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Substances of unknown or variable composition, complex reaction products, and biological materials (UVCBs) are commonly found in the environment. However, assessing their human toxicological risk is challenging due to their variable composition and many constituents. Metal naphthenate salts are one such category of UVCBs that are the reaction products of naphthenic acids with metals to form complex mixtures. Metal naphthenates are often found or used in household and industrial materials with potential for human exposure, but very few of these materials have been evaluated for causing human health hazards. Herein, we evaluate metal naphthenates using predictions derived from read-across and quantitative structure–activity/property relationship (QSAR/QSPR) models. Accordingly, we first built a computational chemistry library by enumerating the structures of naphthenic acids and derived 11,850 QSAR-acceptable structures; then, we used open and commercial in silico tools on these structures to predict a set of physicochemical properties and toxicity endpoints. We then compared the QSAR/QSPR predictions with available experimental data on naphthenic acids to provide a more complete picture of the contributions of the components to the toxicity profiles of metal naphthenate mixtures. The available systematic acute oral toxicity values (LD50) and QSAR LD50 predictions of all the naphthenic acid components indicated low concern for toxicity. The point of departure predictions for chronic repeated dose toxicity for the naphthenic acid components using QSAR models developed from studies on rats ranged from 25 to 50 mg/kg/day. These values are in good agreement with findings from studies on copper and zinc naphthenates, which had no observed adverse effect levels of 30 and 118 mg/kg/day, respectively. Hence, this study demonstrates how published in silico approaches can be used to identify the potential components of metal naphthenates for further testing, inform groupings of UVCBs such as naphthenates, as well as fill the data gaps using read-across and QSAR models to inform risk assessment.

Background: Rumination-focused cognitive behavioral therapy (RF-CBT) is designed to reduce depressive rumination or the habitual tendency to dwell on experiences in a repetitive, negative, passive, and global manner. RF-CBT uses functional analysis, experiential exercises, and repeated practice to identify and change the ruminative habit. This preregistered randomized clinical trial (NCT03859297, R61) is a preregistered replication of initial work. We hypothesized a concurrent reduction of both self-reported rumination and cross-network connectivity between the left posterior cingulate cortex and right inferior frontal and inferior temporal gyri. Methods: Seventy-six youths with a history of depression and elevated rumination were randomized to 10 to 14 sessions of RF-CBT (n = 39; 34 completers) or treatment as usual (n = 37; 28 completers). Intent-to-treat analyses assessed pre-post change in rumination response scale and in functional connectivity assessed using two 5 minute, 12 second runs of resting-state functional magnetic resonance imaging. Results: We replicated previous findings: a significant reduction in rumination response scale and a reduction in left posterior cingulate cortex to right inferior frontal gyrus/inferior temporal gyrus connectivity in participants who received RF-CBT compared with those who received treatment as usual. Reductions were large (z change = 0.84; 0.73, respectively [ps < .05]). Conclusions: This adolescent clinical trial further demonstrates that depressive rumination is a brain-based mechanism that is modifiable via RF-CBT. Here, we replicated that RF-CBT reduces cross-network connectivity, a possible mechanism by which rumination becomes less frequent, intense, and automatic. This National Institute of Mental Health-funded fast-fail study continues to the R33 phase during which treatment-specific effects of RF-CBT will be compared with relaxation therapy.

Summary: A limitation of conventional bulk-tissue proteome studies in amyotrophic lateral sclerosis (ALS) is the confounding of motor neuron (MN) signals by admixed non-MN proteins. Here, we leverage laser capture microdissection and nanoPOTS single-cell mass spectrometry-based proteomics to query changes in protein expression in single MNs from postmortem ALS and control tissues. In a follow-up analysis, we examine the impact of stratification of MNs based on cytoplasmic transactive response DNA-binding protein 43 (TDP-43)+ inclusion pathology on the profiles of 2,238 proteins. We report extensive overlap in differentially abundant proteins identified in ALS MNs with or without overt TDP-43 pathology, suggesting early and sustained dysregulation of cellular respiration, mRNA splicing, translation, and vesicular transport in ALS. Together, these data provide insights into proteome-level changes associated with TDP-43 proteinopathy and begin to demonstrate the utility of pathology-stratified trace sample proteomics for understanding single-cell protein dynamics in human neurologic diseases.

Objective: The corticospinal tract (CST) reveals progressive microstructural alterations in ALS measurable by DTI. The aim of this study was to evaluate fractional anisotropy (FA) along the CST as a longitudinal marker of disease progression in ALS. Methods: The study cohort consisted of 114 patients with ALS and 110 healthy controls from the second prospective, longitudinal, multicentre study of the Canadian ALS Neuroimaging Consortium (CALSNIC-2). DTI and clinical data from a harmonized protocol across 7 centres were collected. Thirty-nine ALS patients and 61 controls completed baseline and two follow-up visits and were included for longitudinal analyses. Whole brain-based spatial statistics and hypothesis-guided tract-of-interest analyses were performed for cross-sectional and longitudinal analyses. Results: FA was reduced at baseline and longitudinally in the CST, mid-corpus callosum (CC), frontal lobe, and other ALS-related tracts, with alterations most evident in the CST and mid-CC. CST and pontine FA correlated with functional impairment (ALSFRS-R), upper motor neuron function, and clinical disease progression rate. Reduction in FA was largely located in the upper CST; however, the longitudinal decline was greatest in the lower CST. Effect sizes were dependent on region, resulting in study group sizes between 17 and 31 per group over a 9-month interval. Cross-sectional effect sizes were maximal in the upper CST; whereas, longitudinal effect sizes were maximal in mid-callosal tracts. Conclusions: Progressive microstructural alterations in ALS are most prominent in the CST and CC. DTI can provide a biomarker of cerebral degeneration in ALS, with longitudinal changes in white matter demonstrable over a reasonable observation period, with a feasible number of participants, and within a multicentre framework.

Assessing the linkage between breeding and non-breeding areas has important implications for understanding the fundamental biology of and conserving animal species. This is a challenging task for marine species, and in sea turtles a combination of stable isotope analysis (SIA) and satellite telemetry has been increasingly used. The Northwest Atlantic (NWA) loggerhead (Caretta caretta) Regional Management Unit, one of the largest sea turtle populations in the world, provides an excellent opportunity to investigate key biological patterns as well as methodological aspects related to the use of stable isotopes to infer spatial distribution of turtles in foraging areas. We provide the first comprehensive assessment of the annual distribution of NWA adult female loggerheads among foraging areas and investigate the efficacy of various analytical approaches as well as the effect of sample size in these types of studies. A total of 5168 individual females were sampled from seven Management Units (MUs) between 2013-2018. We provide the first estimate of the proportion of females originating from each MU that uses each foraging area and show how this proportion varies over time. We also estimate the relative importance (in terms of number of turtles) of each foraging area to the overall loggerhead breeding aggregation nesting in Florida and in the NWA for each year of the study. The foraging area used by reproductively active females differs considerably across MUs. One of these, the Subtropical NWA, is by far the most important foraging area in terms of both number of individuals and genetic diversity, and therefore this region may be considered as a conservation priority. Through simulations, we show that limited sizes of sample groups (unknowns; training; priors) may result in false geographic differentiation and consequently mislead interpretations. We provide thresholds and methodological recommendations for future studies. This study establishes a fundamental baseline for monitoring the annual contribution of foraging area to a terrestrial-based breeding aggregation of a marine animal in a cost-effective way. This type of monitoring allows for early detection of changes in foraging distributions—a possible effect of climate change on marine ecosystems or of area-specific anthropogenic threats.

