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Notch Drives Proliferation And Radiation Resistance Of Cancer Stem Cells In Adenoid Cystic Carcinoma, Michael T. Chang

Yale Medicine Thesis Digital Library

Adenoid cystic carcinoma (ACC) of the salivary gland is an indolent but highly lethal neuroinvasive tumor with a propensity for radiation resistance, recurrence, and metastasis. Molecular understanding of this rare tumor has been hampered by the absence of validated in vitro models and a limited number of xenografts. Therapeutic options for ACC are limited to surgery and radiation and are associated with an unacceptably low rate of cure. Cancer stem cells (CSC) are an attractive therapeutic target, and understanding their role in ACC may advance therapy. Our objectives were: 1) to establish and validate ACC cell cultures, 2) to determine …

Transitioning Of Hiv-Infected Children From Pediatric To Adult Care: A Jamaican Case Study, Flavia De Souza

Yale Medicine Thesis Digital Library

Successful public access to antiretroviral therapy in resource-limited settings (RLS) has resulted in survival of HIV perinatally infected children into adulthood. There are few studies on transition of care in RLS, where 90% of HIV-infected children reside. We aimed to characterize the current landscape of the transfer process of HIV-infected adolescents in one such RLS, Jamaica. We conducted in-depth interviews of 18 HIV-infected adolescents in pediatric care and 21 health care providers. We analyzed the data using the grounded theory approach. Five themes emerged: 1. Pediatric clinics were like families who provided care-taking and developmental support in addition to HIV …

The Role Of Oxytocin In Modulating Neural Oscillations In Nulliparous Women, Xiaoyue Mona Guo

Yale Medicine Thesis Digital Library

The hormone oxytocin (OT) has been implicated in social cognition and behavior as well as in modulating important affiliative relationships such as parenting; meanwhile, intranasal OT administration is gaining popularity as a means to modulate neural activity in brain regions during experimental tasks. However, the neural mechanisms underscoring the changes associated with OT administration have yet to be fully elucidated. Using electroencephalography (EEG), this thesis project aims to further our understanding of how OT affects brain activity and response to infant cues. In a double-blind placebo controlled design, OT’s effect on resting-state neural oscillations and event-related potentials (ERPs) to face …

Restoring Consciousness During Seizures With Deep Brain Stimulation, Adam Joseph Kundishora

Yale Medicine Thesis Digital Library

Impaired consciousness occurs suddenly and unpredictably in people with epilepsy, markedly worsening quality of life and increasing risk of mortality. Focal seizures with impaired consciousness are the most common form of epilepsy, and are refractory to all current medical and surgical therapies in about one sixth of cases. Restoring consciousness during and following seizures would be potentially transformative for these individuals. Here, we investigate deep brain stimulation to improve level of conscious arousal in a rat model of focal limbic seizures. We found that dual-site stimulation of the thalamic intralaminar central lateral nucleus (CL) and pontine nucleus oralis (PnO) bilaterally …

Molecular And Genetic Properties Of Breast Cancer Associated With Local Immune Activity, Anton Safonov

Yale Medicine Thesis Digital Library

The causes of high versus low, or absent, immune cell infiltration in breast cancer is unknown. The goals of this analysis were to examine if total mutation load, neoantigen load, copy number variations (CNV), gene-level or pathway level somatic mutations or germline polymorphisms (SNP) are associated with the level of immune infiltration measured by immune metagene expression levels. We used RNA-Seq, DNA copy number, mutation and germline SNP data from the TCGA representing n=627 ER+, n=207 HER2+ and n=191 TNBC cancers. 13 published immune metagenes were used in correlation and multivariate linear regression analyses performed separately for the 3 major …

Characterizing Pediatric Primary Care In Greater New Haven, Meredith Ann Camp Binford

Yale Medicine Thesis Digital Library

Healthcare access is a complex concept that involves more than insurance coverage and resource utilization. Influenced by milieu, an understanding of the local dimensions of access is essential to develop community strengths as well as create appropriate solutions to access gaps. Accordingly, the objectives of the study were to identify, enumerate, and characterize medical practices delivering primary care to children within greater New Haven.

