NCube/papyrus huggingface dataset:
Optimiser le réchauffement chez le nouveau-né asphyxié soumis à l'hypothermie thérapeutique

Neonatal hypoxic-ischemic encephalopathy (HIE) remains the leading cause of death and mortality in the term infant. A third of the survivors will develop neurological sequelae including cerebral palsy (CP), epilepsy and mental retardation. In order to improve their prognosis, these newborns undergo therapeutic hypothermia (TH), which begins no later than 6 hours after birth, maintained for a total duration of 72 hours and followed by gradual rewarming (0.5°C/h). This neuroprotective therapy has been shown to significantly decrease the extent of brain injury and the frequency of neurological sequelae. Results from animal studies revealed that ongoing hypothermia without proper anesthesia is not beneficial. Based on the observations that have been reported, piglets treated with TH with no analgesics have shown signs of instability and excessive tremors. Until now, the extent to which these results from animal experiments could be generalized to the newborn remained unknown.  Thus, the purpose of my master’s project was to better understand the clinical factors that may compromise the beneficial effects of TH, in an attempt to optimize neuroprotection and improve the neurological outcome of HIE infants. Our main objective was to assess the associations between opioid doses consumed during TH, shivering recorded during TH, and the evolution of EEG discontinuity index over the course of TH, rewarming and up to 12 hours post-TH. To meet the objective, we conducted a study in 21 newborns with HIE undergoing TH, and the results have shown significant associations between high doses of opioid administered (r = - 0.493, p = 0.023), reduced shivering stress (r = 0.513, p = 0.017) and improved EEG background activity. The key findings of the study are described in more detail in Chapter 2, which presents the original manuscript submitted for publication to the “Journal of Pediatrics”, and Chapter 3, which presents a review of the literature in light of our results. In Chapter 4, we discuss future perspectives and the clinical significance of our results. At last, we hope that our study will open up new avenues for improving neuroprotection, by systematically promoting a better management of pain and cooling-induced stress.

Keyphrases: Electroencephalography (EEG), Electromyography (EMG), Hypoxic-ischemic encephalopathy (HIE), Therapeutic hypothermia (TH), Rewarming, Opioid, Shivering
L’isolement cellulaire des détenus associé au risque de récidive violente et non violente : une revue systématique et méta-analyse

Recidivism amongst releasees bears heavy consequences for society in terms of financial costs and public health strain. Placing inmates in solitary confinement (SC) was adopted as a solution for disordered behaviors in prison, without indication as to its impacts on recidivism. Approximately 7% of North American inmates are housed in SC, many of whom will suffer psychological deterioration. Moreover, studies dispute that SC can reduce institutional misconduct, casting doubt on its potential for inspiring behavioral change. To clarify the effects of SC on recidivism would inform recent debates around its cost effectiveness and the evaluation of associated victimization risks. Therefore, a systematic review and meta-analysis were conducted to clarify the impact of SC on recidivism. Random-effects meta-analyses were carried out to quantify the association between SC and rearrest, reincarceration, and violent reoffense. Additional sub-analyses allowed to characterize recidivism risk following different forms of SC, lengthier periods of exposure, and shorter transition time between release from SC and to the community. Our article showed a moderate association between SC and increased recidivism, which remained robust to confounders. SC was associated with an increase in all forms of recidivism. Finally, longer and more recent exposure to SC upon release both further increased recidivism risk. This memoir thus provides further evidence that SC does not present significant benefits that could outweigh its associated mental health and financial costs. Finally, multiple initiatives are discussed in the context that they could facilitate community reentry for inmates exposed to SC.