Mortality risk to imperiled animal populations from anthropogenic hazards can be managed by spatial limits on human behavior if exposure and vulnerability of the animals are known. To provide this information for sea turtles in waters near their nesting beaches, we mapped exposure to vessel strikes, which are a major, lethal hazard to these endangered animals. During the 2021 and 2022 nesting seasons, we carried out standardized transect line surveys off Florida’s Atlantic coast, focusing on Loggerhead and Green Sea Turtles. Using Distance Sampling and Density Surface Modeling, we estimated the distribution of turtles near the surface (thus vulnerable to vessel strikes) based on several covariates. Our results revealed a clustering of vulnerable turtles near the shore and within hotspots identified by adjacent nesting beach density over tens of kilometers. Contrary to risk assessments based on stranding data, our findings present a new perspective on potential strike risk. We propose that our methodology and data can significantly contribute to initiating human behavioral changes required to reduce widespread vessel strikes on sea turtles.

Abstract Background Acute myocardial infarction (AMI) research is challenging as it requires enrollment of acutely ill patients. Patients are generally in a suboptimal state for providing informed consent. Patients’ understanding to verbal assents have not been previously examined in AMI research. Patients Acceptance and Comprehension to Written and Verbal Consent (PAC–VC) compared patients’ understanding and attitudes to verbal and written consents in AMI RCTs. Methods PAC–VC recruited patients from 3 AMI trials using both verbal N = 12 and written N = 6 consents. We compared patients’ understanding using two survey questionnaires. The first questionnaire used open-ended questions with multiple choice answers. The second questionnaire used a 5-point Likert scale to measure patients understanding and attitudes to the consent process. Overall answers average scores were categorized into three groups: Adequate understanding (71–100) %, Partial understanding (41–70)% and Inadequate understanding (0–40)%. Results Responses showed patients with verbal assent had adequate understanding to most components of informed consent, close to those of written consent. Most patients did not read written information entirely and believed that it is not important to make a final decision. Patients favoured to have written information be part of the consent but not necessarily presented during the initial consent process. Patients felt less pressured in the verbal assent arm than those of written consent. Conclusion Patients had adequate understanding to most components of verbal assent and comparable to those of written consent. Utilizing verbal assents in the acute care setting should be further assessed in larger trials.

We measured the relative abundance of sea turtles using standardized transect surveys conducted during the summer and fall of 2013 in neritic waters surrounding the Mississippi River delta in Louisiana, USA. Data comprise sea turtle locations, observation circumstances, and environmental covariates recorded at the beginning of each transect and at the time of each turtle observation. Turtles were recorded by species and size class, as well as location in the water column and the distance the turtle was from the transect line. Transects were performed on an 8.2 meter vessel with two observers atop a 4.5 meter elevated platform, with vessel speed standardized at ∼15 km/hr. These data are the first to describe relative abundance of sea turtles observed from small vessels in this region. Detection of turtles

As the use of surgically implanted sutureless aortic valves has increased over the past decade, we expect to encounter their failure increasingly in coming years. We describe a case of Perceval aortic valve failure with stent infolding and severe stenosis. This condition was treated with valve-in-valve transcatheter aortic valve implantation and complicated by aortic annular rupture at the site of infolding. This case is important because it outlines the limited experience with valve-in-valve transcatheter aortic valve implantation to treat failed sutureless valves and identifies sutureless valve infolding as a potential risk for annular rupture. Résumé: Puisque l’implantation valvulaire aortique sans suture s’est accrue au cours de la dernière décennie, nous nous attendons à rencontrer de plus en plus de défaillances de valves dans les années à venir. Nous décrivons un cas de défaillance de la valve aortique Perceval avec pliage de l’endoprothèse et sténose grave. Le traitement qui consistait en l’implantation valvulaire aortique de type valve-in-valve par cathéter a été compliqué par la rupture de l’anneau aortique au site du pliage. Il s’agit d’un cas important puisqu’il décrit le peu d’expérience en matière d’implantation valvulaire aortique de type valve-in-valve par cathéter dans le traitement des valves sans suture défectueuses et établit que le pliage d’une valve sans suture expose à un risque de rupture de l’anneau.

Background: Data are limited data on the prevalence of cardiovascular disease (CVD) and multimorbidity in contemporary cohorts of high-cost users (HCUs) in Canada.We examined the following: (i) the prevalence of CVD, with a comparison of total healthcare costs among HCUs with vs without CVD; (ii) the contribution of other comorbidities to costs among HCUs with CVD; and (iii) the trajectory of healthcare costs in the years before and after becoming an HCU. Methods: The study included adult Alberta patients in the Canadian Institutes of Health Research/Canadian Institute for Health Information Dynamic Cohort of Complex, High System Users from 2011-2012 through 2014-2015. We examined total healthcare costs, including hospital, ambulatory care, physician services, and drugs. Results: Among 88,536 HCUs, 23.4% had no CVD, 28.9% were hospitalized with a primary diagnosis of CVD, and 47.7% were hospitalized with a secondary diagnosis of CVD. Total healthcare costs were $2.0 billion (20.4% non-hospital costs), $2.8 billion (24.1% non-hospital costs), and $4.9 billion (19.8% non-hospital costs), respectively, in the 3 groups. Many HCUs with CVD were frail (74.2%) and many had diabetes (33.8%) or chronic obstructive pulmonary disease (27.9%), which contributed to higher costs and mortality. Healthcare expenditures in HCUs with CVD were several times higher than per capita health expenditures in the years prior to, and following, their inclusion in the dynamic HCU cohort. Conclusions: CVD is very common in HCUs of healthcare. HCUs with CVD have high rates of frailty and multimorbidity. Further research is needed to identify and intervene earlier, in order to flatten the cost curve in these complex patients. Résumé: Introduction: Les données sur la prévalence des maladies cardiovasculaires (MCV) et de la multimorbidité au sein des cohortes contemporaines de grands utilisateurs (GU) du Canada sont limitées. Nous avons examiné ce qui suit : (i) la prévalence des MCV en comparant les coûts totaux des soins de santé entre les GU atteints de MCV et les GU non atteints de MCV; (ii) la contribution des autres comorbidités aux coûts liés aux GU atteints de MCV; (iii) la trajectoire des coûts des soins de santé dans les années avant et après avoir été considérés comme un GU. Méthodes: L’étude portait sur des patients adultes de l’Alberta de la Cohorte dynamique de grands utilisateurs du système de santé aux besoins complexes de 2011-2012 à 2014-2015 des Instituts de recherche en santé du Canada et de l’Institut canadien d’information sur la santé. Nous avons examiné les coûts totaux des soins de santé, notamment les coûts hospitaliers, les coûts des soins ambulatoires, des services médicaux et des médicaments. Résultats: Parmi les 88 536 GU, 23,4 % n’avaient pas de MCV, 28,9 % étaient hospitalisés et avaient un diagnostic principal de MCV, et 47,7 % étaient hospitalisés et avaient un diagnostic secondaire de MCV. Les coûts totaux des soins de santé des 3 groupes étaient respectivement de 2,0 G$ (20,4 % de coûts non hospitaliers), 2,8 G$ (24,1 % de coûts non hospitaliers) et 4,9 G$ (19,8 % de coûts non hospitaliers). Plusieurs GU atteints de MCV étaient fragiles (74,2 %) et beaucoup avaient le diabète (33,8 %) ou une maladie pulmonaire obstructive chronique (27,9 %), qui contribuaient à des coûts et à une mortalité plus élevés. Les dépenses de santé par personne liées aux GU atteints de MCV étaient beaucoup plus élevées que les dépenses de santé par personne dans les années qui précédaient ou suivaient leur inclusion dans la cohorte dynamique de GU atteints de MCV. Conclusions: Les GU de soins de santé sont très fréquemment atteints de MCV. Les GU atteints de MCV présentent des taux de fragilité et de multimorbidité élevés. D’autres recherches sont nécessaires pour cerner et intervenir plus tôt afin d’aplatir la courbe des coûts chez ces patients aux besoins complexes.

