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<p>Long-acting injectables (LAI) offer many practical benefits for patients in improving drug adherence to therapies for chronic diseases. LAI, administered either subcutaneously (SC) or intramuscularly (IM), can improve drug bioavailability, and reduce frequency of administration as well as regimen complexity. SC also has additional benefits over IM injections as being safer, less painful, and able to be administered at home. However, development and translation of these products into the clinic is often limited because of physiological complexity at injection site, such that absorption rate mechanisms are not well understood. Common predictive and correlative methods used in oral formulations, such as <em>in vitro-in vivo </em>correlations, are not well suited for SC physiology and are only capable of measuring a few parameters at a time, meaning relationships between parameters cannot be discriminately measured.</p> <p><br></p> <p>This project seeks to address this gap in knowledge by using computation to bridge the gap between suboptimal preclinical testing methods and human pharmacokinetic data. A Multiscale framework was developed by integrating a first-principles Multiphysics model of the SC space to experimental plasma concentration profiles using simulated absorption rates. First, our lab’s previous framework for lymphatic absorption of monoclonal antibodies (mAbs) was converted into small molecule absorption into the capillaries. Drug and formulation critical quality attributes (CQA) were determined for a solution injection of methotrexate, and a nanocrystal formulation of medroxyprogesterone acetate (MPA, Depo-SubQ Provera). Two dissolution models were incorporated to compare the difference between using average particle size (Noyes-Whitney) and particle size distributions (Population Balance Model, PBM) as CQA for nanocrystal LAI specifically. Absorption rates were validated using compartmental pharmacokinetic models, and sensitivity analyses were conducted to determine model parametric sensitivity. Overall, the modeling framework was able to determine the importance of and discriminate the effect of parameters on SC absorption rates. </p>

Teenage childbearing is considered a societal ill, despite the evidence failing to demonstrate a causative link between teenage childbearing and negative consequences for teens or their children. This thesis argues that the strongly held assertion that teenage childbearing is detrimental to teens and society is rooted in racist eugenics theories and histories of reproductive coercion. Today, social scientists, health care providers, and public health professionals develop and celebrate programs that reduce rates of teen pregnancy, particularly programs that provide Long Acting Reversible Contraceptives (LARCs) to teens in marginalized communities. While these efforts are well-intentioned, they fail to recognize their perpetuation of histories of reproductive coercion of young women of color. This paper recommends ways in which the medical community can be better informed and respect reproductive autonomy in caring for teens from marginalized communities. / Urban Bioethics

McMaster University MASTER OF SCIENCE (2019) Hamilton, Ontario (Medical Sciences) TITLE: Modulation of cyclic adenosine monophosphate for potentiation of long-acting β2-agonist and glucocorticoids in human airway epithelial cells AUTHOR: Yechan Kim, B.HSc. (McMaster University) SUPERVISOR: Dr. Jeremy Alexander Hirota NUMBER OF PAGES: xiv, 81 / In Canada, asthma is the third most common chronic disease resulting in 250 premature deaths annually and related healthcare expenses exceeding $2.1 billion/year. It is estimated that around 50-80% of asthma exacerbations are due to viral infections. Despite an advanced understanding on how to treat and manage the symptoms of asthma, current therapy is sub-optimal in 35-50% of moderate-severe asthmatics around the world resulting in lung inflammation, persistent impairment of lung function, and increased risk of mortality. Combination of long-acting β2 agonists (LABA) for bronchodilation and glucocorticoids (GCS) to control lung inflammation represent the dominant strategy for the management of asthma. Increasing intracellular cyclic adenosine monophosphate (cAMP) beyond existing combination LABA/GCS are likely to be beneficial for the management of difficult to control asthmatics that are hypo-responsive to mainstay therapy. In human airway epithelial cells (HAEC), cAMP is either exported by transporters or broken down by enzymes, such as phosphodiesterase 4 (PDE4). We have demonstrated that HAEC express ATP Binding Cassette Transporter C4 (ABCC4), an extracellular cAMP transporter. We also show that ABCC4 and PDE4 inhibition can potentiate LABA/GCS anti-inflammatory responses in a human epithelial cell line in a cAMP-dependent mechanism validating the pursuit of novel ABCC4 inhibitors as a cAMP elevating agent for asthma. / Thesis / Master of Science in Medical Sciences (MSMS) / Asthma is a common chronic lung disease characterized by narrow and inflamed airways that cause breathing difficulties. Current management includes the combination of bronchodilators, to relax the airway, and steroids, to decrease inflammation. Unfortunately, this combination therapy is suboptimal in 35-50% of users, increasing the risk of asthma attacks, hospitalization rate, and health care costs. Recently, there have been studies theorizing that we can improve the therapy’s ability to decrease inflammation by increasing cAMP, an important molecule for biological activities. We tested this claim by blocking the breakdown and export of cAMP to increase its levels and measured inflammatory cytokines, molecules that direct the action of immune cells. Our results show that in a model of viral infection, administering the combination therapy while increasing cAMP levels can further decrease inflammatory cytokines prompting further investigation for its potential implication in the clinic.

