n-vitro time-kill assays and semi-mechanistic pharmacokinetic-pharmacodynamic modeling of a beta-lactam antibiotic combination against enterococcus faecalis: Optimizing dosing regimens for the geriatric population

Pharmacokinetic-pharmacodynamic (PKPD) modeling and simulation have emerged as pivotal tools in drug development and usage. Such models characterize typical trends in data and quantify the variability in relationships among dose, concentration, and desired effects. For antibacterial applications, models characterizing bacterial growth and antibiotic-induced bacterial killing offer insight into interactions between antibiotics, bacteria, and the host. Simulations from these models predict outcomes for untested scenarios, refine study designs, and optimize dosing regimens. Enterococcus faecalis, a significant opportunistic bacterial pathogen with increasing clinical relevance, is commonly found in the gastrointestinal tract but can lead to severe infection, such as endocarditis. Treatments for E. faecalis endocarditis involves combination antibiotic therapy, such as beta-lactam antibiotics and aminoglycosides. However, due to the toxicity of aminoglycosides, the primary treatment is typically double beta-lactam therapy—ampicillin and ceftriaxone. Eradicating an E. faecalis infection typically requires a lengthy six-week course of antibiotic treatment. However, keeping patients in hospitals for such an extended duration is impractical. Therefore, the objective of this thesis project is to explore the extension of double beta-lactam therapy to outpatient antibiotic treatment (OPAT). This approach is gaining importance due to the rising risks of hospital-acquired infections and escalating healthcare expenses. Leveraging the stability of penicillin G, which can be stored at room temperature for extended periods, makes it a promising candidate for OPAT, offering potential benefits in terms of both efficacy and cost-effectiveness. Despite limited evidence for penicillin G plus ceftriaxone, this research successfully bridges the gap through in-vitro time-kill assays and the subsequent development of a semi-mechanistic model for this antibiotic combination against E. faecalis isolates. This dissertation research evaluated 21 clinical strains of E. faecalis isolated from infected patients\u27 blood, sourced from Mount Sinai Health System and a hospital in Detroit as part of Dr. Jaclyn Cusumano’s American Association of Pharmacists (AACP) new investigator award research project. The first aim was to conduct susceptibility testing on these isolates. This testing played a pivotal role in guiding antibiotic therapy by determining a drug\u27s minimum inhibitory concentration (MIC) for a specific bacterial strain, offering insight into its effectiveness. The project highlights the importance of knowing a patient\u27s strain susceptibility since it influences the dosing regimen or treatment strategy. After susceptibility testing using broth microdilution techniques, strains were categorized as highly susceptible (MIC ≤ 2 μg/ml) or less susceptible (MIC = 4 μg/ml) to penicillin G. The next phase of the project involved in-vitro time-kill assays—a gold standard method for testing antibiotic concentrations and synergy in combination therapies. All 21 patient isolates were tested with penicillin G monotherapy and in combination with ceftriaxone, along with testing ampicillin and ceftriaxone combination therapies for comparison. It was noted that both combinations showed efficacy for strains highly susceptible to penicillin G (MIC ≤ 2 μg/ml), exhibiting bactericidal and synergistic activity. However, both treatments demonstrated poor performance for the less susceptible strains (MIC = 4 μg/ml). This observation focuses on the importance of in-vitro pharmacodynamic studies in understanding antibiotic action dynamics, forming the basis for the semi-mechanistic model. These 24-hour time-kill assays strongly suggested further investigation into the penicillin G and ceftriaxone combination, while considering the differential effects of the combination on more and less susceptible strains. Semi-mechanistic models were created for two out of the twenty-one tested strains, one with high susceptibility and another with lower susceptibility, with the goal of understanding the bacterial growth and drug kill effect in greater detail along with testing different dosing regimens. Following the typical progression of constructing a semi-mechanistic PK-PD model, a bacterial sub-model was created by employing intensive sampling during time-kill assays. This approach enabled the comprehension of the complete bacterial growth dynamics for both strains. By employing non-linear least squares regression within RStudio, the predictive model was effectively fitted to the observed data, providing estimates of essential bacterial growth parameters. The utilization of the Gompertz growth model yielded a remarkably close match between predicted and observed data, giving confidence in the accuracy of the estimated growth parameters. Subsequently, the focus shifted to obtaining the most suitable pharmacodynamic (PD) parameters to accurately encapsulate the drug\u27s antibacterial effects. This