Now showing items 1-20 of 993

    • Covid-19: Do many people have pre-existing immunity?

      Doshi, Peter (BMJ Publishing Group, 2020-09-17)
    • Mapping Expanded Prostate Cancer Index Composite (EPIC) Questionnaire to EuroQoL-5D (EQ-5D) Utility Weights to Inform Economic Evaluations for Prostate Cancer

      Khairnar, Rahul; Palumbo, Francis Bernard, 1945- (2020)
      OBJECTIVES: To develop a mapping algorithm to obtain EuroQoL-5D-3L (EQ5D) health utilities from Expanded Prostate Cancer Index Composite (EPIC) questionnaire. METHODS: This mapping study utilized baseline data from an international, multicenter, randomized controlled trial (NCT00331773) of patients with low-risk prostate cancer. Patient health-related quality-of-life (HRQoL) data were collected using EPIC and health utilities were obtained using EQ5D. Data were divided into an estimation sample (n=765, 70%) and a validation sample (n=327, 30%). The relationship between the instruments was estimated using ordinary least squares (OLS), Tobit, and two-part models. Five-fold cross-validation (in-sample) was used to compare the predictive performance of the estimated models. Final models were selected based on root mean square error (RMSE). OLS models using baseline cross-sectional data, combined data from all assessment periods, and random effects (RE) models that explicitly model the longitudinal nature of the data were estimated to compare predictive ability of algorithms derived from cross-sectional and longitudinal data. Longitudinal predictive performance of OLS models derived using baseline data was examined in the post-intervention data. RESULTS: A total of 565 patients in the estimation sample had complete information on both EPIC and EQ5D questionnaires at baseline. Mean observed EQ5D utility was 0.90±0.13 (range: 0.28-1) with 55% of patients in full health. Low to moderate correlations were found between EQ5D utility and urinary (r=0.38), bowel (r=0.34) and hormonal (r=0.55) domains of EPIC; sexual domain was weakly correlated (r=0.18) with EQ5D utility. OLS models outperformed their counterpart models for all pre-determined model specifications. The best model fit was: “EQ5D utility = 0.248541 + 0.000748*(Urinary Function) + 0.001134*(Urinary Bother) + 0.000968*(Hormonal Function) + 0.004404*(Hormonal Bother) – 0.376487*(Zubrod) + 0.003562*(Urinary Function*Zubrod)”; RMSE was 0.10462. When comparing cross-sectional vs. longitudinal data, a mapping algorithm obtained using combined EPIC subdomain data outperformed other model types. Mean absolute differences (MDs) between reported and predicted were low in general and decreased as the time of assessment increased. CONCLUSIONS: This study identified mapping algorithms to generate EQ5D utilities from EPIC domain or sub-domain scores, with satisfactory longitudinal predictive performance. The study results will help estimate quality-adjusted life-years in future economic evaluations of prostate cancer treatments.
    • Early Symptom Improvement as a Predictor of Antidepressant Response in Children and Adolescents Diagnosed with Depression: Translating Evidence from Randomized Controlled Trials to Community Practice

      Spence, O'Mareen; dosReis, Susan (2020)
      Statement of the Problem: A common problem among children and adolescents diagnosed with depression who receive care in community settings is that antidepressant regimen changes such as psychotropic augmentation may occur soon after starting treatment. This raises the question as to whether such changes are implemented among youth who would otherwise respond to the antidepressant. Thus, the overarching objectives of this dissertation were to 1) distinguish early in treatment children and adolescents who are likely to respond, and 2) empirically evaluate the association between predicted response and psychotropic augmentation or switching in real world settings. Summary of Methods: Using randomized clinical trial (RCT) data, this research applied a Bayesian approach to predict the likelihood of initial (12 week) and sustained (18 week) response to treatment as a function of early changes in depressive symptoms (i.e. mood, somatic, subjective and behavioral) and other demographic and clinical factors. An innovative application of combined sample multiple imputations (CSMI) was used to estimate the 12-week predicted probability of response among commercially insured adolescents who received care in real-world settings. Each adolescent received a probability of treatment response, which was then used to compare the odds of psychotropic augmentation or switch. Results: Early changes in mood and somatic symptoms within the first six weeks of treatment are primary predictors of initial (at 12 weeks) and sustained (at 18 weeks) response to an antidepressant. Baseline depression severity is an important prognostic factor for initial response, and additional, though minimal improvement, in somatic symptoms from weeks 6 to 12 is indicative of sustained response. In a highly selected cohort of adolescents receiving care in community settings, an augmentation or switch occurred similarly among adolescents with a high versus low likelihood of responding to fluoxetine. Conclusion: The results suggest that other factors beyond expected antidepressant response (or lack thereof) might influence current treatment practices. Our findings have clinical and public health implications that support measurement-based care in pediatric depression. Our application of CSMI highlights several key areas of consideration for future pharmacoepidemiologic research aimed at translating RCT evidence to real world data to better understand clinical practices patterns.
    • A Model for Assessing Professional Association Engagement

