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Searching For Phenotypes Of Sepsis: An Application Of Machine Learning To Electronic Health Records, Michael Jarvis Boyle

Yale Medicine Thesis Digital Library

SEARCHING FOR PHENOTYPES OF SEPSIS: AN APPLICATION OF MACHINE LEARNING TO ELECTRONIC HEALTH RECORDS. Michael J. Boyle (Sponsored by R. Andrew Taylor). Department of Emergency Medicine, Yale University School of Medicine, New Haven, CT.

Sepsis has historically been categorized into discrete subsets based on expert consensus-driven definitions, but there is evidence to suggest it would be better described as a continuum. The goal of this study was to perform an exhaustive search for distinct phenotypes of sepsis using various unsupervised machine learning techniques applied to the electronic health record (EHR) data of 41,843 Yale New Haven Health System emergency department …

Outcomes Among Patients With Chronic Critical Limb Ischemia With No Revascularization Option And Deep Vein Arterialization As A Novel Revascularization Approach: A Systematic Review And Meta-Analysis, Mohammed Imran Riaz Ghare

Yale Medicine Thesis Digital Library

Objective: To quantify the 6- and 12-month amputation-free survival (AFS) in patients with “no-option” Rutherford category 5/6 critical limb ischemia (CLI) in current clinical practice and to characterize outcomes and methods for deep vein arterialization as a possible means for revascularization in patients who are not candidates for conventional surgical or endovascular revascularization. We also sought to determine if there was any trend in amputation-free survival before and after 2003 which was the year of publication for the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7).

Background:

The natural …

A Report Of Us Physicians’ Beliefs About Physician-Assisted Suicide And A Bioethical Analysis Of The Practice, Peter Theodore Hetzler

Yale Medicine Thesis Digital Library

A REPORT OF US PHYSICIANS’ BELIEFS ABOUT PHYSICIAN-ASSISTED SUICIDE AND A BIOETHICAL ANALYSIS OF THE PRACTICE.

Peter T. Hetzler III, James Nie, Amanda Zhou, and Lydia S. Dugdale. Department of Internal Medicine, Yale University, School of Medicine, New Haven, CT.

The goals of this work were two fold. The first was to assess the beliefs of US physicians about the national legalization of physician-assisted suicide (PAS). The second was to determine the moral permissibility of PAS through a bioethical analysis. For the former, we sent a survey to 1000 randomly chosen physicians from around the US. For the last, we …

Localized Hippocampal Glutamine Synthetase Knockout: A Novel Model Of Mesial Temporal Lobe Epilepsy, Maxwell Gerard Farina

Yale Medicine Thesis Digital Library

The purpose of this study was to create and optimize a model of mesial temporal lobe epilepsy through selective depletion of glutamine synthetase (GS) in the mouse hippocampus. Following validation of the model, preliminary studies attempted to characterize morphological astrocytic and synaptic changes that result from GS deficiency. Aim 1 established a novel mouse model of GS knockout in hippocampal astrocytes. Aim 2 tested whether localized hippocampal knockout of GS causes mice to exhibit an epilepsy-like phenotype. Aim 3 characterized the cellular effects of localized GS loss. To generate the knockout, Glul-floxed C57BL/6J mice were injected with four different adeno-associated …

Methods For The Visualization Of Placental Vasculature In Fetoscopic Surgery, Praneeth Sadda

Yale Medicine Thesis Digital Library

Twin-to-twin transfusion syndrome is a potentially fatal disease of placental vasculature in twin pregnancies. It is treated with fetoscopic laser photocoagulation surgery, a procedure in which a surgeon uses an endoscope to find and cauterize abnormal vascular anastamoses on the placental surface. However, even after surgery, mortality remains as high as twenty to forty-eight percent, largely due to anastamoses being missed during the operation. Many technical challenges contribute to anastamoses being missed, including poor endoscopic image quality and a limited field of view. Any tools capable of addressing these challenges would be clinically valuable. This thesis presents the design and …

Drumming To Communicate Emotion: Dual-Brain Imaging Informs An Intervention In A Carceral Setting, Rahil Rojiani

Yale Medicine Thesis Digital Library

Drumming is an ancient nonverbal communication modality for expression of emotion. However, there has been limited exploration of its possible applications in clinical settings. Further, the underlying neural systems engaged during live communication with drumming have not been identified. We investigated the neural response to live, natural communication of emotion via drumming using a novel dual-brain neuroimaging paradigm to discover its unique neurophysiological mechanisms related to drum behavior and cross-brain coherence, and as compared to talking. We then investigated the application of a drumming intervention in an incarcerated, halfway house population to characterize intervention feasibility, elucidate the phenomenology of social …

Career Interests And Mentorship Experiences Of International And Minority Medical Students In Us Medical Schools, Lovemore Simbarashe Kuzomunhu

Yale Medicine Thesis Digital Library

Background: International medical students (IMS) represent a group of students with unique issues that have largely been ignored in the medical literature. This invisibility is because international students make up a very small percentage of the total number of students matriculating into medical school in the US and because most international students are grouped together with domestic underrepresented minority (URM) students and hence are treated as if they were domestic minority students.