Keyphrases: Violence, Prison, Solitary confinement, Segregation, Recidivism, Antisocial behavior, Prison, Restrictive housing, Criminal trajectory
La pression artérielle centrale : ses déterminants et son rôle dans la prédiction du risque cardiovasculaire

Compared to brachial blood pressure (BP), central BP is thought to be a better reflection of the hemodynamic strain on target organs. It is unclear though whether this translates into improved cardiovascular (CV) risk stratification when central BP is compared to brachial BP. The objectives of this thesis are to clarify the role of central BP in CV risk stratification, to define a threshold for the diagnosis of central hypertension and to determine what are the impacts of parameters, such as statins and LDL cholesterol, on central BP. The CARTaGENE database, which is comprised of 20,004 individuals, was used for these studies. The central BP (measured with the SphygmoCor Px device and type I calibration) as well as other CV risk factors were known. Prospective data for the incidence of major adverse cardiovascular events (MACE) was available. Cox proportional hazard models and measures of discrimination and reclassification were used to compare central systolic BP and brachial systolic BP in their ability to predict CV risk. A central hypertension threshold was determined using Youden’s index. The association between central BP, LDL cholesterol and statins were assessed using linear regression models and ANOVA. The interactions between central BP, statins and cholesterol LDL were assessed with a mediation analysis. Central BP was only marginally superior to brachial BP in CV risk prediction. A central hypertension threshold of 120 mmHg was identified. Statins reduced both brachial and central BP in a similar fashion, and cholesterol LDL was only partially responsible for the effect of statins on BP. To conclude, central BP, when assessed using type I calibration, is not superior to brachial BP in CV risk prediction. These studies also clarified the central hypertension threshold and the impact of statins and cholesterol LDL on central BP.

Keyphrases: Hypertension, Central blood pressure, Central hypertension, Cardiovascular diseases, Cardiovascular risk, LDL cholesterol, Statins
Rôle de l’acide urique dans la défaillance d’organes suite au choc hémorragique : une avenue thérapeutique?

While hemorrhagic shock is the first cause of early mortality among severe trauma patients, organ failure leads to late mortality and morbidity in this population. Alarmins, molecules released after ischemia-reperfusion, are able to activate local and systemic inflammatory pathways and potentially represent a therapeutic target to minimize organ failure. Uric acid is a pro-inflammatory and pro-apoptotic molecule released after hemorrhagic shock and its role pertaining to organ failure is incompletely studied. The first part of this thesis presents a proof of concept that uric acid plays a key role in liver and intestinal damage in an animal model of hemorrhagic shock; it will be presented in the format of a submitted article. The second part of this thesis presents preliminary data from a prospective observational clinical study evaluating uric acid kinetics in a cohort of trauma patients.  Animal study  Hemorrhagic shock was induced with blood withdrawal among Wistar rats for a target mean arterial blood pressure of 30-35 mmHg for 60 minutes. Animals were resuscitated with a 1 :1 mix of Ringer Lactate and drawn blood with or without Uricase, a recombinant enzyme that metabolizes uric acid. Results show a statistically significant decrease in hepatocellular damage (plasma AST and ALT), inflammatory markers (ICAM-1, MPO, TNF-alpha, IL-1, Caspase-1) and apoptotic markers (Caspase-3, -8, Bax/BCL-2, pAKT/AKT) among the Uricase group. The intervention on uric acid also prevented increased intestinal permeability and bacterial product (LPS) translocation. Clinical study  Twenty patients sustaining major trauma with hemorrhagic shock were prospectively recruited at Montreal Sacré-Cœur Hospital, in the context of a pilot study funded by the FRSQ trauma consortium. Uric acid concentration was determined serially for 7 days after trauma. Feasibility criteria, notably consent rate (95%), sampling observance rate (90% for first sample, 65% for samples every 4 hours, and 73% for samples every 8 hours) were considered acceptable. Uric acid kinetics were reproducible among the entire cohort (R2 = 0.87). The area under the curve was significantly increased among patients with higher sequential organ failure assessment score at 72h (SOFA³6).   Conclusions  Although mechanisms remain to be elucidated, these studies show that uric acid is an important mediator for the development of organ damage after hemorrhagic shock. This molecule potentially represents a therapeutic target with the ultimate goal of minimizing organ failure after hemorrhagic shock.