      Gorman, Emily; Jackson, K. D.; Harrold, M.W.; Mercer, S.L.; Metcalf, M.; Lebovitz, Lisa; Tucker, Shannon R.; Block, K.F.; Franzini, R.; Coop, Andrew (2020)
      Assessing member engagement with a professional association is critical in determining the success of programs such as the AACP New Investigator Award (NIA), because engagement leads to organizational growth and is key to long term sustainability. A review of the literature indicated that many organizations are focused on increasing engagement, but there are few quantifications of engagement to be used to measures success of initiatives. Use of online communication tools such as AACP Connect can be quantified, and are often used as a proxy for engagement, but the literature is clear that the majority of individuals may be avid readers, but do not post. The authors searched peer-reviewed and organizational literature for published models evaluating organizational engagement to create a modified scale to quantify engagement following the NIA. The American Bar Association published an article assessing engagement of its members with five tiers, explaining the tiers as a continuum. Although presented by ABA as a continuum, this approach was seen by the authors as an approach to measure the depth of engagement.
    • Follicular Lymphoma Stage at Diagnosis: Determinants, Prediction from Administrative Claims Data and Impact on Healthcare Costs

      Albarmawi, Husam; Onukwugha, Eberechukwu (2020)
      Introduction: Follicular lymphoma (FL) stage is an important determinant of survival, treatment options and treatment outcomes. However, the determinants of advanced FL, defined as Ann Arbor stages III and IV, and its impact on the economic burden of FL are unknown. Moreover, for studies that rely on administrative claims data, it is not clear if advanced FL can be accurately predicted from this data source. Methods: Using the linked Surveillance, Epidemiology, and End Results-Medicare database we identified patients newly diagnosed with FL. We estimated a modified Poisson regression to explore the effect of pre-diagnosis healthcare resource utilization patterns and baseline county-level factors on FL stage. We estimated the 1-year and 5-year incremental costs of stages II-IV compared to stage I using generalized linear models. To predict FL stage from claims data, we developed and tested two random forests models. Results: We identified 11,078 patients diagnosed in 2000-2013. Half of the sample had advanced FL. Higher counts of specialist physician visits in the 3 years pre-diagnosis were associated with lower risk of advanced FL (4th quartile vs. 1st quartile: Relative Risk [RR]=0.92; 95% CI=0.86–0.99). The risk of advanced FL was 8% lower among women receiving screening mammography compared to men (RR=0.92; 95% CI=0.88–0.97). Living in counties designated as health professional shortage areas (HPSA) was associated with 7% increased risk of advanced FL (RR=1.07; 95% CI=1.00–1.14, p=0.049). In 2004-2009, FL patients with stages II, III and IV had statistically higher 1-year ($14,911; $15,106; $24,639, respectively, p<0.01) and 5-year costs ($21,590; $23,599; $34,968, respectively, p<0.01) compared to stage I patients. The random forests models exhibited poor accuracy of classifying limited and advanced FL from Medicare claims data (accuracy: ≤64%; sensitivity: ≤72%; specificity: ≤57%). Conclusions: Higher frequencies of specialist physician visits and living in counties with no HPSA can reduce the risk of presenting with advanced FL. Patients with stages II-IV incur significantly higher costs compared to stage I patients. The incremental cost increases with higher FL stage. Predicting advanced FL from claims data may not be feasible and researchers may need to rely on datasets with existing clinical information.
    • Effect of Transient Heat Exposure on Drug Delivery from Transdermal and Topical Products