In partnership with community leaders, a community-based participatory approach was used to design a 57-question and 21-observation item, practice-based survey. The survey was administered in-person to 17 pediatric practices and 19 school-based health centers (SBHCs) in …

Clinical Implications Of Apc-Resistance And Factor 5 Leiden Mutational Testing Over A Five Year Period At Yale-New Haven Hospital, Ezra Baraban

Yale Medicine Thesis Digital Library

An evaluation of the APC resistance and factor five Leiden testing at our hospital between 2010 and 2015 was undertaken. An overabundance of factor five Leiden gene mutation testing and corresponding financial ramifications were considered. Specifically, over 90% of all factor five Leiden mutation tests were negative, representing a potential annual savings of over $40,000. It was also noted that quantitative APC resistance values are directly related to the factor five Leiden genotype. Patients with non-Leiden APC resistance had significantly higher values for APC resistance (1.85 vs. 1.97 with p < 0.005). Discordance between APC resistance testing and factor five Leiden testing was also examined, and autoimmune disease and liver transplantation emerged as common associations. Based on these observations, we propose specific modifications to the thrombophilia diagnostic algorithm that we believe will decrease cost and increase diagnostic clarity.

Genomic Characterization Of Sarcomatoid Transformation In Clear Cell Renal Cell Carcinoma, Xiao Bi

Yale Medicine Thesis Digital Library

The presence of sarcomatoid features in renal cell carcinoma (ccRCC) confers a poor prognosis. The mechanisms that account for these sarcomatoid features are unknown. We performed whole exome sequencing of matched normal-carcinomatous-sarcomatoid specimens from 21 subjects. Two tumors had hypermutation and a mutational signature consistent with mismatch repair deficiency. In the remaining 19 tumors, sarcomatoid and carcinomatous elements shared a mean of 45/108 (41.7%) somatic single nucleotide variants (SSNVs). Sarcomatoid elements had a higher overall SSNV burden (mean 90 vs 63 SSNVs, p=4.0x10-4), increased frequency of non-synonymous SSNVs in Pan-Cancer genes (mean 1.4 vs 0.26, p=0.002), and increased frequency of …

Comorbidities Of Skin Disease In The Homeless And Medical Students Perspectives, Matthew David Coffman

Yale Medicine Thesis Digital Library

The homeless population is at increased risk for skin disease. Exposure to the elements and lack of access to medical care contribute to the problem. To date there have been few studies analyzing the medical comorbidities that put homeless patients at increased risk for skin disease. The aim of this study is to discover what medical conditions are associated with skin disease to allow physicians to better screen their homeless patients for skin disease. The secondary aim of this study is to determine whether medical students are being adequately trained to recognize medical conditions associated with skin disease. Data from …

Language In Schizophrenia: What We Can Learn From Quantitative Text Analysis, Sasha Deutsch-Link

Yale Medicine Thesis Digital Library

LANGUAGE IN SCHIZOPHRENIA: WHAT WE CAN LEARN FROM QUANTITATIVE TEXT ANALYSIS

Sasha Deutsch-Link, Sarah Fineberg, Philip R. Corlett. Department of Psychiatry, Yale University School of Medicine, New Haven, CT.

Background: People living with schizophrenia demonstrate broad language and communication deficits. Prior research has focused on qualitative changes in thought, speech production, and language comprehension. In this thesis I expand upon our understanding of language in schizophrenia, by using a novel, quantitative method for language analysis, Linguistic Inquiry Word Count (LIWC).