In 2010 Medicaid financed approximately 48% of all births in the United States and nearly 30% of all births in Virginia. Due to strict state-specific eligibility criteria, many low-income women qualify for Medicaid coverage exclusively as a result of pregnancy status. As the nation moves forward with the Patient Protection and Affordable Care Act (PPACA), state-elected Medicaid expansion has the potential to expand services to women of reproductive age that would precede pregnancy events and offer continuous access to care postpartum. Despite this potential influx of newly insured women, little is known about how this population may make decisions regarding reproductive healthcare services and if these selections influence process and outcome measures. This study examines two research aims that provide insight into these knowledge gaps. First, utility theory and discrete choice modeling is used to examine clinic and patient level factors associated with clinic type choice. Specifically, this study examines the role of high risk pregnancy status and travel distance to clinic as associated with clinic selection. Second, Donabedian’s Structure, Process, Outcome framework provides a conceptual lens to examine if clinic selection is associated with maternal and infant measures. The linear probability model and logistic regression models are employed to examine two process measures, including prenatal care inadequacy and postpartum visit nonattendance, and three outcome measures including maternal long acting reversible contraceptive method (LARC) use and infant birthweight and gestational age. Results examining clinic type selection reveal significant associations between independent and dependent variables. Women experiencing a high risk pregnancy are significantly more likely to select a hospital based clinic for care, compared to women experiencing a normal risk pregnancy. However, when specifically examining women experiencing their first pregnancy, this association is no longer significant. Additionally, as distance to clinic type increase, women are significantly less likely to select that clinic type for prenatal care. Clinic selection was found to be significantly associated with maternal measures, but not significantly associated with infant outcomes. Selecting a public health department or Federally Qualified Health Center for prenatal care services was associated with a significant decrease in inadequate prenatal care, postpartum visit nonattendance, and non-LARC use compared to a private physician office. Clinic type selection, however, was not found to be significantly associated with infant outcomes including preterm birth and low birthweight babies. Results from Research Aim 1 have a variety of implications for clinic and public policy and offer guidance for future research. Clinics that seek to provide care to pregnant Medicaid beneficiaries should examine local residential patterns of current and potential future pregnant Medicaid recipients and consider how these might affect decisions about future clinic locations. Results suggest that women are more likely to attend clinic types closer to their area of residence, and this close proximity may have additional implications beyond shorter travel time to clinic including the minimization of transportation and childcare issues. Results from Research Aim 2 analyses offer a variety of public policy implications and guidance for future research. This research provides evidence that public health facilities including public health departments and FQHCs have improved prenatal care adequacy and postpartum visit attendance compared to private physician offices, providing evidence that public funding should continue for these facility types. As the United States moves forward with PPACA, healthcare organization administration should turn to the public facilities in their communities to learn how to manage and improve the health of these patient populations and ultimately aim to improve access and quality care among the nation’s most vulnerable populations.

In Tennessee (TN), the rate of unintended pregnancies remains higher than the national rate (32.4% vs. 30.3%). Although long-acting reversible contraceptives (LARCs) are 99% effective in preventing undesired pregnancies; uptake remains low in rural and underserved communities. Previous research has provided some insight into women’s perceptions of LARCs; however, those guided by conceptual frameworks to understand the multiple influences that impact perceptions towards LARCs, especially among rural regions, are scarce. This multimethod qualitative study explored multiple influences that impact northeast Tennessee women’s perceptions and attitudes toward LARCs using the Socio-ecological Model (SEM) as a guiding framework. The study comprised six focus groups and seven individual interviews of women aged 18-44, not pregnant, and current residents of five counties in Northeast TN. Participants’ demographics were administered through REDCap, while qualitative data from focus groups and interviews were recorded via Zoom. Focus groups and interview data were combined, and an a priori list of codes identified from the constructs of the SEM was initially used to deductively code the data. Subsequently, the data were analyzed inductively for new codes and themes that did not apply to the a priori categories. Seventeen themes and 23 sub-themes were identified using the SEM; On the intrapersonal level of the SEM, participants’ contraception utilization history, attitudes towards a method, perception of method features, and perceived side effects were identified as themes that delineate influences on their LARC utilization. Perception of partner support, perceived support from peer/social networks, and provider trust themes were identified on the interpersonal level. On the community level, the cost of the method, access to information, perceived accessibility to a method, social services, and cultural norms themes were identified. The availability of preferred methods in a clinic, the need for multiple clinic visits to use a method, and provider counseling practices were identified as organizational-level themes. On the policy level, insurance, and billing policies, sex education policies were identified as impacting LARC utilization. Study findings highlight the areas of influence that can be addressed to increase LARC uptake and enable women in rural and underserved regions to achieve their personal reproductive goals.