IntroductionAnalysis of task fMRI studies is typically based on using ordinary least squares within a voxel- or vertex-wise linear regression framework known as the general linear model. This use produces estimates and standard errors of the regression coefficients representing amplitudes of task-induced activations. To produce valid statistical inferences, several key statistical assumptions must be met, including that of independent residuals. Since task fMRI residuals often exhibit temporal autocorrelation, it is common practice to perform “prewhitening” to mitigate that dependence. Prewhitening involves estimating the residual correlation structure and then applying a filter to induce residual temporal independence. While theoretically straightforward, a major challenge in prewhitening for fMRI data is accurately estimating the residual autocorrelation at each voxel or vertex of the brain. Assuming a global model for autocorrelation, which is the default in several standard fMRI software tools, may under- or over-whiten in certain areas and produce differential false positive control across the brain. The increasing popularity of multiband acquisitions with faster temporal resolution increases the challenge of effective prewhitening because more complex models are required to accurately capture the strength and structure of autocorrelation. These issues are becoming more critical now because of a trend toward subject-level analysis and inference. In group-average or group-difference analyses, the within-subject residual correlation structure is accounted for implicitly, so inadequate prewhitening is of little real consequence. For individual subject inference, however, accurate prewhitening is crucial to avoid inflated or spatially variable false positive rates.MethodsIn this paper, we first thoroughly examine the patterns, sources and strength of residual autocorrelation in multiband task fMRI data. Second, we evaluate the ability of different autoregressive (AR) model-based prewhitening strategies to effectively mitigate autocorrelation and control false positives. We consider two main factors: the choice of AR model order and the level of spatial regularization of AR model coefficients, ranging from local smoothing to global averaging. We also consider determining the AR model order optimally at every vertex, but we do not observe an additional benefit of this over the use of higher-order AR models (e.g. (AR(6)). To overcome the computational challenge associated with spatially variable prewhitening, we developed a computationally efficient R implementation using parallelization and fast C++ backend code. This implementation is included in the open source R package BayesfMRI.ResultsWe find that residual autocorrelation exhibits marked spatial variance across the cortex and is influenced by many factors including the task being performed, the specific acquisition protocol, mis-modeling of the hemodynamic response function, unmodeled noise due to subject head motion, and systematic individual differences. We also find that local regularization is much more effective than global averaging at mitigating autocorrelation. While increasing the AR model order is also helpful, it has a lesser effect than allowing AR coefficients to vary spatially. We find that prewhitening with an AR(6) model with local regularization is effective at reducing or even eliminating autocorrelation and controlling false positives.ConclusionOur analysis revealed dramatic spatial differences in autocorrelation across the cortex. This spatial topology is unique to each session, being influenced by the task being performed, the acquisition technique, various modeling choices, and individual differences. If not accounted for, these differences will result in differential false positive control and power across the cortex and across subjects.