Aim: We aim to determine what are the career interests of international and domestic underrepresented minority medical students and what factors influence their choices. We also aim to …

Controlling Pregnancy: Fred Lyman Adair And The Influence Of Eugenics On The Development Of Prenatal Care, Florence Hsiao

Yale Medicine Thesis Digital Library

This thesis examines the development of prenatal care in the United States in the early 1900s by focusing on the life and career of Fred Lyman Adair who, as an obstetrician and eugenicist, played a significant role in shaping prenatal care into what it is today. Although prenatal care was a product of infant welfare activists and public health officials, obstetricians like Adair who struggled to establish obstetrics as a legitimate specialty, saw an opportunity in prenatal care to pathologize pregnancy and elevate their specialty. Adair, therefore, became one of the foremost champions of prenatal care, and helped to standardize …

Spatiotemporal Analysis Of Neuronal Activity During The First Second Of Visual Conscious Perception, Anusha Raja

Yale Medicine Thesis Digital Library

Visual conscious perception occurs in less than one second. Using cerebral cortex electrical readings from human subjects during a behavioral visual task, we studied the spatiotemporal sequence of these events. Nine subjects, implanted with 100-300 subdural and depth electrodes in both hemispheres, were enrolled to complete the threshold perception task. The analysis investigated the role of broadband gamma power changes in electric potential in the range of 40-115 Hertz (Hz). In addition to implementing the behavioral task with the research subjects, my contribution focused on using clustering algorithms to analyze the broadband gamma power time-series to visualize the “switch and …

The Application Of Extracorporeal Photochemotherapy To Head And Neck Squamous Cell Carcinoma, Alp Yurter

Yale Medicine Thesis Digital Library

Extracorporeal Photochemotherapy (ECP) is an FDA-approved immunotherapy that has been treating cutaneous T cell lymphoma (CTCL) for over three decades. ECP’s antitumoral effect is a consequence of its generation of functional, physiologic, inflammatory monocyte-derived dendritic cells (MoDCs) and apoptotic, patient-derived tumor, which collectively, stimulate the adaptive immune system. Thus, in CTCL, ECP serves as a therapeutic dendritic cell vaccine against patient-specific neoantigens. This mechanism of action suggests ECP’s potential application to other solid tumors. We tested ECP’s applicability to head and neck squamous cell carcinoma (HNSCC) using a trackable antigen system involving the constitutively expressed HPV16 E7 oncoprotein. We hypothesized …

The Medial Prefrontal Cortex To Dorsal Raphe Circuit In The Antidepressant Action Of Ketamine, Alexandra Thomas

Yale Medicine Thesis Digital Library

Major depressive disorder is a common and debilitating illness for which there is a notable lack of efficient, effective treatment. While currently available pharmacotherapies typically take eight weeks to take effect and fail to do so at all for about a third of patients, the N-methyl-D-aspartate (NMDA) receptor antagonist ketamine has shown a much more favorable effectiveness profile, including improvements in symptoms within hours of administration, even for many patients who do not respond to typical antidepressants. Ketamine, as a modulator of glutamate signaling in the brain, has a distinct mechanism of action from the serotonin and norepinephrine modulators that …

Multimodal Imaging And Asymmetry Of Disease Progression In Rhodopsin-Associated Autosomal Dominant Retinitis Pigmentosa, Lawrence Chan

Yale Medicine Thesis Digital Library

Retinitis pigmentosa (RP) is a group of genetically and clinically heterogeneous inherited retinal degenerative diseases with no known cure to date. The recent gene therapy treatment for Leber’s congenital amaurosis and RP caused by mutations in RPE65 have resulted in dramatic improvements in vision, leading to excitement for other potential gene therapies on the horizon. Upcoming clinical trials will be targeting patients with specific mutations, and measurements of disease progression will be needed for each genetic subtype of RP in order to determine whether treatments are successful. In this retrospective cohort study, we examined 27 RP patients with confirmed autosomal …

