VictorJuiz/thesis huggingface dataset:
The Neural Correlates of Mental Flexibility in Children with Neurodevelopmental Disorders
Keywords: ADHD
ASD
Child
Magnetoencephalography
Mental Flexibility
Neurodevelopmental Disorders

Mental flexibility is an important executive function, facilitating flexibility in thought and action. Neurodevelopmental disorders represent a heterogeneous group of disorders, characterized by impaired brain development and function. Despite shared impairments in mental flexibility, it is not known whether the various neurodevelopmental disorders share the same aberrant neural correlates. To investigate, children [total n=110, ages 8-15 years; 22 typically developing, 38 autism spectrum disorder (ASD), 28 attention deficit hyperactivity disorder (ADHD), 22 obsessive-compulsive disorder (OCD)] completed a mental flexibility task in a magnetoencephalograph (MEG). Results revealed that typically developing children generally relied on the expected fronto-parietal network. However, all clinical groups showed an atypical reliance on the parietal regions, while patterns of delayed and atypical frontal activity differentiated the three clinical groups. This is the first neuroimaging study to elucidate the similarities and differences in the spatio-temporal profiles of neural regions involved in mental flexibility in children with neurodevelopmental disorders.
Oculomotor Function Testing and White Matter Integrity in Patients with Post-Concussion Syndrome
Keywords: Concussion
Post-concussion syndrome
self-paced saccades

Objectives: To assess self-paced saccadic (SPS) eye movements in patients with postconcussion syndrome (PCS), and use diffusion tensor imaging (DTI) to determine the white matter (WM) neural correlates of these eye movements. Methods: Fifty-nine PCS patients with at least two concussions performed the SPS task. We evaluated the relationships between the number of SPS and the number of self-reported symptoms and integrity of major WM tracts involved in visual processing (uncinate fasciculus (UF), cingulum (Cg), superior longitudinal fasciculus, and corpus callosum). Results: Number of SPS was negatively correlated with the total number of symptoms patients reported (r=-0.419, p=0.026). Positive correlations were seen between number of SPS and fractional anisotropy of left UF and left Cg (r=0.421, p=0.013; and r=0.452, p=0.008; respectively). Conclusion: SPS testing may reflect symptom burden in patients with PCS and since it is associated with WM integrity, it could be a diagnostic biomarker in patients with PCS.
Characterizing effects of small molecule inhibition of WDR5 in colorectal cancer
Keywords: Colorectal Cancer
Epigenetics
WDR5

Abstract WDR5 is a core subunit of the MLL-WRAD methyltransferases, NSL-MOF acetyltransferases and MYC-MAX transcription factors. Dysregulation of these complexes has been implicated in numerous cancers. Despite links between colorectal cancer (CRC) and WDR5, little is known about its role. Using OICR11824, an internally developed novel chemical antagonist of WDR5, we investigated the biological effects of targeting the arginine binding pocket of WDR5 in CRC. Firstly, we evaluated the ability of OICR11824 to bind and disrupt WDR5-MLL interaction in cells. We then utilized OICR11824 and shRNA knockdown to investigate effects of WDR5 inhibition on proliferation in CRC cell lines. In addition, Western blot and RT-PCR were performed to confirm modulation of H3K4 methylation and expression of MYC-transcriptional targets. Finally, flow cytometry was used to evaluate effects of WDR5 inhibition on cell cycle. Our research shows that OICR11824 binds and inhibits the WDR5-MLL interaction. As well, OICR11824 displays a range of anti-proliferation potencies in CRC cell lines with the greatest sensitivity seen in COLO205 demonstrating a G1 accumulation and S-phase depletion. Finally, OICR11824 affects the actions of WDR5-complexes in MYC-WDR5 gene targets and H3K4 trimethylation. Our research provides new insights into the role of WDR5 in CRC and will contribute to not only developing new therapeutics against CRC, but will also help elucidate the role of WDR5 complexes in cancer.
Regulation of Hepatic CYP3A4 by 3-Methylcholanthrene in Humanized PXR-CAR-CYP3A4/3A7 Mice
Keywords: aryl hydrocarbon receptor
Cyp3a11
drug metabolism
drug metabolizing enzyme
P450
polycyclic aromatic hydrocarbon

