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This dissertation investigates the ritual theories and practices of a Hindu religious tradition called the Puṣṭimārg (“The Path of Grace”). Through translating the Sanskrit writings of the religion’s founder—Vallabha (1479-1531); and through an examination of Sanskrit, Hindi, and Braj Bhāṣā sectarian literature, English secondary research, and interviews and personal observations with communities of devotees in India, I conclude that ritual behavior is not just one element of the religion, it is what defines and animates it. This is the first study to investigate Puṣṭimārgīya philosophy, theology, cosmology, ethics, literature, and daily activity through the lens of ritual service (sevā), focusing particularly on domestic ritual practice rather than public, temple ritual practice. I argue that the Puṣṭimārg religion should be understood through the lens of ritual, and I conclude that Puṣṭimārgīya ritual stretches far beyond formal praxis, structuring the daily lives of devotees, shaping their worldviews, and serving as a framework for all action. The tradition adheres to a metaphysic of ontological nondualism, yet ritual behavior requires the material differentiation between humans and God, so this study examines ways a religion can be both ontologically monistic and practically pluralistic, forming a religious matrix I’m calling “nondual theism” or “nondual ritualism.” Further, I show that Puṣṭimārgīya ritual can be viewed as an austere practice, though it is materialistic and emotional in nature. The austere activities of maintaining a focused, devotional mindset, dedicating oneself and everything to God, maintaining ritual purity, adhering to dietary restrictions, and practicing nonattachment to materialism and worldliness coexist with the emotional, affective, and materialistic aspects of Puṣṭimārgīya ritual.

High-grade serous ovarian cancer (HGSOC) is the most prevalent and aggressive histological subtype of ovarian cancer, and often presents with metastatic disease. The drivers of metastasis in HGSOC remain enigmatic. APOBEC3A (A3A), an enzyme that generates mutations across various cancers, has been proposed as a mediator of tumor heterogeneity and disease progression. However, the role of A3A in HGSOC has not been explored. We observed an association between high levels of APOBEC3-mediated mutagenesis and poor overall survival in primary HGSOC. We experimentally addressed this correlation by modeling A3A expression in HGSOC which resulted in increased metastatic behavior of HGSOC cells in culture and distant metastatic spread in vivo, which was dependent on catalytic activity of A3A. A3A activity in both primary and cultured HGSOC cells yielded consistent alterations in expression of epithelial-to-mesenchymal transition (EMT) genes resulting in hybrid EMT and mesenchymal signatures, providing a mechanism for their increased metastatic potential. Inhibition of key EMT factors TWIST1 and interleukin-6 (IL-6) resulted in mitigation of A3A-dependent metastatic phenotypes. Our findings define the prevalence of A3A mutagenesis in HGSOC and implicate A3A as a driver of HGSOC metastasis via EMT, underscoring its clinical relevance as a potential prognostic biomarker. Our study lays the groundwork for the development of targeted therapies aimed at mitigating the deleterious impact of A3A-driven EMT in HGSOC.

IntroductionIn the last 60 years, newborn bloodspot screening (NBS) has expanded as a public health intervention from a single severe childhood genetic disease (SCGD) to up to as many as 80 SCGD and testing of ~40 million newborns/year worldwide. However, the gap between current NBS and its potential to increase the efficiency, effectiveness and global equity of healthcare delivery for SCGD is large and rapidly growing. There are now effective therapeutic interventions—drugs, diets, devices and surgeries—for up to 2000 SCGD. Since almost all SCGD can be identified by bloodspot genome sequencing, it has been a longstanding goal to supplement current NBS with genome sequencing-based NBS (gNBS) for all eligible SCGD. We recently described a novel gNBS platform (named Begin Newborn Genome Sequencing (BeginNGS)) with the potential to overcome several major challenges to gNBS (cost, scalability, false positives and an unprepared healthcare workforce). A pilot clinical trial of BeginNGS for 412 SCGD in a level IV neonatal intensive care unit (NICU) had a true positive rate of 4.2%, sensitivity of 83%, positive predictive value of 100% and clinical utility rate of 4.2%, indicating readiness of the platform for use in a powered, multicentre study.Methods and analysisThe BeginNGS study is a single group, international, multicentre, adaptive clinical trial to compare utility, acceptability, feasibility and cost-effectiveness of BeginNGS gNBS (experimental intervention) with standard NBS (control). A minimum of 10 000 neonates (aged <28 days, maximum of 100 000) will be enrolled across 25 racial, ethnic and ancestry populations and five enrolment site types (high-risk obstetrician offices, labour induction office visits, newborn nurseries, NICUs and well-baby visits). BeginNGS is gNBS for circa 2000 SCGD (currently 508 SCGD). The primary objective of the trial is to generate equitable evidence to support broad implementation of gNBS. Enrolled newborns receive both interventions (BeginNGS and standard of care NBS). Newborns who screen positive receive confirmatory testing and medical follow-up for at least 1 year to obtain outcomes data. The primary outcome measure is clinical utility, defined as the proportion of diagnoses identified by BeginNGS and state NBS during infancy that are likely to benefit (likely to have an improved outcome) from treatment. We hypothesise that BeginNGS has a greater rate of clinical utility than standard NBS. An adaptive design was chosen rather than a traditional, fixed design to allow accumulating results to make the trial more efficient, informative, equitable and ethical by addition or removal of SCGD and genetic variants, population enrichment (for under-represented racial, ethnic and ancestral groups) and sample size re-estimation. Adaptive design will also facilitate meta-analysis with other clinical trials of gNBS, providing greater power to test utility in ultra-rare SCGD. Parents will be approached (in person, via phone or via electronic communication) to provide informed consent to enrol their newborns prenatally, postnatally in newborn nurseries or NICUs or at well baby outpatient visits. This study is part of phase III of the BeginNGS programme. Patient and public voices have been engaged in the design and execution of each BeginNGS phase through individuals and groups joining the BeginNGS consortium and participating in the family and community engagement work group. gNBS has the potential to transform the way we diagnose and treat childhood genetic diseases. Preliminary data suggest that national adoption of BeginNGS for all births has the potential to improve outcomes of >50 000 US children per year.Ethics and disseminationThis study was approved by the WCG Clinical institutional review board on 14 February 2024, and the most recent amendment approved on 7 October 2025 (approval number 20235517). Study findings will be shared through research consortium workshops, national and international conferences, community presentations and peer-reviewed journals.Trial registration numberNCT06306521.