Background: In patients with atrial fibrillation (AF) undergoing percutaneous coronary intervention (PCI), selecting an antithrombotic regimen requires balancing risks of ischemic cardiac events, stroke, and bleeding. Methods: We studied 467 patients with AF undergoing PCI in the time period from December 2015 to July 2018 identified via a chart audit by 47 Canadian cardiologists in the CONNECT AF+PCI (the Coordinated National Network to Engage Interventional Cardiologists in the Antithrombotic Treatment of Patients With Atrial Fibrillation Undergoing Percutaneous Coronary Intervention) study, to determine patterns of initial antithrombotic therapy selection. Results: The median (25th, 75th percentile) CHADS2 score was 2 (1, 3), and PCI was performed in the setting of acute coronary syndrome in 62.1%. Triple antithrombotic therapy (TAT) was the initial treatment in 62.7%, dual-pathway therapy in 25.7%, and dual antiplatelet therapy in 11.6%, with a temporal increase in use of dual-pathway therapy during the course of the study; median intended TAT duration was 1 (1, 3) month. Compared with patients selected for TAT, patients selected for dual-pathway therapy were less likely to have prior myocardial infarction (35.8% vs 25.8%, P = 0.045) and prior PCI (33.8% vs 23.3%, P = 0.03), and they received shorter total length of stents (38 [23, 56] vs 30 [20, 46] mm, P = 0.03). Patients selected for dual-pathway therapy had a higher prevalence of prior stroke/transient ischemic attack (13.0% vs 23.3%, P = 0.01). There was no difference in prevalence of anemia (21.5% vs 25.8%, P = 0.30). Use of dual-pathway therapy was similar among patients with acute coronary syndrome and those with stable disease (24.1% vs 28.2%, P = 0.32). Conclusions: Approximately one-quarter of AF patients undergoing PCI are treated with dual-pathway therapy in Canadian practice, with its use increasing during the studied period. Patients selected for dual-pathway therapy have less-complex coronary disease history and intervention. Résumé: Introduction: Les patients atteints de fibrillation auriculaire (FA) qui subissent une intervention coronarienne percutanée (ICP) et choisissent un schéma posologique antithrombotique ont besoin de peser les risques d’événements cardiaques d’origine ischémique, d’accidents vasculaires cérébraux et d’hémorragies. Méthodes: Les 467 patients atteints de FA ayant subi une ICP de décembre 2015 à juillet 2018 qui ont fait l’objet de notre étude ont été trouvés lors de la vérification des dossiers par 47 cardiologues canadiens de l’étude CONNECT AF+PCI (Coordinated National Network to Engage Interventional Cardiologists in the Antithrombotic Treatment of Patients With Atrial Fibrillation Undergoing Percutaneous Coronary Intervention) pour déterminer les schémas de sélection du traitement antithrombotique initial. Résultats: Le score CHADS2 médian (25e, 75e percentile) était de 2 (1, 3), et l’ICP avait été réalisée dans le cadre du syndrome coronarien aigu chez 62,1 % des patients. La trithérapie antithrombotique (TTA) était le traitement initial chez 62,7 % des patients, la bithérapie, chez 25,7 % des patients, et la bithérapie antiplaquettaire, chez 11,6 % des patients, mais il y avait une augmentation temporelle dans l’utilisation de la bithérapie durant l’étude; la durée médiane prévue de la TTA était de 1 (1, 3) mois. Comparativement aux patients sélectionnés pour la TTA, les patients sélectionnés pour la bithérapie étaient moins susceptibles d’avoir eu un infarctus du myocarde précédent (35,8 % vs 25,8 %, P = 0,045) et une ICP précédente (33,8 % vs 23,3 %, P = 0,03), et recevaient des endoprothèses de longueur totale plus courte (38 [23, 56] vs 30 [20, 46] mm, P = 0,03). Les patients sélectionnés pour la bithérapie montraient une prévalence plus élevée d’accidents vasculaires cérébraux/accidents ischémiques transitoires (13,0 % vs 23,3 %, P = 0,01). Il n’existait aucune différence dans la prévalence de l’anémie (21,5 % vs 25,8 %, P = 0,30). L’utilisation de la bithérapie était similaire chez les patients atteints d’un syndrome coronarien aigu et chez les patients dont la maladie était stable (24,1 % vs 28,2 %, P = 0,32). Conclusions: Dans la pratique canadienne, environ le quart des patients atteints de FA qui subissent une ICP sont traités par bithérapie, mais durant la période étudiée, son utilisation avait augmenté. Les patients sélectionnés pour la bithérapie ont des antécédents et des interventions liées aux maladies coronariennes moins complexes.

ABSTRACT: Background: Given changes in the care and outcomes of acute myocardial infarction (AMI) patients over the past several decades, we sought to develop prediction models that could be used to generate accurate risk-adjusted mortality and readmission outcomes for hospitals in current practice across Canada. Methods: A Canadian national expert panel was convened to define appropriate AMI patients for reporting and develop prediction models. Preliminary candidate variable evaluation was conducted using Ontario patients hospitalized with a most responsible diagnosis of AMI from April 1, 2015 to March 31, 2018. National data from the Canadian Institute for Health Information was used to develop AMI prediction models. The main outcomes were 30-day all-cause in-hospital mortality and 30-day urgent all-cause readmission. Discrimination of these models (measured by c-statistics) was compared with that of existing Canadian Institute for Health Information models in the same study cohort. Results: The AMI mortality model was assessed in 54,240 Ontario AMI patients and 153,523 AMI patients across Canada. We observed a 30-day in-hospital mortality rate of 6.3%, and a 30-day all-cause urgent readmission rate of 10.7% in Canada. The final Canadian AMI mortality model included 12 variables and had a c-statistic of 0.834. For readmission, the model had 13 variables and a c-statistic of 0.679. Discrimination of the new AMI models had higher c-statistics compared with existing models (c-statistic 0.814 for mortality; 0.673 for readmission). Conclusions: In this national collaboration, we developed mortality and readmission models that are suitable for profiling performance of hospitals treating AMI patients in Canada. RÉSUMÉ: Contexte: Compte tenu des changements apportés au cours des dernières décennies aux soins des patients ayant subi un infarctus aigu du myocarde (IAM) et aux issues d'un tel événement, nous avons voulu élaborer des modèles prédictifs pouvant servir à calculer de façon précise les résultats relatifs à la mortalité et aux réadmissions, ajustés selon les risques, pour les hôpitaux dans la pratique actuelle au Canada. Méthodologie: Un groupe national d'experts canadiens a été mis sur pied et a reçu le mandat de définir les critères appropriés applicables aux patients ayant subi un IAM aux fins de déclaration des cas et d’élaborer des modèles prédictifs. L’évaluation préliminaire des variables proposées a été effectuée à partir de patients hospitalisés en Ontario entre le 1er avril 2015 et le 31 mars 2018 chez lesquels l'IAM était le diagnostic principal à l'origine de l'hospitalisation. Les données à l’échelle nationale de l'Institut canadien d'information sur la santé (ICIS) ont été utilisées pour élaborer des modèles prédictifs d'IAM. Les deux principales issues évaluées étaient la mortalité hospitalière toutes causes confondues à 30 jours et la réadmission urgente toutes causes confondues à 30 jours. Le pouvoir discriminant de ces modèles (mesuré par la statistique C) a été comparé à celui des modèles existants de l'ICIS dans la même cohorte de l’étude. Résultats: Le modèle de mortalité par IAM a été évalué auprès de patients ayant subi un IAM, dont 54 240 en Ontario et 153 523 dans l'ensemble du Canada. Nous avons observé un taux de mortalité hospitalière à 30 jours de 6,3 % et un taux de réadmission urgente à 30 jours toutes causes confondues de 10,7 % au Canada. Le modèle canadien final de prédiction de la mortalité par IAM était constitué de 12 variables et avait une statistique C de 0,834. Pour la réadmission, le modèle comportait 13 variables et présentait une statistique C de 0,679. Le pouvoir discriminant des nouveaux modèles d'IAM présentait une statistique C supérieure à celle des modèles existants (statistique C de 0,814 pour la mortalité et de 0,673 pour la réadmission). Conclusions: Dans le cadre de cette collaboration nationale, nous avons élaboré des modèles prédictifs de la mortalité et de la réadmission hospitalière qui permettent d’établir un profil des résultats obtenus par les hôpitaux traitant des patients ayant subi un IAM au Canada.