Methods: I examined essays by four groups of authors: people with schizophrenia (n=77), family history of schizophrenia (n=25), psychiatric controls …

Teaching Experiences In Medical School And Projected Confidence In Teaching During Residency And Career Plans In Medical Education., Isha Marina Di Bartolo

Yale Medicine Thesis Digital Library

Teaching experiences in medical school and projected confidence in teaching during residency and career plans in medical education.

Isha Di Bartolo, Michael R. O’Brien, and Michael Green.

Department of Internal Medicine, Yale University School of Medicine, New Haven, CT.

Teaching is an important part of being a physician and of being a physician-in-training. Although training to be an effective teacher is already a part of the curricula of many residency programs, it remains unclear what teaching experiences are available to medical students and how these students are affected by these experiences. The aim of this study is to qualify the …

Retrospective Assessment Of Treatment With T-Dm1 After Pertuzumab In Her2-Positive Metastatic Breast Cancer, Hannah Elizabeth Dzimitrowicz

Yale Medicine Thesis Digital Library

T-DM1/ ado-trastuzumab emtansine, the most recent addition to the HER2-targeted therapies approved to treat HER2-positive metastatic breast cancer (MBC), is an antibody-drug conjugate with a favorable side effect profile. T-DM1 is currently approved for patients with HER2-positive MBC who previously received trastuzumab and a taxane. Since the trial resulting in T-DM1 approval was conducted, the standard first-line therapy for metastatic HER2-positive breast cancer has changed from trastuzumab and a taxane to a three-drug combination of trastuzumab and a taxane plus pertuzumab. Due to the timing of these approvals, there is no clinical trial or observational data on the activity of …

Assessment Of Specific T-Cell Receptor Engagement Without Necessity For Identification Of The Relevant Antigen, Harib Hassan Ezaldein

Yale Medicine Thesis Digital Library

Individual cancers, even of the same cell type, express unique arrays of distinctive tumor antigens, requiring accurate laboratory measurement of induced immunity against them problematic. Fluorescently tagged reagents (dextramers) that selectively engage clonal T-cell receptors (TCR) can cytofluorographically quantify both frequency and avidity antigen-specific T-cells, but cannot be synthesized without prior identification of the relevant antigen. Since clinically evident tumors may contain as many as 300 unique point mutations capable of generating a large number of uniquely antigenic proteins, and since procurement of such information for each cancer is currently unrealistic, it is presently only possible to assess responses to …

Meta-Analysis: Risk Of Tics With Psychostimulant Use In Randomized, Placebo-Controlled Trials, Stephanie Celeste Cohen

Yale Medicine Thesis Digital Library

Clinical practice currently restricts the use of psychostimulant medications in children with tics or a family history of tics for fear that tics will develop or worsen as a side effect of treatment. Our goal was to conduct a meta-analysis to examine the risk of new onset or worsening of tics as an adverse event of psychostimulants in randomized, placebo-controlled trials.

We conducted a PubMed search to identify all double-blind, randomized, placebo-controlled trials examining the efficacy of psychostimulant medications in the treatment of children with attention-deficit/hyperactivity disorder (ADHD). We used a fixed effects meta-analysis with risk ratio of new onset …

Viral Causes Of Gastroenteritis In The Era Of Widespread Rotavirus Vaccination, Dame Idossa

Yale Medicine Thesis Digital Library

Background: It is unknown if widespread use of Rotavirus (RV) vaccine will impact the primary causative agent of viral gastroenteritis (VGE).

Objective: To identify changes in epidemiology of VGE affected by vaccination, determine factors associated with higher severity of illness, and assess agreeability between two clinical severity-grading scales; Clark and Vesikari.