Say-Barber-Biesecker-Young-Simpson syndrome (SBBYSS), also known as Ohdo syndrome SBBYS type, is a rare genetic disorder characterised by dysmorphic facial features and severe intellectual disability, as well as cardiac, dental and hearing abnormalities. There has been little psychiatric or psychological description of children with SBBYSS, although previous reports noted repetitive self-injurious behaviours, sensitivity to light and noise and severe deficits in communication. In this report, a 4-year-old male with SBBYSS is described with a focus on psychiatric and psychological assessment, including formal testing for autism spectrum disorder (ASD). Results of multiple behavioural assessment scales are reported. Testing revealed characteristic ASD features, and the patient met criteria for ASD diagnosis in the context of SBBYSS. His behaviours improved with Applied Behavioural Analysis therapy and communication skills training. This is the first documented case of ASD reported alongside SBBYSS. These results suggest ASD may be a clinical feature of SBBYSS.

After nearly eight years of formal environmental review, in July 2016, the Canadian federal government rejected the French multinational AREVA’s proposal to construct a uranium mine 80 kilometers west of Qamani’tuaq/Baker Lake, a small inland and mainly Inuit hamlet in the Kivalliq region of Nunavut. The decision not to grant a license for resource development was based on a technical uncertainty, that is, AREVA was not able to provide a start-date for the mining project due to the depressed uranium market. Yet, as this thesis will demonstrate, this controversy underlies a far more complex and ongoing negotiation with uncertainty. In order to explore diverging engagements with uncertainty, this thesis develops the concept of sites of uncertainty, which are spaces —physical, temporal, emotional, material, discursive and so on—that are occupied by a “state of not knowing” (Cameron, 2015: 34). Drawing on qualitative fieldwork conducted in Baker Lake in November and December of 2016, this thesis will identify key sites of uncertainty where AREVA, government officials, Inuit organizations, and community residents constructed, negotiated, expressed, transformed, experienced, and responded to uncertainty. The analysis of these sites reveals diverse, dynamic, and conflicting conceptualizations of self-sufficiency, well-being, and ultimately identity, which, this thesis argues, led to muddy responses to AREVA’s proposal as well as imagined futures of Baker Lake. Moreover, this thesis explains how local residents’ calls for improvements in education are reflective of an intermeshing of Inuit and western epistemologies. While Inuit ways of knowing and being have persisted, flourished, and creatively adapted to contemporary resource development controversies, they do so largely by conforming to western norms and knowledge systems.

Underground smouldering fires resurfaced early in 2020, contributing to the unprecedented wildfires that tore through the Arctic this spring and summer. An international effort is needed to manage a changing fire regime in the vulnerable Arctic.

BackgroundThe medical research enterprise depends on public recognition of its societal value. In light of evidence indicating public mistrust, especially among minorities, inadequate enrollment as well as diversity of research participants, and poor uptake of findings, medical research seems to fall short of sufficient public regard. Community engagement in medical research, with special attention to minority communities, may help to remedy this shortfall by demonstrating respect for the communities in practical ways.ApproachWe provided 3 case examples that illustrate how specific approaches to community-engaged research can build trust between researchers and communities, encourage participation among underrepresented groups, and enhance the relevance as well as the uptake of research findings.DiscussionA common attribute of the specific approaches discussed here is that they enable the researchers to demonstrate respect by recognizing community values and interests. The demonstration of respect for the communities has intrinsic ethical importance.ConclusionsThe 2 potential outgrowths of demonstrating respect specifically through community engagement are (1) the production of research that is more relevant to the community and (2) the mitigation of asymmetry in the researcher-community relationship. We summarized practical resources available to researchers who seek to incorporate community engagement in their research.