Medically Applied Artificial Intelligence:From Bench To Bedside, Nicholas Chedid

Yale Medicine Thesis Digital Library

The intent of this thesis was to develop several medically applied artificial intel-ligence programs, which can be considered either clinical decision support tools or pro-grams which make the development of such tools more feasible. The first two projectsare more basic or "bench" in focus, while the final project is more translational. The firstprogram involves the creation of a residual neural network to automatically detect thepresence of pericardial effusions in point-of-care echocardiography and currently hasan accuracy of 71%. The second program involves the development of a sub-type ofgenerative adverserial network to create synthetic x-rays of fractures for several pur-poses including data …

Social Integration And The Mental Health Needs Of Lgbtq Asylum Seekers In North America, Samara Danielle Fox

Yale Medicine Thesis Digital Library

This study examined the mental health burden of LGBTQ asylum seekers and associated psychosocial risk factors with a focus on barriers to social integration. This study also characterized LGBTQ asylum seekers’ interest in interventions aimed at alleviating mental distress and social isolation. Respondents (n = 308) completed an online survey which included the Refugee Health Screener (RHS-15), the NIH loneliness scale, and an adapted scale of sexual identity disclosure. Most respondents (80.20%) screened positive for mental distress. Loneliness (OR = 1.14, 95% CI = 1.09, 1.19) and LGBTQ identity disclosure (OR = 3.46, 95% CI = 1.01, 12.02) were associated …

The Genetics Of Vein Of Galen Malformation And Assessment Of Candidate Genes In Xenopus Tropicalis, Jonathan Read Gaillard

Yale Medicine Thesis Digital Library

The Vein of Galen Malformation (VOGM) is a specific subtype of arteriovenous malformation (AVM) that becomes evident in weeks 6-11 of embryonic development. VOGM comprise less than 1% of all vascular malformations, yet represent 30% of all pediatric intracranial vascular malformations. Depending on their specific characteristics, i.e. its feeding vessels, it can present clinically as devastating congestive heart failure in neonates, hydrocephalus in children, or seizures and headaches in young adults. Advances in treatment provide improved survival, primarily through endovascular surgery. The genetic and molecular etiology of VOGM remains relatively unknown, with the only associated genes being in the context …

Neighborhood Walking Tours For Physicians-In-Training, Jeremiah Cross

Yale Medicine Thesis Digital Library

Social and economic factors have a profound impact on the health of patients served by physician residents. However, education about these factors has not been consistently incorporated into residency training. Experiential education, such as neighborhood walking tours, may help physician residents learn about the social determinants of health and community resources available to patients.

Using a community-based participatory research (CBPR) approach, we implemented a neighborhood walking tour curriculum for physician residents and faculty in the Pediatrics, OB/Gyn, Emergency Medicine, Primary Care and Traditional Medicine programs. In 2017, 86 individuals participated in the tours, 81 physician residents and 5 faculty. Both …

The Care Of The Sexual Assault Patient, Eun Sook Choi

Yale Medicine Thesis Digital Library

Survivors of sexual assault (SA) experience a range of physical and mental health consequences. Despite universal agreement that follow-up care improves outcomes, studies demonstrate only one-third of survivors receive assault related follow-up care. This study aims to describe the patient population presenting after SA, characteristics of their acute care, and rates of follow-up within one-year at two sites of the Yale New Haven Hospital, which includes an urban tertiary care hospital (York Street Campus, YSC), and its satellite community hospital (St Raphael Campus, SRC). A retrospective medical record review was conducted of patients older than 12 years presenting after sexual …

Ossification Of The Phalanges Of The Foot And Its Relationship To Peak Height Velocity And The Calcaneal System, Mekka Garcia

Yale Medicine Thesis Digital Library

Background: There are multiple skeletal maturity grading systems, but none of them utilizes the phalanges of the foot. To minimize radiation, it would be ideal if one could assess the skeletal maturity of a foot based on bones seen on routine foot x-rays, if guided growth is being considered as a treatment option, as in hallux valgus. We developed a system that in combination with the calcaneal system, can closely predict skeletal maturity and help with the timing of surgical interventions of the foot.

Methods: We selected 94 healthy children from the Bolton-Brush study, each with consecutive radiographs from age …

Identifying Quantitative Enhancement-Based Imaging Biomarkers In Patients With Colorectal Cancer Liver Metastases Undergoing Loco-Regional Tumor Therapy, Mansur Abdul Ghani

Yale Medicine Thesis Digital Library

The purpose of this study was to test and compare the ability of radiologic measurements of lesion diameter, volume, and enhancement on baseline magnetic resonance (MR) images to be predictors of overall survival (OS) and markers of treatment response in patients with liver-dominant colorectal cancer metastases undergoing loco-regional tumor therapies.