Methods: We analyzed fecal samples of children, 6 months-5 years of age, evaluated at YNHH for VGE. Fecal samples were tested using a real-time PCR assay. Primer and probe sequences targeted conserved regions of the genome for RV, Norovirus GI/GII, Adenovirus, Astrovirus, and Sapovirus. Data were analyzed using SPSS. …

Identification Of Novel Therapeutic Small-Molecule Inhibitors Of Dna Double-Stranded Break Repair, Vikram Jairam

Yale Medicine Thesis Digital Library

Mammalian cells mainly utilize two DNA repair pathways to repair double stranded breaks (DSB): homologous recombination (HR) and non-homologous end joining (NHEJ). While HR utilizes homologous DNA sequences as a template for repair, NHEJ processes and re-ligates the ends of the breaks. NHEJ is further sub-divided into a DNA-PK-dependent canonical pathway, and alternative pathways, which are more mutagenic. These pathways are essential for cell survival after ionizing radiation, and thus have become important therapeutic targets for radiosensitization. Our group recently performed multiple high-throughput small molecule screens for novel DSB repair inhibitors. These studies identified numerous selective NHEJ and HR inhibitors, …

Malignancies Associated With Inflammatory Bowel Diseases, Nicole Gong Jawitz

Yale Medicine Thesis Digital Library

Inflammatory Bowel Diseases (IBD), specifically Crohn’s disease and ulcerative colitis, have been associated with numerous intestinal and extra- intestinal malignancies. Recent studies have suggested use of immunomodulator therapies has increased risks of malignancies, including melanoma, non-epithelial skin cancers, cervical cancer, and bladder and urinary tract cancers. The question regarding how biologic agents, which became a mainstay therapy of IBD in the early 2000s, have influenced malignancy risk among patients with IBD has yet to be definitely answered.

The aims of this study were to characterize prevalence of comorbid malignancies among hospitalized patients with IBD and how it has changed over …

Characterizing Parental Adherence To Amblyopia Therapy At Menelik Ii Referral Hospital In Addis Ababa, Ethiopia, Bethlehem Dessalegn Mekonnen

Yale Medicine Thesis Digital Library

There are limited studies completed in the East African region to assess barriers to adherence with amblyopia treatment and outcomes of this treatment. Our study aims to identify factors which are associated with higher adherence in amblyopia treatment. Institutional Review Board (IRB) approval was obtained and a hospital-based retrospective and prospective observational study was performed at the pediatric ophthalmology clinic of Menelik II Referral Hospital in Addis Ababa, Ethiopia from March 2015 to June 2015. Included in the study were Ethiopian children, between the ages of 4 and 8, with a clinical diagnosis of amblyopia defined as interocular acuity difference …

Language At Rest: A Longitudinal Study Of Intrinsic Functional Connectivity In Preterm Children, Megan Alysse Rowlands

Yale Medicine Thesis Digital Library

Preterm (PT) children show early cognitive and language deficits and display altered cortical connectivity for language compared to term (T) children. Developmentally, functional connectivity networks become more segregated and integrated through the weakening of short-range and strengthening of long-range connections. The specific aims of this study are: (1) To use residual fMRI data to investigate intrinsic connectivity development from ages 8 to 16 years in PT vs. T controls; and (2) To correlate intrinsic connectivity to cognitive and language scores. Longitudinal intrinsic connectivity distribution (ICD) values were assessed in PT (n = 13) compared to T children (n = 12) …

Association Of Tuberculosis And Macrophage Migration Inhibitory Factor In A South African Population, Duncan Reid Reid

Yale Medicine Thesis Digital Library

Macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine that plays an important role in the pathogenesis of autoimmune inflammatory diseases. Functional promoter variants in the MIF gene influence host susceptibility to different infectious diseases, including tuberculosis (TB). However, the effect of functional MIF promoter variants in subjects with co-infection with human immunodeficiency virus (HIV) and TB, who comprise over 12 percent of new TB cases globally and 60 percent of new TB cases in South Africa, has been examined only in one prior study. Here, an association study was carried out in a clinically well-defined rural population in KwaZulu-Natal, …

Carboplatin And Cyclosporin A In The Treatment Of Recurrent Epithelial Ovarian Cancer, Eve Elizabeth Overton