Polycyclic aromatic hydrocarbons (PAHs) are environmental pollutants that activate the aryl hydrocarbon receptor, triggering many biological effects typified by induction of cytochrome P450 1A1 (CYP1A1). Interestingly, little is known about their effects on human CYP3A4, despite this enzymeâ s clinical relevance. Controversially, studies have reported both inductive and suppressive effects of PAHs on CYP3A expression. The current study used 3-methylcholanthrene (3-MC) to study the effects of PAHs on CYP3A4 activity and expression in humanized PXR-CAR-CYP3A4/3A7 mice. Adult mice were treated by intraperitoneal injection with 3-MC (80 mg/kg), or corn oil vehicle, and euthanized 24 or 72 hours later. Basal hepatic CYP3A4 activity and expression was significantly higher in female vs. male mice. 3-MC decreased CYP3A4 activity and expression in female mice at 72 hours, whilemales showed similar, but non-statistically significant, trends. This mouse model will facilitate further in vivo studies of the mechanisms and consequences of CYP3A4 suppression by PAHs.
Evaluating Pre-existing Cognitive Impairment and Anticholinergic Burden as Predictors of Post-operative Delirium following TAVI (Transcatheter Aortic Valve Implantation)
Keywords: cardiology
geriatric
pharmacology
psychiatry
treatment optimization

Post-operative delirium (POD) is common following Transcatheter Aortic Valve Implantation (TAVI) and is associated with adverse health outcomes. We hypothesized that cognitive impairment and anticholinergic burden may exacerbate risk of POD in TAVI due to their effects on cholinergic pathways underlying delirium. Cognitive deficits were screened using the Mini-Cog test before TAVI and anticholinergic burden assessed using the Anticholinergic Cognitive Burden (ACB) scale. Logistic regression adjusted for age, history of stroke, atrial fibrillation, diabetes and anesthesia found that neither the Mini-Cog (OR: 6.62, p=0.09) nor the ACB scale (OR: 1.62, p=0.17) were significant independent predictors of POD when assessed individually. When assessed together, patients screening positive on the Mini-Cog and with a high ACB scale score (OR 6.94, p=0.01) predicted increased risk of POD in a significant model (Ď 2 (6) =29.1, p
Determining the Natural History of Men with Initially Negative Prostate Biopsies
Keywords: Diagnosis
Population Health
Prostate Biopsy
Prostate Cancer
Sensitivity and Specificity
Survival

Prostate biopsies have significant false negative rates. Thus, men with negative results may undergo continued evaluation for prostate cancer. Long-term prostate cancer diagnosis, mortality, and treatment rates are currently unknown in North American men with a negative prostate biopsy. We thus aimed to determine the long-term rates and predictors of these outcomes. Using linked health administrative data, we identified 95,655 men with a single negative prostate biopsy. The outcomes cumulative rates were determined under a competing risk setting and regression analysis was used to assess potential predictors. The 20-year prostate cancer diagnosis and mortality cumulative rates were 23.7% and 1.8%, respectively. Older patients had higher cancer diagnosis and mortality risks; whereas men of higher socioeconomic status and urban residence had increased cancer diagnosis, yet lower cancer mortality risks. These results will allow physicians to inform patients of their cancer-specific outcomes and identify men at higher risk of adverse long-term outcomes.
The Role of Family Physicians in Palliative Care: Perspectives of Patients with Advanced Cancer
Keywords: Early Palliative Care
Family Physicians
General Practitioners
Palliative Care
Palliative Care Physicians
Supportive Care

Introduction: Early palliative care is recommended for advanced cancer patients and can be provided by family physicians(FPs). This study examines patient perspectives of FPs’ palliative care involvement. Methods: Advanced cancer patients attending an Oncology Palliative Care Clinic(OPCC) completed a survey about FP involvement. Eligible patients were English-speaking, ≥18years old, had >1prior OPCC visit, passed a cognitive screen, and had a FP within 5years. Results: Of 79 patients, 58%(46/79) were female; mean age was 58.25±13.11. Seventy-seven(97.5%) currently had a FP and 33%(26/79) had seen them recently for palliative care. As hypothesized, most patients preferred to receive palliative care from their palliative care physician. Possible barriers to FP-provided palliative care included lack of knowledge of FP services, timely access to care, and perceived role of the FP. Conclusion: Patients were overall engaged with their FPs but many had not seen their FP for palliative care. Possible barriers to this care were identified.
Resting-state functional MRI predictors and correlates of response to rTMS in major depression
Keywords: fMRI
major depression
rTMS
salience network
ventromedial network

