Determinants of bed net use in The Gambia: implications for malaria control

Malaria is still one of the biggest health threats in the developing world, with an estimated 300 million episodes per year and one million deaths, most of which are in sub-Saharan Africa. Although the efficacy and cost-effectiveness of treated bed nets has been widely reported, little is known about the range, strength, or interaction between different factors that influence their demand at the household level. This study modeled the determinants of bed net ownership as well as the factors that influence the number of bed nets purchased. Data was collected from 1,700 randomly selected households in the Farafenni region of The Gambia. Interviews were also held with 129 community spokespersons to explore the extent to which community level factors such as the quality of roads and access to market centers also influence demand for bed nets. The results of each model of demand and their policy implications are discussed.

Insights into Nonpilus Adhesin Functionality and the Molecular Determinants of Nontypeable Haemophilus influenzae Colonization

Bacterial colonization of the upper respiratory tract is the first step in the pathogenesis of nontypeable Haemophilus influenzae (NTHi) disease. Examination of the determinants of NTHi colonization process has been hampered by the lack of an appropriate animal model. To address this, we have developed a model of NTHi colonization in adult rhesus macaques that involves intranasal inoculation of 1x105 CFU and results in persistent colonization of the upper respiratory tract for at least three weeks with no signs of disease, mimicking asymptomatic colonization of humans. Using this model, we assessed the contributions to colonization of the HMW1 and HMW2 adhesive proteins. In competition experiments, the parent strain expressing both HMW1 and HMW2 was able to efficiently out-compete an isogenic mutant strain expressing neither HMW1 nor HMW2. In experiments involving inoculation of single isogenic derivatives of NTHi strain 12, the strains expressing HMW1 or HMW2 or both were able to colonize efficiently, while the strain expressing neither HMW1 nor HMW2 colonized inefficiently. Furthermore, colonization resulted in antibody production against HMW1 and HMW2 in one-third of the animals, demonstrating that colonization can be an immunizing event. In conclusion, we have established that NTHi is capable of colonizing the upper respiratory tract of rhesus macaques, in some cases associated with stimulation of an immune response. The HMW1 and HMW2 adhesive proteins play a major role in the process of colonization.

After establishing that the HMW1 and HMW2 proteins are colonization factors we further investigated the determinants of HMW1 function. HMW1 is encoded in the same genetic locus as two other proteins, HMW1B and HMW1C, with which HMW1 must interact in order to be functional. Interaction with HMW1C in the cytoplasm results in the glycosylation of HMW1. By employing homologues of HMW1C that glycosylate HMW1 in slightly different patterns we show that the pattern of modification is critical to HMW1 function. Structural analysis showed a change in protein structure when the pattern of HMW1 modification differed. We also identified two specific sites which must be glycosylated for HMW1 to function properly. These point mutations did not have a significant effect on protein structure, suggesting that glycosylation at those specific sites is instead necessary for interaction of HMW1 with its receptor. HMW1B is an outer membrane pore through which HMW1 is transported to reach the bacterial cell surface. We observed that HMW1 isolated from the cytoplasm has a different structure than HMW1 isolated from the bacterial cell surface. By forcing HMW1 to be secreted in a non-HMW1B dependent manner, we show that secretion alone is not sufficient for HMW1 to obtain a functional structure. This leads us to hypothesize that there is something specific in the interaction between HMW1 and HMW1B that aids in proper HMW1 folding.

The NTHi HMW1C glycosyltransferase mediates unconventional N-linked glycosylation of HMW1. In this system, HMW1 is modified in the cytoplasm by sequential transfer of hexose residues. To determine if this mechanism of N-linked glycosylation is employed by species other than NTHi, we examined Kingella kingae and Aggregatibacter aphrophilus homologues of HMW1C. We found both homologues to be functional glycosyltransferases and identified their substrates as the K. kingae Knh and the A. aphrophilus EmaA trimeric autotransporter proteins. LC-MS/MS analysis revealed multiple sites of N-linked glycosylation on Knh and EmaA. Without glycosylation, Knh and EmaA failed to facilitate wild type levels of bacterial autoaggregation or adherence to human epithelial cells, establishing that glycosylation is essential for proper protein function.

