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Distinct maternal DNA methylation associations with gestational age at early and late-mid term pregnancy in a low- and middle-income country: evaluation of biological, genetic, and psychosocial contributors
No full textAbstract Mothers undergo physiological and molecular changes over the course of gestation. These modifications “get under the skin” and may be reflected in the maternal epigenome through processes such as DNA methylation. Such an epigenetic mark may offer insights into maternal responses to prenatal influences and biological cues from the developing fetus, thereby functioning as an indirect indicator of the conditions the fetus experiences in utero. We measured whole blood DNA methylation using the MethylationEPIC BeadChip Infinium microarray v1.0 in 22 pregnant women from Pakistan, a low- and middle-income country (LMIC), at two timepoints during their term pregnancies (early: 10–19 weeks and late-mid: 22–29 weeks). We used DNA methylation profiles to predict immune cell proportions and tested differences in these proportions and DNA methylation patterns between the two timepoints. Further, we evaluated DNA methylation associations with gestational age at each timepoint and examined the contribution of genetic, psychosocial, and biological factors. Our analyses documented changes in immune cell proportions and DNA methylation profiles over the course of gestation, albeit in a small percentage of the measured DNA methylome. We also observed timepoint-specific DNA methylation associations with gestational age, predominantly at early pregnancy, with predicted interleukin-6 level and socioeconomic status contributing to a few of these associations. On comparing to three external cohorts from different sociocultural contexts, we also noted these signatures to be unique to LMIC settings. Overall, these changes measured in term pregnancies may be used to assess both fluctuations in pregnancy and birth outcomes, particular in women from LMIC settings
The Development of Different Strategies Using Clinically Translatable Models for the Treatment of Triple Negative Breast Cancer
No full textTriple negative breast cancer (TNBC) is an aggressive form of breast cancer, that lacks targeting therapy, making chemotherapy the primary treatment option. However, chemotherapy leads to the enrichment of a subpopulation of cells with tumor initiating capacities called cancer stem cells (CSCs), that are implicated in treatment resistance, metastasis, and recurrence. To address this, I developed a triple-drug combination therapy targeting multiple aspects of tumorigenesis. Due to the limitation of conventional drug treatment, the use of nanoparticles (NPs) as a delivery system was introduced to increase therapeutic index. This triple-drug NPs suppressed bulk TNBC cells, CSC enrichment, and angiogenesis, both in vitro and in the clinically relevant patient-derived xenograft (PDX) model, paving the way for potential clinical application.
RNA based therapeutics have emerged as a promising alternative in cancer treatment due to higher specificity in targeting key drivers of tumorigenesis. Using NPs as a delivery system, I showed the successful delivery of mRNA agents in PDX models, highlighting the promise of RNA-based NP therapies for overcoming limitations of conventional treatments in TNBC. As tumors are heterogenous with multiple drivers in play, I developed a NP-based co-delivery platform to deliver siRNA and mRNA for multitargeted gene regulation in cancer. These RNA-loaded NPs simultaneously knocked down and expressed target genes in TNBC in vitro and in vivo, highlighting their potential for multi-targeted therapy. Overall, throughout this thesis, using PDX models, I showed the effective delivery of both Drugs-NP and RNA- agents, laying the groundwork for future therapeutic strategies in TNBC treatment
Plasmonic III-V Lasers and Waveguide Bragg Gratings
No full textThis thesis investigates two building-blocks of integrated photonics, hybrid plasmonic semiconductor lasers and waveguide Bragg gratings (WBGs), with the goal of improving tunability, sensing performance, and grating design. The first part examines plasmonic-III-V integration as a platform for tunable lasers aimed at data-center applications, using loss-based mode control to enable wavelength tuning. I also explore the use of hybrid plasmonic semiconductor laser in biosensing and additionally, design an electrically driven LED refractometer as a compact sensing device. The second part of the thesis focuses on WBGs, reviewing weak and strong grating regimes with established simulation techniques. I introduce a new class of gratings, Dirac gratings, whose spectral response remains unchanged with grating order. Finally, I develop an efficient analysis tool based coupled-mode theory for design and optimization of distributed-feedback lasers and reflectors
Du contrôle à la quête sensorielle : l'oscillation posturale revisitée