      Thomas, Sherin; Stinchcomb, Audra L. (2020)
      Heating pads and electric blankets are widely used for relief from pain and to provide warmth, respectively. Their unintentional application simultaneously with a transdermal or topical system can result in unexpected drug levels in systemic circulation. Designing well-characterized in vitro and in vivo methods are vital to understanding the effect of heat and hence can aid in the development and evaluation of these products. The objective of this work was to evaluate the effect of heat on products with the same active pharmaceutical ingredient (API) but different inactive ingredients. Four drug molecules with different physicochemical properties were chosen. For each drug, formulations with different excipients were selected. In vivo serum drug profile and in vitro flux profile data can provide mechanistic understanding of heat effect on these formulations. Four topical diclofenac formulations were evaluated for heat effect in vitro under continuous heat exposure. Their flux profiles demonstrated the influence of formulation design and excipients on drug permeation at elevated skin temperature. Serum profiles of two different oxybutynin formulations evaluated under heat exposure showed very different magnitude of enhancement in serum levels under similar heat exposure conditions. Another objective of this work was establishing an in vitro - in vivo correlation (IVIVC) of heat effect on topical and transdermal formulations. This will help in characterizing and predicting heat effect minimizing the need of clinical trials and support the regulatory evaluation of these dosage forms. For buprenorphine patch, study design for in vitro permeation testing (IVPT) using human skin was well characterized to align with and mimic in vivo conditions of heat exposure. Level A and Level C IVIVC were established under normal as well as elevated temperature conditions. For lidocaine patches, IVIVC was observed for early heat effect. However, poor correlation was observed for late heat effect. The findings from this work determined IVPT studies can correlate with and be predictive of in vivo results under normal temperature conditions. But under suboptimal conditions like heat exposure, IVPT may have limitations and should be used in addition to other methods to evaluate heat effect.
    • Evaluation of the Equivalency of Generic Drugs

      Das, Sharmila; Polli, James E. (2020)
      The objective of this dissertation is to assess the bioequivalence of generic drugs. Patients with epilepsy complain about more seizures and side effects after brand-generic or generic-generic switching of an anti-epileptic drug (AED). Generic brittleness (GB) is the familiar notion that, upon switching between AEDs of pharmaceutical equivalents, a patient experiences negative outcome. Aim 1 is to probe the individual patient attributes thought to predispose a patient to generic brittleness. At the University of Maryland Medical Center, 148 patients from the outpatient epilepsy clinic were recruited for an observational case-control study. An algorithm for being GB (40% of patients) and not GB was devised. A patient with epilepsy was categorized as GB if the patient negatively opined about generics and was taking brand of their most problematic AED when generic was available. Two demographic factors that increased the odds of being GB were a patient currently taking a problem AED and increasing total number of current medications. Interestingly, taking lamotrigine increased and taking any one of six “protective” anti-epileptic drugs decreased the odds of being GB, respectively. Furthermore, no genetic, clinical laboratory or neuropsychiatry tests or their sub-elements differentiated GB patients from not GB patients. Aim 2 involves a comparative pharmacokinetic (PK) analysis upon challenging sixteen GB patients to brand-generic or generic-generic switch of an AED that they are currently on, using a four-way crossover replicate design. For each patient, test and reference PK profiles were the same, despite patients being GB. Aim 3 is to assess the noninferiority of the generic sodium ferric gluconate (SFG) against the reference product Ferrlecit with respect to drug bound iron (DBI), after single dose intravenous administration of brand and generic SFG in 44 healthy volunteers. Using a two-way crossover replicate design, plasma PK profiles of SFG to Ferrlecit were the same across two iron species (e.g. DBI and NTBI), although adverse event rates differed. In conclusion generics of AEDs and intravenous sodium ferric gluconate are bioequivalent to the brand-name drugs. Results support FDA criteria for bioequivalence in regards to AEDs and complex iron products.
    • Integrated Drug Reviews at the US Food and Drug Administration-Reply