Sequence and Structural Determinants of Specificity Differences between Paralogous Transcription Factors

Transcription factors (TFs) control the temporal and spatial expression of target genes by interacting with DNA in a sequence-specific manner. Recent advances in high throughput experiments that measure TF-DNA interactions in vitro and in vivo have facilitated the identification of DNA binding sites for thousands of TFs. However, it remains unclear how each individual TF achieves its specificity, especially in the case of paralogous TFs that recognize distinct target genomic sites despite sharing very similar DNA binding motifs. In my work, I used a combination of high throughput in vitro protein-DNA binding assays and machine-learning algorithms to characterize and model the binding specificity of 11 paralogous TFs from 4 distinct structural families. My work proves that even very closely related paralogous TFs, with indistinguishable DNA binding motifs, oftentimes exhibit differential binding specificity for their genomic target sites, especially for sites with moderate binding affinity. Importantly, the differences I identify in vitro and through computational modeling help explain, at least in part, the differential in vivo genomic targeting by paralogous TFs. Future work will focus on in vivo factors that might also be important for specificity differences between paralogous TFs, such as DNA methylation, interactions with protein cofactors, or the chromatin environment. In this larger context, my work emphasizes the importance of intrinsic DNA binding specificity in targeting of paralogous TFs to the genome.

Outcomes and Predictors of Mortality in Neurosurgical Patients at Mbarara Regional Referral Hospital

Background:

Knowing the scope of neurosurgical disease at Mbarara Hospital is critical for infrastructure planning, education and training. In this study, we aim to evaluate the neurosurgical outcomes and identify predictors of mortality in order to potentiate platforms for more effective interventions and inform future research efforts at Mbarara Hospital.

Methods:

This is retrospective chart review including patients of all ages with a neurosurgical disease or injury presenting to Mbarara Regional Referral Hospital (MRRH) between January 2012 to September 2015. Descriptive statistics were presented. A univariate analysis was used to obtain the odds ratios of mortality and 95% confidence intervals. Predictors of mortality were determined using multivariate logistic regression model.

Results:

A total of 1876 charts were reviewed. Of these, 1854 (had complete data and were?) were included in the analysis. The overall mortality rate was 12.75%; the mortality rates among all persons who underwent a neurosurgical procedure was 9.72%, and was 13.68% among those who did not undergo a neurosurgical procedure. Over 50% of patients were between 19 and 40 years old and the majority of were males (76.10%). The overall median length of stay was 5 days. Of all neurosurgical admissions, 87% were trauma patients. In comparison to mild head injury, closed head injury and intracranial hematoma patients were 5 (95% CI: 3.77, 8.26) and 2.5 times (95% CI: 1.64,3.98) more likely to die respectively. Procedure and diagnostic imaging were independent negative predictors of mortality (P <0.05). While age, ICU admission, admission GCS were positive predictors of mortality (P <0.05).

Conclusions:

The majority of hospital admissions were TBI patients, with RTIs being the most common mechanism of injury. Age, ICU admission, admission GCS, diagnostic imaging and undergoing surgery were independent predictors of mortality. Going forward, further exploration of patient characteristics is necessary to fully describe mortality outcomes and implement resource appropriate interventions that ultimately improve morbidity and mortality.

