La rage entraîne plus de 60,000 décès par an dans le Monde, dont 800 au Cambodge, pays fortement endémique pour la rage canine.La mort survient dans près de 100% des cas de rage, maladie évitable dans presque 100% des cas par l’accès à une prophylaxie post-exposition (PPE) antirabique adéquate et en temps utile. L’amélioration de l’accès à une PPE dans les zones rurales des pays endémiques permettra d’épargner des vies humaines à court terme. Cette thèse en épidémiologie a tiré parti des données collectées auprès des patients consultant au centre antirabique et les chiens testés à l’Institut Pasteur du Cambodge (IPC), Phnom Penh. Suite à un bilan épidémiologique de la situation et des obstacles auxquels sont confrontés les patients cherchant à accéder à la PPE adéquate et en temps utile, elle vise à contribuer à améliorer 1/ l’accès géographique et 2/ l’accès financier à une PPE pour les populations rurales du Cambodge. Nous avons développé une stratégie originale d’identification des poches de populations à haut risque d’incomplétude vaccinale après une exposition potentielle à la rage. Ceci devrait permettre d’améliorer l’accès géographique à la PPE et se concrétiser par l’ouverture en Juillet 2018 d’un centre périphérique de prévention de la rage dans l’Ouest du Cambodge. Cette stratégie d’identification de difficultés d’accès aux soins est applicable à d’autres thématiques de santé, sous certaines conditions. Notre rappel des patients et l’analyse des décès par rage parmi les patients n’ayant pas complété de leur propre chef le protocole PPE de 4 sessions intradermales sur 1 mois ne permettent pas de mettre en évidence une différence de mortalité par rage parmi les patients n’ayant reçu que 3 sessions sur 1 semaine, par rapport à au moins 4 sessions/1mois. Le raccourcissement du protocole à 1 semaine permet de réduire les coûts directs et indirects et l’absence de revenus pendant la durée du traitement en capitale. La mise en place de ce protocole doit s’accompagner d’un suivi d’au moins 6 mois des patients après leur prise en charge initiale. L’ensemble de ces travaux a des implications qui dépassent le cadre du Cambodge: Dans ses recommandations d’Avril 2018, l’OMS recommande désormais ce nouveau protocole IPC– le premier protocole PPE antirabique abrégé à 1 semaine. / Rabies causes more than 60,000 deaths worldwide each year, including 800 in Cambodia, where canine-mediated rabies virus circulates. Death occurs in nearly 100% of rabies cases, a disease which is nearly 100% avoidable by timely and adequate rabies post-exposure prophylaxis (PEP). Improving access to PEP in rural areas of endemic countries will spare human lives in the short term. This epidemiology PhD used the data collected in patients referred to the rabies prevention clinic and tested dogs at Institut Pasteur du Cambodge (IPC), Phnom Penh. After a baseline assessment of access to and obstacles to access timely and adequate PEP in Cambodia, this PhD aims to contribute to improving: 1/ geographical access and 2/ financial access to PEP for rural populations in Cambodia. We developed an original strategy to identify populations with a high risk of PEP noncompletion after a bite by a potentially rabid dog. This should help improve geographical access to PEP following the implementation in July 2018 of a peripheral rabies prevention center in Western Cambodia. This strategy can be applied to identify difficulties in accessing health services relevant to other health issues, under certain conditions. After patient callback and analysis of rabies deaths among those who did and did not complete the 4-sessions/1-month intradermal PEP regimen of their own accord, we were unable to demonstrate a difference in rabies mortality among patients who only received 3 vaccine sessions over the first week compared to those receiving at least 4 sessions/one month. Abridging the protocol to one week would reduce direct and indirect costs and the loss of income during PEP in the Capital. The adoption of this abridged regimen must be associated with a strengthened clinical monitoring system for at least 6 months following patients’ initial PEP.The work presented in this PhD has implications which reach beyond Cambodia: WHO recommends this new IPC regimen – the first approved one-week, abridged rabies PEP regimen – in its April 2018 guidelines.

