OBJECTIVE: Opioids are considered standard of care for pain treatment for infants undergoing painful procedures. In addition, prolonged opioid administration is used for sedation during non-surgical treatment (e.g. infants that require intubation and prolonged ventilation). Intubated infants often receive sedative drugs for a prolonged period of time, which leads to opioid dependence and tolerance. The long-term sequelae of such treatment involving the prolonged administration of opioids are unknown. There is evidence in cell cultures and animal models that prolonged opioid exposure is associated with increased neuronal apoptosis (neuronal cell death). In addition, human studies in premature children have suggested that prolonged opioid treatment is associated with decreased visual intelligence, social skills, and memory function. The goal of this study was to identify the population of the youngest patients (less than one year old) that requires prolonged administration of opioids for pain and sedation management. Our overarching hypothesis is that a select group of patients might be at risk for long-term neurologic sequelae from prolonged opioid treatment. METHODS: A retrospective chart review for admission cases over a period of one year was conducted to identify infants that received prolonged administration of opioids and/or benzodiazepines for their treatment. Infants were included if they were less than one year old, full-term (born 37-42 weeks of gestational age), and received prolonged treatment with opioids (e.g. fentanyl, morphine, hydromorphone) and/or benzodiazepines (e.g. midazolam, diazepam, lorazepam). Data on their diagnoses and sedation management at Boston Children's Hospital, including total dose of drugs received and if they developed dependence, was collected. RESULTS: Out of the 221 charts reviewed, only 46 infants were exposed to prolonged sedation and were full-term. Of these 46 infants, the largest proportion (35%; 16/46) was diagnosed with congenital anomalies. The other diagnoses included respiratory diseases (24%; 11/46), neurological diseases (13%; 6/46), and the remaining infants had a combination of two to three of these diagnoses (28%; 13/46). Infants with congenital diseases had a longer duration of sedation management (59.3 days ± 31.3 days) than infants with respiratory distress/infection (5.9 days ± 3.4 days). Those receiving the longest opioid treatments also exhibited signs of withdrawal when drugs were discontinued, which suggested the development of opioid dependence and required weaning treatment. Patients with sedation for 4 days or less did not show withdrawal symptoms, while those with sedation of 6 days or more required an opioid and benzodiazepine weaning regimen. CONCLUSION: The chart review was valuable from several perspectives. Sedation management at Boston Children's Hospital included prolonged administration not only of opioids, but also benzodiazepines. Such treatment is considered the standard of care. Even otherwise healthy, full-term children that received such sedation for the management of an acute illness (e.g. pneumonia) were at risk for opioid and benzodiazepine dependence if they required intubation and sedation for longer than 4 days. However, the majority of full-term children at risk for potential long-term sequelae of prolonged sedation presented with other confounding factors (e.g. congenital diseases, surgeries, exposure to anesthetic agents). In summary, future research on potential long-term sequelae of prolonged opioid administration should include infants with complex medical diseases as they were exposed to such treatment the longest.

Neuropilin 2 (NRP2) is a transmembrane protein receptor originally discovered in neurons, and their precursors, neural crest cells (NCC), which are a transient, migratory precursor population derived from neural ectoderm. NRP2 serves as both a vascular endothelial growth factor (VEGF) co-receptor to initiate a pro-angiogenic signaling cascade and as a receptor for the class 3 semaphorin family molecules (primarily SEMA3F). Binding of SEMA3F induces a strong repulsive and antiangiogenic signal. NRP2 was discovered on melanocytes, which was a novel finding. NRP2-positive melanocytes were first identified in the hair follicles of Nrp2+/gfp transgenic mouse model. It is known that melanocytes reside in the bulb of the hair, where they provide pigment. Melanocyte stem cell populations are found in the bulge, a superficial structure also containing keratinocyte precursors. NRP2 has also been suggested as a potential biomarker in cases of malignant melanoma. The aim of this study was to elucidate the role of NRP2 three areas: in the growth and development of hair, in melanocytes, and in malignant melanoma. A greater understanding of the role of NRP2 in these locales may have significant clinical significance in disease states such as alopecia, vitiligo, and melanoma. It was discovered that Nrp2 expression was strongest within the bulge region of the hair follicle where melanocyte stem cells reside. Additionally, human and mouse primary melanocytes express NRP2, whereas keratinocytes do not. Neither melanocytes nor melanoma express VEGFR2, indicating NRP2 may be serving as a SEMA3F receptor. The NRP2 receptor was functional in melanocytes as treatment with SEMA3F inhibited migration of both melanocytes and melanoma cultured lines. Melanoma cells downregulate expression of SEMA3F and upregulate the expression of NRP2. In the patient samples analyzed, the expression of NRP2 correlated with disease progression.