No full textLe contrôle postural a longtemps été associé à la capacité de maintenir le corps en équilibre avec un minimum de mouvement, comme s'il fallait rester « le plus immobile possible ». Pourtant, la magnitude de l'oscillation posturale n'est pas toujours un indicateur de la qualité du contrôle. À l'aide d'un protocole d'immobilisation, Carpenter et al. (2010) ont montré qu'une partie de l'oscillation pouvait possiblement être fonctionnelle. En immobilisant le centre de masse de participants, ils ont observé une augmentation du mouvement du centre de pression, suggérant que le système nerveux central chercherait à générer du mouvement pour explorer l'environnement. Ce concept d'oscillation exploratoire repose cependant largement sur ce paradigme d'immobilisation, qui présente certaines limites. La présente thèse revisite et optimise ce protocole afin de déterminer si les comportements observés lors de l'immobilisation du centre de masse relèvent réellement de l'exploration. L'étude 1 consistait à reprendre le paradigme de Carpenter et al. (2010) avec certaines modifications, dont l'ajout de mesures dynamiques du centre de pression. Les résultats ont montré que l'immobilisation augmentait la variabilité du centre de pression tout en réduisant sa complexité. L'étude 2 a révélé que l'immobilisation seule du centre de masse, sans restreindre l'ensemble du corps, produisait des effets opposés. Toutefois, le mouvement du centre de pression ne diminuait pas dans la même mesure que celui du centre de masse. Les études 3 et 4 ont examiné l'effet de la rétroaction visuelle du centre de pression sur le contrôle postural et montré qu'elle réduit l'oscillation tout en augmentant sa complexité. L'étude 5 a ensuite combiné la rétroaction visuelle avec l'immobilisation et a montré que l'effet réducteur de cette rétroaction sur la magnitude du centre de pression s'annulait en condition d'immobilisation. Un maintien d'un niveau minimal de mouvement du centre de pression serait ainsi possiblement recherché lors de l'immobilisation. Des analyses additionnelles ont également montré que le comportement observé lors de l'immobilisation ne serait que peu influencé par la vision, l'alignement corporel au moment de l'immobilisation ou la flexibilité des chevilles. Dans l'ensemble, cette thèse suggère qu'une partie du déplacement du CdP pourrait être indépendante de la stabilisation immédiate du centre de masse. Malgré l'immobilisation, la rétroaction visuelle et l'optimisation de la procédure, un mouvement du CdP persiste. Il reste cependant incertain si ce mouvement correspond réellement à un comportement exploratoire ou à un autre processus non lié à la stabilisation. L'évaluation du contrôle postural par l'analyse de l'oscillation devrait tout de même être faite avec prudence, car l'oscillation pourrait à la fois refléter une stabilisation posturale et d'autres fonctions qui n'y sont pas liées. --
Postural control has long been associated with the ability to keep the body in balance with minimal movement, as if the goal were to remain "as still as possible". However, the magnitude of postural sway is not always a reliable indicator of control quality. Using an immobilization protocol, Carpenter et al. (2010) showed that part of this sway may be functional. By immobilizing the center of mass, they observed an increase in the movement of the center of pressure, suggesting that the central nervous system may generate movement to stimulate sensory receptors and explore the environment. This concept of exploratory sway, however, largely relies on this immobilization paradigm, which has notable limitations. The present thesis revisits and optimizes this protocol to determine whether the behaviors observed during immobilization of the center of mass truly reflect exploration. Study 1 replicated Carpenter et al. (2010) paradigm with modifications, including the use of dynamic measures of the center of pressure. Results showed that immobilization increased the variability of the center of pressure while reducing its complexity. Study 2 revealed that immobilizing only the center of mass, without restraining the entire body, produced opposite effects. However, the movement of the center of pressure did not decrease to the same extent as that of the center of mass. Studies 3 and 4 examined the effect of visual biofeedback of the center of pressure on postural control and showed that it reduced sway while increasing complexity. Study 5 combined visual biofeedback with immobilization and revealed that its beneficial effects on center of pressure movement disappeared under immobilization. A minimal level of center of pressure movement may therefore be desired during immobilization. Additional analyses also indicated that the behavior observed during immobilization was not strongly influenced by vision, body alignment at the time of immobilization, or ankle flexibility. Overall, this thesis suggests that part of the displacement of the center of pressure may be independent of the immediate stabilization of the center of mass. Despite immobilization, visual biofeedback, and protocol optimization, movement of the center of pressure persists. It remains uncertain whether this movement reflects exploratory behavior or another process not directly related to stabilization. Nevertheless, the evaluation of postural control through sway analysis should be approached with caution, as sway may reflect both stabilization and other functions not directly linked to balance
Therapeutic Presence in Videoconferencing Psychotherapy: Therapist Experiences of Connecting Across the Digital Divide
