Background: Extreme heat is a leading weather-related cause of illness and death in many locations across the globe, including subtropical Australia. The possibility of increasingly frequent and severe heat waves warrants continued efforts to reduce this health burden, which could be accomplished by targeting intervention measures toward the most vulnerable communities.

Objectives: We sought to quantify spatial variability in heat-related morbidity in Brisbane, Australia, to highlight regions of the city with the greatest risk. We also aimed to find area-level social and environmental determinants of high risk within Brisbane.

Methods: We used a series of hierarchical Bayesian models to examine city-wide and intracity associations between temperature and morbidity using a 2007–2011 time series of geographically referenced hospital admissions data. The models accounted for long-term time trends, seasonality, and day of week and holiday effects.

Results: On average, a 10°C increase in daily maximum temperature during the summer was associated with a 7.2% increase in hospital admissions (95% CI: 4.7, 9.8%) on the following day. Positive statistically significant relationships between admissions and temperature were found for 16 of the city’s 158 areas; negative relationships were found for 5 areas. High-risk areas were associated with a lack of high income earners and higher population density.

Conclusions: Geographically targeted public health strategies for extreme heat may be effective in Brisbane, because morbidity risk was found to be spatially variable. Emergency responders, health officials, and city planners could focus on short- and long-term intervention measures that reach communities in the city with lower incomes and higher population densities, including reduction of urban heat island effects.

Background: While there is ample evidence for health risks associated with heat and other extreme weather events today, little is known about the impact of weather patterns on population health in preindustrial societies.

Objective: To investigate the impact of weather patterns on population health in Sweden before and during industrialization.

Methods: We obtained records of monthly mortality and of monthly mean temperatures and precipitation for Skellefteå parish, northern Sweden, for the period 1800-1950. The associations between monthly total mortality, as well as monthly mortality due to infectious and cardiovascular diseases, and monthly mean temperature and cumulative precipitation were modelled using a time series approach for three separate periods, 1800−1859, 1860-1909, and 1910-1950.

Results: We found higher temperatures and higher amounts of precipitation to be associated with lower mortality both in the medium term (same month and two-months lag) and in the long run (lag of six months up to a year). Similar patterns were found for mortality due to infectious and cardiovascular diseases. Furthermore, the effect of temperature and precipitation decreased over time.

Conclusions: Higher temperature and precipitation amounts were associated with reduced death counts with a lag of up to 12 months. The decreased effect over time may be due to improvements in nutritional status, decreased infant deaths, and other changes in society that occurred in the course of the demographic and epidemiological transition.

Contribution: The study contributes to a better understanding of the complex relationship between weather and mortality and, in particular, historical weather-related mortality.

Background: The cytokine MIF (Macrophage Migration Inhibitory Factor) has diverse physiological roles and is present at elevated concentrations in numerous disease states. However, its molecular heterogeneity has not been previously investigated in biological samples. Mass Spectrometric Immunoassay (MSIA) may help elucidate MIF post-translational modifications existing in vivo and provide additional clarity regarding its relationship to diverse pathologies.

Results: In this work, we have developed and validated a fully quantitative MSIA assay for MIF, and used it in the discovery and quantification of different proteoforms of MIF in serum samples, including cysteinylated and glycated MIF. The MSIA assay had a linear range of 1.56-50 ng/mL, and exhibited good precision, linearity, and recovery characteristics. The new assay was applied to a small cohort of human serum samples, and benchmarked against an MIF ELISA assay.

Conclusions: The quantitative MIF MSIA assay provides a sensitive, precise and high throughput method to delineate and quantify MIF proteoforms in biological samples.

Introduction: Quiescin sulfhydryl oxidase 1 (QSOX1) oxidizes sulfhydryl groups to form disulfide bonds in proteins. Tumor specific expression of QSOX1 has been reported for numerous tumor types. In this study, we investigate QSOX1 as a marker of breast tumor progression and evaluate the role of QSOX1 as it relates to breast tumor growth and metastasis.

Methods: Correlation of QSOX1 expression with breast tumor grade, subtype and estrogen receptor (ER) status was gathered through informatic analysis using the "Gene expression based Outcome for Breast cancer Online" (GOBO) web-based tool. Expression of QSOX1 protein in breast tumors tissue microarray (TMA) and in a panel of breast cancer cell lines was used to confirm our informatics analysis. To investigate malignant cell mechanisms for which QSOX1 might play a key role, we suppressed QSOX1 protein expression using short hairpin (sh) RNA in ER+ Luminal A-like MCF7, ER+ Luminal B-like BT474 and ER- Basal-like BT549 breast cancer cell lines.