necessitated the use of a mathematical model. A widely employed model for this purpose is the Sigmoidal Emax model—an empirical model that is widely published. This model emerged as a valuable tool for formalizing the interpretation of experimental data and understanding the influence of altering penicillin G concentrations, both individually and in conjunction with ceftriaxone. Leveraging the data analysis capacity of RStudio, nonlinear least squares regression analysis was used to intricately fit the sigmoidal Emax equation to the observed data. This led to obtaining vital parameters, including Emax (maximum effect), EC50 (half-maximal effective concentration), and the sigmoidicity factor. Subsequent evaluation of goodness of fit based visual predictive checks and low standard errors in estimated parameters confirmed the favorable alignment between the predicted model and observed data. Physiologically based pharmacokinetic (PBPK) modeling and simulation stands as a well-established approach that bridges insights from preclinical studies to clinical outcomes. By combining drug-specific information with a comprehensive understanding of physiological and biological processes at the organism level, PBPK models mechanistically depict the behavior of drugs within biological systems. This enables the a priori simulation of drug concentration-time profiles. What distinguishes PBPK modeling is its unique capability to account for physiological variations within specific populations, offering predictive insights into pharmacokinetics tailored to those groups. This thesis project ventured into two vital applications of PBPK models: extrapolating novel clinical scenarios and exploring pharmacokinetics in special populations, particularly the geriatric demographic. With the aim of comprehending the pharmacokinetics of penicillin G and ceftriaxone, the project leveraged the Simcyp® Simulator, a modeling and simulation tool that is widely used in drug development. This platform pools the anatomical, physiological, drug-related, and trial design parameters to generate plasma drug concentration profiles. The simulated concentrations were compared against published data, with the fold error—a ratio of simulated to observed values—serving as a benchmark for model accuracy. Typically, predictions within a fold error range of 0.5 to 2 are deemed acceptable. Upon verification within the healthy population, the models were extended to geriatric subjects utilizing the Simcyp® population library. The same fold error criteria were applied, and the models adeptly predicted concentrations across both young and elderly populations. Remarkable differences in pharmacokinetics were seen in the geriatric cohort compared to a young adult population. Notably, for penicillin G, the AUC increased by 46% in the elderly due to an almost 47% decline in total clearance, stemming from a 49% reduction in glomerular filtration rate (GFR). Further expanding the PBPK model for penicillin G, the inclusion of a pharmacodynamic (PD) component led to the final goal of this project. Lua scripting in Simcyp® was utilized to build the PD model. This model used an equation that combined the bacterial growth model with the drug\u27s inhibitory effect via the Emax model. The impacts of monotherapy and combination were explored through the modulation of PD parameters. Consequently, when co-administered with ceftriaxone, kill rates for penicillin G increased, and IC50 values decreased, indicative of ceftriaxone\u27s augmentative effect. The free (unbound) plasma concentration-time profile from the developed PBPK model was linked as input to the PD model, facilitating testing and simulation of diverse penicillin G dosing regimens. Notably, penicillin G, a time-dependent beta-lactam antibiotic, exhibited a strong correlation with the PK/PD index %fT\u3eMIC (% of the dosing interval with a free concentration above MIC). This was especially pertinent for high-susceptibility strains, wherein continuous infusion of penicillin G led to the most significant reduction in bacterial density, irrespective of combination therapy or monotherapy. However, for low-susceptibility strains, the scenario differed, revealing that reliance on a single PK/PD index is not all-encompassing. For the geriatric population, the PBPK-PD model aligned with literature-backed dosing modifications for penicillin G. For highly susceptible strains, increasing the dosing interval or reducing the dose resulted in comparable reductions in bacterial density. Conversely, in low7 susceptibility strains, even an increase in AUC within the geriatric demographic failed to eradicate the bacteria. In summary, this comprehensive thesis journey navigates through the in-vitro bacterial studies and pharmacokinetic-pharmacodynamic (PKPD) modeling and simulation. This project sheds light on the ability to integrate in-vitro data with PBPK models which not only predict untested scenarios but also help dosing strategies. Overall, by addressing the clinical challenge of E. faecalis infections, the project showcased the extension of double beta-lactam therapy to penicillin G and ceftriaxone combination through a stepwise development of semi-mechanistic PK/PD model

