Molecular Mechanisms of Airway Epithelial Progenitor Cell Maintenance and Repair.

The lungs are vital organs whose airways are lined with a continuous layer of epithelial cells. Epithelial cells in the distal most part of the lung, the alveolar space, are specialized to facilitate gas exchange. Proximal to the alveoli is the airway epithelium, which provides an essential barrier and is the first line of defense against inhaled toxicants, pollutants, and pathogens. Although the postnatal lung is a quiescent organ, it has an inherent ability to regenerate in response to injury. Proper balance between maintaining quiescence and undergoing repair is crucial, with imbalances in these processes leading to fibrosis or tumor development. Stem and progenitor cells are central to maintaining balance, given that they proliferate and renew both themselves and the various differentiated cells of the lung. However, the precise mechanisms regulating quiescence and repair in the lungs are largely unknown. In this dissertation, ionizing radiation is used as a physiologically relevant injury model to better understand the repair process of the airway epithelium. We use in vitro and in vivo mouse models to study the response of a secretory progenitor, the club cell, to various doses and qualities of ionizing radiation. Exposure to radiation found in space environments and in some types of radiotherapy caused clonal expansion of club cells specifically in the most distal branches of the airway epithelium, indicating that the progenitors residing in the terminal bronchioles are radiosensitive. This clonal expansion is due to an increase in p53-dependent apoptosis, senescence, and mitotic defects. Through the course of this work, we discovered that p53 is not only involved in radiation response, but is also a novel regulator of airway epithelial homeostasis. p53 acts in a gene dose-dependent manner to regulate the composition of airway epithelium by maintaining quiescence and regulating differentiation of club progenitor cells in the steady-state lung. The work presented in this dissertation represents an advance in our understanding of the molecular mechanisms underlying maintenance of airway epithelial progenitor cells as well as their repair following ionizing radiation exposure.

Temporal Coding of Volumetric Imagery

'Image volumes' refer to realizations of images in other dimensions such as time, spectrum, and focus. Recent advances in scientific, medical, and consumer applications demand improvements in image volume capture. Though image volume acquisition continues to advance, it maintains the same sampling mechanisms that have been used for decades; every voxel must be scanned and is presumed independent of its neighbors. Under these conditions, improving performance comes at the cost of increased system complexity, data rates, and power consumption.

This dissertation explores systems and methods capable of efficiently improving sensitivity and performance for image volume cameras, and specifically proposes several sampling strategies that utilize temporal coding to improve imaging system performance and enhance our awareness for a variety of dynamic applications.

Video cameras and camcorders sample the video volume (x,y,t) at fixed intervals to gain understanding of the volume's temporal evolution. Conventionally, one must reduce the spatial resolution to increase the framerate of such cameras. Using temporal coding via physical translation of an optical element known as a coded aperture, the compressive temporal imaging (CACTI) camera emonstrates a method which which to embed the temporal dimension of the video volume into spatial (x,y) measurements, thereby greatly improving temporal resolution with minimal loss of spatial resolution. This technique, which is among a family of compressive sampling strategies developed at Duke University, temporally codes the exposure readout functions at the pixel level.

Since video cameras nominally integrate the remaining image volume dimensions (e.g. spectrum and focus) at capture time, spectral (x,y,t,\lambda) and focal (x,y,t,z) image volumes are traditionally captured via sequential changes to the spectral and focal state of the system, respectively. The CACTI camera's ability to embed video volumes into images leads to exploration of other information within that video; namely, focal and spectral information. The next part of the thesis demonstrates derivative works of CACTI: compressive extended depth of field and compressive spectral-temporal imaging. These works successfully show the technique's extension of temporal coding to improve sensing performance in these other dimensions.

Geometrical optics-related tradeoffs, such as the classic challenges of wide-field-of-view and high resolution photography, have motivated the development of mulitscale camera arrays. The advent of such designs less than a decade ago heralds a new era of research- and engineering-related challenges. One significant challenge is that of managing the focal volume (x,y,z) over wide fields of view and resolutions. The fourth chapter shows advances on focus and image quality assessment for a class of multiscale gigapixel cameras developed at Duke.

Along the same line of work, we have explored methods for dynamic and adaptive addressing of focus via point spread function engineering. We demonstrate another form of temporal coding in the form of physical translation of the image plane from its nominal focal position. We demonstrate this technique's capability to generate arbitrary point spread functions.

The Land of the Savior: Óscar Romero and the Reform of Agriculture

This study approaches Óscar Romero by attending to his intimate involvement in and concern for the problematic surrounding the reform of Salvadoran agriculture and the conflict over property and possession underlying it. In this study, I situate Romero in relation to the concentration of landholding and the production of landlessness in El Salvador over the course of the twentieth century, and I examine his participation in the longstanding societal and ecclesial debate about agrarian reform provoked by these realities. I try to show how close attention to agrarian reform and what was at stake in it can illumine not only the conflict that occasioned Romero’s martyrdom but the meaning of the martyrdom itself.

Understanding Romero’s involvement in the debate about agrarian reform requires sustained attention to how it takes its bearings from the line of thinking about property and possession for which Pope Leo XIII’s 1891 encyclical Rerum novarum stands as a new beginning. The enclyclical tradition developing out of Leo’s pontificate is commonly referred to as Catholic social doctrine or Catholic social teaching. Romero’s and the Church’s participation in the debate about agrarian reform in El Salvador is unintelligible apart from it.