No full textTelepsychology has become increasingly prevalent, primarily due to the COVID-19 pandemic (Madigan et al., 2021), shifting psychotherapy from physical face-to-face settings to screen-based formats. This drastic change inevitably produced varied perspectives on telepsychology and raised numerous questions regarding best practices (Connolly et al., 2020). Online therapeutic presence is one such area necessitating greater exploration. While research supports therapists bringing their whole self into session to foster deep connections with their client on multiple levels (Geller & Greenberg, 2023), less is known about applying such models online. Therefore, this study focuses on understanding therapist perspectives on therapeutic presence within telepsychology. Two research questions guided this study: (1) what are psychotherapists' experiences of therapeutic presence throughout videoconferencing psychotherapy sessions? and (2) how do psychotherapists overcome the challenges and barriers in videoconferencing psychotherapy? A semi-structured interview protocol was used to gather qualitative data from ten experienced therapists through 45-60-minute interviews. Braun and Clarke's (2021) six-step reflexive thematic analysis was used to analyse the data. Six main themes and 12 subthemes emerged through the data analysis. The study's findings support therapeutic presence's relevance in VC therapy, lending credence to the common factor hypothesis (Geller & Greenberg, 2023). Yet, some therapists felt less connected with certain clients online, indicating that the medium of VC psychotherapy may not appeal to all equally. Most reported barriers and challenges aligned with past research (Batastini et al., 2020), were surmountable, and did not greatly impact therapeutic presence
Engaging families to create a better post-pandemic future: semi-structured interviews with youth and parents in Canada
No full textAbstract Background International reports highlight important impacts of the COVID-19 pandemic on the wellbeing of youth. There is limited knowledge of the experiences and perspectives of youth, and their parents during the COVID-19 pandemic. Examining these experiences can help us identify existing gaps in support and which policy adjustments, resources, and programs are needed to enhance the wellbeing of youth and families in the aftermath of the pandemic. Methods In this qualitative descriptive study Canadian youth (11-18year) and their parents (≥ 18year) who participated in a previous national survey looking at public perceptions of the COVID-19 pandemic, were invited to participate. Youth and their parents across all ten Canadian provinces were interviewed separately between June and September 2022. Interview guides were developed and refined iteratively with experts on child development along with youth and parent partners. Responses we coded inductively and a qualitative descriptive analysis was performed. We conducted and reported this study according to the Consolidated Criteria for Reporting Qualitative Research checklist. Results We interviewed 14 youth-parent dyads (28 interviews). Most participants identified as Black, Indigenous, or persons of colour (18/ 28, 64%) and as cis-gender women/girls (15/28, 54%); the median ages were 14 (interquartile range (IQR) 12–16) and 46 (IQR 40–50), for youth and parents respectively. All parents (14/14, 100%) were married. We generated four topic summaries in the data, relevant to youth and family wellbeing throughout the COVID-19 pandemic and in the post-pandemic period: (1) connectedness (a sense of being cared for and supported), (2) motivation and drive (activating and sustaining behaviour toward a goal despite difficulties), (3) mental health (including emotional, psychological, and social wellbeing, develop fulfilling relationships, and adapting to change) and (4) coping mechanisms (strategies used to adjust to stressful events to help maintain overall wellbeing). Findings highlight negative impacts of increased isolation associated with COVID-19 pandemic and their interconnectedness. Results underscore the importance of employing integrated policies that address these complex challenges while informing the tailoring of existing policies, resources, and programs to better support and improve the well-being of youth and families as they navigate the ongoing impacts of the pandemic. Conclusions Canadian youth and parents in our sample provided detailed descriptions on how the COVID-19 pandemic impacted their wellbeing and the strategies they used to reduce these impacts as much as possible. There is a need for support both at-home and in-school, emphasizing the importance of having a range of programs that address challenges across all facets of youths’ lives
L'interférence contraceptive dans les relations intimes des adultes émergents
No full textL’autonomie contraceptive, qui renvoie aux conditions nécessaires pour qu’une personne puisse déterminer ses préférences en matière de contraception et soit en mesure de mettre en œuvre ses décisions, est une composante essentielle de la santé sexuelle et reproductive. Ces conditions sont notamment influencées par les déterminants sociaux de la santé sexuelle et reproductive, ainsi que les normes sociales qui traversent les relations intimes. Dans le contexte canadien, ces normes sociales impliquent, par exemple, de faire porter la responsabilité contraceptive principalement aux femmes et aux personnes d’autres identités de genre susceptibles de devenir enceint.es, ou de prioriser le plaisir sexuel masculin au détriment d’une sexualité sécuritaire. Dans cette perspective, un champ de recherche émergent explore les situations où, bien qu’une personne souhaite exercer son autonomie contraceptive, celle-ci est freinée ou empêchée par les comportements d’un partenaire intime. Ces situations renvoient à de l’interférence contraceptive, laquelle réfère à tout comportement visant à entraver l’usage souhaité d’une méthode de contraception ou d’une méthode barrière. Ce type de comportement peut se situer au croisement d’autres formes de violence, telles que la violence sexuelle, psychologique, émotionnelle, physique, ou encore le contrôle coercitif.