Keyphrases: Hemorrhagic shock, Trauma, Alarmins, Uric acid, Organ failure
Étude rétrospective sur l’adhésion aux lignes directrices canadiennes (CAMESA) de monitoring des effets métaboliques des antipsychotiques de seconde génération chez les enfants et les adolescents

Second generation antipsychotics (SGA) can induce metabolic effects such as weight gain, cardiometabolic disorders, endocrine effects and in very rare cases sudden cardiac death. The potential metabolic side effects of second generation antipsychotics need to be monitored. The Canadian Alliance for Monitoring the Efficacy and Safety of Antipsychotics (CAMESA) offers guidelines for this purpose. The objectives of this retrospective study are to evaluate, the long-term rates of youths receiving monitoring in mental health clinics and document the factors that may influence them. To this end, the charts of 180 children and adolescents (average age 13.3 ± 3.1 years, 54.4 % males) receiving SGA treatment for the first time between January 2016 and June 2018 were reviewed. Monitoring was divided into baseline and 1 to 6 and 9 to 24-month periods. The population under study was stratified into children (4-12 years) vs adolescents (13-18 years). Sociodemographic characteristics, psychiatric diagnosis and comorbidities, prescribed SGAs and comedications, anthropometric measurements (AM), blood pressure (BP), blood tests (BT), electrocardiogram (ECG) and the psychiatrist’s years of practice were collected. Cross tables were used to present the monitoring rates. Categories were compared by covariate analysis. Rates of patients monitored across categories were compared using Fisher’s exact test. Our results show that monitoring rates for AM, BT, and BP were: 55 %, 47.8 %, and 46.7 % at baseline, 50 %, 41.7 %, and 45.2 % at 1 to 6 months, and 47.2 %, 41.5 %, and 40.6 % at 9 to 24 months, respectively. Higher monitoring rates were significantly associated with adolescent status vs child (baseline AM, BT, and BP; 1-6-month AM and BP), a diagnosis of psychotic and/or affective disorder (baseline AM, BT, and BP; 1-6-month AM and BP; 9-24-month BT), having ≤ 1 psychiatric comorbidities (1-6-month BT), and clinician’s experience (1-6-month BT and ECG). In conclusion, five years after publication of the CAMESA guidelines, metabolic monitoring is conducted for less than half of patients and decreases over time. In our sample, age, diagnostic category, psychiatric comorbidities, and clinician’s experience influenced the monitoring rates. Major progress still needs to be made before reaching a satisfactory level of monitoring.

Keyphrases: Pediatric population, Outpatient psychiatric clinics, Second-generation antipsychotics, metabolic adverse events, metabolic monitoring guidelines
Étude de la fonction du récepteur aux acides gras GPR120/FFAR4 dans la régulation de l’homéostasie du glucose

In obese patients, type 2 diabetes stems from the failure of the insulin-secreting beta cells to compensate for insulin resistance. Increasing insulin secretion is therefore a viable treatment strategy. In this regard, G protein-coupled receptors (GPCR) are proven therapeutic targets. Activation of the GPCR for long-chain saturated and unsaturated fatty acid GPR40 and GPR120 increase insulin secretion in response to glucose. However, exactly how GPR120 potentiates insulin secretion is unknown. GPR120 and GPR40 both regulate glucose homeostasis and therefore could act in a complementary manner. We aimed to decipher GPR120 signalling in the pancreatic islets and study the complementary roles of GPR120 and GPR40 in maintaining glucose homeostasis. To this aim, we first measured insulin, glucagon and somatostatin secretion following GPR120 activation in isolated islets from mice with a global or somatostatin-cell-specific knock-out of GPR120. Then we studied glucose metabolism in mice with global deletion of GPR120, GPR40 or both, under a high fat diet for 12 weeks. We observed increased insulin and glucagon secretions mirrored by a decreased in somatostatin release following GPR120 activation in isolated islets, an effect abolished by a global or δ-specific deletion of GPR120. A double deletion of GPR120 and GPR40 did not have more impact on glucose metabolism or beta-cell function compared to a simple deletion of either receptor. A better understanding of the GPR120 role in islet function is crucial and could lead to the discovery of new therapeutic options.