Yale Medicine Thesis Digital Library

The aim of this study is to report our institutional experience with the use of carboplatin (carbo) and concurrent cyclosporin A (CsA; combined

treatment abbreviated as carbo/CsA) for recurrent epithelial ovarian cancer (EOC) and to assess the efficacy and tolerability of this regimen in treatment of the treatment of EOC. The medical records of patients diagnosed with ovarian cancer and treated with carbo/CsA from 2000 to 2015 at Yale New Haven Hospital were reviewed. Histological classification and staging were determined by the World Health Organization and Ann Arbor systems, respectively. Kaplan-Meier was used to calculate progression free survival (PFS) and …

Short-Term Outcomes And Long-Term Prognosis In Oral Cavity Cancer, Zachary Gregg Schwam

Yale Medicine Thesis Digital Library

SHORT-TERM OUTCOMES AND LONG-TERM PROGNOSIS OF ORAL CAVITY CANCER. Zachary G. Schwam, Benjamin L. Judson (advisor). Section of Otolaryngology, Department of Surgery, Yale University School of Medicine, New Haven, CT.

We sought to characterize short-term morbidity and mortality outcomes as well as long-term changes in prognosis for oral cancer patients. We predicted that clinical and demographic variables would affect short- and long-term outcomes. Retrospective analyses of the National Surgical Quality Improvement Program (NSQIP) and National Cancer Database (NCDB) were performed on 408 and 13,655 patients, respectively. Chi-square, Kaplan Meier, logistic regression, and Cox proportional hazards regression were performed. In the …

Ethical Challenges In Student Global Health Research Projects, Katherine Rebecca Standish

Yale Medicine Thesis Digital Library

U.S. students are participating in global health electives and research in low- and middle-income countries (LMIC) in increasing numbers, yet the significant ethical challenges they face have not been well documented. We conducted a mixed methods study of graduate, health professional and undergraduate students at a research-focused university about their experiences conducting global health research activities, focusing on ethical challenges and support for addressing those challenges. An online, structured questionnaire was completed by 123 participants, and in-depth, semi-structured interviews were conducted with 17 participants and analyzed using the constant comparison method. Among questionnaire respondents, 31% reported a significant or moderate …

Emergency Medical Services Utilization And Interventions By Paramedics During A Blizzard, Shalom Sokolow

Yale Medicine Thesis Digital Library

EMERGENCY MEDICAL SERVICES UTLIZATION AND INTERVENTIONS BY PARAMEDICS DURING A BLIZZARD.

Shalom Sokolow (Sponsored by Sandy Bogucki). Department of Emergency Medicine, Yale University, School of Medicine, New Haven, CT.

On February 8th, 2013, southern Connecticut was struck by a powerful blizzard. Emergency Medical Services (EMS) crews experienced significantly increased call volume along with increased response and transport times. This study examined which types of EMS calls increased or decreased during the storm and whether paramedics performed more or fewer advanced life support (ALS) interventions.

EMS calls were differentiated by call type and analyzed to determine which types increased or decreased …

Clinical And Histologic Features Of Cutaneous Toxicities Due To Anti-Programmed Cell Death-1 Therapy, Veronica Shi

Yale Medicine Thesis Digital Library

Novel immunotherapies for oncologic treatment include anti-programmed cell death-1 (PD-1) and anti-programmed cell death ligand-1 (PD-L1) agents. These therapies activate the body’s inherent immune response against tumor cells by stimulating T cell proliferation. With the recent approval of agents such as nivolumab and pembrolizumab for the treatment of melanoma, lung cancer, and renal cell cancer, there is a growing need to better characterize their toxicity profiles. This study sought to provide a clinical and histologic description of the cutaneous toxicities seen in patients receiving anti-PD-1/PD- L1 treatment. Cases of patients on anti-PD-1/PD-L1 therapy who developed cutaneous adverse effects were collected …

Creation Of Novel Inducible Cell Line To Study Alveolar Rhabdomyosarcoma, Kaoru Takasaki

Yale Medicine Thesis Digital Library

CREATION OF NOVEL INDUCIBLE CELL LINE TO STUDY ALVEOLAR RHABDOMYOSARCOMA. Kaoru Takasaki, Ranjini K. Sundaram, Ranjit S. Bindra. Departments of Therapeutic Radiology and of Pathology, Yale University, School of Medicine, New Haven, CT.