      Doshi, Peter; Morten, Christopher J; Herder, Matthew (American Medical Association, 2020-07-27)
    • University of Maryland School of Pharmacy. Annual Report 2017-2018

      University of Maryland, Baltimore. School of Pharmacy, 2018
    • Maryland Mentor : 2020

      University of Maryland, Baltimore. School of Pharmacy. Experiential Learning Program, 2020
    • From Data to Decisions: Utilizing Pharmacometrics to Optimize Clinical Therapeutics and Drug Development in Neuropsychiatry

      Kalaria, Shamir; Gopalakrishnan, Mathangi (2020)
      At least 50% of clinical trials of neuropsychiatric compounds fail due to an unclear understanding of disease pathophysiology and drug pharmacology. Further, lack of dosing information in special patient populations for approved neuropsychiatric drugs could contribute to suboptimal outcomes. The current research highlights the role of pharmacometrics in (i) optimizing therapeutics in patients receiving antiepileptics and continuous renal replacement therapy (CRRT) and (ii) informing efficient trial design for binge eating disorder (BED). Currently, no dosing recommendations exist for CRRT patients receiving antiepileptics. Real-world clinical studies were conducted to characterize the pharmacokinetics of levetiracetam and lacosamide in patients (N=18) receiving CRRT at the University of Maryland Medical Center. Major determinants for drug clearance were drug-specific extraction coefficient (EC) approximated to fraction unbound (levetiracetam: 0.89, lacosamide: 0.80), effluent flow rate, and preserved non-renal clearance. Ex-vivo models of CRRT were developed using human plasma and normal saline containing albumin solutions. The developed ex-vivo in-vivo correlation model demonstrated an average bias of <15% in predicting in-vivo CRRT clearance for levetiracetam and lacosamide. Similarity in ECs justified the ability to bridge dosing information across CRRT modalities. This research, in combination with a priori knowledge of drug pharmacokinetics, confirms the use of ex-vivo CRRT models to establish dosing recommendations and alleviate the need for CRRT pharmacokinetic studies. The development of BED therapies are challenged by high placebo response and high dropout rates in clinical trials. A comprehensive disease-drug-trial (DDT) model was developed using data from 12 different investigator-led BED clinical trials (N = 578; 6 to 16-week duration) to inform optimal clinical trial design elements. Baseline BED severity metrics were predictors for placebo response and dropouts. Stimulants and anticonvulsants demonstrated 1.8 times higher effect differences as compared to antidepressants. Among the clinical trial designs (placebo run-in, drug run-in, sequential parallel comparison design) evaluated in-silico, placebo-controlled trial of shorter (6-week) duration with model-based analysis demonstrated superior trial design properties (40% lower sample size with 50% lower dropouts) as compared to current 12-week registration trials for BED. The proposed DDT framework can inform efficient trial design and potentially increase the number of therapeutic options for BED.
    • Adjuvant-containing control arms in pivotal quadrivalent human papillomavirus vaccine trials: restoration of previously unpublished methodology

      Bourgeois, Florence; Hong, Kyungwan; Lee, Haeyoung; Shamseer, Larissa; Spence, O'Mareen; Jefferson, Tom; Doshi, Peter; Jones, Mark A., B.Sc., Ph.D. (BMJ, 2020-03-17)
      Purpose: Trustworthy reporting of quadrivalent human papillomavirus (HPV) vaccine trials is the foundation for assessing the vaccine’s risks and benefits. However, several pivotal trial publications incompletely reported important methodological details and inaccurately described the formulation that the control arms received. Under the Restoring Invisible and Abandoned Trials initiative (RIAT), we aim to restore the public record regarding the content and rationale of the controls used in the trials. Methods: We assembled a cohort (five randomised controlled trials) described as placebo-controlled using clinical study reports (CSRs) obtained from the European Medicines Agency. We extracted the content and rationale for the choice of control used in each trial across six data sources: trial publications, register records, CSR synopses, CSR main bodies, protocols and informed consent forms. Results: Across data sources, the controlwas inconsistently reported as ‘placebo’- containing aluminium adjuvant (sometimes with dose information). Amorphous aluminium hydroxyphosphate sulfate (AAHS) was not mentioned in any trial registry entry, but was mentioned in all publications and CSRs. In three of five trials, consent forms described the control as an ‘inactive’ substance. No rationale for the selection of the control was reported in any trial publication, register, consent form, CSR synopsis or protocol. Three trials reported the rationale for choice of control in CSRs: to preserve blinding and assess the safety of HPV virus-like particles as the ‘safety profile of (AAHS) is well characterised’. Conclusions: The stated rationale of using AAHS control—to characterise the safety of the HPV virus-like particles—lacks clinical relevance. A nonplacebo control may have obscured an accurate assessment of safety and the participant consent process of some trials raises ethical concerns. Trial registration numbers NCT00092482, NCT00092521, NCT00092534, NCT00090220, NCT00090285.
    • Pharmacometric Approaches to Precision Therapeutic Management for Antimicrobials