Due to the pathophysiology of atherosclerosis, the management for coronary artery disease and peripheral arterial disease (PAD) were considered homogenous, with therapies focused on the use of lipid-lowering medications, antiplatelet therapy, glucose control, and blood pressure management. However, more recently, studies have supported the use of tailored therapeutics and medical targets for patients with PAD that sometimes differ from those for coronary artery disease. Moreover, we are now witnessing large randomized PAD-specific trials that have altered therapeutic regimens and targets. Given these updates, dissemination of knowledge is lacking, as evidenced by discordant guideline recommendations. This comprehensive review provides an overview of contemporary therapeutic options for secondary prevention for patients with PAD. Résumé: En raison de la physiopathologie de l'athérosclérose, les stratégies de prise en charge de la coronaropathie et de la maladie artérielle périphérique (MAP) étaient considérées comme homogènes, les traitements étant axés sur l'utilisation d'agents hypolipidémiants et d'agents antiplaquettaires, sur l’équilibre glycémique et sur la maîtrise de la pression artérielle. Toutefois, des études plus récentes sont venues appuyer l'utilisation de cibles thérapeutiques et médicales adaptées pour la MAP qui diffèrent parfois de celles qui sont définies pour la coronaropathie. Ainsi, nous voyons maintenant de vastes essais à répartition aléatoire portant expressément sur la MAP dans lesquels les schémas et cibles thérapeutiques ont été modifiés. Compte tenu de ces mises à jour, la diffusion des connaissances est déficiente, comme en témoignent les recommandations divergentes dans les lignes directrices. Cette revue exhaustive fournit un survol des options thérapeutiques actuelles pour la prévention secondaire chez les patients atteints de MAP.

Longitudinal fMRI studies hold great promise for the study of neurodegenerative diseases, development and aging, but realizing their full potential depends on extracting accurate fMRI-based measures of brain function and organization in individual subjects over time. This is especially true for studies of rare, heterogeneous and/or rapidly progressing neurodegenerative diseases. These often involve small samples with heterogeneous functional features, making traditional group-difference analyses of limited utility. One such disease is amyotrophic lateral sclerosis (ALS), a severe disease resulting in extreme loss of motor function and eventual death. Here, we use an advanced individualized task fMRI analysis approach to analyze a rich longitudinal dataset containing 190 hand clench fMRI scans from 16 ALS patients (78 scans) and 22 age-matched healthy controls (112 scans). Specifically, we adopt our cortical surface-based spatial Bayesian general linear model (GLM), which has high power and precision to detect activations in individual subjects, and propose a novel longitudinal extension to leverage information shared across visits. We perform all analyses in native surface space to preserve individual anatomical and functional features. Using mixed-effects models to subsequently study the relationship between size of activation and ALS disease progression, we observe for the first time an inverted U-shaped trajectory of motor activations: at relatively mild motor disability we observe enlarging activations, while at higher levels of motor disability we observe severely diminished activation, reflecting progression toward complete loss of motor function. We further observe distinct trajectories depending on clinical progression rate, with faster progressors exhibiting more extreme changes at an earlier stage of disability. These differential trajectories suggest that initial hyper-activation is likely attributable to loss of inhibitory neurons, rather than functional compensation as earlier assumed. These findings substantially advance scientific understanding of the ALS disease process. This study also provides the first real-world example of how surface-based spatial Bayesian analysis of task fMRI can further scientific understanding of neurodegenerative disease and other phenomena. The surface-based spatial Bayesian GLM is implemented in the BayesfMRI R package

Background: Although ST-elevation myocardial infarction (STEMI) management has evolved substantially over the past decade, its effect on bleeding and transfusion rates are largely unknown in a contemporary population. Methods: Our study cohort included patients 20 years of age or older who were hospitalized for STEMI between 2007 and 2016 across all Canadian provinces, except Quebec. Unadjusted rates of bleeding and of transfusion during STEMI episodes were calculated overall and for each province according to fiscal year. Patients were stratified into 4 groups according to their bleeding/transfusion. Characteristics, treatment, and outcomes were compared between groups. Multivariate logistic regression modelling was used to assess the association between bleeding and transfusion on in-hospital mortality. Results: Using 108,832 STEMI episodes, rates of in-hospital bleeding and transfusion declined between 2007 and 2016 from 3.9% to 2.8% (P < 0.0001) and 4.7% to 3.8% (P < 0.0001), respectively. However, variation in bleeding and transfusion rates were observed across Canadian provinces. Patients with bleeding or transfusion, were older, female, and had more comorbidities. Compared with patients who did not bleed or receive a transfusion, individuals who bled, were transfused, or bled and were transfused, had higher in-hospital mortality (18.6%, 30.3%, and 30.4%, respectively [P < 0.0001]). The association remained after adjustment: bleeding (odds ratio [OR], 2.0; 95% confidence interval [CI], 1.8-2.4), transfusion (OR, 4.4; 95% CI, 3.9-4.9), and bleeding and transfusion (OR, 3.8; 95% CI, 3.2-4.6). Conclusions: The proportion of Canadian STEMI patients who experienced in-hospital bleeding and transfusion has decreased over the past 9 years. However, patients with bleed or transfusion remain at higher risk of adverse outcomes. Résumé: Introduction: Bien que la prise en charge de l’infarctus du myocarde avec élévation du segment ST (STEMI) ait considérablement ait considérablement évoluée au cours de la dernière décennie, on ignore en grande partie ses répercussions sur les taux d’hémorragies et de transfusions dans la population contemporaine. Méthodes: Notre étude de cohorte regroupait des patients de 20 ans ou plus qui avaient été hospitalisés en raison d’un STEMI entre 2007 et 2016 dans toutes les provinces canadiennes, excepté le Québec. Nous avons calculé globalement et pour chacune des provinces les taux non ajustés d’hémorragies et de transfusions durant les épisodes de STEMI en fonction de l’année financière. Nous avons réparti les patients en quatre groupes en fonction de leurs hémorragies/transfusions. Nous avons comparé les caractéristiques, le traitement et les issues entre les groupes. Nous avons utilisé la modélisation par régression logistique multivariée pour évaluer l’association entre les hémorragies et les transfusions par rapport à la mortalité à l’hôpital. Résultats: À partir des 108 832 épisodes de STEMI, les taux d'hémorragies et de transfusions à l’hôpital ont baissé entre 2007 et 2016 de 3,9 % à 2,8 % (P < 0,0001) et de 4,7 % à 3,8 % (P < 0,0001), respectivement. Toutefois, nous avons observé la variation des taux d’hémorragies et de transfusions dans toutes les provinces canadiennes. Les patients qui avaient des hémorragies ou des transfusions, étaient plus âgés, de sexe féminin, et avaient plus de comorbidités. Comparativement aux patients qui n’avaient pas d’hémorragie ou qui ne recevaient pas de transfusion, les individus qui avaient une hémorragie, subissaient une transfusion, ou avaient une hémorragie et subissaient une transfusion étaient exposés à une mortalité à l’hôpital plus élevée (18,6 %, 30,3 % et 30,4 %, respectivement [P < 0,0001]). L’association a subsisté après l’ajustement : hémorragie (ratio d’incidence approché [RIA], 2,0; intervalle de confiance [IC] à 95 %, 1,8-2,4), transfusion (RIA, 4,4; IC à 95 %, 3,9-4,9), et hémorragie et transfusion (RIA, 3,8; IC à 95 %, 3,2-4,6). Conclusions: La proportion de patients canadiens atteints de STEMI qui subissaient des hémorragies ou des transfusions à l’hôpital a diminué au cours des 9 dernières années. Toutefois, les patients qui avaient une hémorragie ou une transfusion demeuraient exposés à un risque plus élevé d’issues défavorables.