INTRODUCTION: Recently, the faculty from the Department of Family Medicine in conjunction with the Vertical Integration Group at Boston University School of Medicine (BUSM) developed the Finding Information Framework or FIF to assist medical students in building skills utilizing Evidence Based Medicine (EBM). The FIF is an educational algorithm that guides students on how to ask a clinical question and then assists them in finding the most appropriate online resource. This past year, together with the Division of Graduate Medical Sciences and the Alumni Medical Library, the FIF tool was developed into an EBM mobile application (app) to help the students transition from their second to third year of medical school, where they transition from a more didactic to clinical curriculum. This current study aims to assess the aesthetics as well as functionalities of the FIF mobile app by surveying current medical students. METHODS: The author presented initial outlines of the survey to the research team following a review of relevant studies. From this, the final survey was created and submitted for Boston University (BU) Institutional Review Board Approval (IRB) for a study on human subjects. A recruitment email, requesting volunteers to participate in the survey study, was sent to the third and fourth year medical students. RESULTS: Data were categorized into four sections: (1) preliminary questions, (2) app-specific questions, (3) clinical questions, and (4) open-ended questions. Survey results were divided into two parts: part one was with a mixed population and part two was exclusively for third and fourth year medical students. Ease of use and aesthetic appeal generally received higher scores than potential future use of the app. Clinical question responses varied significantly. DISCUSSION: The survey assessing the FIF mobile app shed light into potential areas that the research team should address in further improvements to the app. These areas include easier log-in, preferably earlier in the app to assure easier access to databases, and the option to go directly to a specific known resource without requiring movement through the decision tree if desirable. A major limitation of the study was the small sample size. Further studies would help in further validating the results gained in this study.

CONTEXT & OBJECTIVE: This study aimed to assess whether HIV+ women at Boston Medical Center had an increased likelihood of developing intraepithelial neoplastic changes in the up to 6 years following a normal Pap smear and negative HPV (Human Papillomavirus) test when compared to the general population. The development of the neoplastic changes was also compared in HIV+ women with positive or negative HPV results. DESIGN & SETTING: We performed a retrospective chart review of the patient records of HIV+ women at Boston Medical Center. METHODS: HIV+ women, aged ¡Ý 30, screened between 2008-2010, with a normal cervical cytology result (Negative for Intraepithelial Lesion or Malignancy) and a concurrent HPV testing result and at least one subsequent cytology result were identified through the electronic medical record data warehouse at a single institution. These women were divided into two groups based on their HPV test result, either positive or negative. The medical records of these women were then evaluated through the end of 2014. The primary endpoint was the diagnosis of CIN-2 or 3, and the secondary endpoint was the diagnosis of other high-grade anogenital dysplasia. We examined the distribution of outcomes with a Chi-squared test or Fischer¡¯s test for discrete values and Student t-test for continuous data. Logistic regression analysis was performed to evaluate the relationship between variables and control for confounders like age and ethnicity. The crude and adjusted Odds Ratios (OR) were calculated and presented. We considered p-value < 0.05 to be statistically significant. RESULTS: 378 HIV+ women were identified- 307 women were HPV-negative, and 71 patients were HPV-positive at baseline. Women ranged in age from 30-81 years. HPV-negative patients had a mean age of 47¡À9, and HPV-positive patients had a slightly higher mean age of 49¡À9 at time of final evaluation. A total of eight (2%) women developed CIN-2, and five (62.5%) of them were HPV- positive at baseline (p-value of 0.001). Three individuals developed CIN-3, and two (66%) of them were also HPV-positive at baseline (p-value of 0.03). 23 (6.1%) individuals received at least one abnormal histology result, and of these, 13 (56.5%) were HPV-positive at baseline. After adjusting for age and race/ethnicity, there was still a significant difference of CIN-2/3 in HPV-positive compared to the HPV-negative group (OR 5.64 95%CI1.2-26.1), p<0.03). CONCLUSION: The results demonstrated that the likelihood of the development of CIN-2/3 in HIV+ women with normal pap tests and a positive HPV co-test is significantly higher in comparison to HIV+ women with a normal pap test and a negative HPV co-test. Therefore, HIV+ women with negative HPV tests had a greater incidence of CIN-3 than the general population (0.3% compared to 0.16%). Although HIV+ women with a negative HPV co-test are less likely to develop CIN-2/3 than HIV+ women a positive HPV co-test, a negative HPV test result is not as reassuring against the development of CIN-2/3 in HIV+ populations as it is in the general population.