Congenital heart defects (CHDs) constitute a major proportion of clinically significant birth defects and are an important component of pediatric cardiovascular disease. Atrioventricular septal defects (AVSDs) include a range of anomalies characterized by atrial, ventricular, and atrioventricular (AV) valve defects. AVSDs commonly occur in the presence of a syndrome, most frequently Down syndrome; they also occur in isolation and are referred to as non-syndromic AVSDs (NSAVSDs). These studies were performed to evaluate for presence of an intermediate phenotype in parents and siblings of a child with a NSAVSD, risk factors associated with NSAVSDs, and prognostic risk factors for left AV valve replacement following primary repair of an AVSD. It was shown that the mean body surface area-standardized AV septal length (AVSL) was significantly shorter in the NSAVSD parents and siblings than in parents and siblings of syndromic AVSD case and control children. Using age- and gender-adjusted body surface area-standardized AVSL, it was determined that there was evidence for two component distributions in parents and siblings of NSAVSD children, suggesting the presence of an intermediate. Broadening the definition of AVSD to include those with a shortened AVSL may increase the power of genetic association and mapping studies to identify susceptibility genes. Risk factors associated with NSAVSD were examined using the 1997-2005 National Birth Defects Prevention Study database. Mothers who actively smoked or were exposed to passive smoke anytime from one month prior to pregnancy through the end of the first trimester were more likely to have an infant with a NSAVSD. There was a suggestive association between AVSDs and use of antibacterial, antifungal, and antiviral medications. Additional investigations are warranted to investigate associations with specific medications as well as to uncover possible gene-environment interaction effects that may modify these risks in order to develop improved primary prevention strategies. Using the Pediatric Cardiac Care Consortium database, factors associated with time to first reoperation and time to replacement following primary AVSD repair were evaluated. Type of AVSD repair, closure of the mitral valve cleft, moderate to severe postoperative left AV valve regurgitation, and presence of postoperative complete heart block were associated with earlier time to reoperation after adjusting for age and weight at AVSD repair. Down syndrome and presence of postoperative mitral stenosis were associated with earlier time to replacement. Prognostic risk factors following left AV valve replacement in children who had previously undergone AVSD repair were also identified. A prosthetic valve size to body weight ratio of greater than 3 and the presence of Down syndrome were identified as predictors of in-hospital death following left AV valve replacement. By adding to our knowledge of the AVSD familial and environmental risk factors from these studies, we will be able to (1) improve genetic counseling, (2) identify other family members for genetic testing, (3) begin to devise primary prevention strategies, and (4) improve treatment modalities. By recognizing prognostic factors which influence survival, optimal patient care can be devised which will not only improve treatment modalities, but also long-term survival.

Objective: Treatment compliance in children with Crohn’s disease is associated with higher levels of symptom remission. We hypothesized that the management, comorbidities, and complications for children with Crohn’s disease would differ based on a diagnosis of noncompliance. Methods: Using the Kids’ Inpatient Database for 2006-2012, we identified young patients (<21 >years) with a diagnosis of Crohn’s disease. Diagnoses and procedures were analyzed according to a recorded diagnosis of noncompliance. Multivariable logistic regression analysis was performed to examine the association between noncompliance and the outcomes of interest. Results: There were 28,337 pediatric Crohn’s disease hospitalizations identified with 1,028 (3.6%) hospitalizations having a diagnosis of both Crohn’s disease and noncompliance. The mean age of the study population was 15.9 years and 48.9% were girls. Black patients ( multivariable adjusted odds ratio, aOR,2.27; 95% CI:1.84-2.79) and those in the lowest income quartile (aOR 1.57; 95% CI:1.20-2.05) had an increased likelihood of a noncompliance diagnosis than respective comparison groups. Noncompliant patients had an increased likelihood of concurrent depression, nutritional deficiency, and anemia. Patients with a diagnosis of noncompliance had lower rates of intestinal obstruction (4.0% vs 6.3%), intraabdominal abscesses (2.0% vs 4.2%,), and underwent fewer major surgical procedures (aOR 0.40; 95% CI:0.31-0.53) and large bowel resections (aOR 0.44; 95% CI:0.31-0.64) than patients without this diagnosis. Conclusions: We found significant differences in socioeconomic status and race among hospitalized children with Crohn’s disease with, as compared to those without, a diagnosis of noncompliance. Children with noncompliance have different comorbidities, disease-related complications, and are managed differently. Possible explanations for observed treatment differences include a reluctance to offer surgery to those with a diagnosis of noncompliance, a refusal of intervention by noncompliant patients, or implicit bias. Further investigation is warranted to better define noncompliance in this population and to determine the implications of this diagnosis.

