Background: The initial systolic blood pressure (SBP) in patients with acute heart failure (AHF) can be used as a guide when choosing specific pharmacologic treatments by helping identify the underlying type of HF (e.g., HF with preserved ejection fraction). Clinical experience and research data from our medical center suggests that AHF with elevated SBP may be presenting less frequently than in the past. This may call into question the utility of initial SBP as a clinical guide. The goal of this Master’s Thesis is to test the hypothesis that the frequency of AHF patients with a SBP>160mmhg has declined over time. Methods: This observational study compares data from 4 cohorts of adult patients admitted with AHF in central MA. Data were obtained from a contemporary (2011-2013) study of patients with AHF as well as from the 1995, 2000, 2006 Worcester Heart Failure Study (WHFS) cohorts. The Framingham criteria the diagnostic criterion for AHF. The main outcome was the proportion of patients with AHF with a SBP > 160 mmHg who presented in each of the 4 study cohorts and was examined by multivariate logistic regression. Results: 2,366 patients comprised the study population. The average age was 77 years, 55% were female, 94% white, and 75% had prior HF. In 1995 33.6% of AHF patients had a SBP >160 mmHg compared to 19.5% in 2011-2013 (p160 mmHg in 2006 (0.64, (0.42-0.96)) and 2011-13 (0.46, (0.28-0.74)). Conclusion: The proportion of patients with AHF and an initial SBP >160 mmHg has significantly declined over time. This may warrant a reexamination of the utility of SBP to inform diagnosis and treatment in patients with AHF.

The integrin α6β4 (referred to as β4) is expressed in epithelial cells where it functions as a laminin receptor. Integrin β4 is important for the organization and maintenance of epithelial architecture in normal cells. Particularly, β4 is shown to be essential for mammary gland development during embryogenesis. Integrin β4 also plays important roles in tumor formation, invasion and metastasis in breast cancer. However, the mechanism of how integrin β4 mediates breast tumor formation has not been settled. A few studies suggest that integrin β4 is involved in cancer stem cells (CSCs), but the mechanism is not clear. To address this problem, I examined the expression of β4 in breast tumors and its potential role involved in regulating CSCs. My data shows that β4 is expressed heterogeneously in breast cancer, and it is not directly expressed in CSCs but associated with a basal epithelial population. This work suggests that β4 can regulate CSCs in a non-cell-autonomous manner through the interactions between β4+ non-CSC population and β4- CSC population. My data also shows that β4 expression is associated with CD24+CD44+ population in breast tumor. To further study the role of β4 in breast cancer progression, I generated a β4 reporter mouse by inserting a p2A-mCherry cassette before ITGB4 stop codon. This reporter mouse can be crossed with breast tumor models to track β4+ population during tumor progression.

Mobile genetic elements represent a large portion of the genome in many species. Posing a danger to the integrity of genetic information, silencing and structural machinery has evolved to suppress the mobility of foreign and transposable elements within the genome. Condensin proteins – which regulate chromosome structure to promote chromosome segregation – have been demonstrated to function in repetitive gene regulation and transposon silencing in several species. In model system Caenorhabditis elegans, microarray analysis studies have implicated Condensin II subunit HCP-6 in the silencing of multiple loci, including DNA transposon MIRAGE. To address the hypothesis that HCP-6 has a direct function in transcriptional gene silencing of the MIRAGE transposon, we queried MIRAGE expression and chromatin profiles in wild-type and hcp-6 mutant animals. Our evidence confirms that HCP-6 does indeed function during silencing of MIRAGE. However, we found no significant indication that HCP-6 binds to MIRAGE, nor that HCP-6 mediates MIRAGE enrichment of H3K9me3, the repressive heterochromatin mark observed at regions undergoing transcriptional silencing. We suggest that the silencing of MIRAGE, a newly evolved transposon and the only tested mobile element considerably derepressed upon loss of HCP-6, is managed by HCP-6 indirectly.

Background: Treatment decisions for elderly patients with gallbladder pathology are complex. Little is known about what factors go into treatment decisions in this population. We used Medicare data to examine gender-based differences in the use of cholecystectomy vs. cholecystostomy tube placement in elderly patients with acute cholecystitis. Methods: We queried a 5% random sample of Medicare data (2009-2011) for patients >65 admitted for acute cholecystitis (by ICD-9 code) who subsequently underwent a cholecystectomy and/or cholecystostomy tube placement. Demographic information (age, race), clinical characteristics (Elixhauser index, presence of biliary pathology), and hospital outcomes (case fatality rate, length of stay, need for ICU care) were compared by gender. A multivariable model was used to examine predictors of cholecystectomy vs. cholecystostomy tube placement. Results: Of 4063 patients admitted with cholecystitis undergoing the procedures of interest just over half (58%) were women. The majority of patients (93%) underwent cholecystectomy. Compared to women, men were younger (average age 76 vs. 78, p value < 0.01) and had few comorbidities (average Elixhauser 1.2 vs. 1.4 p value < 0.01). Case fatality rate was similar between men (2.5%) and women (2.4% p value 0.48). A higher percentage of men spent time in the ICU (36%) compared to women (31% p value < 0.01). On multivariable analysis men were 30% less likely to undergo cholecystectomy (OR 0.69, 95% CI 0.53-0.91). Conclusion: Elderly men are less likely than elderly women to undergo cholecystectomy for acute cholecystitis despite being younger with less co morbidity and are more likely to spend time in the ICU. More research is needed to determine whether a difference in treatment is contributing to the higher rate of ICU utilization in elderly men with acute cholecystitis.