Results: GOBO analysis revealed high levels of QSOX1 RNA expression in ER+ subtypes of breast cancer. In addition, Kaplan Meyer analyses revealed QSOX1 RNA as a highly significant predictive marker for both relapse and poor overall survival in Luminal B tumors. We confirmed this finding by evaluation of QSOX1 protein expression in breast tumors and in a panel of breast cancer cell lines. Expression of QSOX1 in breast tumors correlates with increasing tumor grade and high Ki-67 expression. Suppression of QSOX1 protein slowed cell proliferation as well as dramatic inhibition of MCF7, BT474 and BT549 breast tumor cells from invading through Matrigel™ in a modified Boyden chamber assay. Inhibition of invasion could be rescued by the exogenous addition of recombinant QSOX1. Gelatin zymography indicated that QSOX1 plays an important role in the function of MMP-9, a key mediator of breast cancer invasive behavior.

Conclusions: Taken together, our results suggest that QSOX1 is a novel biomarker for risk of relapse and poor survival in Luminal B breast cancer, and has a pro-proliferative and pro-invasive role in malignant progression partly mediated through a decrease in MMP-9 functional activity.

Background: HDL carries a rich protein cargo and examining HDL protein composition promises to improve our understanding of its functions. Conventional mass spectrometry methods can be lengthy and difficult to extend to large populations. In addition, without prior enrichment of the sample, the ability of these methods to detect low abundance proteins is limited. Our objective was to develop a high-throughput approach to examine HDL protein composition applicable to diabetes and cardiovascular disease (CVD).

Methods: We optimized two multiplexed assays to examine HDL proteins using a quantitative immunoassay (Multi-Analyte Profiling- MAP) and mass spectrometric-based quantitative proteomics (Multiple Reaction Monitoring-MRM). We screened HDL proteins using human xMAP (90 protein panel) and MRM (56 protein panel). We extended the application of these two methods to HDL isolated from a group of participants with diabetes and prior cardiovascular events and a group of non-diabetic controls.

Results: We were able to quantitate 69 HDL proteins using MAP and 32 proteins using MRM. For several common proteins, the use of MRM and MAP was highly correlated (p < 0.01). Using MAP, several low abundance proteins implicated in atherosclerosis and inflammation were found on HDL. On the other hand, MRM allowed the examination of several HDL proteins not available by MAP.

Conclusions: MAP and MRM offer a sensitive and high-throughput approach to examine changes in HDL proteins in diabetes and CVD. This approach can be used to measure the presented HDL proteins in large clinical studies.

This essay will provide an analysis of the responsiveness of the world's hospitals to the crisis of the COVID 19 pandemic. This analysis will be focused on determining the previous adaptiveness of these hospitals and how they became and can become more adaptable in order to effectively handle the next global crisis that we will face. The essay will first examine some of the underlying issues that existed within healthcare institutions immediately prior to the onset of the COVID-19 pandemic. After this, it will next observe some of the general challenges posed by the circumstances of the pandemic, followed by an exploration of what changes took place within hospitals in order to combat these challenges. After this the essay will provide an analysis of the effectiveness of these changes. Lastly, the essay will give recommendations on how international healthcare facilities can take broad steps to be better prepared for the next global health crisis.

Society is heavily dependent on a reliable electric supply; all infrastructure systems depend on electricity to operate. When the electric system fails, the impacts can be catastrophic (food spoilage, inoperable medical devices, lack of access to water, etc.). The social impacts, defined as the direct and indirect impacts on people, of power outages must be explored as the likelihood of power outages and blackouts are increasing. However, compared to other hazards, such as heat and flooding, the knowledge base on the impacts of power outages is relatively small. The purpose of this thesis is to identify what is currently known about the social impacts of power outages, identify where gaps in the literature exist, and deploy a survey to explore power outage experiences at the household level. This thesis is comprised of two chapters, a systematic literature review on the current knowledge of the social impacts of power outages and a multi-city survey focused on power outage experiences.

The first chapter comprised of a systematic literature review using a combined search of in Scopus which returned 762 candidate articles were identified that potentially explored the social impacts of power outages. However, after multiple filtering criteria were applied, only 45 articles met all criteria. Four themes were used to classify the literature, not exclusively, including modeling, social, technical, and other. Only papers that were classified as “social” - meaning they observed how people were affected by a power outage - or in combination with other categories were used within the review.

From the literature, populations of concern were identified, including minority demographics - specifically Blacks or African Americans, children, elderly, and rural populations. The most commonly reported health concerns were from those that rely on medical devices for chronic conditions and unsafe generator practices. Criminal activity was also reported to increase during prolonged power outages and can be mitigated by consistent messaging on where to receive assistance and when power will be restored. Providing financial assistance and resources such as food and water can reduce the crime rate temporarily, but the crime rate can be expected to increase once the relief expires. Authorities should expect looting to occur, especially in poorer areas, during prolonged power outages. Gaps in the literature were identified and future directions for research were provided.

