A ‘spoon full of sugar’ helps the medicine go down: how a participant friendly version of a psychophysics task significantly improves task engagement, performance and data quality in a typical adult sample

Few would argue that the unique insights brought by studying the typical and atypical development of psychological processes are essential to building a comprehensive understanding of the brain. Often, however, the associated challenges of working with non-standard adult populations results in the more complex psychophysical paradigms being rejected as too complex. Recently we created a child (and clinical group) friendly implementation of one such technique – the reverse correlation Bubbles approach and noted an associated performance boost in adult participants. Here, we compare the administration of three different versions of this participant-friendly task in the same adult participants to empirically confirm that introducing elements in the experiment with the sole purpose of improving the participant experience, not only boost the participant’s engagement and motivation for the task but results in significantly improved objective task performance and stronger statistical results

A Key Role for Neurotensin in Chronic-Stress-Induced Anxiety-Like Behavior in Rats

Accepted ManuscriptChronic stress is a major cause of anxiety disorders that can be reliably modeled preclinically, providing insight into alternative therapeutic targets for this mental health illness. Neuropeptides have been targeted in the past to no avail possibly due to our lack of understanding of their role in pathological models. In this study we use a rat model of chronic stress-induced anxiety-like behaviors and hypothesized that neuropeptidergic modulation of synaptic transmission would be altered in the bed nucleus of the stria terminalis (BNST), a brain region suspected to contribute to anxiety disorders. We use brain slice neurophysiology and behavioral pharmacology to compare the role of locally released endogenous neuropeptides on synaptic transmission in the oval (ov) BNST of non-stressed (NS) or chronic unpredictably stressed (CUS) rats. We found that in NS rats, post-synaptic depolarization induced the release of vesicular neurotensin (NT) and corticotropin-releasing factor (CRF) that co-acted to increase ovBNST inhibitory synaptic transmission in 59% of recorded neurons. CUS bolstered this potentiation (100% of recorded neurons) through an enhanced contribution of NT over CRF. In contrast, locally released opioid neuropeptides decreased ovBNST excitatory synaptic transmission in all recorded neurons, regardless of stress. Consistent with CUS-induced enhanced modulatory effects of NT, blockade of ovBNST NT receptors completely abolished stress-induced anxiety-like behaviors in the elevated plus maze paradigm. The role of NT has been largely unexplored in stress and our findings highlight its potential contribution to an important behavioral consequence of chronic stress, that is, exaggerated avoidance of open space in rats.CPN was funded by CIHR Vanier Graduate Scholarship (338319); APVS was funded by Fundação para a Ciência e Tecnologia (SFRH/BPD/52078/2013); ERH was funded by CIHR Postdoctoral Fellowship (MFE-123712); SA was funded by a Queen Elizabeth II Graduate Scholarship in Science and Technology; ÉCD was funded by the Canadian Institute of Health Research (MOP-25953)info:eu-repo/semantics/publishedVersio

Leveraging Biomaterial Properties to Reprogram Immune Function in Autoimmunity

Autoimmune diseases occur when immune cells incorrectly identify and attack the body’s tissues as foreign. In Multiple Sclerosis (MS), the immune system targets myelin, the protective layer that insulates nerves. Current MS therapies reduce disease severity without treating the cause, requiring frequent treatments to slow disease progression. Further, existing therapies cannot differentiate between dysfunctional myelin-reactive inflammatory cells and normal lymphocytes, leaving patients vulnerable to infection. To overcome these limitations, this dissertation investigated biodegradable polymeric microparticles (MPs) co-loaded with myelin peptides and rapamycin, an immunomodulatory signal. Directly injecting these tolerogenic MPs into key immune tissues (e.g. lymph nodes, LNs), induces myelin-specific regulatory immune cells that selectively control myelin-specific inflammation. This work aimed to advance pre-clinical studies and motivate clinical research in two ways: investigating the systemic impact of intra-LN tolerogenic MPs in two MS models, and enhancing MP stability using Chemistry, Manufacturing, and Controls (CMC) considerations. This work showed that across both progressive and relapsing-remitting disease, one tolerogenic intra-LN treatment promoted long-lasting improvements in disease-induced paralysis. Tolerogenic MPs delivered prior to symptom onset promoted tolerance and protected against disease. Treatment at peak disease reversed paralysis and prevented relapse, while treatment during relapse limited disease progression. Strikingly, mice vaccinated against a foreign protein on the same day as intra-LN treatment generated protein-specific T cells and antibodies at similar levels to healthy vaccinated mice, while simultaneously exhibiting significantly reduced paralysis – highlighting the myelin-specific nature of this therapy. While the low dosage requirements of these studies allowed for on-demand preparation, clinical translation requires investigation into manufacturing, preservation, storage, and stability of this immunotherapy. Thus, this dissertation also tested the impact of lyophilization (freeze-drying) and excipients (stabilizing molecules) on MP stability after storage. Lyophilization with low concentrations of excipients significantly improved MP stability and formulation recovery after reconstitution. Storage for 5 months at room temperature did not negatively impact cargo loading, MP size, or biofunctionality. MP formulations with excipients could deactivate inflammatory signaling and restrict myelin-specific immune cell proliferation as well as formulations without excipients. Together, these studies motivate the development of intra-LN delivery of tolerogenic MPs as a potential MS immunotherapy for clinical translation