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Die Erkrankung Diabetes mellitus stellt eine wesentliche medizinische und ökonomische Her-ausforderung für das deutsche Gesundheitssystem dar. Weitgehend ungeklärt sind jedoch die Kostenunterschiede alternativer Behandlungsstrategien. In der vorliegenden Arbeit wurde die Wirtschaftlichkeit von Insulin glargin gegenüber relevanten Therapiealternativen bei Patien¬ten mit insulinbehandeltem Typ-2-Diabetes aus der Perspektive der deutschen GKV unter-sucht. Dazu wurden vier pharmakoökonomische Evaluationen mittels Kosten-Minimierungs-Ansatz auf der Basis von Studien- und Routinedaten durchgeführt. Die therapeutische Äqui-valenz der verglichenen Behandlungsverfahren wurde als gesichert vorausgesetzt. In allen vier Wirtschaftlichkeitsanalysen konnte die Kosteneffektivität von Insulin glargin ge-genüber relevanten Komparatoren gezeigt werden. Beim Vergleich der basalunterstützten ora-len Therapie (BOT) mit der prandialen Insulintherapie (SIT) ergaben sich auf Basis der APOLLO-Studie jährliche Pro-Kopf-Einsparungen in Höhe von 722 € zugunsten von Insulin glargin. Geringere Behandlungskosten zeigten sich auch gegenüber Insulin detemir in der BOT auf Basis der Rosenstock-RCT sowie in der Basal-Bolus-Therapie (ICT) auf Basis der Hollander-RCT. Die jährlichen Pro-Kopf-Einsparungen zugunsten von Insulin glargin betru-gen 486 € in der BOT und 684 € in der ICT. Schließlich ergab auch der Behandlungs¬kosten¬vergleich von Insulin glargin mit dem langwirksamen NPH-Insulin auf der Basis ambulanter Routinedaten niedrigere jährliche Behandlungskosten zugunsten von Insulin glargin. Die Ein-sparungen pro Patient und Jahr betrugen 198 € und waren unabhängig vom Behandlungsre-gime (BOT oder ICT). Die Ergebnisse der vorliegenden Arbeit unterstreichen den Stellenwert qualitätsgesicherter Wirtschaftlichkeitsanalysen zur rationalen Ressourcenallokation im Rahmen der Insulin¬therapie des Typ-2-Diabetes mellitus.

Blood glucose management in Type 1 diabetes is crucial in preventing several diabetic complications. Blood glucose management is a complex task requiring diabetics too carefully administer the correct dosages of insulin by taking their blood glucose levels, food consumption, exercise, stress, illnesses and several other factors into account. Improved bolus calculation greatly aids in controlling blood glucose levels within a tight range. This study investigates how the ets-concept (Equivalent Teaspoons Sugar-concept) can be used to develop products to calculate insulin boluses. A cellular phone based software application was developed to calculate insulin boluses using the ets-concept. This product was tested in a clinical trial. A blood glucose characterization procedure was also developed to characterize the blood glucose response of a Type 1 diabetic to carbohydrate ingestion and insulin administration. The characterization procedure was used during the clinical trial to characterize patients in order to customize the bolus calculation products for the specific diabetic user. / Thesis (Ph.D. (Mechanical Engineering)--North-West University, Potchefstroom Campus, 2006

Blood glucose management in Type 1 diabetes is crucial in preventing several diabetic complications. Blood glucose management is a complex task requiring diabetics too carefully administer the correct dosages of insulin by taking their blood glucose levels, food consumption, exercise, stress, illnesses and several other factors into account. Improved bolus calculation greatly aids in controlling blood glucose levels within a tight range. This study investigates how the ets-concept (Equivalent Teaspoons Sugar-concept) can be used to develop products to calculate insulin boluses. A cellular phone based software application was developed to calculate insulin boluses using the ets-concept. This product was tested in a clinical trial. A blood glucose characterization procedure was also developed to characterize the blood glucose response of a Type 1 diabetic to carbohydrate ingestion and insulin administration. The characterization procedure was used during the clinical trial to characterize patients in order to customize the bolus calculation products for the specific diabetic user. / Thesis (Ph.D. (Mechanical Engineering)--North-West University, Potchefstroom Campus, 2006