastropods bearing a gill and a lung, thus showing different degrees of amphibiousness. In particular, Pomacea canaliculata (Caenogastropoda, Ampullariidae) is an obligate air-breather that relies mainly or solely on the lung for dwelling in poorly oxygenated water, for avoiding predators, while burying in the mud during aestivation, and for oviposition above water level. In this paper, we studied the morphological peculiarities of the gill in this species. We found (1) the gill and lung vasculature and innervation are intimately related, allowing alternation between water and air respiration; (2) the gill epithelium has features typical of a transporting rather than a respiratory epithelium; and (3) the gill has resident granulocytes within intraepithelial spaces that may serve a role for immune defence. Thus, the role in oxygen uptake may be less significant than the roles in ionic/osmotic regulation and immunity. Also, our results provide a morphological background to understand the dependence on aerial respiration of Pomacea canaliculata. Finally, we consider these findings from a functional perspective in the light of the evolution of amphibiousness in the Ampullariidae, and discuss that master regulators may explain the phenotypic convergence of gill structures amongst this molluscan species and those in other phyla.

Are Traumatic Brain Injuries Associated With Criminality After Taking Account of Childhood Family Social Status and Disruptive Behaviors?

OBJECTIVE: The authors aimed to elucidate the links between traumatic brain injuries (TBIs) and criminal convictions in a sample of 724 Canadian males with and without criminal records followed up to age 24. METHODS: Prospectively collected data were analyzed to determine whether prior TBIs predicted subsequent criminal convictions after taking account of family social status (FSS) and childhood disruptive behaviors. At age 24, diagnoses of TBIs were extracted from health records and convictions from official criminal records. In childhood, teachers rated disruptive behaviors and parents reported FSS. RESULTS: Proportionately more individuals with offender status than nonoffender status sustained a TBI from age 18 to age 24 but not before age 18. Individuals with offender status who had sustained a TBI before and after their first conviction were similar in numbers, were raised in families of low social status, and presented high levels of disruptive behaviors from age 6 to age 12. When FSS and childhood disruptive behaviors were included in multivariable regression models, sustaining a prior TBI was not associated with an increased risk of juvenile convictions for any type of crime, for violent crimes, for convictions for any crime or violent crime from age 18 to age 24, or for a first crime or a first violent crime from age 18 to age 24. CONCLUSIONS: Among males, there was no evidence that prior TBIs were associated with an increased risk of subsequent criminal convictions from age 12 to age 24 when taking account of FSS and childhood disruptive behaviors, although these latter factors may be associated with an increased prevalence of TBIs among adult offenders.

Assessment of the kidney and lung as immune barriers and hematopoietic sites in the invasive apple snail Pomacea canaliculata.

Knowledge on the immune system of Pomacea canaliculata is becoming increasingly important, because of this gastropod's role as intermediate host and vector of Angiostrongylus cantonensis, the etiologic agent of eosinophilic meningitis in humans and domestic animals. Immune defenses of this gastropod comprise both humoral and cellular components, but they may also involve organs that act as immune barriers to prevent the spread of alien molecules and organisms. Both the kidney and lung are here shown to serve this function, because of (1) their positions in blood circulation, (2) the intricate architecture of their blood spaces, and (3) the proliferative and nodulation reactions of hemocytes to an immune challenge. However, these organs differ in that only the kidney shows permanent hemocyte aggregations. Microcirculation in the kidney was found to flow through an intricate vascular bed containing the permanent aggregations, which occurred either as hemocyte islets anchored by cytoplasmic projections of the renal epithelium or as perivascular accretions. Within 96 h of the injection of yeast cells, hemocyte nodules were formed both in the kidney and lung. Moreover, cell proliferation in renal hemocyte islets was measured by bromodeoxyuridine (BrdU) incorporation. The proportion of BrdU positive nuclei increased 48 h after injection. Signs of nodule regression (apoptotic bodies, lipofuscin-like deposits) and a decrease in the proportion of BrdU positive nuclei were found at 96 h. In addition, the area of renal hemocyte islets was significantly increased 96 h after injection. Nevertheless, the high complexity of the small vascular chambers that constitute the lung's respiratory lamina would also facilitate hemocyte-antigen contacts, required to elicit cellular aggregation, and hence, nodulation. To our knowledge, this paper includes the first quantitative indication of hemocyte proliferation after an immune challenge among Caenogastropoda.

Nanochannel Electroporation as a Platform for Living Cell Interrogation in Acute Myeloid Leukemia.

A living cell interrogation platform based on nanochannel electroporation is demonstrated with analysis of RNAs in single cells. This minimally invasive process is based on individual cells and allows both multi-target analysis and stimulus-response analysis by sequential deliveries. The unique platform possesses a great potential to the comprehensive and lysis-free nucleic acid analysis on rare or hard-to-transfect cells.

T cell therapy for nasopharyngeal carcinoma.

Among the novel biologic therapeutics that will increase our ability to cure human cancer in the years to come, T cell therapy is one of the most promising approaches. However, with the possible exception of tumor-infiltrating lymphocytes therapy for melanoma, clinical trials of adoptive T-cell therapy for solid tumors have so far provided only clear proofs-of-principle to build on with further development. Epstein-Barr virus (EBV)-associated malignancies offer a unique model to develop T cell-based immune therapies, targeting viral antigens expressed on tumor cells. In the last two decades, EBV-specific cytotoxic T-lymphocytes (CTL) have been successfully employed for the prophylaxis and treatment of EBV-related lymphoproliferative disorders in immunocompromised hosts. More recently, this therapeutic approach has been applied to the setting of EBV-related solid tumors, such as nasopharyngeal carcinoma. The results are encouraging, although further improvements to the clinical protocols are clearly necessary to increase anti-tumor activity. Promising implementations are underway, including harnessing the therapeutic potential of CTLs specific for subdominant EBV latent cycle epitopes, and delineating strategies aimed at targeting immune evasion mechanisms exerted by tumor cells.