Attitudes towards vaccines and intention to vaccinate against COVID-19: a cross-sectional analysis - implications for public health communications in Australia

Objective To examine SARS-CoV-2 vaccine confidence, attitudes and intentions in Australian adults as part of the iCARE Study. Design and setting Cross-sectional online survey conducted when free COVID-19 vaccinations first became available in Australia in February 2021. Participants Total of 1166 Australians from general population aged 18-90 years (mean 52, SD of 19). Main outcome measures Primary outcome: responses to question € If a vaccine for COVID-19 were available today, what is the likelihood that you would get vaccinated?'. Secondary outcome: analyses of putative drivers of uptake, including vaccine confidence, socioeconomic status and sources of trust, derived from multiple survey questions. Results Seventy-eight per cent reported being likely to receive a SARS-CoV-2 vaccine. Higher SARS-CoV-2 vaccine intentions were associated with: increasing age (OR: 2.01 (95% CI 1.77 to 2.77)), being male (1.37 (95% CI 1.08 to 1.72)), residing in least disadvantaged area quintile (2.27 (95% CI 1.53 to 3.37)) and a self-perceived high risk of getting COVID-19 (1.52 (95% CI 1.08 to 2.14)). However, 72% did not believe they were at a high risk of getting COVID-19. Findings regarding vaccines in general were similar except there were no sex differences. For both the SARS-CoV-2 vaccine and vaccines in general, there were no differences in intentions to vaccinate as a function of education level, perceived income level and rurality. Knowing that the vaccine is safe and effective and that getting vaccinated will protect others, trusting the company that made it and vaccination recommended by a doctor were reported to influence a large proportion of the study cohort to uptake the SARS-CoV-2 vaccine. Seventy-eight per cent reported the intent to continue engaging in virus-protecting behaviours (mask wearing, social distancing, etc) postvaccine. Conclusions Most Australians are likely to receive a SARS-CoV-2 vaccine. Key influencing factors identified (eg, knowing vaccine is safe and effective, and doctor's recommendation to get vaccinated) can inform public health messaging to enhance vaccination rates

The State of US health, 1990-2010: Burden of diseases, injuries, and risk factors

Understanding the major health problems in the United States and how they are changing over time is critical for informing national health policy. To measure the burden of diseases, injuries, and leading risk factors in the United States from 1990 to 2010 and to compare these measurements with those of the 34 countries in the Organisation for Economic Co-operation and Development (OECD) countries. We used the systematic analysis of descriptive epidemiology of 291 diseases and injuries, 1160 sequelae of these diseases and injuries, and 67 risk factors or clusters of risk factors from 1990 to 2010 for 187 countries developed for the Global Burden of Disease 2010 Study to describe the health status of the United States and to compare US health outcomes with those of 34 OECD countries. Years of life lost due to premature mortality (YLLs) were computed by multiplying the number of deaths at each age by a reference life expectancy at that age. Years lived with disability (YLDs) were calculated by multiplying prevalence (based on systematic reviews) by the disability weight (based on population-based surveys) for each sequela; disability in this study refers to any short- or long-term loss of health. Disability-adjusted life-years (DALYs) were estimated as the sum of YLDs and YLLs. Deaths and DALYs related to risk factors were based on systematic reviews and meta-analyses of exposure data and relative risks for risk-outcome pairs. Healthy life expectancy (HALE) was used to summarize overall population health, accounting for both length of life and levels of ill health experienced at different ages. US life expectancy for both sexes combined increased from 75.2 years in 1990 to 78.2 years in 2010; during the same period, HALE increased from 65.8 years to 68.1 years. The diseases and injuries with the largest number of YLLs in 2010 were ischemic heart disease, lung cancer, stroke, chronic obstructive pulmonary disease, and road injury. Age-standardized YLL rates increased for Alzheimer disease, drug use disorders, chronic kidney disease, kidney cancer, and falls. The diseases with the largest number of YLDs in 2010 were low back pain, major depressive disorder, other musculoskeletal disorders, neck pain, and anxiety disorders. As the US population has aged, YLDs have comprised a larger share of DALYs than have YLLs. The leading risk factors related to DALYs were dietary risks, tobacco smoking, high body mass index, high blood pressure, high fasting plasma glucose, physical inactivity, and alcohol use. Among 34 OECD countries between 1990 and 2010, the US rank for the age-standardized death rate changed from 18th to 27th, for the age-standardized YLL rate from 23rd to 28th, for the age-standardized YLD rate from 5th to 6th, for life expectancy at birth from 20th to 27th, and for HALE from 14th to 26th. From 1990 to 2010, the United States made substantial progress in improving health. Life expectancy at birth and HALE increased, all-cause death rates at all ages decreased, and age-specific rates of years lived with disability remained stable. However, morbidity and chronic disability now account for nearly half of the US health burden, and improvements in population health in the United States have not kept pace with advances in population health in other wealthy nations