Abstract Background Adolescent-onset depression often results in a chronic and recurrent course, and is associated with worse outcomes relative to adult-onset depression. Targeting habitual depressive rumination, a specific known risk factor for relapse, may improve clinical outcomes for adolescents who have experienced a depressive episode. Randomized controlled trials (RCTs) thus far have demonstrated that rumination-focused cognitive behavioral therapy (RFCBT) reduces depressive symptoms and relapse rates in patients with residual depression and adolescents and young adults with elevated rumination. This was also observed in a pilot RCT of adolescents at risk for depressive relapse. Rumination can be measured at the self-report, behavioral, and neural levels- using patterns of connectivity between the Default Mode Network (DMN) and Cognitive Control Network (CCN). Disrupted connectivity is a putative important mechanism for understanding reduced rumination via RFCBT. A feasibility trial in adolescents found that reductions in connectivity between DMN and CCN regions following RFCBT were correlated with change in rumination and depressive symptoms. Method This is a phase III two-arm, two-stage, RCT of depression prevention. The trial tests whether RFCBT reduces identified risk factors for depressive relapse (rumination, patterns of neural connectivity, and depressive symptoms) in adolescents with partially or fully remitted depression and elevated rumination. In the first stage, RFCBT is compared to treatment as usual within the community. In the second stage, the comparator condition is relaxation therapy. Primary outcomes will be (a) reductions in depressive rumination, assessed using the Rumination Response Scale, and (b) reductions in resting state functional magnetic resonance imaging connectivity of DMN (posterior cingulate cortex) to CCN (inferior frontal gyrus), at 16 weeks post-randomization. Secondary outcomes include change in symptoms of depression following treatment, recurrence of depression over 12 months post-intervention period, and whether engagement with therapy homework (as a dose measure) is related to changes in the primary outcomes. Discussion RFCBT will be evaluated as a putative preventive therapy to reduce the risk of depressive relapse in adolescents, and influence the identified self-report, behavioral, and neural mechanisms of change. Understanding mechanisms that underlie change in rumination is necessary to improve and further disseminate preventive interventions. Trial registration ClinicalTrials.gov Identifier: NCT03859297 , registered 01 March 2019.

Background: Following the occurrence of an acute coronary syndrome (ACS), patients are at high risk for subsequent cardiovascular events. Therapies to lower the level of low-density lipoprotein (LDL) cholesterol remain a pillar in secondary prevention approaches following ACS. Significant variability remains in the application of therapies to lower cholesterol level in clinical practice. Methods: A cross-sectional, online survey was conducted of 200 cardiovascular and lipid specialists across Canada who routinely care for patients following the occurrence of ACSs. The survey consisted of 50 multiple-choice questions with opportunities for free-text entry exploring knowledge of lipid guidelines and recent clinical trials, and in-hospital and outpatient management of lipids and familial hypercholesterolemia. Results: A total of 67.5% (n = 135) of participants stated that a lipid panel would routinely be obtained during the first 24 hours of an admission for an ACS, and 68.5% (n = 137) stated that their hospitals had standing orders for statin initiation at ACS presentation. In high-risk patients, the majority (75.5%; n = 151) of participants indicated that they target an LDL cholesterol level of 70% of their ACS patients were at or below guideline-recommended LDL cholesterol levels. Respondents generally underappreciated the prevalence of familial hypercholesterolemia in both the general population and ACS patients. Conclusions: There is significant variation in practice patterns involving therapies to lower LDL cholesterol level in the post–ACS onset period. To improve management of lipids in this high-risk population, changes to institutional policies, shared responsibility of lipid management across multiple disciplines, and physician education are required. Résumé: Contexte: Après un syndrome coronarien aigu (SCA), le risque qu’un autre événement cardiovasculaire survienne est élevé. Les traitements visant à réduire le taux de cholestérol des lipoprotéines de basse densité (C-LDL) demeurent l’un des piliers de la prévention secondaire après un SCA. Dans la pratique clinique, l’utilisation de ces traitements varie considérablement d’un praticien à l’autre. Méthodologie: Nous avons mené une enquête transversale en ligne auprès de 200 spécialistes de la santé cardiovasculaire et des lipides de partout au Canada, qui traitent régulièrement des patients ayant subi un SCA. L’enquête comprenait 50 questions à choix multiples; les participants pouvaient aussi donner des réponses détaillées permettant d’évaluer leurs connaissances des lignes directrices en matière de maîtrise des lipides et des essais cliniques récents, ainsi que de la prise en charge de la lipidémie et de l’hypercholestérolémie familiale en contexte hospitalier et ambulatoire. Résultats: Au total, 67,5 % (n = 135) des participants ont déclaré demander systématiquement un bilan lipidique complet dans les 24 heures suivant l’admission d’un patient en raison d’un SCA, et 68,5 % (n = 137) des participants ont dit que la norme dans leur hôpital était d’instaurer un traitement par statine chez tous les patients ayant subi un SCA. Dans le cas des patients présentant un risque élevé, la majorité des participants (75,5 %, n = 151) ont indiqué qu’ils ciblaient un taux de C-LDL de moins de 1,8 mmol/l. Une partie de ces répondants (22 %; n = 4) ont dit cibler un taux de C-LDL encore plus bas, soit de 0,5 à 1,7 mmol/l. Seulement 32,0 % (n = 64) des répondants ont déclaré que plus de 70 % de leurs patients ayant subi un SCA avaient un taux de C-LDL à la limite ou en deçà du taux recommandé dans les lignes directrices. Les répondants ont en général sous-estimé la prévalence de l’hypercholestérolémie familiale dans la population générale et chez les patients ayant subi un SCA. Conclusions: Les pratiques varient considérablement d’un praticien à l’autre en ce qui concerne les traitements visant à diminuer le taux de C-LDL après la survenue d’un SCA. Afin d’améliorer la prise en charge de la lipidémie dans cette population exposée à un risque élevé, il conviendrait de revoir les politiques des établissements, de répartir la responsabilité de la prise en charge de la lipidémie entre les intervenants de différentes disciplines et de mieux informer les médecins.