Social-Cognitive Determinants of Success in Online Communities for Weight Management

Background: Online communities may be an effective, convenient, and relatively inexpensive intervention platform for individuals seeking assistance with weight management. Recent research suggests that these communities may be as effective as in-person treatments for weight management; however, very little is known about the characteristics that predict weight loss amongst those using an online community. Methods: Within a social-cognitive framework, we sought to identify the psychosocial characteristics that are associated with successful weight management for users of MyFitnessPal, a popular online community for weight management. We recruited participants who were new to the online community and asked them to complete 2 surveys (one at baseline and one 3 months later) that assessed various psychosocial constructs as well as self-reported height and weight. Results: Participants in our sample reported losing, on average, 4.55 kg during the 3-month time period. We found that engaging in weight control behaviors (e.g., monitoring food intake, weighing oneself, etc.) fully mediated the relationship between several of our variables of interest (i.e., baseline self-efficacy and perceived social support within the community) and weight loss. We also found that participants who expected to lose more weight at baseline were significantly more likely to have lost more weight at follow-up. Conclusions: On average, participants in our study lost a clinically meaningful amount of weight. Predictors of weight loss within this community included perceived support within the community (mediated by weight control behaviors), baseline self-efficacy (mediated by weight control behaviors), and baseline outcome expectations. Results of this study can ultimately serve to inform the design of future eHealth interventions for weight management.

Statistically robust representation and comparison of mortality profiles in archaeozoology

Archaeozoological mortality profiles have been used to infer site-specific subsistence strategies. There is however no common agreement on the best way to present these profiles and confidence intervals around age class proportions. In order to deal with these issues, we propose the use of the Dirichlet distribution and present a new approach to perform age-at-death multivariate graphical comparisons. We demonstrate the efficiency of this approach using domestic sheep/goat dental remains from 10 Cardial sites (Early Neolithic) located in South France and the Iberian Peninsula. We show that the Dirichlet distribution in age-at-death analysis can be used: (i) to generate Bayesian credible intervals around each age class of a mortality profile, even when not all age classes are observed; and (ii) to create 95% kernel density contours around each age-at-death frequency distribution when multiple sites are compared using correspondence analysis. The statistical procedure we present is applicable to the analysis of any categorical count data and particularly well-suited to archaeological data (e.g. potsherds, arrow heads) where sample sizes are typically small.

Looking for Determinants of Ontological Security in the Spain of the Crisis

The concept of ontological security has a remarkable echo in the current sociology to describe emotional status of men of late modernity. However, the concept created by Giddens in the eighties has been little used in empirical research covering various sources of risk or uncertainty. In this paper, a scale for ontological security is proposed. To do this, we start from the results of a research focused on the relationship between risk, uncertainty and vulnerability in the context of the economic crisis in Spain. These results were produced through nine focus groups and a telephone survey with standardized questionnaire applied to a national sample of 2,408 individuals over 18 years. This work is divided into three main sections. In the fi rst, a scale has been built from the results of the application of different items present in the questionnaire used. The second part explores the relationships of the scale obtained with the variables further approximate the emotional dimensions of individuals. The third part observes the variables that contribute to changes in the scale: These variables show the structural feature of the ontological security.

Mindfulness and Spirituality as determinants of Existential Loneliness in the Dutch

Existential loneliness is a concept that is largely ignored in the psychological research tradition, although from a philosophical perspective it is deeply connected to inherent human longings of connection and meaning. This research investigated the relationship between existential loneliness and two variables that are theoretically closely related to the concepts of connection and meaning, namely mindfulness (connection to oneself and others) and spiritual well-being (connection to a larger whole). This was done in a sample of n = 180 individuals (61.7% female; mean age 41.72, SD = 12.16) of the Dutch population. A multiple regression analysis was conducted. It can be concluded that there is a negative relationship between mindfulness and existential loneliness, as well as between spiritual well-being and existential loneliness. This means that people with a higher level of mindfulness and/or a higher level of spiritual well-being experience a lower level of existential loneliness. At the same time, people with a lower level of mindfulness and/or spiritual well-being experience a lower level of existential loneliness. There are some limitations to this study, for example the use of a non-random sampling method, a limited sample group, a scale that has not been widely tested, and a potential bias towards the higher educated. However, these limitations are inherent to exploratory research and does not diminish the main strength of this thesis, namely that it has provided more insight into an important and prevalent societal phenomenon, that had not been extensively researched previously, that has so far only been addressed in more philosophical instead of scientific debates, and linked almost exclusively to negative concepts, such as terminal illness. This research provides a first understanding of two positive determinants of existential loneliness, which could potentially be used to help make sense of this inherently humane condition, as well as to actively cope with the potential (adverse) effects of it.

Novel Genetic Determinants of Diabetic Kidney Disease

Diabetic kidney disease (DKD) is a devastating diabetes complication, with known heritability not fully revealed by previous genetics studies. We performed the largest genome-wide association study of type 1 DKD to date, in a 13-cohort consortium of 15,590 individuals of European ancestry genotyped on the Illumina HumanCoreExome Beadchip, which allows exploration of coding variation in addition to genomic markers.

As prior work has shown that different characterizations of the DKD phenotype highlight distinct genetic associations, we investigated a spectrum of DKD definitions based on proteinuria and renal function criteria. Controls were DKD-free after a minimum of 15 years diabetes duration; cases had diabetes for at least 10 years prior to DKD diagnosis. We also performed a quantitative trait analysis of estimated glomerular filtration rate in all participants.

Our top finding was a missense mutation in COL4A3, rs55703767 (Asp326Tyr); the minor allele is common in Europeans (20%) and East Asians (13%) but not Africans (2%). This SNP had a genome-wide significant association with traditionally defined DKD (macroalbuminuria or end-stage renal disease [ESRD], (OR= 0.79, P=1.9×10-9), and a suggestive association with macroalbuminuria (OR= 0.79, P=1.6×10-6) and ESRD (OR= 0.79, P=4.5×10-5) individually. Though its PolyPhen score is 0.3 (benign), this SNP has been implicated as a splice site disruptor.

The COL4A3 gene encodes the alpha 3 subunit of Type IV collagen, the major structural component of basement membranes. Pathogenic mutations in COL4A3 have been identified in thin basement membrane nephropathy, familial focal segmental glomerulosclerosis, and Alport syndrome. A proxy (r2=0.6) for rs55703767 had no significant associations in the CKDGen consortium, suggesting its pathogenicity occurs solely in the setting of hyperglycemia.

By significantly increasing sample size we have discovered a novel locus underlying DKD risk, paving the way for better understanding of pathology, prevention, and treatment.

Insight into determinants of substrate binding and transport in a multidrug efflux protein

Multidrug resistance arising from the activity of integral membrane transporter proteins presents a global public health threat. In bacteria such as Escherichia coli, transporter proteins belonging to the major facilitator superfamily make a considerable contribution to multidrug resistance by catalysing efflux of myriad structurally and chemically different antimicrobial compounds. Despite their clinical relevance, questions pertaining to mechanistic details of how these promiscuous proteins function remain outstanding, and the role(s) played by individual amino acid residues in recognition, binding and subsequent transport of different antimicrobial substrates by multidrug efflux members of the major facilitator superfamily requires illumination. Using in silico homology modelling, molecular docking and mutagenesis studies in combination with substrate binding and transport assays, we identified several amino acid residues that play important roles in antimicrobial substrate recognition, binding and transport by Escherichia coli MdtM, a representative multidrug efflux protein of the major facilitator superfamily. Furthermore, our studies suggested that 'aromatic clamps' formed by tyrosine and phenylalanine residues located within the substrate binding pocket of MdtM may be important for antimicrobial substrate recognition and transport by the protein. Such 'clamps' may be a structurally and functionally important feature of all major facilitator multidrug efflux proteins.

Determinants of Capital Structure of Swedish limited companies : Testing Trade-off Theory Against Pecking Order Theory

Research question- This thesis investigates the determinants of capital structure of the Swedish companies. In order to do so, the two dominant theories of the corporate structure are studied and their assumptions are tested. Thus, the study researches which one of the two theories is more appealing for the Swedish market. Methodology-The study follows a purely quantitative study, by conducting an econometric analysis. The data are collected from a secondary source and more particularly the "Retriever" database, which contains financial data of the Swedish companies. Findings- The findings indicate that the determinants of the corporate structure for the Swedish market do not differ from other studies which have been conducted in other countries. However, there is a difference when it comes to tax and non-tax shields. The results suggest that in most cases the Pecking Order Theory appears to be more representative for the Swedish market, since most of the coefficient appear to be in favour of it. Moreover, the significance of the effect of the industry for the financial leverage is confirmed.

Making life better: Monitoring the wider social determinants of health and well being - key indicators 2015

This report monitors progress against the key indicators of Northern Ireland’s public health strategy ‘Making Life Better’ launched by the Department of Health, Social Services & Public Safety (DHSSPS) in 2014. In addition to presenting the revised baseline positions for each of the key indicators of the framework, the report also monitors progress against each indicator by comparing the latest position with the baseline.

Hepatocyte determinants of susceptibility to pre-erythrocytic Plasmodium infection

Thesis (Ph.D.)--University of Washington, 2016-08

Is "football for all" safe for all? : Cross-Sectional Study of Disparities as Determinants of 1-Year Injury Prevalence in Youth Football Programs

Football (soccer) is endorsed as a health-promoting physical activity worldwide. When football programs are introduced as part of general health promotion programs, equal access and limitation of pre-participation disparities with regard to injury risk are important. The aim of this study was to explore if disparity with regard to parents' educational level, player body mass index (BMI), and self-reported health are determinants of football injury in community-based football programs, separately or in interaction with age or gender. Methodology/Principal Findings Four community football clubs with 1230 youth players agreed to participate in the cross-sectional study during the 2006 season. The study constructs (parents' educational level, player BMI, and self-reported health) were operationalized into questionnaire items. The 1-year prevalence of football injury was defined as the primary outcome measure. Data were collected via a postal survey and analyzed using a series of hierarchical statistical computations investigating associations with the primary outcome measure and interactions between the study variables. The survey was returned by 827 (67.2%) youth players. The 1-year injury prevalence increased with age. For youths with parents with higher formal education, boys reported more injuries and girls reported fewer injuries than expected; for youths with lower educated parents there was a tendency towards the opposite pattern. Youths reporting injuries had higher standardized BMI compared with youths not reporting injuries. Children not reporting full health were slightly overrepresented among those reporting injuries and underrepresented for those reporting no injury. Conclusion Pre-participation disparities in terms of parents' educational level, through interaction with gender, BMI, and self-reported general health are associated with increased injury risk in community-based youth football. When introduced as a general health promotion, football associations should adjust community-based youth programs to accommodate children and adolescents with increased pre-participation injury risk.

A systematic review of methods to assess intake of fruits and vegetables among healthy European adults and children: a DEDIPAC (DEterminants of DIet and Physical Activity) study

Evidence suggests that health benefits are associated with consuming recommended amounts of fruits and vegetables (F&V), yet standardised assessment methods to measure F&V intake are lacking. The current review aims to identify methods to assess F&V intake among children and adults in pan-European studies and inform the development of the DEDIPAC (DEterminants of DIet and Physical Activity) toolbox of methods suitable for use in future European studies. A literature search was conducted using three electronic databases and by hand-searching reference lists. English-language studies of any design which assessed F&V intake were included in the review. Studies involving two or more European countries were included in the review. Healthy, free-living children or adults. The review identified fifty-one pan-European studies which assessed F&V intake. The FFQ was the most commonly used (n 42), followed by 24 h recall (n 11) and diet records/diet history (n 7). Differences existed between the identified methods; for example, the number of F&V items on the FFQ and whether potatoes/legumes were classified as vegetables. In total, eight validated instruments were identified which assessed F&V intake among adults, adolescents or children. The current review indicates that an agreed classification of F&V is needed in order to standardise intake data more effectively between European countries. Validated methods used in pan-European populations encompassing a range of European regions were identified. These methods should be considered for use by future studies focused on evaluating intake of F&V.