Background Fewer than one-third of nursing home residents with atrial fibrillation were treated with the only available oral anticoagulant, warfarin, historically. Management of atrial fibrillation has transformed in recent years with the approval of 4 direct-acting oral anticoagulants (DOACs) since 2010. Methods Using the national Minimum Data Set 3.0 linked to Medicare Part A and D claims, we first described contemporary (2011-2016) warfarin and DOAC utilization in the nursing home population (Aim 1). In Aim 2, we linked residents to nursing home and county level data to study associations between resident, facility, county, and state characteristics and anticoagulant treatment. Using a new-user active comparator design, we then compared the incidence of safety (i.e., bleeding), effectiveness (i.e., ischemic stroke), and mortality outcomes between residents initiating DOACs versus warfarin (Aim 3). Results The proportion of residents with atrial fibrillation receiving treatment increased from 42.3% in 2011 to 47.8% as of December 31, 2016, at which time 48.2% of treated residents received DOACs. Demographic and clinical characteristics of residents using DOACs and warfarin were similar in 2016. Half of the 8,734 DOAC users received standard dosages and most were treated with apixaban (54.4%) or rivaroxaban (35.8%) in 2016. Compared with warfarin, bleeding rates were lower and ischemic stroke rates were higher for apixaban users. Ischemic stroke and bleeding rates for dabigatran and rivaroxaban were comparable to warfarin. Mortality rates were lower versus warfarin for each DOAC. Conclusions In nursing homes, DOACs are being used commonly and with equal or greater benefit than warfarin.

Background: The epidemiology of SARS-CoV-2 infection in the pediatric population, with a focus on racial and ethnic disparities and impact of societal public health measures, remains poorly understood. Methods: This large observational study used electronically abstracted data from pediatric (≤ 19 years of age) patients who received a molecular test for SARS-CoV-2 at a UMass Memorial Health Care (UMMHC) site between March 8, 2020 and April 3, 2021 which was further supplemented by manual chart review of a subset of pediatric SARS-CoV-2 cases. Multivariable logistic regression models with interaction terms were used to identify risk factors for SARS-CoV-2 infection. Segmented regression analysis using Poisson models was used to estimate the effect of public health measures on the weekly incidence of SARS-CoV-2 infection. Results: A total of 25,426 unique pediatric patients were tested for SARS-CoV-2 among whom 2,920 (11.5%) tested positive. The average age of those who tested positive was 10.8 years (SD: 5.8) and 48.1% were female. In the subset analysis, nearly three-quarters (75.9%) of SARS-CoV-2 diagnoses occurred through a telephone encounter, meaning that the child was not physically examined by a provider prior diagnosis and only 2.0% were admitted for inpatient care at diagnosis. Results of multivariable regression revealed that children or parents who self-reported Black race, Hispanic ethnicity, and non-English primary language were associated with approximately twice the odds of testing positive in comparison with White or English-speaking patients. Furthermore, increasing age was associated with increased odds of testing positive for SARS-CoV-2 (aOR: 1.1 (1-4 years), 1.2 (5-9 years), 1.4 (10-14 years), 1.6 (15-17 years), 1.7 (18-19 years)). However, this association between age and positivity rate, varies by race/ethnicity and primary language such that Non-Hispanic Black, Hispanic, and non-English speaking children had markedly greater odds of testing positive during adolescence in comparison to Non-Hispanic White and English-speaking counterparts. Results from segmented regression analysis demonstrated a decline in weekly incidence of cases 9.9% (95% CI: 7.8 – 11.9) after the Massachusetts state mask mandate was implemented. During the winter holidays, the rate of increase in the weekly incidence of cases was 12.1% (95% CI: 11.9 – 12.3) in this pediatric population. Conclusions: Many SARS-CoV-2 cases have been diagnosed at UMMHC sites and notable racial/ethnic disparities exist that vary based on patient age. Public health measures are effective at preventing transmission of SARS-CoV-2 among children.