This retrospective study included 88 patients with colorectal cancer (CRC) liver metastases, treated with transarterial chemoembolization (TACE) or Y90 transarterial radioembolization (TARE) between 2001 and 2014. All patients received contrast-enhanced MRI prior to therapy. Semi-automated whole liver and tumor segmentations of three dominant lesions were performed on baseline MRI to …

A Genomic Approach To Idiopathic Liver Disease In Adults, Aaron Hakim

Yale Medicine Thesis Digital Library

Adult patients suffering from liver disease of unknown cause represent an understudied and underserved population. Over the past 15 years, next-generation sequencing technologies have matured into an inexpensive, effective, and widely available set of tools to do genomic analysis. One of these technologies, whole-exome sequencing (WES), allows for high throughput sequencing of all of the genome’s protein coding regions (exons). In pediatric cohorts, WES combined with deep clinical phenotyping has been shown to be an effective and unbiased method of identifying rare protein-altering coding variants in individual genes. WES has also contributed to the diagnosis and individualization of medical care …

The Worsening Trajectory Of Social Impairment In Preterm Born Young Adults And Its Association With Altered Amygdalar Functional Connectivity, Christina Johns

Yale Medicine Thesis Digital Library

Survivors of preterm birth experience long-lasting behavioral problems characterized by increased risk of depression, anxiety, and impaired social functioning. The amygdala is a key region for social functioning, and alterations in amygdalar structure and connectivity are thought to underlie social functioning deficits in many disorders, including preterm birth. However, the trajectory of social impairments in PT and their association with functional connectivity of the amygdala are not well-studied in former preterm born individuals (PTs).

It was hypothesized that PTs would show impaired social functioning compared to term controls beginning in early childhood and continuing to young adulthood. It was also …

Outcomes Of Human Papillomavirus-Associated Head And Neck Cancers, Hong Li

Yale Medicine Thesis Digital Library

Head and neck cancers are the 6th most common solid cancer in the world. Human papillomavirus (HPV) infections are now accepted to be a previously unrecognized causative agent for head and neck squamous cell carcinomas (HNSCCs). However, research surrounding HPV’s effect at non-oropharynx sub-site is limited. There is also mixed literature over the prognostic effect of patient sex and age on overall survival in HNSCCs. We sought to utilize the National Cancer Database from 2004-2013 to evaluate the outcomes of the aforementioned objectives. Univariate and multivariate survival analyses were conducted with chi-square tests, Kaplan-Meier estimates, log-rank tests, and Cox proportional …

Inflammatory Markers As Predictors In Primary Liver Cancers With Emphasis On Chronic Viral Hepatitis, Cortlandt Mercy Sellers

Yale Medicine Thesis Digital Library

Inflammatory Markers as Predictors in Primary Liver Cancers with Emphasis on Chronic Viral Hepatitis

Cortlandt M. Sellers and Hyun S. Kim. Section of Interventional Radiology, Department of Radiology and Biomedical Imaging, Yale University, Yale School of Medicine, New Haven, CT, USA.

Inflammation and the immune system significantly impact the development, progression, and treatment response of primary liver cancers (PLC), namely hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). This retrospective study investigated the peripheral blood neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and systemic immune-inflammatory index (SII) as prognostic biomarkers in patients with PLC in the setting of advanced liver disease and …

Patient Versus Physician Perceptions Of Prognosis And End-Of-Life Outcomes In Acute Leukemia, Sophia Elana Shimer

Yale Medicine Thesis Digital Library

PATIENT VERSUS PHYSICIAN PERCEPTIONS OF PROGNOSIS AND END-OF-LIFE OUTCOMES IN ACUTE LEUKEMIA.

Sophia Shimer and Kerin Adelson. Section of Medical Oncology, Department of Internal Medicine, Yale School of Medicine, New Haven, CT.

Background: Acute leukemia poses unique challenges for prognostication. In many cases, cure is possible but unlikely and treatment is risky. Little is known about how patients perceive their prognosis. The purpose of this study was to assess prognostic understanding and end-of-life outcomes in patients with acute leukemia.