      Wang, Hechuan; Ivaturi, Vijay (2020)
      Antimicrobials have been widely used for decades in the treatment of various types of bacterial infections and their properties have been thoroughly characterized in pediatric and adult patients. However, high variability and unpredictability of antimicrobials’ pharmacokinetics (PK) in patients still exist, which reinforces the value of precision dosing. The research in this thesis highlights the role of pharmacometrics in precision therapeutic management of two prototype antimicrobials, gentamicin and rifampin. The first project developed a Bayesian forecasting algorithm for precision dosing of gentamicin in pediatrics. We developed the first population PK model for gentamicin across the whole pediatric age spectrum ranging from 1-day-old newborns to 19-year-old young adults. The model utilized physiologically plausible covariate parameterization driven by principles of allometric scaling. Renal function changes manifested by glomerular filtration were described by postmenstrual age, and serum creatinine was standardized by age. The model was used as a prior in the subsequent full Bayesian analyses in pediatric patients. A full Bayesian analysis-based model-informed precision dosing (MIPD) was introduced for gentamicin dosing in pediatric patients. With a predefined probability of target attainment (PTA) criteria of 70% for both maximum and trough concentrations, the dosing regimens recommended by the empirical dosing guideline NeoFax could achieve the predefined criteria in about 5% of the 1013 patients, in comparison with 90% of the patients when the initial dosing recommendation from the MIPD approach was used. Finally, a workflow was designed for a new patient in a clinical scenario to provide MIPD for initial dosing recommendation and dosing adjustment after TDM level becomes available via a full Bayesian approach. The second project focuses on dose optimization of rifampin in adult patients with tuberculosis through dynamic positron emission tomography (PET) scans. A semi-mechanistic PK-lung-biodistribution model was developed based on plasma and intralesional drug concentration data measured by PET scans. The model could well predict the mass spectrometry data from therapeutic dose and PET data from 11C-labled micro-dose. The developed model was externally validated through exposure predictions in the therapeutic range of 10-35 mg/kg. Based on the projected drug exposure in the cavity walls at higher rifampin doses, the bacterial killing curves obtained from hollow fiber systems were used to predict the clinical cure rates in humans for higher rifampin doses (>600mg). Standard oral rifampin dosing of 10 mg/kg would achieve a 95% probability of cure in 6-9 months of treatment. Similarly, an oral rifampin dose of at least 35 mg/kg would be needed to cure patients in 4 months.
    • Evaluation of skin tape stripping in healthy human volunteers as a methodology for quantifying local drug bioavailability from dermal products

