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Diarrhea is the second leading cause of death in children under-5; it kills more children than HIV/AIDS, measles, and malaria combined. Despite this significant health burden, our ability to anticipate and prepare for diarrhea outbreaks remains limited. Precipitation and temperature variability have been shown to affect diarrhea dynamics and therefore contribute to outbreak predictions, but the observed environment-diarrhea relationships are complex and context-specific, depending on local pathogen distribution, host population behavior, and physical environments. To date, studies in sub-Saharan Africa, where the burden of under-5 diarrhea is particularly high, are limited due to sparse diarrheal disease surveillance data. In this dissertation, we leverage unique under-5 diarrhea incidence data to explore the effects of meteorological variability on childhood diarrhea incidence and develop a real-time forecasting system for diarrheal disease in Botswana, where diarrhea remains an important cause of childhood morbidity and mortality. The study focuses in Chobe District, which has an annual dry (April – September) and wet (October – March) season, during which the Chobe River, the primary source of drinking water in the region, floods. Weekly cases of under-5 diarrhea in Chobe District exhibit strong seasonal dynamics with biannual outbreaks occurring during the wet and the dry season. In Chapter 1, we show that wet season diarrhea incidence is strongly associated with increased rainfall and Escherichia coli concentrations in the Chobe River, while dry season incidence is associated with declines in Chobe River flood height and increased total suspended solids in the river. In Chapter 2, we confirm the existence of an El Niño-Southern Oscillation teleconnection with southern Africa by demonstrating that La Niña conditions are associated with cooler temperatures, increased rainfall, and higher flooding in Chobe District during the wet season. In turn, we show that La Niña conditions lagged 0-5 months are associated with higher than average incidence of under-5 diarrhea in the early wet season (December – February). In Chapter 4, we develop and test an epidemiological forecast model for childhood diarrheal disease in Chobe District. The prediction system uses a compartmental susceptible-infected-recovered-susceptible (SIRS) model coupled with Bayesian data assimilation to infer relevant epidemiological parameter values and generate retrospective forecasts. The model system accurately forecasts diarrhea outbreaks up to six weeks before the predicted peak of the outbreak, and prediction accuracy increases over the progression of the outbreak. Many forecasts generated by the model system are more accurate than predictions made using only historical data trends. This dissertation work is an important step forward in our understanding of the links between proximal and distal climatic variability and childhood diarrhea in arid regions of sub-Saharan Africa. Furthermore, it advances methods for generating accurate long-term and short-term forecasts of under-5 diarrhea. We demonstrates the potential use of ENSO data, which are publicly available, to prepare for and mitigate diarrheal disease outbreaks in a low-resource setting up to 5 months in advance, and develop a model-inference system that can generate accurate predictions during an outbreak. Deaths caused by diarrhea are preventable using low-cost treatments. Hence, accurate predictions of diarrhea outbreak magnitudes could help healthcare providers and public health officials prepare for and mitigate the significant morbidity and mortality resulting from diarrhea outbreaks.

This dissertation examines factors associated with healthcare-associated infections (HAIs) in four acute care hospitals located in New York City. Specifically, this investigation focuses on the role that the physical environment plays with regard to patient-to-patient transmission. The initial analyses describe the scope of the problem by reporting the incidence of HAIs and antimicrobial resistance over a seven-year period in the study institutions. In total, 19,052 HAIs were identified among 761,426 discharges. HAI rates fell over time within all hospitals and for all organisms and infection types included in the study, and the odds of acquiring an HAI decreased significantly over time for all organisms. Resistance levels were stable for Enterococcus spp., Staphylococcus aureus, Acinetobacter baumannii, and Streptococcus pneumoniae. Multidrug resistance increased for Pseudomonas aeruginosa and decreased for Klebsiella pneumoniae, though imipenem resistance among K. pneumoniae climbed sharply in 2011. A systematic literature review is presented to summarize what is known and unknown about how patients’ exposure to infected or colonized concurrent roommates and prior bed occupants affects their risk of developing HAIs. Eighteen articles meeting the inclusion criteria were identified. More than half reported at least one statistically significant positive association between the infection/colonization status of a roommate or previous room occupant and the development of HAIs. Only a single article identified a statistically significant negative association. The remainder found no associations that reached statistical significance, though this may be due to the fact that they were insufficiently powered. The dissertation concludes with a matched case-control study designed to quantify the association between having a prior bed occupant or roommate with a positive blood, respiratory, urine, or wound culture and subsequent infection with the same organism. In a multivariable analysis controlling for patient characteristics and mutually controlling for each exposure, the odds of being exposed to a prior bed occupant with the same organism were 5.83 (95% Confidence Interval [3.62, 9.39]) times greater for cases versus controls and the odds of being exposed to a roommate with the same organism were 4.82 [3.67, 6.34] times greater.