Neuropeptide Y (NPY) is a neurotransmitter that has been implicated in the development of anxiety and mood disorders. Low levels of NPY have been associated with risk for these disorders, and high levels with resilience. Anxiety and depression are associated with altered intrinsic functional connectivity of brain networks, but the effect of NPY on functional connectivity is not known. Here, we test the hypothesis that individual differences in NPY expression affect resting functional connectivity of the default mode and salience networks. We evaluated static connectivity using graph theoretical techniques and dynamic connectivity with Leading Eigenvector Dynamics Analysis (LEiDA). To increase our power of detecting NPY effects, we genotyped 221 individuals and identified 29 healthy subjects at the extremes of genetically predicted NPY expression (12 high, 17 low). Static connectivity analysis revealed that lower levels of NPY were associated with shorter path lengths, higher global efficiency, higher clustering, higher small-worldness, and average higher node strength within the salience network, whereas subjects with high NPY expression displayed higher modularity and node eccentricity within the salience network. Dynamic connectivity analysis showed that the salience network of low-NPY subjects spent more time in a highly coordinated state relative to high-NPY subjects, and the salience network of high-NPY subjects switched between states more frequently. No group differences were found for static or dynamic connectivity of the default mode network. These findings suggest that genetically driven individual differences in NPY expression influence risk of mood and anxiety disorders by altering the intrinsic functional connectivity of the salience network.

Annular rupture is a rare but life-threatening complication of transcatheter aortic valve replacement (TAVR). Mortality rates are high if immediate intervention, most often necessitating surgical repair, is not performed. Herein, we describe an 87-year-old man who, after deployment of TAVR, experienced acute decompensation and required urgent conversion to a midline sternotomy to repair an aortic annular rupture. This case demonstrates an example of a rare but severe complication of TAVR. This report provides an in-depth description of the surgical approach to repair an aortic annular rupture and demonstrates the utility of performing minimally invasive procedures inside a hybrid operating room.

Background: Although appropriate noninvasive cardiac tests (NICTs) after an acute coronary syndrome (ACS) provide useful prognostic information, inappropriate use leads to inefficient expenditure of existing healthcare resources. By using the Alberta Contemporary Acute Coronary Syndrome Patient Invasive Treatment Strategies (COAPT) Registry, we evaluated the use and costs of NICTs among patients discharged within 1 year after ACS. Methods: All patients discharged from the hospital with a primary diagnosis of ACS in Alberta between 2004/2005 and 2015/2016 were included. Frequency of NICTs (stress tests [± imaging] and nonstress imaging tests) was determined from linked provincial databases. Costs were obtained from the Alberta Health Care Insurance Plan Medical Procedure List. Results: Of 55,516 patients with ACS, 30,760 had at least 1 NICT (55.4%), with 13,505 (24.3%) having > 1 NICT performed within 1 year. Temporal trends of NICT increased over time (stress tests: P trend < 0.001; nonstress imaging tests: P trend < 0.001). NICT most commonly occurred within the first 4 months after hospital discharge (stress tests at 2 months; nonstress imaging tests at 3-4 months). In 2015/2016, the total estimated costs of NICT were $1.35M, a 22.4% increase from 2004/2005 (1.10M) (P < 0.001), whereas a decrease in incidence of ACS over the same time period was noted (P = 0.008). Conclusions: Rates of NICT 1 year after ACS are high and increasing over time. Estimated costs of NICT appear to be escalating out of proportion to the ACS growth. Further investigation is warranted because it is speculative whether the increase in NICT and costs results in clinical benefit after ACS. Résumé: Contexte: Bien que les différents examens cardiaques non effractifs (ECNE) effectués après un syndrome coronarien aigu (SCA) fournissent des renseignements utiles au pronostic, leur emploi dans des situations inappropriées entraîne un gaspillage des ressources en santé. À l’aide du registre COAPT (Contemporary Acute Coronary Syndrome Patient Invasive Treatment Strategies) de l’Alberta, nous avons évalué l’emploi des ECNE et les coûts qui y sont associés chez les patients qui ont reçu leur congé de l’hôpital dans l’année suivant un SCA. Méthodologie: Tous les patients qui ont reçu leur congé de l’hôpital après un diagnostic primaire de SCA en Alberta entre 2004-2005 et 2015-2016 ont été inclus. La fréquence des ECNE (épreuves d’effort [avec ou sans examen d’imagerie] et examens d’imagerie au repos) a été déterminée à partir des bases de données provinciales couplées. Les coûts ont été établis à partir de la liste des actes médicaux du régime d’assurance-maladie de l’Alberta. Résultats: Des 55 516 patients ayant présenté un SCA, 30 760 ont subi au moins un ECNE (55,4 %) dans l’année qui a suivi l’événement; 13 505 (24,3 %) d’entre eux ont subi plus d’un ECNE. Les tendances temporelles en matière d’ECNE affichent une hausse (épreuves d’effort : p tendance < 0,001; examens d’imagerie au repos : p tendance < 0,001). Les ECNE ont généralement été effectués au cours des 4 premiers mois après la sortie de l’hôpital (épreuves d’effort, dans les 2 mois; examens d’imagerie au repos, dans les 3 à 4 mois). Le coût total des ECNE effectués en 2015-2016 a été évalué à 1,35 M$, soit une hausse de 22,4 % par rapport à 2004-2005 (1,10 M$) (p < 0,001), tandis que l’incidence des SCA a diminué au cours de la même période (p = 0,008). Conclusions: Les taux d’ECNE effectués dans l’année suivant un SCA sont élevés et augmentent au fil du temps. Le coût estimatif de ces ECNE semble s’accroître de façon disproportionnée par rapport à la croissance des SCA. Une enquête plus approfondie s’impose; à l’heure actuelle, on ne peut que spéculer quant aux bienfaits cliniques qui découlent de l’augmentation des ECNE effectués après un SCA et des coûts qu’ils engendrent.

Munoz-Alia and colleagues1 demonstrate that neutralizing antibody immunity to measles resists viral evolutionary escape because it targets numerous distinct viral epitopes. Their work contributes to our understanding of what determines whether a virus can evolve to evade immunity.

Estimates of the risk of recurrent cardiovascular events (residual risk) among patients with acute coronary syndromes have largely been based on clinical trial populations. Our objective was to estimate the residual risk associated with common comorbidities in a large, unselected, population-based cohort of acute coronary syndrome patients. 31,056 ACS patients (49.5%-non-ST segment elevation myocardial infarction [NSTEMI], 34.0%-ST segment elevation myocardial infarction [STEMI] and 16.5%-unstable angina [UA]) hospitalised in Alberta between April 2010 and March 2016 were included. The primary composite outcome was major adverse cardiovascular events (MACE) including: death, stroke or recurrent myocardial infarction. The secondary outcome was death from any cause. Cox-proportional hazard models were used to identify the impact of ACS type and commonly observed comorbidities (heart failure, hypertension, peripheral vascular disease, renal disease, cerebrovascular disease and diabetes). At 3.0 +/- 3.7 years, rates of MACE were highest in the NSTEMI population followed by STEMI and UA (3.58, 2.41 and 1.68 per 10,000 person years respectively). Mortality was also highest in the NSTEMI population followed by STEMI and UA (2.23, 1.38 and 0.95 per 10,000 person years respectively). Increased burden of comorbidities was associated with an increased risk of MACE, most prominently seen with heart failure (adjusted HR 1.83; 95% CI 1.73-1.93), renal disease (adjusted HR 1.52; 95% CI 1.40-1.65) and diabetes (adjusted HR 1.51; 95% CI 1.44-1.59). The cumulative presence of each of examined comorbidities was associated with an incremental increase in the rate of MACE ranging from 1.7 to 9.98 per 10,000 person years. Rates of secondary prevention medications at discharge were high including: statin (89.5%), angiotensin converting enzyme inhibitor/angiotensin receptor blocker (84.1%) and beta-blockers (85.9%). Residual cardiovascular risk following an acute coronary syndrome remains high despite advances in secondary prevention. A higher burden of comorbidities is associated with increased residual risk that may benefit from aggressive or novel therapies.