Background: Following passage of the Affordable Care Act in 2010, 30-day hospital readmissions have come under greater scrutiny. Excess readmissions for certain medical conditions and procedures now result in penalizations on all Medicare reimbursements. We examined the risk factors, outcomes, and costs of 30-day readmissions after colorectal surgery (CRS). Methods: The University HealthSystem Consortium database was queried for adults (≥ 18 years) who underwent colorectal resection for cancer, diverticular disease, inflammatory bowel disease, or benign tumors between January 2008 and December 2011. Our outcomes of interest were readmission within 30-days of the patient’s index discharge, hospital readmission outcomes, and total direct hospital costs. Results: A total of 70,484 patients survived the index hospitalization after CRS during the years under study, 13.7% (9,632) of which were readmitted within 30 days of discharge. The strongest independent predictors of readmission were: LOS ≥4 days (OR 1.44; 95% CI 1.32-1.57), stoma (OR 1.53; 95% CI 1.45-1.61), and discharge to skilled nursing (OR 1.63; 95% CI 1.49-1.76) or rehabilitation facility (OR 2.93; 95% CI 2.54-3.40). Of those readmitted, half occurred within 7 days of the index admission, 13% required ICU care, 6% had a reoperation, and 2% died during the readmission stay. The median combined total direct hospital cost was over twice as high ($26,917 v. $13,817) for readmitted than for nonreadmitted patients. Conclusions: Readmissions following colorectal resection occur frequently and incur a significant financial burden on the healthcare system. Future studies aimed at targeted interventions for high-risk patients may reduce readmissions and curb escalating healthcare costs. Categorization: Outcomes research; Cost analysis; Colon and Rectal Surgery

Coronary vessel development is a crucial part of heart development requiring the interplay of the epicardial, myocardial and endocardial layers of the heart for proper formation. Coronary vascularization is regulated by a host of transcription factors further regulated by chromatin remodeling enzymes, including Histone Deacetylases (HDACs). To investigate the functions of HDACs in coronary vascular development, we have deleted Hdac3 in endocardial cells using Cre LoxP technology. Endocardial cell-­‐specific deletion of Hdac3 results in aberrant coronary vessel formation and complete postnatal lethality. We have thus shown that Hdac3 is a critical regulator of the coronary vascular development pathway.

Objective: Chronic obstructive pulmonary disease (COPD) is a common comorbidity in patients with heart failure, yet little is known about the impact of this condition in patients with acute decompensated heart failure (ADHF), especially from a more generalizable, community-based perspective. The primary objective of this study was to describe the in-hospital and post discharge mortality and treatment of patients hospitalized with ADHF according to COPD status. Methods: The study population consisted of patients hospitalized with ADHF at all 11 medical centers in central Massachusetts during 4 study years: 1995, 2000, 2002, and 2004. Results: Of the 9,748 patients hospitalized with ADHF during the years under study, 35.9% had a history of COPD. The average age of this population was 76.1 years, 43.9% were men, and 93.3% were white. At the time of hospital discharge, patients with COPD were less likely to have received evidence-based heart failure medications, including beta-blockers and ACE inhibitors/angiotensin receptor blockers, than patients without COPD. Multivariable adjusted in-hospital death rates were similar for patients with and without COPD. However, among patients who survived to hospital discharge, patients with COPD had a significantly higher risk of dying at 1 (adjusted RR 1.10; 95% CI 1.06, 1.14) and 5-years (adjusted RR 1.40; 95% CI 1.28, 1.42) after hospital discharge than patients who were not previously diagnosed with COPD. Conclusions: COPD is a common co-morbidity in patients hospitalized with ADHF and is associated with a worse long-term prognosis. Further research is required to understand the complex interactions of these diseases and to ensure that patients with ADHF and COPD receive optimal treatment modalities.