Background: Dual antiplatelet therapy (DAPT) is a mainstay treatment for hospital survivors of an acute myocardial infarction (AMI). However, there are extremely limited data on the prescribing patterns of DAPT among patients hospitalized with AMI. Objective: To examine decade-long trends (2001-2011) in the use of DAPT versus antiplatelet monotherapy and patient characteristics associated with DAPT use. Methods: The study population consisted of 2,389 adults hospitalized with an initial AMI at all 11 central Massachusetts medical centers on a biennial basis between 2001 and 2011. DAPT was defined as the discharge use of aspirin plus either clopidogrel or prasugrel. Logistic regression analysis was used to identify patient characteristics associated with DAPT use. Results: The average age of the study population was 65 years, and 69% of them were discharged on DAPT. The use of DAPT at the time of hospital discharge increased from 49% in 2001 to 74% in 2011; this increasing trend was seen across all age groups, both sexes, types of AMI, and in those who underwent a PCI. After multivariable adjustment, older age was the only factor associated with lower odds of receiving DAPT, while being male, receiving additional evidence-based cardioprotective therapy and undergoing cardiac stenting were associated with higher odds of receiving DAPT. Conclusions: Between 2001 and 2011, the use of DAPT increased markedly among patients hospitalized with AMI. However, a significant proportion of patients were not discharged on this therapy. Greater awareness is needed to incorporate DAPT into the management of patients with AMI.

Background: Sepsis, a leading cause of US deaths, is associated with high mortality, although advances in early recognition and treatment have increased survivorship. Many aspects of sepsis pathophysiology and epidemiology have not been fully elucidated; the heterogeneous nature of infections that lead to sepsis has made fully characterizing the underlying epidemiology challenging. Methods: The University HealthSystem Consortium (UHC) from 2011-2014 and the Cerner HealthFacts® database from 2008-2014 were used. We examined associations between infection source and in-hospital mortality in the UHC dataset, stratified by age and presenting sepsis stage. We examined recent temporal trends in present-on-admission (POA) sepsis diagnoses and mortality and predictors of 30-day sepsis readmissions following sepsis hospitalizations using the HealthFacts® dataset. Results: Patients with sepsis due to genitourinary or skin, soft tissue, or bone sources had lower mortality than patients with sepsis due to respiratory sources regardless of age or presenting sepsis stage. Overall diagnoses of sepsis increased from 2008-2014; however, POA diagnoses and case fatality rates decreased. Factors that predicted re-hospitalization for sepsis included discharge to hospice, admission from or discharge to a skilled nursing facility, and abdominal infection. Conclusion: Further investigation will reveal more detail to explain the impact of infection source on in-hospital sepsis mortality for all age groups and sepsis stages. Decreasing mortality rates for all POA sepsis stages and all age groups suggest current approaches to sepsis management are having broad impact. Sepsis survivors are at significant risk for re-hospitalization; further studies are needed to understand the post discharge risks and needs of survivors.

Despite tremendous progress in the understanding of breast cancer (BC), gaps remain in our knowledge of the molecular basis underlying the aggressiveness of BC and BC disparities. Nuclear respiratory factor 1 (NRF1) is a transcription factor (TF) known to control breast cancer cell cycle progression. DNA response elements bound by NRF1 positively correlate with the progression of malignant breast cancer. Mechanistic aspects by which NRF1 contributes to susceptibility to different breast tumor subtypes are still not fully understood. Therefore, the primary objective of this dissertation was to decipher mechanisms by which NRF1 coordinates changes in the transcriptional and chromatin landscape affecting development and progression of invasive breast cancer. Our hypothesis was that NRF1 reprogramming the transcription of tumor initiating gene(s) and tumor suppressor gene(s) contribute in the development and progression of invasive breast cancer. To test this hypothesis, we proposed three specific aims: (a) Decipher regulatory landscape of NRF1 networks in breast cancer. (b) Determine the role of NRF1 gene networks in different subtypes of breast cancer. (c) Determine differential NRF1 gene network sensitivity contributing to breast cancer disparities. Our approach to test these aims consisted of a systematic integration of ChIP DNA-seq, RNA-Seq, NRF1 protein-DNA motif binding, signal pathway analysis, and Bayesian machine learning. We uncovered a novel oncogenic role for NRF1. This discovery strongly supported the supposition that NRF1 overexpression is sufficient to derive breast tumorigenesis. We also observed new roles for NRF1 in the acquisition of breast tumor initiating cells, regulation of epithelial to mesenchymal transition (EMT), and invasiveness of BC stem cells. Furthermore, through the use of Bayesian network structure learning we found that the NRF1 motif was enriched in 14 associated with HER2 amplified breast cancer. Three genes—GSK3B, E2F3, and PIK3CA—were able to predict HER2 breast tumor status with 96% to100% confidence. The findings of this study also showed the roles of NRF1 sensitivity to development of lobular A, Her2+, and TNBC in different racial/ethnic groups of breast cancer patients. In summary, our study revealed for the first time the role of NRF1 in the pathogenesis of invasive BC and BC disparities.