      Shukla, Sagar; Stinchcomb, Audra L.; Hassan, Hazem (2020)
      Stratum corneum (SC) tape stripping is a valuable methodology that has been used for quantifying bioavailability (BA) of topical drug products at the site of action. Although the Food and Drug Administration (FDA) tape stripping guidance was withdrawn several years ago due to variable results, with an appropriate study design, tape stripping procedures can be a reproducible BA method. Therefore, the objective of this work was to investigate the use of tape stripping to quantify BA and evaluate in vitro/in vivo correlations (IVIVC) of two model compounds (lidocaine and diclofenac). These compounds were selected for their differing physicochemical properties and skin permeation rates. Two healthy human volunteer pharmacokinetic and tape stripping studies were conducted to quantify the BA in the SC and measure the elimination rate constant through the skin (kesc). Investigator variability from the in vivo tape stripping study was also examined, and the method variability potentially induced by the investigator can be mitigated by the quality by design (QBD) approach of using transepidermal water loss (TEWL) for determining when most of the SC has been removed in each individual volunteer. TEWL readings assisted the investigator by representing the SC tape stripping endpoint, and the SC masses removed from each volunteer were similar for the two investigators. Harmonized IVPT studies were also conducted and key parameter estimates were determined (absolute bioavailability (F) and (kesc)). These parameter estimates were used to simulate in vivo SC drug concentrations. The error in the SC drug concentration predictions from both in vivo studies was usually less than 20% compared to observed values, which demonstrates the predictive power of carefully harmonized IVPT studies. IVPT studies require less time and expense than human studies, and therefore these models play an important role in the early stages of drug development to predict in vivo SC drug concentrations, and absorption of drug through the skin. In this study, in vivo kesc for a quickly permeating drug (lidocaine) appears to be well predicted by IVPT; however, further work needs to be done to predict a slowly permeating drug’s (diclofenac) SC drug concentrations and kesc.
    • Therapeutic Effect of Anti-Progranulin/GP88 Antibody AG01 in Triple Negative and Letrozole Resistant ER+ Breast Cancer Cells

      Guha, Rupa; Serrero, Ginette (2020)
      Progranulin (GP88, PCDGF, granulin/epithelin precursor, acrogranin) is a secreted autocrine growth/survival glycoprotein that functions as a biological driver of tumor cell proliferation, tumorigenesis, survival, invasiveness and drug resistance in several cancers, including breast cancer. Progranulin is found in the serum of breast cancer patients at higher levels than in healthy subjects and pathological studies have shown that in ER+ tumor biopsies, progranulin/GP88 is an independent prognostic factor of recurrence. Although TNBC represents a small percentage (15-20%) of breast cancer diagnoses, it is clinically important because of its highly aggressive nature and the fact that the disease progresses to metastasis within an exceedingly shorter period. Higher progranulin levels have also been shown to be associated with TNBC cases. Progranulin represents a therapeutic and diagnostic target in breast cancer. We have characterized a recombinant neutralizing anti-human progranulin/GP88 monoclonal antibody AG01 that inhibits progranulin biological effect in vitro and in vivo. Since GP88 is associated with poor outcomes in BC patients, we have investigated the effect of AG01 to inhibit proliferation and enhance letrozole responsiveness of letrozole resistance breast cancer cell lines as well as inhibit proliferation and migration of TNBC cells, two breast cancer areas with unmet medical needs for targeted therapy. We found that progranulin levels were sharply elevated in letrozole resistant cells as compared to the parent cell lines. Simultaneously, TNBC cells showed an increase in progranulin expression while it is undetectable in normal mammary cells. This emphasized the importance of targeting PGRN to treat letrozole resistance in ACLRTUSM as well as provide a therapeutic agent in TNBC cells. We report here that treatment of ACLRTUSM with anti-PGRN antibody (AG01) not only reduced their proliferation but increased the sensitivity of ACLRTUSM cells towards letrozole treatment. In several TNBC models, AG01 treatment reduced cell proliferation, migration, and invasion. Taken together, the research work discussed here provides new information to better understand the targeting progranulin and the effectiveness of AG01 as a potential therapeutic agent in breast cancer. Future work continuing characterization of AG01 will provide further insight into its role in regulating cancer biology.
    • Impact of the Medicare Annual Wellness Visit on Geographic Variation in Dementia Diagnosis