The second chapter consists of a multi-city survey that targeted three major cities across the United States (Detroit, MI; Miami, FL; and Phoenix, AZ). The survey was disseminated through Amazon’s Mechanical Turk and hosted by Qualtrics. 896 participants from the three cities qualified to complete the full version of the survey. Three criteria had to be met for participants to complete the full survey including residing in one of the three target cities, living at their primary address for a majority of the year, and indicate they had experienced a power outage within the last five years.

Participants were asked questions regarding the number of outages experienced in the last five years, the length of their most recent and longest outage experienced, if they owned a generator, how they managed their longest power outage, if participants or anyone in their household relies on a medical device, the financial burden their power outage caused, and standard demographic- and income-related questions. Race was a significant variable that influenced the outage duration length but not frequency in Phoenix and Detroit. Income was not a significant variable associated with experiencing greater economic impacts, such as having thrown food away because of an outage and not receiving help during the longest outage. Additional assessments similar to this survey are needed to better understand household power outage experiences.

Findings from this thesis demonstrate traditional metrics used in vulnerability indices were not indicative of who experienced the greatest effects of power outages. Additionally, other factors that are not included in these indices, such as owning adaptive resources including medical devices and generators in Phoenix and Detroit, are factors in reducing negative outcomes. More research is needed on this topic to indicate which populations are more likely to experience factors that can influence positive or negative outage outcomes.

Access to air conditioned space is critical for protecting urban populations from the adverse effects of heat exposure. Yet there remains fairly limited knowledge of penetration of private (home air conditioning) and distribution of public (cooling centers and commercial space) cooled space across cities. Furthermore, the deployment of government-sponsored cooling centers is not based on the location of existing cooling resources (residential air conditioning and air conditioned public space), raising questions of the equitability of access to heat refuges.

Using Los Angeles County, California and Maricopa County, Arizona (whose county seat is Phoenix) we explore the distribution of private and public cooling resources and access inequities at the household level. We do this by evaluating the presence of in-home air conditioning and developing a walking-based accessibility measure to air conditioned public space using a combined cumulative opportunities-gravity approach. We find significant inequities in the distribution of residential air conditioning across both regions which are largely attributable to building age and inter/intra-regional climate differences. There are also regional disparities in walkable access to public cooled space.

At average walking speeds, we find that official cooling centers are only accessible to a small fraction of households (3% in Los Angeles, 2% in Maricopa) while a significantly higher number of households (80% in Los Angeles, 39% in Maricopa) have access to at least one other type of public cooling resource which includes libraries and commercial establishments. Aggregated to a neighborhood level, we find that there are areas within each region where access to cooled space (either public or private) is limited which may increase the health risks associated with heat.

Our previous studies show reduced abundance of the β-subunit of mitochondrial H+-ATP synthase (β-F1-ATPase) in skeletal muscle of obese individuals. The β-F1-ATPase forms the catalytic core of the ATP synthase, and it is critical for ATP production in muscle. The mechanism(s) impairing β-F1-ATPase metabolism in obesity, however, are not completely understood. First, we studied total muscle protein synthesis and the translation efficiency of β-F1-ATPase in obese (BMI, 36±1 kg/m²) and lean (BMI, 22±1 kg/m²) subjects. Both total protein synthesis (0.044±0.006 vs 0.066±0.006%·h^-1) and translation efficiency of β-F1-ATPase (0.0031±0.0007 vs 0.0073±0.0004) were lower in muscle from the obese subjects when compared to the lean controls (P<0.05). We then evaluated these same responses in a primary cell culture model, and tested the specific hypothesis that circulating non-esterified fatty acids (NEFA) in obesity play a role in the responses observed in humans. The findings on total protein synthesis and translation efficiency of β-F1-ATPase in primary myotubes cultured from a lean subject, and after exposure to NEFA extracted from serum of an obese subject, were similar to those obtained in humans. Among candidate microRNAs (i.e., non-coding RNAs regulating gene expression), we identified miR-127-5p in preventing the production of β-F1-ATPase. Muscle expression of miR-127-5p negatively correlated with β-F1-ATPase protein translation efficiency in humans (r = – 0.6744; P<0.01), and could be modeled in vitro by prolonged exposure of primary myotubes derived from the lean subject to NEFA extracted from the obese subject. On the other hand, locked nucleic acid inhibitor synthesized to target miR-127-5p significantly increased β-F1-ATPase translation efficiency in myotubes (0.6±0.1 vs 1.3±0.3, in control vs exposure to 50 nM inhibitor; P<0.05). Our experiments implicate circulating NEFA in obesity in suppressing muscle protein metabolism, and establish impaired β-F1-ATPase translation as an important consequence of obesity.