Keyphrases: GPR120, GPR40, cellules delta, cellules alpha, FFAR4, FFAR1, Pancreatic islet, Type 2 diabetes, Somatostatin-secreting cells, Beta cells, Alpha cells
Enquête sur les préférences en santé chez les patients et familles atteints d’allergies alimentaires

Background: The lack of a value set allowing the calculation of quality-adjusted life-years (QALY) is an important limitation when establishing the value of emerging therapies to treat food allergy. To be valid, QALYs must be calculated from questionnaires adapted to the target population because of varying deficits and preferences across populations and diseases, which was not the case in previous studies. This study aimed to develop a Short-Form Six-Dimension version 2 (SF-6Dv2) preference value set for the calculation of health utilities from the Canadian food allergic population. Methods: Two hundred ninety-five parents of patients aged 0-17 years old and 154 patients aged 12 years old and above with food allergy were recruited in the clinic and online. Participants were asked to complete a self-administered online questionnaire including generic health-related quality of life questionnaires. Various health states described by the SF-6Dv2 were valued with time-trade-off and discrete choice experiments. Data from elicitation techniques were combined using the hybrid regression model. Results: A total of 241 parents and 125 patients performed 3904 time trade-off and 5112 discrete choice experiments. Utility decrements were estimated for each level of each SF-6Dv2 dimension. Utility values calculated based on the validated preference set were on average 0.15 lower (95% CI: 0.12-0.18) and were poorly correlated (R2=0.46) with those derived from the EQ-5D-5L generic questionnaire in the same cohort.  Conclusion: A representative preference value set for patients with food allergy was determined using the SF-6Dv2 generic questionnaire. This adapted preference value set will contribute to improve the validity of future utility estimates in this population for the appraisal of upcoming potentially impactful but sometimes costly therapies.

Keyphrases: food allergy, health preference, health-related quality of life, quality-adjusted life-year, utility
Efficacité d'un programme d'activité physique basé sur le modèle transthéorique et sur les préférences-patient chez des individus atteints de troubles psychotiques

Introduction: Although 90 minutes or more/week of physical activity (PA) is recommended, few individuals with early psychosis (IEP) practice it despite the frequent presence of metabolic complications. The literature suggests that a PA intervention including their preferred PA and motivational counseling would facilitate their adherence. Objectives: To determine the feasibility, acceptability and impact of a PA intervention on PA motivation, PA level, sedentary time and social participation. Methods: Open clinical trial (pilot study) conducted with IEP. The PA intervention of 24 supervised PA sessions is based on “patients-preferences” and includes motivational counseling using the transtheoretical model. Feasibility and acceptability were measured by drop-out rates and attendance and satisfaction level. PA motivation, PA level, level of physical inactivity and social participation were measured pre and post intervention. Results: Of the 40 IEP (age: 25.63 ± 4.22 years, 52.5% of women) recruited, 40% dropped out and the attendance rate was 67.5%. The satisfaction was rated (94%) “very satisfied” to “very much”. The PA level increased from 52,71 to 91.79 minutes/week (reaching recommendations) and physical inactivity decreased from 90,85 to 33.75 ± 49.16 minutes. The intervention had no impact on PA motivation and social participation. Conclusion: Our preliminary results suggest that an intervention based on patient preferences is feasible and acceptable in IEP. Future randomised controlled trials would allow to determine if the decreased physical inactivity and increased PA levels are due to this intervention and if it may contribute to reduce the frequent metabolic complications in IEP.

Keyphrases: motivation, Mental health, Psychotic disorder, First episode psychosis, Physical activity, Patient preferences, Trans theoretical model, Behavior change
Étude des conséquences immunomodulatrices des solutés cristalloïdes

Intensive care unit patients' inflammatory status can switch from an early pro-inflammatory to a late anti-inflammatory phase, which favors infections. They can receive different crystalloids, either Normal Saline (NS), Ringer’s Lactate (RL) or Plasma-Lyte (PL). NS has high NaCl concentrations which has been associated with inflammatory effects on immune cells.  Our aim is to evaluate the impact of these three different crystalloid fluids on immune cells in healthy subjects and on a whole blood model of acute inflammation. Using our comprehensive immunomonitoring platform, we assessed the immunological phenotype of peripheral blood mononuclear cells (PBMC) and neutrophils in humans. 11 healthy subjects received a liter of NS, RL and PL in a randomized cross-over fashion. Blood samples were taken before and 6h later. PBMC and neutrophil phenotypes were assessed by flow cytometry and cytokine concentrations were measured by a multiplex assay. Ex vivo assays were performed by exposing whole blood to the different crystalloids following a stimulation with LPS. Study of healthy subject’s PBMCs suggested that RL and PL reduced activation of neutrophils compared to NS. Total and classical monocytes were increased with NS compared to RL and PL. RL and PL also increase plasma levels of anti-inflammatory cytokine Interleukin (IL)-10 and pro-repair cytokine basic Fibroblast Growth Factor (bFGF) compared to NS, while NS increased plasma levels of the pro-inflammatory cytokine IL-17A. In whole blood assays, following LPS stimulation, NS increased monocytic activation compared to LR and PL. In T cells, PL decreased early activation. Conclusions: Our results suggest that crystalloids have different immune consequences with NS being more immune activating than RL and PL. A better understanding of their immune modulation could lead to personalization of their use according to the inflammatory status of patients to restore their immune homeostasis.