Drosophila is host to the steroid hormone ecdysone, which regulates development and immune functions using a common group of transcription factors. Developmentally-induced ecdysone pulses activate the expression of the EcR, BR-C, HR46, Eip74EF, Eip75B, Eip78C, and Eip93F, which assume control of hundreds of other genes involved in the transition from larva to pupa stage. Many of the transcription factors are related to mammalian nuclear hormone receptors by homology. In addition to these transcription factors, the ecdysoneregulated GATA factors SRP and PNR are required for the proper expression of the peptidoglycan sensor PGRP-LC, which belongs to a conserved class of proteins in innate immunity. Although the transcriptional network has been elucidated in development, it is unclear why ecdysone control of PGRP-LC gene activity involves these nine transcription factors and how ecdysone is regulated in the context of an infection in vivo. An ecdysone-activated enhancer was located upstream of the PGRP-LC locus using a reporter plasmid. Female flies that lacked the enhancer had reduced PGRP-LC expression, but survived infection. Male flies did not experience these changes. Therefore, PGRP-LC enhancer appears to be a female-specific cis-regulatory element. The lack of survival phenotype could be caused by using an improper injection site. Bioinformatics software was used to identify putative individual and overlapping binding sites for some transcription factors. Site-directed mutations of the motifs reduced PGRP-LC promoter activity without abolishing the signal. These results suggest that the transcription factors assemble at multiple locations on the PGRP-LC enhancer and form strong protein-protein bonds. Septic injury led to elevated ecdysone in whole flies, which could be a neuroendocrine response to stress similar to the mammalian system. Steroid hormone regulation of immune receptors is a common theme in humans and flies, and these results could advance our understanding of the transcriptional regulation of related genes and gender differences observed in innate immune responses at the transcriptional level.

Background: Traumatic injury remains a major cause of mortality in the US. Older Americans experience lower rates of injury and higher rates of death at lower injury severity than their younger counterparts. The objectives of this study were to explore pre-injury factors and injury patterns that are associated with post-discharge mortality among injured elderly surviving index hospitalization. Methods: We queried a 5% random sample of Medicare beneficiaries (n=2,002,420) for any hospitalization with a primary ICD-9 diagnosis code for injury. Patients admitted without urgent/emergent admission were excluded, as well as patients presenting from inpatient hospitalization or rehabilitation. The primary endpoint was all-cause mortality. Patients were categorized into three mortality groups: death within 0-30 days, 31-90 days, or 91- 365 days post-discharge from the index hospitalization. These groups were compared with those who survived greater than one year post-discharge. Univariate tests of association and multivariable logistic regression models were utilized to identify factors associated with mortality during the 3 examined periods. Results: 83,439 elderly patients (4.2%) were admitted with new injuries. 63,628 met inclusion criteria. 1,936 patients (3.0%) died during their index hospitalization, 2,410 (3.8%) died within 0-30 days, 3,084 (4.8%) died within 31-90 days, and 5,718 (9.0%) died within 91- 365 days after discharge. In multivariable adjusted models, advanced age, male sex, and higher Elixhauser score were associated with post-discharge mortality. The presence of critical injury had the greatest effect on mortality early after injury (0-30 days, OR 1.81, CI 1.64-2.00). Discharge to anywhere other than home without services was associated with an increased odds of dying. Conclusions: Socio-demographic characteristics, disposition, and co-morbid factors were the strongest predictors of post-discharge mortality. Efforts to reduce injury-related mortality should focus on injury prevention and modification of co-morbidities.

Depression is the leading cause of disability among women of reproductive age worldwide. Upwards of 1 in 5 women suffer from perinatal depression. This condition has deleterious effects on several birth outcomes, infant attachment, and children’s behavior/development. Maternal suicide causes 20% of postpartum deaths in depressed women. Although the vast majority of perinatal women are amenable to being screened for depression, screening alone does not improve treatment rates or patient outcomes. Obstetrics/Gynecology (Ob/Gyn) clinics need supports in place to adequately address depression in their patient populations. The primary goal of this thesis is to develop, refine, and pilot test a new low-cost and sustainable stepped care program for Ob/Gyn clinics that will improve perinatal women’s depression treatment rates and outcomes. We developed and beta tested the Rapid Access to Perinatal Psychiatric Care in Depression (RAPPID) Program, to create a comprehensive intervention that is proactive, multifaceted, and practical. RAPPID aims to improve perinatal depression treatment and treatment response rates through: (1) access to immediate resource provision/referrals and psychiatric telephone consultation for Ob/Gyn providers; (2) clinic-specific implementation of depression care, including training support and toolkits; and (3) proactive depression screening, assessment, and treatment in OB/Gyn clinics. RAPPID builds on a low-cost and widely disseminated population-based model for delivering psychiatric care in primary care settings. Formative data and feedback from key stakeholders also informed the development of RAPPID. Our formative and pilot work in real-world settings suggests RAPPID is feasible and has the potential to improve depression detection and treatment in Ob/Gyn settings. The next step will be to compare two active interventions, RAPPID vs. enhanced usual care (access to resource provision/referrals and psychiatric telephone consultation) in a cluster-randomized trial in which we will randomize 12 Ob/Gyn clinics to either RAPPID or enhanced usual care.