Major depressive disorder (MDD) is a debilitating and prevalent psychiatric illness for which an emerging treatment is repetitive transcranial magnetic stimulation (rTMS). Several recent studies have used functional brain imaging modalities to characterize neural predictors and correlates of rTMS response in MDD. Specifically, responders to rTMS may exhibit varying functional abnormalities among brain regions that play roles in cognition, attention, or reward response. Here, using a cohort of 303 patients who received one of two rTMS stimulation protocols, we aimed to identify functional MRI predictors and correlates of response to left dorsolateral prefrontal cortex (dlPFC)- rTMS. Based on baseline and post-treatment change in whole-brain functional connectivity to a selection of cortical, striatal, and network-wide seed regions, we identified several predictors and correlates of treatment response that comprise a ventromedial and orbitofrontal functional loop. This study represents a step to understanding maladaptive network interactions in MDD, the impact of non-invasive brain stimulation on improving inter-network function, and the role of functional brain networks in motivation, valuation, and behaviour.
Examining Brain and Body Correlates of Cerebrovascular Reactivity Among Adolescents with and without Bipolar Disorder
Keywords: adolescents
bipolar disorder
blood-oxygenation-level dependent
breath-hold
cerebrovascular reactivity
magnetic resonance imaging

Cardiovascular disease (CVD) is excessive and premature among individuals with bipolar disorder (BD). Cerebrovascular reactivity (CVR), a marker of cerebrovascular health, is the capacity of the brainâ s blood vessels to vasodilate when induced by vasoactive substances. We examined this topic for the first time in BD. CVR was measured in 25 adolescents with BD and 25 age and sex-matched psychiatrically healthy controls (HCs). Whole-brain analyses showed that BDs have lower CVR in the posterior cingulate gyrus and periventricular white matter. When controlling for differences in body mass index (BMI), additional between group CVR differences were observed in the temporal poles, supramarginal gyrus and lingual gyrus. There were no significant clusters of the brain that were BD>HC. Our results suggest that CVR may be a proxy for future risk of CVD and/or cerebrovascular disease, given the location of anomalous CVR within regions where cerebrovascular pathology occurs in mid-life.
Investigating the central role of astrocytes in mediating postanesthetic memory deficits
Keywords: Anesthesia
Astrocytes
Electrophysiology
Memory
Îł-aminobutyric acid

Anesthetics cause postanesthetic memory deficits in animal models, and similar deficits may contribute to postoperative delirium and cognitive dysfunction in patients. We previously showed using a mouse model that etomidate-induced persistent memory deficits result from increased tonic GABAA receptor-mediated inhibitory current in the hippocampus, through an astrocyte-mediated mechanism. However, the underlying mechanisms are uncertain. The aims of this study were to: 1) determine whether widely used anesthetic and sedative agents persistently increase tonic GABAA current; 2) determine whether human astrocytes mediate the increase, and 3) identify the underlying mechanisms. The results show that several GABAergic drugs persistently increase tonic current and human astrocytes release soluble factors that mediate etomidateâ s effect on tonic current. Furthermore, etomidate and sevoflurane act through astrocytic GABAA receptors to trigger a pro-inflammatory signaling pathway, which underlies the persistent increase in tonic current. These results increase the mechanistic understanding of postanesthetic memory deficits and delineate treatment targets.
Elucidating the Regulation of ADAM17 Mediated Shedding of CX3CL1 from Vascular Endothelial Cells
Keywords: ADAM17
CX3CL1
Endothelial Cells
Single Particle Tracking
Vascular Inflammation