Cette thèse doctorale par articles s’appuie sur une étude qualitative et une étude quantitative pour documenter les situations d’interférence contraceptive rapportées par les jeunes femmes et les personnes trans et non binaires de 16 à 25 ans. L’objectif est de mieux comprendre les formes que prend l’interférence contraceptive dans les relations intimes, ses répercussions sur la santé, le bien-être et la sexualité, ainsi que sa prévalence. En adoptant des perspectives féministes et en s’intéressant à l’équité en santé sexuelle et reproductive, cette thèse explore comment l’autonomie contraceptive est compromise dans ces contextes.
Les résultats mettent en évidence une diversité de formes d’interférence contraceptive, allant de la résistance à l’usage du condom, en passant par la manipulation et le contrôle liés à l’usage, ou non, d’une méthode contraceptive ou prophylactique, jusqu’à l’imposition de relations sexuelles non protégées. Les conséquences rapportées sont significatives et peuvent perdurer après la fin de la relation intime. Celles-ci renvoient à la perception de soi et des autres, au rapport à l’intimité et à la sexualité, ainsi qu’au bien-être mental. La majorité des jeunes ayant participé à l’enquête quantitative rapportent avoir vécu au moins un de ces comportements en relation intime.
Ces constats appellent à une reconnaissance accrue de l’interférence contraceptive dans les pratiques de prévention, de dépistage et d’intervention en santé sexuelle et reproductive. Ils soulignent également l’importance de poursuivre son exploration conceptuelle et empirique afin de mieux comprendre cette forme de violence spécifique
Development of a PRISMA extension for systematic reviews of health economic evaluations (PRISMA-EconEval): a project protocol
No full textAbstract Background Systematic reviews of health economic evaluations are key for evidence-based decisions but lack standardised reporting. This project aims to develop a Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) extension for systematic reviews of health economic evaluations (PRISMA-EconEval). Methods Project stages include the following: (1) scoping review, (2) Delphi surveys, (3) consensus meeting, (4) piloting, and (5) finalisation and dissemination. The project is overseen by the international multidisciplinary PRISMA-EconEval Management Group (PMG), Advisory Group, and Patient and Public Involvement Group. (1) The scoping review aims to identify candidate reporting items, with the protocol published elsewhere. The global applicability of these items to systematic reviews of health economic evaluations will be evaluated using sample papers from the scoping review, supplemented by nominations from the health economics community or other sources, where necessary. (2) A multi-round online Delphi survey will be conducted to achieve consensus on items for inclusion. A purposive sample of panellists (approximately 200) will be selected, ensuring representation of the following: health economists, systematic reviewers, information specialists, guideline developers, journal editors, healthcare decision-makers, research funders, and public representatives. Across two to three rounds, panellists will use a 1–9 scale to rate each candidate item’s ability to represent the minimum required for reporting, be relevant to all systematic reviews of health economic evaluations, facilitate complete and transparent reporting, and support the quality assessment of both the review and included studies. (3) An online consensus meeting (approximately 30 participants) will refine the wording of items and resolve any disagreements by vote. (4) Health economists independent of the project will apply the draft guidelines to a sample of published studies and identify practical challenges. (5) The PMG will meet to finalise the wording and presentation of the reporting items, ensure consistency with PRISMA 2020, and produce an explanation and elaboration document. Dissemination channels will include peer-reviewed health economics journals, conferences, and the EQUATOR network. Discussion PRISMA-EconEval aims to improve clarity, consistency, transparency, quality, and overall value of systematic reviews of health economic evaluations. This will benefit researchers, peer reviewers, editors, decision-makers, and ultimately patients and the public through supporting decisions on healthcare resource allocation
Multimodal Neuroimaging Approaches to Understanding Suicide-Related Thoughts, Behaviours and Clinical Risk Factors in Treatment Resistant Depression