Keyphrases: Inflammation, Peripheral blood leucocytes, Intensive care, Flow cytometry
When pain offset induces pleasure : a psychophysical and fMRI study

Background: A localized painful stimulation can produce diffused analgesia through the inhibitory conditioned pain modulation system (ICPM). Analgesia can also be induced by pleasant stimuli (e.g. music) or by the interruption of a painful stimuli (pleasant pain relief). Because pleasure has analgesic benefits, the effect of pleasant pain relief could be a confounding factor in ICPM. Furthermore, pain offset induces activations in reward regions, though results showing the deactivation of reward regions during pain onset have been inconsistent. Objectives: 1) investigate the possible relationship between pleasant pain relief and ICPM using psychophysical measures and 2) investigate cerebral activations/deactivations during pain onset. This will allow a better comprehension of the pain/reward interaction. Methodology: In study 1, ICPM was measured (N=27) by administering noxious heat (thermode) before and after the cold pressor test (CPT). After a 30 minutes break, the CPT was re-administered to measure pleasant pain relief (0-100) for 4 minutes. In study 2, a modified CPT (gel) was administrated (N=26) during an fMRI session to investigate cerebral activations/deactivations during pain onset. Results: In study 1, interruption of the CPT induced a mean pleasant pain relief of almost 40%. ICPM and pleasant pain relief did not correlate. In study 2, we found significant activations in the insula, the precuneus and the middle frontal gyrus and a significant deactivation in the medial orbital frontal gyrus during pain onset, when compared to the neutral stimulus. Discussion: Deactivation of reward regions illustrates the disruption in homeostasis caused by pain onset, which is later reinstated during pain offset (pleasant pain relief), therefore showing a compensatory effect. This allowed an enhanced comprehension of the opponent process theory.

Keyphrases: ICPM, Pleasant pain relief, Reward, Pain, fMRI
Les rôles de genre professionnels en lien avec la charge allostatique et le fonctionnement psychosocial de travailleurs d'hôpital psychiatrique

Gendered inequalities in workplace stress are linked to sex-specific health trajectories that are poorly understood. Measuring these gendered inequalities are challenging but an essential endeavor to better explain individual differences in occupational health. The aim of this exploratory, retrospective study was to investigate pathways linking layers of individual-level (e.g., sociocultural gender-roles) and macro-level (e.g., occupational gender-roles) gender factors to measures of allostatic load (23 biomarkers), workplace stress (e.g., job strain, effort-reward imbalance) and mental health (e.g., depressive symptoms, burnout symptoms, trauma symptoms) in a sample of psychiatric hospital workers (N=192). We propose a practical web-based survey approach to measure macro-level gendered occupational factors for retrospective analyses that could also be integrated in novel experimental designs. Our findings show that individual-level masculine gender-roles were positively associated with psychological demands and social support. Masculine and feminine occupational gender-roles were positively associated with decisional latitude and overcommitment. Both individual masculine and feminine gender-roles had protective effects on depressive symptoms and burnout symptoms but only individual masculine gender-roles had protective effects on trauma symptoms; however occupational gender-roles had no effects on mental health. No associations were found with allostatic load. Moving beyond an individual’s gender-roles, our study demonstrates the utility of measuring occupational gender-roles to delineate challenging associations between subjective stressors and health outcomes that should be applied in analyses for future studies of sex differences in occupational health.

Keyphrases: Trauma, Sex differences, Individual gender-roles, Occupational gender-roles, Workplace stress, Depression, Burnout, Trauma, Allostatic load