CX3CL1 is an inducible chemokine that functions either as a transmembrane adhesion molecule, or when cleaved, as a soluble chemoattractant for leukocytes. Exposure to inflammatory mediators induces extensive proteolysis of CX3CL1 by the transmembrane protease ADAM17 in endothelial cells. The mechanisms governing this shedding remain undefined. Using single particle tracking, we found that CX3CL1 and ADAM17 were segregated at the plasma membrane. After stimulation with ADAM17 activator, PMA, CX3CL1 mobility remained unchanged while a small amount of ADAM17 was released from confinement. A modest increase in freely diffusing ADAM17 was observed after disruption of the actin cytoskeleton. Our data suggest that PMA has a modest effect on ADAM17 mobility and that the remodeling of actin cytoskeleton is unlikely to be the main mechanism of ADAM17-mediated proteolysis of CX3CL1. Even though Î˛1 integrin activation has been suggested to regulate ADAM17 activity, our data suggests that it is insufficient for PMA-induced CX3CL1 shedding.
Assessing the Relationship of White Matter Hyperintensities and Grey Matter to Neuropsychiatric Symptoms in Alzheimer's Disease and Mild Cognitive Impairment
Keywords: Alzheimer's disease
grey matter
mild cognitive impairment
neuropsychiatric symptoms
white matter hyperintensities

Neuropsychiatric symptoms (NPS), including apathy, irritability and depression, are frequently encountered in patients with Alzheimer's disease (AD). Focal brain lesions, particularly in the frontotemporal regions, have been linked to the development of NPS. Cerebrovascular disease (CVD) can cause focal lesions and is common among patients with AD. CVD can be detected on MRI as white matter hyperintensities (WMH). The current study aimed to evaluate WMH burden and regional cortical atrophy in MCI and AD and determine their relationship with NPS. WMH and grey matter lobar volumes were measured and NPS were assessed using the Neuropsychiatric Inventory. We found lower frontal, temporal and parietal GM volume and higher frontal WMH volume to be associated with NPS, with GM atrophy associated with symptom progression over 2 years. This study could provide a better understanding of the pathophysiology of NPS in AD and other dementias.
The Behavioural and Neural Correlates of Social Cognition: A Dimensional Approach in Youth with Mental Illness
Keywords: Clustering
Similarity Network Fusion
Social Cognition
Structural MRI
Subtyping
Youth Mental Health

Heterogeneity in social cognitive performance and social function is a major obstacle in the identification of consistent biomarkers of impairment for schizophrenia spectrum disorders (SSD), autism spectrum disorders (ASD), and bipolar disorder (BD). Improved etiological subtyping and a better understanding of mediating mechanisms in neural circuits could facilitate targeted treatment development based on underlying pathology. This thesis explores the usefulness of Similarity Network Fusion (SNF), a transdiagnostic and data-driven clustering approach, in uncovering more neurobiologically homogenous groups of individuals with social cognitive impairments. The integration of multi-modal neuroimaging, social cognitive, neurocognitive, and demographic data reveal four distinct groups of participants across SSD, ASD, BD, and healthy youth with differing neuroanatomical profiles in key nodes of the fronto-parietal and cortical midline circuits. Our findings suggest that structural neural circuit deficits may help explain poor social cognitive performance in SSD, ASD, and BD.
Maximizing Survival Through the Staged Surgical Management of Hypoplastic Left Heart Syndrome and its Related Malformations
Keywords: Dynamic risk profile
Hypoplastic left heart syndrome
Real time risk assessment
Single ventricle palliation
Timing of surgery

Objective: Mortality during 3-stage single ventricle palliation is much greater before vs. after stage-2-palliation (S2P). We investigated how the timing of S2P and post-Norwood events affect survival. Methods: The optimal timing of S2P was determined with conditional survival analysis. Post-Norwood events and measures, as time-varying covariates (TVC), were used to generate dynamic, patient-level risk profiles. Results: In low/intermediate-risk infants, performing S2P at ≥3 months old was associated with 89±3% and 82±3% 2-year survival, respectively. In high-risk infants, 2-year survival was ≤63±5% when S2P was performed at ≤6 months old. When accounting for post-Norwood events, weights, and SaO2, TVCs displaced baseline and operative characteristics. Because risk factors occurred over time, an infant’s mortality risk varied. Conclusion: S2P should be performed after age 3 months for low/intermediate-risk infants. High-risk infants are unlikely to complete three-stage palliation. By visually depicting risk
Management of Stroke Risk in Patients on Hemodialysis with Non-Valvular Atrial Fibrillation: A Comparison of Cardiologists and Nephrologists in Canada
Keywords: anticoagulant
antiplatelet
atrial fibrillation
bleed
hemodialysis
stroke