      Hanna, Maya; Perfetto, Eleanor M. (2020)
      Background: Alzheimer's-disease-and-related-dementia (ADRD) is often misdiagnosed or diagnosis is late in disease progression. Diagnosis variations can be driven by access variations related to geographic location. To improve timely and accurate ADRD diagnosis, the Medicare Annual Wellness Visit (AWV) required a cognitive assessment, starting in 2011, which may reduce diagnosis variations. Objective: Assess impact of the AWV on geographic variation in ADRD diagnosis and outcomes. Methods: Aim 1: ADRD patients and caregivers from western, central, and eastern Maryland were interviewed to understand diagnosis-pathway geographic differences. Data were analyzed using interpretative phenomenological analysis to identify themes. Aim 2: Using the CMS Chronic Condition Data Warehouse (CCW) and HRSA Area Health Resource Files, 5-year, county-level ADRD cumulative incidence were compared pre- (2006-2010) and post- (2011-2015) AWV implementation in Mid-Atlantic states. Geographically-weighted, generalized linear models assessed the association between the AWV and ADRD cumulative incidence, controlling for demographic and access measures. Aim 3: A retrospective cohort study using CCW was conducted in newly diagnosed ADRD individuals. Health care utilization (HCU) was compared for individuals with an AWV pre-diagnosis versus no AWV. Difference-in-difference models assessed 10-month outcomes between exposure groups. Results: Aim 1: Average time from first doctor visit (concerning signs/symptoms) to ADRD diagnosis was 3.3, 2, and 5.3 years for western, central, and eastern regions, respectively. Aim 2: AWV participation was not significantly associated with increased 5-year ADRD cumulative incidence. The association between AWV and 5-year ADRD cumulative incidence varied by county with stronger associations clustered in eastern Virginia, Maryland, and Delaware. Aim 3: Receiving an AWV pre-diagnosis was associated with increased HCU [ED (rate ratio [RR]: 1.20, 95% confidence interval [CI]: 1.11, 1.30), hospitalizations (RR: 1.26, 95% CI: 1.13, 1.40), and outpatient (RR: 1.08, 95% CI: 1.04, 1.12)]. Conclusions: Longer times to ADRD diagnosis were observed in rural versus urban regions. The AWV demonstrates the potential to minimize geographic differences by increasing diagnosis rates and HCU. Due to low and variable participation during early implementation, the true impact of the AWV is yet to be established. It may take longer to see impacts on longer-term outcomes.
    • Effects of Static Growth on P. aeruginosa Iron Homeostasis and Virulence

      Brewer, Luke; Oglesby, Amanda G.; Kane, Maureen A. (2020)
      Pseudomonas aeruginosa is a Gram-negative, opportunistic pathogens that causes life-threatening, antimicrobial resistant infections in vulnerable patient populations, including patients with cystic fibrosis, cancer, and chronic wounds. During infection, P. aeruginosa requires iron to maintain critical aspects of its metabolism, and possesses numerous virulence factors and iron uptake mechanisms that allow it to compete for this essential metallo-nutrient in the iron-limiting host environment. These systems are tightly regulated by iron-responsive regulatory mechanisms, which ensure adequate uptake while preventing iron toxicity. Because of the essential role of these regulatory mechanisms in maintaining iron homeostasis, they are considered a promising approach for treating P. aeruginosa infections. One prominent regulator of P. aeruginosa iron homeostasis is the PrrF small RNA (sRNA) regulator, which is essential for virulence in acute murine lung infection. Unfortunately, the exact contribution of PrrF to P. aeruginosa pathogenesis has not yet been elucidated. Moreover, our current understanding of PrrF and other iron regulatory mechanisms is largely based on studies using shaking and highly aerated cultures, which are not likely representative of microbial communities in vivo. To address these gaps, the work in this thesis utilizes proteomic, metabolic, and genetic approaches to determine the impact of static growth on iron-responsive regulatory mechanisms in P. aeruginosa, including PrrF sRNAs. We demonstrate that iron regulation paradigms in P. aeruginosa are dramatically altered in static conditions, due in part to changes in PrrF activity. Notably, we identify type 6 secretion systems (T6SS) as a target of enhanced iron regulation in P. aeruginosa in static conditions, and demonstrate that this altered regulation is caused by changes in the production and activity of the PrrF-regulated quorum signaling molecules, 2-alkyl-4(1H)-quinolones (AQs). Furthermore, we demonstrate that altered AQ activity may modulate clinically-significant interactions with other opportunistic pathogens, such as S. aureus, In turn, the work described herein has broad implications for the study of P. aeruginosa infections, and highlights the need to further probe essential P. aeruginosa iron homeostasis mechanisms in static conditions.