Doctor of Philosophy

dissertationThis study compared females and males with an autism spectrum disorder (ASD) and normal intelligence to explore sex differences in onset and trajectory of ASD symptoms as well as developmental tasks and social functioning. Personality traits were also studied, as was the presence of psychiatric problems. Twenty-one females and 21 males with ASD between the ages of 13 and 35 years of age participated in the study. Although these 42 individuals are the "participants," their parents provided important information about development of symptoms and functioning that the individuals with ASD may not have recalled. Both participants and parents of participants completed comprehensive structured interview and rating scales that evaluated ASD symptoms and social-behavioral functioning. Parents also completed a symptom report form, and participants with ASD completed an IQ test to determine eligibility for the study and a personality test. Results show that parents of female participants noticed ASD symptoms at a later age than parents of males (e.g., sensory symptoms and abnormal social interactions) and reported these to professionals at a later age (i.e., around 7 years for females compared to 3 years, 9 months for males). Professionals, often the child's pediatricians, also showed a tendency to normalize the behaviors of females with ASD more often than males, and did not refer females as often for follow-up evaluations. Despite all of this, no differences were found in the ages at which an ASD diagnosis was made for both sexes, which was on average about 10 years, 9 months. Parents of females reported a more fluctuating symptom presentation than did parents of males, and also reported greater improvement over time. Despite this, female participants reported more distress over social difficulties than males, and this seemed to be consistent over time. Parents of females tended to notice their daughters having more frustration and anger than parents of males, and also observed them to engage more in self-injurious behaviors. Personality testing further showed that the older female participants endorsed more psychological problems than the younger females or the males, including problems with anxiety and depression

Contact-Tracing Technologies and the Problem of Trust—Framing a Right of Social Dialogue for an Impact Assessment Process in Pandemic Times

While technologies offer potentially powerful tools to help address complex social challenges, experience shows that they may fail to meet expectations and may also raise challenges of their own, including for privacy and other data rights. To what extent can these difficulties be ascribed to a lack of public trust undermining the technologies’ effectiveness and disputing their legitimacy? The Australian and Dutch pandemic contact-tracing apps considered in this article suggest part of an answer to this question. As our case studies show, the greater efforts made by the Dutch Government to address a range of rights and provide for wide consultation in the CoronaMelder app’s various impact assessments paid off in terms of a better-designed app that was more broadly conversant with human rights than its Australian COVIDSafe counterpart, and was also more trusted—even if these benefits were still marginal compared to manual contact-tracking, especially in already marginalised communities. We argue that the Dutch experience should now be taken further to frame a right of social dialogue allowing data rights subjects to participate fully in the impact assessment process. We hope (and expect) this would result in better decision-making and improved public trust in ‘truly trustworthy’ technologies developed and deployed in response to a pandemic. However, ultimately, our more basic argument is that rights, premised on dignity and liberty, are of value and should be respected, including—indeed especially—in pandemic times

A programme for risk assessment and minimisation of progressive multifocal leukoencephalopathy developed for vedolizumab clinical trials

Introduction Over the past decade, the potential for drug-associated progressive multifocal leukoencephalopathy (PML) has become an increasingly important consideration in certain drug development programmes, particularly those of immunomodulatory biologics. Whether the risk of PML with an investigational agent is proven (e.g. extrapolated from relevant experience, such as a class effect) or merely theoretical, the serious consequences of acquiring PML require careful risk minimisation and assessment. No single standard for such risk minimisation exists. Vedolizumab is a recently developed monoclonal antibody to α4β7 integrin. Its clinical development necessitated a dedicated PML risk minimisation assessment as part of a global preapproval regulatory requirement. Objective The aim of this study was to describe the multiple risk minimisation elements that were incorporated in vedolizumab clinical trials in inflammatory bowel disease patients as part of the risk assessment and minimisation of PML programme for vedolizumab. Methods A case evaluation algorithm was developed for sequential screening and diagnostic evaluation of subjects who met criteria that indicated a clinical suspicion of PML. An Independent Adjudication Committee provided an independent, unbiased opinion regarding the likelihood of PML. Results Although no cases were detected, all suspected PML events were thoroughly reviewed and successfully adjudicated, making it unlikely that cases were missed. Conclusion We suggest that this programme could serve as a model for pragmatic screening for PML during the clinical development of new drugs

Co-transfer of tumor-specific effector and memory CD8+ T cells enhances the efficacy of adoptive melanoma immunotherapy in a mouse model

Abstract Background Adoptive cell transfer (ACT) is a promising cancer immunotherapeutic strategy that remains ineffective for a large subset of patients. ACT with memory CD8+ T cells (Tmem) has been shown to have superior efficacy compared to traditional ACT with effector CD8+ T cells (Teff). Teff and Tmem have complementary physiological advantages for immunotherapy, but previous publications have not examined ACT using a combination of Teff and Tmem. Methods Splenocytes harvested from Ly5.1+/C57BL/6 mice during and after infection with lymphocytic choriomeningitis virus (LCMV) were used to generate bona fide effector and memory CD8+ T cells specific for the LCMV epitope peptide GP33. Congenic Ly5.2+/C57BL/6 mice were inoculated with B16F10 melanoma cells transfected to express very low levels of GP33, then treated with ACT 7 days later with GP33-specific Teff, Tmem, or a combination of Teff + Tmem. Results Inhibition of melanoma growth was strongest in mice receiving combinatorial ACT. Although combinatorial ACT and memory ACT resulted in maximal intratumoral infiltration of CD8+ T cells, combinatorial ACT induced stronger infiltration of endogenous CD8+ T cells than Tmem ACT and a stronger systemic T cell responsiveness to tumor antigen. In vitro assays revealed rapid but transient melanoma inhibition with Teff and gradual but prolonged melanoma inhibition with Tmem; the addition of Tmem enhanced the ability of Teff to inhibit melanoma in a manner that could be reproduced using conditioned media from activated Tmem and blocked by the addition of anti-IL-2 blocking antibody. Conclusions These findings suggest that a novel combinatorial approach that takes advantage of the unique and complementary strengths of tumor-specific Teff and Tmem may be a way to optimize the efficacy of adoptive immunotherapy.https://deepblue.lib.umich.edu/bitstream/2027.42/143864/1/40425_2018_Article_358.pd

Prevalence of Nicotine Delivery Systems by Biological Sex in the Spit for Science Study

Nicotine intake usage trends have changed over recent decades given the wide variety of nicotine delivery systems including cigarettes, vaping, hookah, and snubs/chewables. These trends also vary by demographic factors, such as race/ethnicity, sex, and socioeconomic status (SES). For example, studies in rat populations, as well as humans, have found that females tend to be more dependent on nicotine products and have a more difficult time quitting than male rats and humans (Pogun et al., 2017). Also, race/ethnicity may impact the frequency of nicotine usage in different populations; in that non-white Hispanics were more susceptible to smoking through adolescence with a peak at ages 12 and 16; whereas non-Hispanic Asian Americans were less susceptible to smoking at ages 11 and 15 (El-Toukhy et al., 2016). Certain nicotine delivery methods may be more available or perhaps more socially accepted by certain groups of people. While lower SES is associated with more prevalent cigarette advertisements and usage, individuals with a higher SES were associated with an increased prevalence of e-cigarette advertisements, leading to an increased frequency of e-cigarette usage among adolescents (Simon et al., 2018). This project aims to document rates of nicotine use across different nicotine delivery systems in college students by demographic factors. We use the Spit for Science (S4S) database to investigate prevalence rates and study if they differ by sex, race/ethnicity, or SES. It is hypothesized that higher SES individuals will have an increased frequency of use with nicotine products that are non-cigarette based, non-white Hispanics will have greater frequency with nicotine usage, and females within the study sample will display a higher dependency on nicotine products than males. Preliminary analyses reveal that there are more female participants than males throughout the S4S cohorts collected between 2020 and 2022. Across cohorts, prevalence of all nicotine delivery systems differs in female and male participants across all products. Larger differences in prevalence between females and males are observed for cigarettes, smokeless tobacco, and cigars than for products that have been introduced more recently, such as hookah, vaping, and heat-not-burn products. Further analyses will focus on patterns of use in relation to race/ethnicity and SES. Understanding nicotine usage trends within our sample could pave the way for additional research (i.e., genetic studies) and allow for the development of prevention/intervention models tailored to our sample populations.https://scholarscompass.vcu.edu/uresposters/1436/thumbnail.jp

Metolachlor metabolite (MESA) reveals agricultural nitrate-N fate and transport in Choptank River watershed

Over 50% of streams in the Chesapeake Bay watershed have been rated as poor or very poor based on the index of biological integrity. The Choptank River estuary, a Bay tributary on the eastern shore, is one such waterway, where corn and soybean production in upland areas of the watershed contribute significant loads of nutrients and sediment to streams. We adopted a novel approach utilizing the relationship between the concentration of nitrate-N and the stable, water-soluble herbicide degradation product MESA {2-[2-ethyl-N-(1- methoxypropan-2-yl)-6-methylanilino]-2-oxoethanesulfonic acid} to distinguish between dilution and denitrification effects on the stream concentration of nitrate-N in agricultural subwatersheds. The ratio of mean nitrate-N concentration/(mean MESA concentration * 1000) for 15 subwatersheds was examined as a function of percent cropland on hydric soil. This inverse relationship (R2 = 0.65, p b 0.001) takes into consideration not only dilution and denitrification of nitrate-N, but also the stream sampling bias of the croplands caused by the Choptank River. The relationship between nitrate-N and MESA concentrations in samples collected over three years was linear (0.95 ≤ R2 ≤ 0.99) for all eight sampling dates except one where R2 = 0.90. This very strong correlation indicates that nitrate-N was conserved in much of the Choptank River estuary, that dilution alone is responsible for the changes in nitrate-N and MESA concentrations, and more importantly nitrate-N loads are not reduced in the estuary prior to entering the Chesapeake Bay. Thus, a critical need exists to minimize nutrient export from agricultural production fields and to identify specific conservation practices to address the hydrologic conditions within each subwatershed. In well drained areas, removal of residual N within the cropland is most critical, and practices such as cover crops which sequester the residual N should be strongly encouraged. In poorly drained areas where denitrification can occur, wetland restoration and controlled drained structures that minimize ditch flow should be used to maximize denitrification

Patterns of Natural and Human-Caused Mortality Factors of a Rare Forest Carnivore, the Fisher (Pekania pennanti) in California.

Wildlife populations of conservation concern are limited in distribution, population size and persistence by various factors, including mortality. The fisher (Pekania pennanti), a North American mid-sized carnivore whose range in the western Pacific United States has retracted considerably in the past century, was proposed for threatened status protection in late 2014 under the United States Endangered Species Act by the United States Fish and Wildlife Service in its West Coast Distinct Population Segment. We investigated mortality in 167 fishers from two genetically and geographically distinct sub-populations in California within this West Coast Distinct Population Segment using a combination of gross necropsy, histology, toxicology and molecular methods. Overall, predation (70%), natural disease (16%), toxicant poisoning (10%) and, less commonly, vehicular strike (2%) and other anthropogenic causes (2%) were causes of mortality observed. We documented both an increase in mortality to (57% increase) and exposure (6%) from pesticides in fishers in just the past three years, highlighting further that toxicants from marijuana cultivation still pose a threat. Additionally, exposure to multiple rodenticides significantly increased the likelihood of mortality from rodenticide poisoning. Poisoning was significantly more common in male than female fishers and was 7 times more likely than disease to kill males. Based on necropsy findings, suspected causes of mortality based on field evidence alone tended to underestimate the frequency of disease-related mortalities. This study is the first comprehensive investigation of mortality causes of fishers and provides essential information to assist in the conservation of this species

Zonisamide, Topiramate, and Levetiracetam: Efficacy and Neuropsychological Effects in Alcohol Use Disorders

Abstract The anticonvulsant topiramate not only decreases ethanol consumption in alcohol dependence (AD) but also may produce several adverse events including cognitive impairment. Zonisamide is a structurally related anticonvulsant that is a promising agent for the treatment of AD and may have greater tolerability than topiramate. This study evaluated the effects of zonisamide (400 mg/d) on alcohol consumption and its neurotoxic effects in subjects with AD. A double-blind placebo-controlled clinical trial was conducted using 2 comparator anticonvulsant drugs, topiramate (300 mg/d) and levetiracetam (2000 mg/d), which does not impair cognition. Study medications were administered for 14 weeks, including a 2-week taper period. Medication adherence was facilitated using Brief Behavioral Compliance Enhancement Treatment. The neurotoxicity of the study drugs was assessed using neuropsychological tests and the AB-Neurotoxicity Scale. Compared with placebo, both zonisamide and topiramate produced significant reductions in the drinks consumed per day, percent days drinking, and percent days heavy drinking. Only the percent days heavy drinking was significantly decreased in the levetiracetam group. The topiramate cell was the only group that had a significant increase on the mental slowing subscale of the Neurotoxicity Scale compared with placebo at study weeks 11 and 12. Topiramate and zonisamide both produced modest reductions in verbal fluency and working memory. These findings indicate that zonisamide may have efficacy in the treatment of AD, with effect sizes similar to topiramate. Both of these drugs produced similar patterns of cognitive impairment, although only the topiramate group reported significant increases in mental slowing

Concert recording 2017-04-23b

[Track 1]. Slowing down. I. Rotations in an emergency [Track 2]. II. Under the city [Track 3]. III. Forfeit [Track 4]. IV. Something comfortable to fall into / Jeremiah Flannery

Inhibition of HCK in myeloid cells restricts pancreatic tumor growth and metastasis

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with a low 5-year survival rate and is associated with poor response to therapy. Elevated expression of the myeloid-specific hematopoietic cell kinase (HCK) is observed in PDAC and correlates with reduced patient survival. To determine whether aberrant HCK signaling in myeloid cells is involved in PDAC growth and metastasis, we established orthotopic and intrasplenic PDAC tumors in wild-type and HCK knockout mice. Genetic ablation of HCK impaired PDAC growth and metastasis by inducing an immune-stimulatory endotype in myeloid cells, which in turn reduced the desmoplastic microenvironment and enhanced cytotoxic effector cell infiltration. Consequently, genetic ablation or therapeutic inhibition of HCK minimized metastatic spread, enhanced the efficacy of chemotherapy, and overcame resistance to anti-PD1, anti-CTLA4, or stimulatory anti-CD40 immunotherapy. Our results provide strong rationale for HCK to be developed as a therapeutic target to improve the response of PDAC to chemo- and immunotherapy