Evaluation of E-governance Implementation: A Multi-attribute Analysis of E-Government Services Associated with The Annual Hajj Pilgrimage in Saudi Arabia

The Hajj pilgrimage is an annual global event in Saudi Arabia. It draws millions of pilgrims worldwide because of its religious significance as the fifth pillar of Islam. Its organization is a massive endeavor for the Saudi government. This research analyzes the Hajj-related E-Government service systems (websites and mobile apps). This research utilizes a multi-attribute evaluative framework to address two areas of Hajj E-Government services: usability (RQ1) and interaction with the services (RQ2). A combination of heuristic evaluation and survey methods was used. The heuristic evaluation by three expert evaluators revealed accessibility, interactivity, and functional issues. Users with disabilities or limited digital literacy faced challenges, while the system was ineffective in providing feedback. Functionality issues included confusing menu structures, inconsistent labeling, and unclear search results. Privacy and security concerns were addressed, but presentation issues hindered optimal use. The survey study with 138 pilgrims found that Hajj pilgrims have an overall positive user experience and acceptance of E-Government services despite moderate satisfaction. The top three most important Hajj services were the accuracy of information, the ability to overcome challenges, and guidance throughout the journey. These findings suggest that the government can improve E-Government services for Hajj pilgrims by making them more user-friendly and accessible, providing more training and support resources, improving usability through detailed instructions, and continually addressing technical issues by evaluatio

Maladaptive perfectionism and regulation of negative affect after failure: The influences of self-esteem and mindfulness

The aim of the present study was to investigate the use of emotion regulation strategies among adaptive and maladaptive perfectionists and determine if there are differences. It proposed a model that maladaptive perfectionists experience heightened negative affect in response to their perceived deficiencies, and that both self-esteem and mindfulness contribute to emotion regulation strategy choice. A sample of 336 participants, ages 18 and older, completed online self-report measures related to perfectionism, self-esteem, mindfulness, current affect, and emotion regulation strategy choice, along with a manipulated failure task. Results showed that after a perceived failure, maladaptive perfectionists had lower odds of choosing adaptive emotion regulation strategies than adaptive perfectionists did, and were more likely to use maladaptive strategies; and, conversely, adaptive perfectionists had lower odds of choosing maladaptive emotion regulation strategies, and were more likely to use adaptive ones. However, neither self-esteem, or mindfulness, contributed to this proposed model. This study demonstrates that after being confronted with failure, maladaptive perfectionists engage in emotion regulation strategies that are considered maladaptive as opposed to adaptive perfectionists, adding to the literature that supports a multidimensional view of perfectionism, and that some dimensions can be considered maladaptive

The effects of attachment insecurity and cognitive flexibility on mentalization in psychotherapists

The wounded healer concept suggests that one\u27s therapeutic ability is rooted in one\u27s own experiences of pain and suffering. The present study used this concept as a theoretical framework from which to explore issues related to therapist insecure attachment and therapist skill. It examined the role of therapist cognitive flexibility in the relationship between therapist attachment insecurity and therapist mentalization capacity. Participants were 158 therapists from different clinical fields of study and varying levels of clinical experience who completed an online protocol. Results indicated that avoidant attachment negatively predicted mentalization capacity, validating in a therapist sample what previous studies have demonstrated with non-therapist samples. Additionally, results showed that when therapists’ self-reported cognitive flexibility was high, the relationship between attachment anxiety and mentalization was negative, such that as attachment anxiety increased, mentalization capacity decreased. This was contrary to expectations. Finally, correlations revealed no relationships among a self-report, a neuropsychological, and an observer-rated measure of cognitive flexibility. This study was the first to validate the use of the Emotion Card Sort Test (ECST; Deveney & Deldin, 2006) (a modified version of the Wisconsin Card Sorting Test using emotional stimulus words) to assess cognitive flexibility in therapists. Additionally, it was the first to validate the use of the Reflective Functioning Scale (RFS; Fonagy et al., 1998) to code the Five-Minute Speech Sample (FMSS; Gottschalk & Gleser, 1969) in a therapist population. Implications for psychotherapy and psychotherapy training as well as study limitations and future directions for research are discussed