Cardiac dysfunction is often associated with a shift in substrate preference for ATP production. Hyperpolarized (HP) 13 C magnetic resonance spectroscopy (MRS) has the unique ability to detect real-time metabolic changes in vivo due to its high sensitivity and specificity. Here a protocol using HP [1- 13 C]pyruvate and [1- 13 C]butyrate is used to measure carbohydrate versus fatty acid metabolism in vivo . Metabolic changes in fed and fasted Sprague Dawley rats (n = 36) were studied at 9.4 T after tail vein injections. Pyruvate and butyrate competed for acetyl-CoA production, as evidenced by significant changes in [ 13 C]bicarbonate (−48%), [1- 13 C]acetylcarnitine (+113%) and [5- 13 C]glutamate (−63%), following fasting. Butyrate uptake was unaffected by fasting, as indicated by [1- 13 C]butyrylcarnitine. Mitochondrial pseudoketogenesis facilitated the labeling of the ketone bodies [1- 13 C]acetoacetate and [1- 13 C]β-hydroxybutyryate, without evidence of true ketogenesis. HP [1- 13 C]acetoacetate was increased in fasting (250%) but decreased during pyruvate co-injection (−82%). Combining HP 13 C technology and co-administration of separate imaging agents enables noninvasive and simultaneous monitoring of both fatty acid and carbohydrate oxidation. This protocol illustrates a novel method for assessing metabolic flux through different enzymatic pathways simultaneously and enables mechanistic studies of the changing myocardial energetics often associated with disease.

The airborne AirSWOT instrument suite, consisting of an interferometric Ka-band synthetic aperture radar and color-infrared (CIR) camera, was deployed to northern North America in July and August 2017 as part of the NASA Arctic-Boreal Vulnerability Experiment (ABoVE). We present validated, open (i.e., vegetation-free) surface water masks produced from high-resolution (1 m), co-registered AirSWOT CIR imagery using a semi-automated, object-based water classification. The imagery and resulting high-resolution water masks are available as open-access datasets and support interpretation of AirSWOT radar and other coincident ABoVE image products, including LVIS, UAVSAR, AIRMOSS, AVIRIS-NG, and CFIS. These synergies offer promising potential for multi-sensor analysis of Arctic-Boreal surface water bodies. In total, 3167 km2 of open surface water were mapped from 23,380 km2 of flight lines spanning 23 degrees of latitude and broad environmental gradients. Detected water body sizes range from 0.00004 km2 (40 m2) to 15 km2. Power-law extrapolations are commonly used to estimate the abundance of small lakes from coarser resolution imagery, and our mapped water bodies followed power-law distributions, but only for water bodies greater than 0.34 (±0.13) km2 in area. For water bodies exceeding this size threshold, the coefficients of power-law fits vary for different Arctic-Boreal physiographic terrains (wetland, prairie pothole, lowland river valley, thermokarst, and Canadian Shield). Thus, direct mapping using high-resolution imagery remains the most accurate way to estimate the abundance of small surface water bodies. We conclude that empirical scaling relationships, useful for estimating total trace gas exchange and aquatic habitats on Arctic-Boreal landscapes, are uniquely enabled by high-resolution AirSWOT-like mappings and automated detection methods such as those developed here.

The purpose of this study was to evaluate whether loss of consciousness (LOC), retrograde amnesia (RA), and anterograde amnesia (AA) independently influence a particular aspect of post-concussion cognitive functioning-across-test intra-individual variability (IIV), or cognitive dispersion. Concussed athletes (N = 111) were evaluated, on average, 6.04 days post-injury (SD = 5.90; Mdn = 4 days; Range = 1-26 days) via clinical interview and neuropsychological assessment. Primary outcomes of interest included two measures of IIV-an intra-individual standard deviation (ISD) score and a maximum discrepancy (MD) score-computed from 18 norm-referenced variables. Analyses of covariance (ANCOVAs) adjusting for time since injury and sex revealed a significant effect of LOC on the ISD (p = .018, ηp2 = .051) and MD (p = .034, ηp2 = .041) scores, such that athletes with LOC displayed significantly greater IIV than athletes without LOC. In contrast, measures of IIV did not significantly differ between athletes who did and did not experience RA or AA (all p > .05). LOC, but not RA or AA, was associated with greater variability, or inconsistencies, in cognitive performance acutely following concussion. Though future studies are needed to verify the clinical significance of these findings, our results suggest that LOC may contribute to post-concussion cognitive dysfunction and may be a risk factor for less efficient cognitive functioning.