What Romero and the encyclical tradition share, I argue, is an understanding of creation as a common gift, from which follows a distinctive construal of property and the demands of justice with respect to possessing it. On this view, property does not name, as it is often taken to mean, the enclosure of what is common for the exclusive use of its possessors—something to be held by them over and against others. Rather, property and everything related to its holding derive from the claim that creation is a gift given to human creatures in common. The acknowledgement of creation as a common gift gives rise to what I describe in this study as a politics of common use, of which agrarian reform is one expression.

In Romero’s El Salvador, those who took the truth of creation as common gift seriously—those who spoke out against or opposed the ubiquity of the concentration of land and who clamored for agrarian reform so that the landless and land-poor could have access to land to cultivate for subsistence—suffered greatly as a consequence. I argue that, among other things, their suffering shows how, under the conditions of sin and violence, those who work to ensure that others have access to what is theirs in justice often risk laying down their lives in charity. In other words, they witness to the way that God’s work to restore creation has a cruciform shape. Therefore, while the advocacy for agrarian reform begins with the understanding of creation as common gift, the testimony to this truth in word and in deed points to the telos of the gift and the common life in the crucified and risen Lord in which it participates

The Barriers to the Integration of the Uterine Balloon Tamponade into South Africa and Ghana's Health Systems for the Management of Postpartum Hemorrhage

Background

Postpartum hemorrhage is the most significant contributor to maternal mortality globally, claiming 140,000 lives annually. Postpartum hemorrhage is a leading cause of maternal death in South Africa, with the literature indicating that 80 percent of the postpartum hemorrhage deaths in South Africa are avoidable. Ghana, as of 2010, witnesses 2700 maternal deaths annually, primarily because of poor quality of care in health facilities and services being difficult to access. As per WHO recommendations, uterotonics are integral to treating postpartum hemorrhage as soon as it is diagnosed. In case of persistent bleeding or limited availability of uterotonics, the uterine balloon tamponade (UBT) can be used as a second line of defense. If both these measures are unable to counter the bleeding, providers must perform surgical interventions. Literature on the UBT, as one tool in the protocol to address postpartum hemorrhage, has shown it to have success rates ranging from 60 to 100 percent. Despite the potential to lower the number of postpartum hemorrhage deaths in South Africa and Ghana, the UBT has not been incorporated widely in South Africa and Ghana. The aim of this study is to describe the barriers involved with integrating the UBT into South Africa and Ghana’s health systems to address postpartum hemorrhage.

Methods

The study took place in multiple sites in South Africa (Cape Town, Johannesburg, Durban and Mpumalanga) and in Accra, Ghana. South Africa and Ghana were selected because postpartum hemorrhage contributes greatly to their maternal mortality numbers and there is potential in both countries to lower those rates through greater use of the UBT. A total of 25 participants were interviewed through purposive sampling, snowball sampling and participant referrals, and included various categories of stakeholders integral to the integration process of a medical device. Individual in-depth interviews were used for data collection, with interview questions being tailored to each stakeholder category. The focus of the interviews was on the protocol used to counter postpartum hemorrhage, the frequency with which the UBT is used as part of the protocol, and the process of integrating it into the South Africa and Ghana’s health systems. The data collected were coded using NVivo and analyzed using content analysis.

Results

The barriers to integration of the uterine balloon tamponade to address postpartum hemorrhage in South Africa and Ghana were evident on the political, economic and health delivery levels. The results indicated that the barriers to integration in South Africa included the low recognition of postpartum hemorrhage as a problem, the lack of clarity surrounding the role of the Medicines Control Council as a regulatory body for medical devices, and low awareness of the UBT as an intervention to control postpartum hemorrhage. The barriers in Ghana were the cash constraints experienced by the Ghana Health Services to fund medical devices, a heavy reliance on donors for funding, and the lack of consistent knowledge on processes involving clinical trials for new medical devices in Ghana.

Conclusion

Existing literature on methods to counter postpartum hemorrhage to reduce maternal mortality has focused on and emphasized the efficacy of the UBT. Despite overwhelming evidence supporting the use of the UBT, many health systems across the world, particularly low-income countries, do not have access to the device owing to numerous barriers in integrating the device into obstetric care. This study illustrates the need to focus on incorporating the UBT into health systems for greater availability to health workers and its use as standard of care. Ultimately, this study can be used as a stepping-stone for more research on this subject, providing evidence to influence policymakers to integrate the UBT into their protocols for postpartum hemorrhage response.

Neural mechanisms of negative reinforcement in children and adolescents with autism spectrum disorders.

BACKGROUND: Previous research has found accumulating evidence for atypical reward processing in autism spectrum disorders (ASD), particularly in the context of social rewards. Yet, this line of research has focused largely on positive social reinforcement, while little is known about the processing of negative reinforcement in individuals with ASD. METHODS: The present study examined neural responses to social negative reinforcement (a face displaying negative affect) and non-social negative reinforcement (monetary loss) in children with ASD relative to typically developing children, using functional magnetic resonance imaging (fMRI). RESULTS: We found that children with ASD demonstrated hypoactivation of the right caudate nucleus while anticipating non-social negative reinforcement and hypoactivation of a network of frontostriatal regions (including the nucleus accumbens, caudate nucleus, and putamen) while anticipating social negative reinforcement. In addition, activation of the right caudate nucleus during non-social negative reinforcement was associated with individual differences in social motivation. CONCLUSIONS: These results suggest that atypical responding to negative reinforcement in children with ASD may contribute to social motivational deficits in this population.