The leading cause of dementia globally is Alzheimer’s disease, and its incidence is increasing. Besides the immense clinical impact on the afflicted patient, Alzheimer’s disease has a significant social impact on the patient’s family and friends. Pharmacological interventions have shown modest results and are lacking in successful disease-modifying therapies. Three of the most common nonpharmacological interventions for Alzheimer’s disease are cognitive, exercise, and nutritional methods. The goal of this study was to analyze the efficacy of these interventions in an effort to uncover the most promising nonpharmacological strategies with which to utilize moving forward. This thesis reviewed a large number of studies evaluating different cognitive, exercise, and nutritional interventions for patients suffering from Alzheimer’s disease. The review considered each study by looking at both the methods used and the results obtained. The cognitive intervention studies revealed modest results, with cognitive rehabilitation being the most promising cognitive intervention. Exercise interventions showed positive results for the patients’ activities of daily living and quality of life. Although nutritional interventions produced modest improvements, the Mediterranean diet had the most encouraging results. Based on the analysis of these studies, this thesis concludes that cognitive rehabilitation, exercise, and the Mediterranean diet are the most effective nonpharmacological interventions for managing patients with Alzheimer’s disease in the future.

Psychiatric conditions including attention disorders, mood disorders, anxiety disorders, and schizophrenia pose some of the most debilitating effects on the patient population worldwide. Treatments currently used to combat such illnesses have been a significant area of research in the medical community. As more molecular mechanisms are elucidated and a deeper pathophysiologic basis is discovered for such ailments, newer pharmacologic modalities pave way to provide greater symptomatic relief and treatment with fewer side effects. Enter L-theanine, a non-essential amino acid found in green tea leaves which has been touted to have anxiolytic and cognitive enhancing properties on a wide variety of patient demographics. Furthermore, it has been recently studied for its neuroprotective qualities and antihypertensive effects. This study delves into the current understanding of common psychiatric conditions, as well as providing a summary into the current understanding of L-theanine in its potential to a wide variety of psychiatric and neurologic conditions. The apparent potential in utilizing L-theanine as a treatment modality is promising, and the limited studies available warrant continued research to provide a safe, non-toxic way in alleviating psychiatric and neurologic conditions.