Collectivism and efficacy: Relationship to academic performance in early adolescents

This study explored the mathematics efficacy beliefs of 270 South Asian (Indo American) immigrant and Anglo American nonimmigrant 7th grade students. Self-efficacy beliefs strongly predicted mathematics performance for both cultural groups, but there were differences between the 2 groups in the sources of self-efficacy, the predictiveness of the secondary motivation variables. It is argued that the Indo American students are more vertical or hierarchical than the Anglo-American students and that comparison with others strongly influences their motivation beliefs and the formation of their efficacy beliefs. Self-efficacy in some cultures may be more other-oriented than is typically seen in Western cultures. A caution against generalizing about Asian populations is given, and implications

A Comparative Study on Parent Engagement Through the Lens of Instrumental Music

Lowel Mason highlights the importance of integrating music learning into the curriculum alongside other fundamental skills such as reading, promoting his belief in the transformative power of music education and its impact on child development. Mason stated, “Children must be taught music as they are taught to read” (Pemberton, 1992). The benefits of music extend beyond mere enjoyment among children, as they actively participate in class by singing, dancing, and playing instruments. The arts offer cognitive benefits that extend beyond student engagement, and researchers continue to explore the association between music and academic achievement. Participating in a string orchestra or concert band provides children with a sense of teamwork. Similar to the contributions of a defensive player on a soccer team, each member of an instrumental group provides a critical role in the overall success of the entire group. These contributions give students ownership over their own learning and create greater opportunities for children to demonstrate success. Researchers continue to examine the perceived connection between music and intelligence, demonstrating a range of possible explanations and opportunities for expanded discussion and future research. While there are clear examples that children with music education outperform their non-musically trained peers, attempts to account for this among researchers remain inconsistent. Parent engagement and their partnership with a school certainly may contribute to student achievement as well. On one hand, ensuring that music remains part of the instructional program is supported by legislation; on the other, parent engagement varies widely, and government doesn’t appear poised to begin legislating whether or not a parent reads emails from their teacher or double-checks that their child completes their homework each night. On the Federal level, Every Student Succeed Act (ESSA) establishes music as part of an educational program. Locally, this has not translated to music becoming front and center in schools. In fact, in my 11 years as a New York City Principal, funding was a major hurdle in starting an instrumental music program. For this study, I will examine parent involvement and identify preferred types of involvement of middle school students that play an instrument compared to those who do not. To examine this, middle school parents of a Long School District will be surveyed to identify their preferred type of parent engagement

Effects on SLP Graduate Students’ Clinical Skills Following “Case Study Nights”

This poster describes the evolution of graduate students in their clinical knowledge and attitudes before and after participating in case study nights. Speech- Language Pathology students from Long Island University (LIU) -Brooklyn had the opportunity to observe a professional describe various clinical etiologies, assessments, and treatments coupled with a client presentation during two semesters. Student evaluations measured clinician’s outcome with respect to service delivery and treatment approaches when working with multiple clients with communication disorders