No full textDespite extensive research contributions, suicide risk assessment still relies heavily on subjective and clinician judgement. In recent years, the search for suicide biomarkers has gained significant momentum, and an expansive body of literature has provided diverse and convincing evidence of biological involvement in suicide. This thesis is presented as a collection of articles with three primary aims. First, to use structural and resting-state functional magnetic resonance imaging (MRI) techniques to study gray matter volume, cortical thickness, and functional connectivity correlates of suicidal ideation (SI) severity in treatment-resistant depression (TRD). Second, to use resting-state functional MRI to examine functional connectivity differences among healthy controls and participants with TRD and a lifetime history of SI only (SI group), and those with a lifetime history of both SI and suicide attempt (SA group). Additionally, associations between functional connectivity alterations and clinical features that may differentiate SI and SA groups were examined, including hopelessness, anxiety, depression, aggression, impulsivity, and childhood trauma. Third, to use proton magnetic resonance spectroscopy (1H-MRS) to compare levels of glutamate (Glu), Glx (combined glutamine/glutamate), myo-inositol (mI), N-aceylaspartate (NAA), and creatine (Cr) in the dorsal anterior cingulate cortex (ACC) in participants with TRD and a lifetime history of SI to a healthy control group. Associations between neurometabolite concentrations and suicide-related symptoms and traits, including depression, suicidal ideation severity, impulsivity, and aggression were also investigated. Participants underwent a single MRI session, and structural, resting-state functional, and 1H-MRS data were collected. Overall, findings included: 1) increased SI severity correlated with reduced right lateral occipital cortical thickness, and widespread functional connectivity correlates centered on the right posterior parietal cortex (Manuscript 1), 2) functional connectivity differences in fronto-temporo-limbic regions differentiating participants with SA history from those with SI only, with connectivity markers meaningfully related to clinical features in the SA group (Manuscript 2), and 3) glutamatergic alterations in the dorsal ACC in participants with TRD and SI associated with higher trait impulsivity (Manuscript 3). Collectively, this thesis provides evidence of neural abnormalities associated with suicide risk in TRD, thereby advancing the search for clinically meaningful suicide biomarkers which may inform identification of treatment targets
3D Photoelectron Velocity Map Imaging and Four-Wave Mixing of Cylindrical Vector Modes
No full textThe 2D photoelectron velocity map imaging (VMI) technique is commonly employed in gas-phase molecular spectroscopy and dynamics investigations due to its ability to efficiently extract photoelectron spectra and angular distributions in a single experiment. However, the standard technique is restricted to specific light-source polarization geometries by the need to perform a mathematical inversion of the measured 2D detector-plane projections in order to recover the spherical 3D particle distribution. This has led to significant interest in the development of 3D VMI techniques which are capable of measuring, at a detector, the transverse position (x, y) and time-of-flight (TOF, t) of individual events in order to obtain a full set of 3D coordinates, thus avoiding the need for inversion and the associated constraints. These techniques employ curved velocity-mapping electric field lines, making the general transformation of (x, y, t)-data into initial 3D recoil momentum vectors (p_x, p_y, p_z) a challenging problem which, until now, was not fully addressed. Here I present and demonstrate a novel time-stretched, 13-lens 3D VMI photoelectron spectrometer which has sub-camera-pixel spatial resolution and 72 ps (σ) TOF resolution. This instrument employs a kHz CMOS camera to image a standard 40 mm diameter microchannel plate (MCP)/phosphor anode detector (providing x and y positions), combined with a digitizer pickoff from the phosphor to obtain the electron TOF. This thesis contains my work on testing and evaluating the performance of this spectrometer, as well as developing a complete data processing and analysis protocol to convert raw 3D VMI data (camera images and digitizer waveforms) into 3D charged particle recoil momentum vectors. I demonstrate the advantages of the 13-element design, showing that the greater spread in electron TOF permits an accurate time- and position-stamping of up to six electrons per laser shot at a 1 kHz repetition rate.
In a second project, I develop a theoretical description of the nonlinear optical process of four-wave mixing (FWM) as it applies to a type of structured light mode called cylindrical vector (CV) beams. The CV modes are eigenmodes of optical fibre and, as such, they have a broad range of application, such as telecommunications, quantum cryptography, and fundamental optics research. Despite this, their nonlinear optical properties are not yet well understood. Here I derive the selection rules which determine the allowed FWM processes involving CV modes in optical fibre