Background The ISCHEMIA (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches) trial failed to show a reduction in hard clinical end points with an early invasive strategy in stable ischemic heart disease (SIHD). However, the influence of left main disease and high‐risk coronary anatomy was left unaddressed. In a large angiographic disease‐based registry, we examined the modulating effect of revascularization on long‐term outcomes in anatomically high‐risk SIHD. Methods and Results 9016 patients with SIHD with high‐risk coronary anatomy (3 vessel disease with ≥70% stenosis in all 3 epicardial vessels or left main disease ≥50% stenosis [isolated or in combination with other disease]) were selected for study from April 1, 2002 to March 31, 2016. The primary composite of all‐cause death or myocardial infarction (MI) was compared between revascularization versus conservative management. A total of 5487 (61.0%) patients received revascularization with either coronary artery bypass graft surgery (n=3312) or percutaneous coronary intervention (n=2175), while 3529 (39.0%) patients were managed conservatively. Selection for coronary revascularization was associated with improved all‐cause death/MI as well as longer survival compared with selection for conservative management (Inverse Probability Weighted hazard ratio [IPW‐HR] 0.62; 95% CI 0.58 to 0.66; P

Clinical trials registrationNCT01905267, https://clinicaltrials.gov/ct2/show/NCT01905267.

Transcatheter aortic valve replacement has transitioned from an experimental procedure to an important alternative therapy for patients with symptomatic aortic stenosis and high surgical risk. We present a case outlining an approach to deal with the issue of “failure to cross” the aortic valve in transcatheter aortic valve replacement from the transfemoral retrograde approach. Résumé: Le remplacement valvulaire aortique par cathéter est passé d’une intervention expérimentale à un traitement alternatif important pour les patients atteints d’une sténose aortique symptomatique et exposés à un risque opératoire élevé. Nous présentons un cas qui décrit une approche pour remédier au problème d’« échec à traverser » la valvule aortique lors du remplacement valvulaire aortique par cathéter selon une approche par voie rétrograde fémorale.

Abstract Cutaneous mucormycosis is an emerging fungal infection caused by opportunistic fungi of the phylum Glomeromycota. It is frequent in poorly controlled diabetic patients and individuals with immunosuppression. It is usually acquired by direct inoculation through trauma. The clinical presentation is nonspecific, but an indurated plaque that rapidly evolves to necrosis is a common finding. Diagnosis should be confirmed by demonstration of the etiological agent and new molecular diagnostic tools have recently been described. It is an invasive life-threatening disease and in order to improve survival, a prompt diagnosis and multidisciplinary management should be provided. The treatment of choice is amphotericin B, but new azoles, such as posaconazole and isavuconazole, must be considered.

Objectives: The goal of this study was to better understand the changes in tissue microstructure that underlie white matter diffusion changes in ALS patients. Methods: Diffusion tensor imaging was carried out in postmortem brains of 4 ALS patients and two subjects without neurological disease on a 7T MRI scanner using steady-state free precession sequences. Fractional anisotropy (FA) was measured in the genu, body, and splenium of the corpus callosum in formalin-fixed hemispheres. FA of the body and genu was expressed as ratio to FA of the splenium, a region unaffected in ALS. After imaging, tissue sections of the same segments of the callosum were stained for markers of different tissue components. Coded image fields were rated for pathological changes by blinded raters. Results: The FA body/FA splenium ratio was reduced in ALS patients compared to controls. Patchy areas of myelin pallor and cells immunostained for CD68, a microglial-macrophage marker, were only observed in the body of the callosum of ALS patients. Blinded ratings showed increased CD68+ microglial cells in the body of the corpus callosum in ALS patients, especially those with C9orf72 mutations, and increased reactive astrocytes throughout the callosum. Conclusion: Reduced FA of the corpus callosum in ALS results from complex changes in tissue microstructure. Callosal segments with reduced FA had large numbers of microglia-macrophages in addition to loss of myelinated axons and astrogliosis. Microglial inflammation contributed to reduced FA in ALS, and may contribute to a pro-inflammatory state, but further work is needed to determine their role. Keywords: 7T MRI, Amyotrophic lateral sclerosis, Microglia, Motor neuron disease, Pathology, Steady-state free precession

Chelonid alphaherpesviruses 5 and 6 (ChHV5 and ChHV6) are viruses that affect wild sea turtle populations. ChHV5 is associated with the neoplastic disease fibropapillomatosis (FP), which affects green turtles (Chelonia mydas) in panzootic proportions. ChHV6 infection is associated with lung-eye-trachea disease (LETD), which has only been observed in maricultured sea turtles, although antibodies to ChHV6 have been detected in free-ranging turtles. To better understand herpesvirus prevalence and host immunity in various green turtle foraging aggregations in Florida, USA, our objectives were to compare measures of innate and adaptive immune function in relation to (1) FP tumor presence and severity, and (2) ChHV5 and ChHV6 infection status. Free-ranging, juvenile green turtles (N = 45) were captured and examined for external FP tumors in Florida’s Big Bend, Indian River Lagoon, and Lake Worth Lagoon. Blood samples were collected upon capture and analyzed for ChHV5 and ChHV6 DNA, antibodies to ChHV5 and ChHV6, in vitro lymphocyte proliferation using a T-cell mitogen (concanavalin A), and natural killer cell activity. Despite an overall high FP prevalence (56%), ChHV5 DNA was only observed in one individual, whereas 20% of turtles tested positive for antibodies to ChHV5. ChHV6 DNA was not observed in any animals and only one turtle tested positive for ChHV6 antibodies. T-cell proliferation was not significantly related to FP presence, tumor burden, or ChHV5 seroprevalence; however, lymphocyte proliferation in response to concanavalin A was decreased in turtles with severe FP (N = 3). Lastly, green turtles with FP (N = 9) had significantly lower natural killer cell activity compared to FP-free turtles (N = 5). These results increase our understanding of immune system effects related to FP and provide evidence that immunosuppression occurs after the onset of FP disease.