Methods: In this observational study, we surveyed patients admitted with acute leukemia and their treating hematologists. We elicited patient preferences for …

Metabolic Inflexibility Revisited: Muscle Substrate Oxidation Is Dissociated From Muscle Insulin Resistance, Joongyu Daniel Song

Yale Medicine Thesis Digital Library

Alterations in basal metabolic substrate preference were proposed as early derangements in the development of skeletal muscle insulin resistance. Here, we report that alterations in muscle substrate oxidation are not associated with muscle insulin resistance in rats or humans. In this study we used a novel stable isotope tracer ([U-13C]glucose) liquid chromatography-tandem mass spectrometry (LCMS/

MS) method to measure the ratio of mitochondrial glucose oxidation by pyruvate dehydrogenase flux (VPDH) relative to rates of citrate synthase flux (VCS) in skeletal muscle. We found that high fat diet (HFD) fed insulin resistant rats did not have altered substrate oxidation in soleus …

Neurodevelopmental Risks Of Non-Syndromic Craniosynostosis, Robin T. Wu

Yale Medicine Thesis Digital Library

Purpose: Nonsyndromic craniosynostosis may manifest with complex cognitive,

language, behavioral, and emotional sequelae, depending on the suture fusion involved.

De-novo or rare transmitted mutations in the SMAD6 gene affect midline synostosis in

7% of patients. Current standards of assessment, such as the Bayley Scales of Infant

Development (BSID), may not predictive of long-term development, paving the way for

newer assessments such as functional magnetic resonance imaging (fMRI) and the event

related potentials (ERP), which measures passive neurological responses to speech

sounds.

Methods: Cranially-mature, post-operative unilateral coronal, metopic, midline SMAD6

mutated and age/race/gender/synostosis/operation matched non-SMAD6 controls from

the Yale Craniofacial Clinic …

Development Of Pancreatic Cancer Organoid Model For Studying Immune Response In Pancreatic Cancer, Jin Woo Yoo

Yale Medicine Thesis Digital Library

The importance of immune system in pancreatic ductal adenocarcinoma (PDAC) pathogenesis and therapy remains poorly understood largely due to the lack of effective model systems. Cell lines are not physiologic as they cannot recapitulate the cancer stroma and lose genetic heterogeneity over time. Genetically engineered mouse models of PDAC are more physiologic than cell lines but lack neoantigens needed to mount T cell responses against tumor. Organoid models of PDAC offer unique opportunity to study immune mechanisms in PDAC since organoids can model complex layering of multiple cell types, creating a physiologically relevant system that is highly tractable for genetic …

Evaluation Of The Mechanisms Of Anti-Cancer Immune Responses, Noel Turner

Yale Medicine Thesis Digital Library

Metastatic melanoma historically carries a grim prognosis, with a median survival of 9 months and a long-term survival rate of 10%. Melanoma is highly immunogenic, and the development of immunotherapies has dramatically changed the landscape of metastatic melanoma treatment. To study the immune mechanisms engaged by these therapies, the Bosenberg lab developed YUMMER, an immunogenic mouse melanoma line that forms tumors when injected into mice. This and other immunogenic murine cancer models were used to demonstrate that B cell depletion does not impair the anti-PD-1-induced anti-tumor immune response in mice. In addition, supplementing immune checkpoint inhibition with therapies targeting myeloid …

Impact Of Fdaaa On Registration, Results Reporting, And Publication Of Clinical Trials Evaluating New Neuropsychiatric Drugs Approved Between 2005 And 2014, Constance Xuanyi Zou

Yale Medicine Thesis Digital Library

Evidence-based medicine (EBM) promotes the use of randomized controlled trials (RCTs) published in peer reviewed medical journals as the “gold standard”. However, up to 50% of the completed clinical trials are never published and trials with results in favor of studied interventions are 2-4 times more likely to have been published then those with non favorable results. Publication bias seems to be a particularly severe problem for RCTs evaluating newly approved brand-name neuropsychiatric drugs. Mandatory trial registration, and later results reporting, were proposed to mitigate selective clinical trial publication and outcome reporting. Congress enacted the FDA Amendments Act (FDAAA) on …

Influence Of Medicare Formulary Restrictions On Evidence-Based Prescribing Practices, Aishwarya Vijay

Yale Medicine Thesis Digital Library

Controlling the cost of prescription drugs is integral to improving health outcomes, and patient access and adherence to treatment. While prescription drugs can often provide essential therapeutic benefit, previous studies have suggested that inappropriate prescription drug use is a principal cause of adverse drug events as well as abuse and diversion of drugs. Thus, balancing the benefits and harms to promote appropriate prescription drug use is an essential component of healthcare delivery in the United States. There are multiple ways appropriate prescription drug use is promoted. Black-box warnings and drug labeling controlled by the FDA as well as guidelines released …