Antithrombotic therapy for stroke prevention in atrial fibrillation (AF) is standard practice, but for hemodialysis (HD) patients, the benefits are unclear and risks are high. Our study objectives were to compare cardiologistsâ and nephrologistsâ stroke prevention practices in this population and their associated decisional certainty. A cross-sectional, online survey was distributed to members of three Canadian physician societies (Nephrology, Cardiovascular, Heart Rhythm), and to cardiologists at three Universities. The questionnaire included four scenarios of AF in HD patients with varying stroke and bleeding risks. Respondents selected from treatment options and rated their level of certainty. Cardiologists were 3 times more likely than nephrologists to choose anticoagulant therapy, regardless of stroke or bleeding risk. Level of certainty differed between specialties across scenarios; however, this finding is not conclusive. Due to the low response rate (9%), results must be considered tentative. Physicians in Canada are encouraged to consider these differences in prescribing.
Predictors of Mammographic Density among Women at a High Risk for Breast Cancer
Keywords: breast cancer
family history
lifestyle
mammographic density

Whether mammographic density, a strong predictor of breast cancer risk, is associated with breast cancer risk factors in women at an increased risk of familial breast cancer is unclear. Therefore, this study evaluated the associations between reproductive, hormonal, anthropometric, and lifestyle risk factors and measures of mammographic density (percent density, dense area, non-dense area) among high-risk, BRCA mutation-negative women. Overall, parity and body weight were inversely associated with percent density and positively associated with non-dense area. Increasing height was positively associated with percent density and inversely associated with non-dense area. A later age at smoking and alcohol initiation were positively associated with mammographic density. Among postmenopausal women only, past smoking was inversely associated with mammographic density. In premenopausal women only, an increasing duration of smoking was inversely associated with mammographic density. These findings suggest that mammographic density is associated with several modifiable breast cancer risk factors among this high-risk cohort.
Examining the Heterogeneity in Schizophrenia Using Top-Down and Bottom-Up Approaches
Keywords: Diffusion Tensor Imaging (DTI)
Meta-Analysis
Resting-State Functional Magnetic Resonance Imaging (rsfMRI)
Schizophrenia
Sex
White Matter

Schizophrenia is a heterogeneous disorder. Demographic, clinical, neurobiological and methodological sources of heterogeneity have all likely impeded biomarker discovery. The objectives of this work were to use a ‘top-down’ and ‘bottom-up’ approach respectively to begin to disentangle 1) the effect of sex on structural connectivity 2) and the effect of variable spatial organization of the brain on functional connectivity in schizophrenia. In study 1, larger differences in white matter diffusion-based measures between patients and controls were observed in females compared to males. One interpretation of this result is that female patients require a larger biological hit to manifest schizophrenia symptoms. In study 2, correcting for variability in the topography of the brain reduced or eliminated several functional connectivity differences between schizophrenia patients and controls. These findings provide new windows of understanding into the heterogeneity of brain structure and function in people with schizophrenia.
Automated Immunohistochemical Analysis of the Orbitofrontal Cortex in Patients with Schizophrenia, Bipolar Disorder and Major Depressive Disorder
Keywords: CUX2
Immunohistochemistry
Post-mortem brain tissue
ZNF312

Previous studies have found evidence for orbitofrontal cortex (OFC) pathology in major depressive disorder (MDD), bipolar disorder (BP) and to a lesser extent schizophrenia (SCZ). However, given that the OFC is a large heterogeneous area, it is difficult to assess how findings from small subareas translate to the entire region. The aim of this thesis is to analyze the entire OFC in patients with MDD, BP and SCZ. Using a novel approach with layer-specific immunohistochemical markers and an automated counting protocol, we were able to analyze the cortical width, cell density, cell area and distance from pia in the entire OFC of 60 post-mortem brain samples (15 control, 15 MDD, 15 BP, 15 SCZ). We did not find strongly significant differences between patients and control subjects. Our findings suggest that inconsistencies in the literature may arise from sampling only small areas of the cortex in a limited number of subjects.