This study examines the "Spanish" influenza pandemic of 1918-1919 in the U.S. South, using case-studies of Jacksonville, Savannah, New Orleans, and Nashville to sculpt a "Southern flu" more identical to the Global South and the developing world than the rest of the U.S. I examine poverty and political and economic paralysis in the years between the end of Reconstruction and 1918, and the poor results of political indifference on public health and disease control. I also analyze the social and institutional racism against persons of color that defined high infectious disease mortality in Southern cities. I argue that Southerners faced higher flu mortality than other parts of the country due to the regional poverty and public health underdevelopment that defined previous diseases and made the South distinct in the national epidemiological narrative, namely through yellow fever, malaria, hookworm, and pellagra. I also challenge the conventional orthodoxy by arguing that within the South, African Americans faced exorbitant mortality rates compared to whites. I argue against the myth of a democratic killer flu, but rather, the existence of deep social inequalities and inequities that furthered mortality among the impoverished and marginalized. I argue that the pandemic was like most epidemics and pandemics in Western history, in that it disproportionately killed minorities and those without access to medical care and social services due to conducive social architecture. While pestilence shapes societies, societies simultaneously shape the course of pestilence. This study is divided into five chapters. An introductory chapter examines the scholarship and Southern public health before 1918. The second chapter addresses the pandemic in Jacksonville and Savannah, the third chapter examines New Orleans, and the fourth chapter assesses Nashville. A concluding chapter compares the U.S. South with the Global South, tethering the U.S. South to the global pandemic.

<p>Introduction: Globally, more than 200 million patients undergo major non-cardiac surgery each year and more than 10 million patients will be exposed to postoperative myocardial ischemia, a condition strongly associated with 30-day mortality. The majority of these events go undetected without postoperative Troponin screening. Methods: We conducted a model-based cost-consequence analysis comparing a postoperative Troponin T screening vs. standard care in patients undergoing noncardiac surgery. In a first model, we evaluated the incremental number of detected perioperative myocardial infarctions and the incremental costs. A second model assessed the effect of the screening and consequent treatment on 1-year survival and the related cost. Model inputs based on the Vascular events In Non-cardiac Surgery patIents cOhort evaluatioN (VISION) Study, a large international cohort. We run probability sensitivity analyses with 5,000 iterations. We conducted extensive sensitivity analyses.</p> <p>Results: The cost to avoid missing an event amounted to CAD$ 5,184 for PMI and CAD$ 2,983 for isolated Troponin T. The cost-effectiveness of the postoperative Troponin screening was higher in patients’ subgroups at higher risk for PMI, e.g. patients undergoing urgent surgery. The incremental costs at 1 year of a postoperative PMI screening by 4 Troponin T measurements were CAD$ 169.20 per screened patient. The cost to prevent a death at 1 year amounted to CAD$ 96,314; however, there was relevant model uncertainty associated with the efficacy of the treatment in the 1-year model.</p> <p>Conclusion: Based on the estimated incremental cost per health gain, the implementation of a postoperative Troponin T screening after noncardiac surgery seems appealing, in particular in patients at high risk for perioperative myocardial infarction. However, decision-makers will have to consider it in terms of opportunity costs, i.e. in relation to the cost-effectiveness of other potential programs within the broader health care context.</p> / Master of Science (MSc)