Rhabdomyosarcoma (RMS) is a group of relatively rare mesenchymal malignancies classically associated with skeletal muscle and most frequently seen in the pediatric population. While chemotherapy, radiation, and surgical resection can confer long-term event-free survival rates of up to 85-95%, the prognosis for alveolar rhabdomyosarcoma (ARMS), particularly those positive for either the t(2;13) PAX3-FOXO1 or t(1;13) PAX7- FOXO1 translocation, is significantly worse. As such, the development of therapies …

Student Perspectives On Interprofessional Education: Implications For Curriculum Development, Jacob Alan Weatherly

Yale Medicine Thesis Digital Library

Background

The Yale Schools of Medicine and Nursing and the Yale Physician Associate (PA) Program are collaborating to implement an interprofessional curriculum. Although healthcare organizations have called for interprofessional education (IPE), such initiatives have been difficult to implement. Per the Kern framework of curriculum development, design and implementation is likely to be more successful if a needs assessment is done as the first step.

Objective

To better understand healthcare professional students’ perspectives about IPE as part of a needs assessment for developing an IPE curriculum.

Methods

Because little is known about stakeholder perceptions of IPE, we used a qualitative, content …

Using “Big Data” To Study Orthopaedic Trauma Populations: Looking At Fractures From A Bird’S Eye View As Illustrated By Three Studies, Andre Michael Samuel

Yale Medicine Thesis Digital Library

Background

“Big data” is increasingly being used for orthopaedic research. However, the acute and complex nature of orthopaedic trauma makes data collection and data analysis difficult. This thesis presents three different clinical studies, which together illustrate how databases may best be used to answer clinical questions in orthopaedic trauma. Specifically the studies aim to show (1) how different databases capture trauma populations, (2) how databases may be used for hypothesis discovery studies, and (3) how databases may be used for hypothesis testing studies.

Study Questions

(1) How do populations of femoral shaft fracture patients differ in three commonly used national …

Effects Of Race, Socioeconomic Factors On Emergency Management Of Threatened And Early Pregnancy Loss, Connie Yu Heng Cheng

Yale Medicine Thesis Digital Library

Our study aims to determine the effects of race, insurance, and hospital characteristics on the management of threatened abortion and early pregnancy loss. In this retrospective cohort study using the National Hospital Ambulatory Medical Care Survey, patient record files from 2002-2010 with diagnoses of threatened abortion, hemorrhage in pregnancy, or incomplete, inevitable, or unspecified spontaneous abortion were examined using logistic regression. Primary outcomes were rates of admission and active management, defined as surgical termination or use of abortifacients misoprostol or Cytotec. Covariates included race/ethnicity, age, insurance, and hospital location, ownership, and metropolitan status.

Of 5,882,623 ED visits for threatened abortion …

Insulin Dependence Heralds Adverse Events After Hip And Knee Arthroplasty, Matthew Webb

Yale Medicine Thesis Digital Library

ABSTRACT

Background – Total hip arthroplasty (THA) is one of the most frequently performed orthopaedic procedures. As the prevalence of diabetes mellitus (DM) continues to increase the burden of its sequelae and associated surgical complications have also increased. For these reasons, it is important to understand the associations between DM and the rates of perioperative adverse events in patients with DM who will undergo THA.

Methods – The American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) database records perioperative adverse events as well as patient factors including demographics and comorbidities. Patients who underwent THA between 2005 and …