Cancer is a genetic disease caused by an unregulated expansion of a clone of cells (Sompayrac, 2004). The genetic abnormalities in cancer are the consequences of defective DNA replication, repair, maintenance, and modification, genetic background, and exposure to mutagens (Alexandrov et al., 2013). Ionizing radiation (IR), a mutagen exposed to cancer patients during clinical radiotherapy (RT), can cause DNA damage, genomic instability, and mutagenesis (Sherborne et al., 2015). While RT has been effective in treating cancer, it increases the risk of second malignant neoplasm (SMN), a severe delayed complication associated with mainly pediatric cancer survivors many decades after the treatment of their first cancer (Robison & Hudson, 2014). As the mortality of patients with childhood cancer has been decreasing, cases of radiation-induced cancers has been increasing (Robison & Hudson, 2014). The considerable contribution by RT to SMN risk illustrate the need to characterize the genetic mechanism directly responsible for radiation-induced malignancies. To better our understanding of the mutational landscape of SMNs, our specific aims are to identify potential driver mutations implicated in radiation-induced malignancies through genome and transcriptome analysis and to assess whether genetic background, specifically germline polymorphisms and mutations in tumor suppressor gene TP53, has an impact on the formation of secondary malignancies.

RATIONALE: Infectivity of patients with pulmonary tuberculosis who are HIV infected is not clear compared to those who are non-HIV infected. There is an association between cough aerosol production and T.B transmission with great variability in the amount of aerosol produced by infected patients; therefore aerosol production can be used as surrogate marker of infectivity OBJECTIVES: To evaluate the amount of cough aerosol produced in patients with pulmonary tuberculosis who are HIV infected compared to those who are non-HIV infected; and to evaluate the association between immunosuppression and aerosol production. METHODS: Data from two different cohorts with available information on the amount of cough aerosol produced and HIV status were merged to increase validity of the study Measurements and main results: Secondary data analysis performed on the merged data using the amount of mycobacterial tuberculosis colony forming unit produced in cough aerosol by patients with pulmonary tuberculosis as our outcome variable and compared HIV infected patients with non-HIV infected; thereafter in the HIV-subgroup we ran data analysis to evaluate the association between aerosol production and degree T-cell count. CONCLUSION: HIV infection is associated with decrease aerosol production in patients with pulmonary tuberculosis, other factor included degree of AFB smear the duration on TB treatment before aerosol collection modified this association. In HIV infected person the degree of immunosuppression dose not correlate with the amount of aerosol produced.

Waiting times in the Emergency Department cause considerable delays in care and in patient satisfaction. There are many moving parts to the ED visit with multiple providers delivering care for a single patient. Factors that have been shown to delay care in the ED have been broken down into input factors such as triaging, throughput factors during the visit, and output factors, which include discharge planning and available inpatient beds for admitted patients. Research has shown that throughput factors are an area of interest to decrease time spent in the ED that will lead to decrease waiting room times. In this Quality Improvement project, we will develop a systematic check in system with ED providers that will allow providers to identify any outstanding issues that may be delaying care or discharge. We hypothesize that this system will increase throughput in the ED by resolving any lab, radiology, or treatments that were overlooked. Reviewing the results of this QI project will allow us to see if we were effective in our timing of scheduled check-ins. Ultimately, this will reduce time spent in the waiting room by allowing more patients to be seen. In the era of the Affordable Care Act, more patients have access to affordable healthcare and will increase volume in the ED. This check-in system will allow more patients to be seen smoothly and in a timely manner that will improve and increase patient care and satisfaction in the ED.

This thesis is comprised of a comprehensive literature review focused on identifying factors that protect children from early adversity and a proposed intervention and accompanying program evaluation intended to improve health outcomes for traumatized children. The literature review summarizes the impact and prevalence of adverse childhood experiences and provides evidence for a hypothesized mechanism by which ACEs damage health: ACEs induce neuroendocrine changes while simultaneously predisposing children to engage in health risk behaviors. This literature review identifies and documents evidence for five modifiable resilience factors to improve the long- and short-term health outcomes for children who have experienced early adversity. They include improving parenting, enhancing social support, supporting maternal mental health, teaching self-care skills, and fostering understanding of trauma. The thesis proposes a pilot trauma-informed medical home (TIMH) designed to leverage the identified modifiable resilience factors for a group of pediatric patients in CPS custody at a large urban pediatric practice. The thesis includes an evaluation plan to formatively and summatively gain insight into TIMH’s effectiveness and enable program improvement.