UNCOVERING THE MENTAL WORLD OF CHILDREN: ATTACHMENT QUALITY, MENTALIZATION, AND CHILDREN’S DRAWINGS

Although we have long been aware of the widespread benefits of drawing for children (Goodenough, 1926), there is much to learn from a clinical perspective about children’s attachment patterns and mentalization capacities in analyzing their drawings. The present study utilized archival data to uncover trends associated with children’s drawing characteristics, attachment qualities, and mentalization capacities. This study further explored the extent to which mentalization mediates the relationship between attachment quality and Formal Elements (FE) scores as well as the relationship between attachment quality and Content scores of children’s drawings. Two samples of 5–12-year-old children and their caregivers were recruited: one child sample from a public elementary school in White Plains, NY (n = 54), and the other child sample recruited consecutively following admission to a child psychiatric inpatient unit in White Plains, NY (n = 45). Each of the 99 children, including both the inpatient and nonpatient samples, completed three drawings: a drawing of family, primary caregiver, and self, totaling 297 drawings. These drawings were coded using the Formal Elements and Content rating scales (Tuman, 1998, 1999a). Attachment quality and mentalization data for these samples were obtained from previous studies, using the Attachment Story-Completion Task (ASCT) and Children’s Apperception Test (CAT). Attachment quality was found to have a significant positive relationship with the Content scores of family drawings within the inpatient sample. Attachment quality was also found to have a significant positive relationship with mentalization in both the nonpatient and inpatient samples. Mentalization was found to have a significant positive relationship with the Content and FE scores of children’s drawings. This relationship held true for Content scores of caregiver drawings and FE scores of family drawings within the nonpatient sample, and for both the Content and FE scores of family drawings within the inpatient sample. In general, drawings appear to hold promise as tools to access both psychiatrically compromised and nonpatient children’s internal working models and mental states. Gender differences and clinical implications are discussed

AN EXPLORATORY CONSTRUCTIVIST GROUNDED THEORY STUDY: HOW SECONDARY SCHOOL SCIENCE TEACHERS INTERPRET STUDENTS’ SCIENTIFIC MODELS THAT ARE COMPRISED OF DRAWING ACTIVITIES

Extant literature lacks an explanation of the thought processes used by secondary school science teachers to interpret students’ scientific models that are comprised of drawing activities. In this exploratory study, a constructivist grounded theory (CGT) was developed to generate an interpretive understanding. The CGT was generated from observations, interviews, and document analyses of five research participants consisting of secondary school science teachers from lower New York State. To generate a CGT, concepts, terms, assumptions, and definitions from selected theories—decolonizing methodologies theory (DMT), visual semiotic theory (VST), and cultural studies theory (CST)—collectively provided a fresh onto-epistemological lens for initially examining and bringing transparency to the invisible influences on the intangible thought processes of science teachers when they interpret students’ scientific models. At the end of the study, a CGT was developed which is expressed as nine assertions, a diagrammatic display/axial coding paradigm, and an explanation consisting of found poetry developed from the research findings. Using reflective and reflexive analytical memos, this study revealed that the thoughts of secondary school science teachers consist of five themes: (1) direction or rules, (2) forms of communication, (3) creations (4) interpretation or understanding, and (5) problem-solving heuristics during students’ struggle. In addition, the theory illustrated that in the context of lower New York State, science disciplinary culture works by crossing borders (Aikenhead & Elliott, 2010; Carter, 2011; New York State Education Department, 2019a; Rasheed, 2001, 2006; Snively & Corsiglia, 2001) between Western cultural thoughts and non-Western/Indigenous cultural thoughts. This study will benefit both stakeholders and scholars. For stakeholders, this study offers a substantive theory for understanding the assessment practices of science teachers. For scholars, this study provides a CGT that integrates theories/subdisciplines that are epistemologically distant/close and generates ongoing research. In particular, the theory provides scholars with findings that can be used to subsequently conduct a quantitative study, whereby a culturally sensitive survey instrument can be generated and validated

Minority Parents and School Choice: A Multiple Case Study

Low levels of academic achievement among minority students in U.S. schools continues to be problematic. Although school choice, via enrollment in public charter or private schools, is one strategy that may improve academic achievement among minorities, little is known about how parents of minority students understand and exercise school choice. The purpose of this multiple case study was to explore understandings of school choice among parents with students enrolled in three types of schools: (a) public charter, (b) private, and (c) traditional public. The framework consisted of three theories: bounded rationality, the economic theory of school choice, and critical race theory. Data were collected via three focus groups with parents from three types of schools. . Through axial coding, a total of seven themes were identified, including definitions of school choice provided by minority parents, social perceptions of school choice, economic perceptions of school choice are negative, strategies used to access information, factors in parents’ school choice decisions, school choice information is inaccessible or unavailable, and parents should be informed of school choice. Eleven subthemes emerged, including parents unfamiliar with school choice, school choice describes options for parents and students, tools available for school choice, positive perceptions, negative perceptions, networking, proactive research, financial factors, student-level factors, parent preference factors, and school-level factors. While school choice has the potential to improve academic outcomes for minority students, the current research highlighted challenges in parent’s decision-making processes that may undermine the potential of school choice to improve educational equity