Community-associated methicillin-resistant Staphylococcus aureus has been an increasing public health problem since its emergence in the 1990s and incarcerated populations are at disproportionately high-risk for colonization and infection. However, few studies have investigated why levels of S. aureus remain endemic in correctional settings in the absence of an outbreak. The overall objective of this dissertation was to evaluate S. aureus transmission in two maximum-security prisons using a molecular epidemiologic approach and data collected on over 2,700 inmates from 2009 – 2013. The objective of this dissertation was met using three aims. First, a systematic literature review was conducted to identify studies that used social network analysis (SNA) to evaluate infectious disease transmission via non-sexual/non-injection drug use contact pathways to detect influences of social networks on disease risk. Results of the review demonstrated that SNA approaches in infectious disease epidemiology are flexible and can be used to enhance traditional contact investigations, reveal granular patterns of transmission, evaluate influences of high-risk behaviors and activities, and identify both protective and causal effects resulting from context-specific social interactions. Second, changes in the distribution and diversity of S. aureus isolates with increasing length of incarceration were assessed. The results revealed some evidence for S. aureus transmission based on greater representation of certain strains; however, the genetic diversity of S. aureus was high regardless of length of time served. Third, the influence of social interactions among prison inmates on S. aureus colonization status was examined using SNA. The results showed that S. aureus colonized inmates were more likely to spend time in social groups and that the mechanisms of transmission differed for men and women. For women, the association was driven by being centrally located in the social network and for men it was driven by higher proportions of colonized inmates in close proximity. Overall, the results of this dissertation support the hypothesis that S. aureus is transmitted within prisons as a result of direct skin-to-skin contact and/or exposure to contaminated environmental surfaces. However, the results also demonstrate that, in the absence of an outbreak, S. aureus transmission within prisons is low indicating that endemic levels of S. aureus are primarily maintained by the constant introduction of clones into prisons from jails and the community.

Background: Human leukocyte antigens play an integral role in the cytotoxic T-cell pathway and serve as ligands for natural killer cell receptors. We have investigated the role of two HLA class I; genes on disease progression and maternal-infant HIV-1 transmission using 222 South African mother-infant pairs recruited as part of a mother-to-infant HIV-1 transmission study. Methods: High resolution genotyping of HLA class I; B and Cw loci was performed using a sequence-based typing strategy and alleles were collapsed to a four-digit assignment for purpose of analysis. Results: B*5802 and Cw*0602 were significantly associated with high viral load (VL) (P = 0.038 and P = 0.017 respectively) and low CD4 count (P < 0.001 and P = 0.005 respectively). These two alleles are in linkage disequilibrium (D' = 1.00; P < 0.001) and the most prevalent haplotype amongst Black South Africans (f = 9.94%). The B*5802-Cw*0602 haplotype was also significantly associated with low CD4 count (P = 0.001) and showed a trend with high VL (P = 0.073). Furthermore, B*4501 showed a trend with high VL (P = 0.086) and low CD4 count (P = 0.062). B*4201 was significantly associated with low VL (P = 0.045) and another prevalent haplotype, B*4201-Cw*1701 (f = 9.65%), was significantly associated with low VL (P = 0.049). The Cw allotype groups (C1&C2) showed no significant association with markers of disease severity, whereas, contrary to other studies, Bw4/Bw4 homozygosity was significantly associated with high VL (P = 0.038) and low CD4 count (P = 0.015). B*0801 showed a trend (P = 0.064) of lower representation amongst infected infants compared to exposed uninfected infants. Transmitting mothers had significantly higher representation of B*1402 (P = 0.034) and a trend of lower representation of B*4201 (P = 0.082) compared to non-transmitting mothers. No Cw* alleles or allotype groups showed significant association with HIV-1 transmission. Conclusion: This study highlights the different roles played by HLA in disease progression and maternal-infant HIV-1 transmission and also serves as a basis for future work that will study the role of KIR-HLA in the same contexts.