published_or_final_version / Medicine / Master / Doctor of Medicine

published_or_final_version / Nursing Studies / Master / Master of Nursing

published_or_final_version / China Development Studies / Master / Master of Arts in China Development Studies

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.

The human non-integrin laminin receptor (LamR) is a multifunctional protein which is localised to a number of sub-cellular locations. LamR is a component of the ribosome and has a number of intracellular functions; it also acts as an extracellular receptor for laminin, growth factors, pathogenic microorganisms, prion proteins, toxins and the anticarcinogen epigallocatechin gallate (ECGC). Although LamR is present in most cellular compartments, its overexpression in many types of cancer cells suggests a vital role for LamR in tumor-cell migration and invasion. There are two isoforms of laminin receptor: the monomeric 37-kDa laminin receptor precursor (37LRP) and the mature 67-kDa laminin receptor (67LR). Although the precise molecular nature of 67LR is unclear, accumulating evidence strongly suggest that 37LRP can undergo homo- and/or hetero-dimerization with Galectin-3 (Gal-3) to form mature 67LR. A recent study demonstrated that both homo- and heterodimer LamR forms are present on the cell surface, where they form distinct populations. Neisseria meningitidis, Streptococcus pneumoniae and Haemophilus influenzae type b (Hib) are major causes of bacterial meningitis. The contribution of LamR in traversal of the blood brain barrier (BBB) by neurotropic viruses is well established and interaction with LamR was recently found to be critical for initiation of bacterial contact with the blood brain barrier (BBB). These bacteria bind LamR via the surface protein adhesins: meningococcal PilQ and PorA; pneumococcal CbpA; and H. influenzae OmpP2. Further investigations showed that the fourth and second extracellular loops of meningococcal PorA and OmpP2 of H. influenzae, respectively, are responsible for LamR binding. The work presented here consists of two complementary projects in which a number of approaches were taken to characterise the ligand-binding domains of LamR. The first project aimed to identify sites on LamR that are critical for binding the ligands of bacterial meningeal pathogens. The second project aimed to identify residues that contribute to the stability of LamR homodimers and the heterodimer with Gal-3. Several mutations were introduced into full-length human LamR, either by deletion mutations within the C-terminal domain (CTD) of LamR using inverse polymerase chain reaction (IPCR), or by single-amino acid substitution in the N-terminal domain (NTD) of LamR using site-directed mutagenesis. Protocols for large-scale expression of full-length and truncated LamR proteins in human cells were developed, as well as non-denaturing purification protocols. We hypothesised that bacteria-binding domains could be located on both the NTD and CTD of LamR. In vivo examination using ELISA assays, in which the interaction of LamR and whole bacteria or purified recombinant PorA or PilQ were tested identified several novel sites on LamR that contributed significantly to binding of the bacterial ligands. These sites include amino acids 206-229 and 263-282, located within the CTD, and Tyrosine 156 in the NTD, each of which contributed to the binding of meningococcal PorA, and more specifically it’s fourth extracellular loop. Furthermore, three sites on LamR comprising amino acids 206-229 and 263-282 within the CTD and Tyrosine 139 in the NTD were shown to contribute to binding pneumococcal CbpA, OmpP2 and Loop two of OmpP2 of H. influenzae. These results indicate that the three neuroinvasive bacteria share the same binding sites on LamR. Bimolecular fluorescence complementation (BifC) coupled with flow cytometry and confocal microscopy revealed the vital contribution of amino acid residues Arginine 155, Tyrosine 156 and Lysine 166 (all within the NTD of LamR) for the homodimerization and heterodimerization of LamR with Gal-3. The dimerization of two meningococcal host receptors, LamR and Gal-3, may help to extend spectrum of their bacterial adhesins, which may act cooperatively or synergistically at different stages of infection. Information about the residues in LamR that contribute to the stabilization of LamR dimers has implications for the role of LamR dimers in the pathogenesis of bacterial meningitis. