<p> The pediatric mental health burden in the United States (US) is substantial, with more than 4 million children meeting diagnostic criteria for a mental health disorder. As of 2014, this number represented 20% of US children and adolescents. In 2010, mental health disorders are estimated to cost children and their families $247 billion dollars annually and severely impact quality of life for children and their families. From 2007 to 2010, inpatient admissions for mental health disorders in pediatric patients increased 24% and mood disorder admissions in pediatric patients increased 80% from 1997&ndash;2010. An estimated $11.6 billion was spent on pediatric mental health hospitalizations from 2006 through 2011, with public sources such as Medicaid and Medicare responsible for approximately 50% of the payments, leaving 50% to private payers. This economic and clinical concern has led pediatric medical associations and health quality agencies to increase support and funding for pediatric mental health research and treatment. </p><p> Medication therapy is a common intervention in mental health treatment and atypical antipsychotics are increasing in utilization, often becoming first-line therapy. Despite available data describing the need to treat pediatric mental health conditions, the available evidence for clinical effectiveness and economic impact of atypical antipsychotics (AAPs) has many shortfalls. Most available research is derived from patients utilizing publicly-funded medical care, such as Medicaid or Medicare resources, with little data available about patients with privately-funded care. To help address this gap in the literature, we used a large, privately-insured, US population for our analysis. We examined if the increased trend in AAP utilization from previous research is also present in this pediatric population. Considering the payer perspective, we evaluated the cost of AAP medication therapy based on most recent utilization. </p><p> Available studies lack information about the direct costs of pediatric mental health treatment and efficacy of psychiatric medications in the pediatric population. Most efficacy studies are based on clinical trials necessary for pediatric indication approval from regulatory agencies such as the Food and Drug Administration (FDA). Many of the AAP medications do not have pediatric clinical trial evidence available and are frequently utilized without pediatric indications. The available data suggests that off-label prescribing is not an uncommon practice in the pediatric patient population. </p><p> Approximately half of atypical antipsychotics do not have pediatric indications but are increasingly used, particularly in treating behavior disorders, due to such factors as improved patient compliance and improved side effect profiles. Limited formal studies examining atypical antipsychotic use compared to other agents in the class have been conducted. Studies with direct comparisons have yet to be conducted in the pediatric population with mental health disorders. </p><p> The manuscripts that comprise this dissertation aim to provide new insights into available trend and utilization patterns of atypical antipsychotic medication use in children. This research characterized the prevalence of atypical antipsychotic use in pediatric patient with mental health conditions in a large, privately insured US population, evaluating the diagnoses associated with treatment and estimate the cost of AAP medication therapy in this population. This research determined if the trends observed in publicly-insured children persist in the privately-insured, pediatric patient. The analysis evaluated annual trends in prevalent use of atypical antipsychotic medication over 6-year period in this pediatric population and evaluated the appropriate use of AAPs for mental health diagnoses. Lastly, an evaluation determined if specific antipsychotic therapy delayed time to readmission among privately-insured children following a psychiatric hospital admission. The results of this dissertation will provide new insights regarding the trends and direct medication costs of atypical antipsychotic agents when utilized in pediatric patients with mental health disorders. </p><p> <u>Manuscript 1:</u> This analysis focused on characterizing the most recent (2015) AAP use in the pediatric population, using a large, US population of privately- insured children. The study evaluated if the prevalence data observed among publicly insured children persists. Characterization of the prescribing trends for atypical antipsychotics and the medication costs of the use in this population were examined. Patterns of use across demographics and associated mental health diagnoses were characterized by the class of medication. This study focused on the prevalent use of AAPs in pediatric patients, evaluated the mental health diagnoses associated with AAPs and the direct cost burden of medication therapy associated with this use of AAP in the pediatric population to the private payer. </p><p> <u>Manuscript 2:</u> This research evaluated the trends in the prescribing of atypical antipsychotic medications from 2010 through 2015 in this privately-insured pediatric population. The trends of AAP use in the pediatric population over six years were examined. The associated mental health diagnoses corresponding with AAP prescribing were described to examine the off-label diagnoses treatment prevalence in this population. (Abstract shortened by ProQuest.) </p><p>

<p> <i><b>Introduction:</b></i> In humans, bruxism is defined as the grinding or clenching of the teeth. Pathological bruxism can cause damage to dental surfaces, joint pain and many other dentally related issues. Bruxism can be displayed while awake or during sleep. In humans, L-dopa can attenuate bruxism during sleep. To grind down continuously growing teeth, rats display a brux-like behavior while awake. L-dopa&rsquo;s effect on brux-like motor patterns in rats have never been characterized. The influence of L-dopa on masticatory motor patterns has not been investigated in rats or humans. This pilot study used electromyography in three masticatory muscles to test the effects of acute L-dopa on brux-like motor patterns and mastication in rats. </p><p> <i><b>Methods:</b></i> Electromyography (EMGs) fine silver wire electrodes were surgically implanted into the anterior superficial masseter, anterior digastric, and posterior superficial masseter muscles of laboratory rats (<i>Rattus norvegicus</i>) (n=10). The fine silver wire electrodes were run sub-dermally to an electrode pedestal, which was secured to the skull via screws and dental cement. A preamplifier (X10) was attached to the headcap, and sent to a secondary amplifier (x100). This amplified signal was sent to an A/D converter, and digitally recorded with a personal computer. Rats received an IP injection of L-dopa (10mg/kg)/Benserazide (15mg/kg) or saline vehicle. We recorded brux-like EMG bursts for one hour after injection. After the initial hour of brux-like recording, the rats were given food and masticatory EMG bursts were recorded. After recording, at least one hundred onsets and offsets were collected for each behavior. This was done for every animal. For brux-like behavior, the number of episodes per hour, average episode duration, and total time displaying brux-like activity was obtained for each animal and compared using a Mann-Whitney U test. For brux-like and masticatory motor patterns, cycle period (onset-to-onset), burst duration (onset-to-offset), between burst (offset-onset), and cycles per second were recorded for every animal and compared using a Mann-Whitney U test. Phase values, which compare the timing of two muscles, was also obtained. Treatment groups were compared to assess L-dopa&rsquo;s effects on brux-like and masticatory motor patterns. </p><p> <i><b>Results:</b></i> The number of brux-like episodes per hour in controls (&mu;=47.8, SD=18.7) was greater than the group that received the L-dopa treatment (&mu;=16, SD= 12.53); (<i>U</i>=2, p&lt;0.05). Average episode duration and total time displaying brux-like activity per hour did not change (NS). Anterior superficial masseter cycle period, burst duration, between burst, and cycles per second were not different between treatments (NS). Anterior digastric cycle period, burst duration, and between burst were not different between treatments (NS). For the anterior digastric, the L-dopa treatment group had a higher rate of cycles per second (&mu;=7.271, SD=0.973) than the control group (&mu;=9.034, SD=1.422) (<i>U</i>=2, p=.05). We compared the phase relationships between the anterior superficial masseter and anterior digastric using a Watson-Williams F test and found the phase values to be similar (NS). Not enough posterior superficial masseter muscle traces were obtained for statistical test to be performed. The obtained results for the posterior superficial masseter muscle were characterized for future experiments.</p><p> <i><b>Conclusion:</b></i> Although L-dopa attenuates sleep bruxism in humans, it has not been used to assess brux-like motor patterns in rats. Rats display a conscious, brux-like motor pattern that is used to prevent tooth overgrowth. This study is the first to establish that brux-like motor patterns in the conscious rats are attenuated by acute doses of L-dopa. Brux-like motor patterns were attenuated with only a change to anterior digastric cycle period. L-dopa likely plays a role in initiating brux-like motor patterns, but it does not control rhythmogenesis. To our knowledge, mastication has not been examined in detail while under the influence of L-dopa in humans or rats, making this study the first to look at L-dopa&rsquo;s effect on the motor pattern. The masticatory motor patterns remained unchanged between treatment groups (NS). Our study is the first to show that acute L-dopa exposure does not alter masticatory motor patterns. L-dopa does not have a strong influence over the masticatory CPG. This study established an animal model for use on future studies of brux-like behavior. The developed model can be applied in the future for drug interactions and basal ganglion studies.</p><p>

<p> Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related deaths worldwide in both men and women. Of relevance to our research presented herein are the Transforming growth factor &beta; (TGF-&beta;) signaling pathways and the heat shock response in the context of NSCLC. Dysregulation of TGF-&beta; signaling often results in disease and is a common feature of many cancers including NSCLC where it governs cell fate and epithelial plasticity through the epithelial-to-mesenchymal transition (EMT). Another key feature of oncogenic TGF-&beta; signaling is the crosstalk with other oncogenic pathways, like the NOTCH signaling pathway, which aids to restrict differentiation and modulates proliferation. Our research identified a mechanistic link between histone deacetylase 6 (HDAC6) and TGF-&beta;1-induced Notch1 signaling. When HDAC6 is knocked down with siRNA or its deacetylase function is pharmacologically inhibited TGF-&beta;1 activation of Notch signaling is abrogated. Within this paradigm we identified a protein complex consisting of HDAC6, heat shock protein 90 (HSP90), and the Notch1 receptor. In response to TGF-&beta;1 stimulation, HDAC6 rapidly deacetylates HSP90 at lysine 294 which corresponds with cleavage and activation of Notch1.</p><p> Our investigations also uncovered a unique feature of HSP90 function in NSCLC. Activation of the heat shock response triggers activation of Notch1 signaling. We demonstrated that HDAC6 regulates this heat shock-induced Notch1 signaling through modulation of HSP90 function of cytoplasmic sequestration of the key transcription factor that governs the heat shock response, heat shock factor 1 (HSF1). Brief exposure of NSCLC cells to 42&deg;C activates heat shock-induced Notch1 signaling, knockdown of HDAC6 with siRNA or pharmacological inhibition of HDAC6 abrogated this induction. In our investigations employing this combined strategy of targeting both HDAC6 and HSP90 we discovered that this treatment had an additive effect to enhance apoptotic markers and inhibit cell cycle progression in NSCLC cells. Individual HDAC6 or HSP90 inhibition slowed tumorigenesis and enhanced apoptosis of NSCLC in vivo. Taken altogether, our research identifies HDAC6 and HSP90 as regulators of key oncogenic pathways required for EMT and that combined inhibition of both these targets is a rational strategy to selectively kill NSCLC cells.</p>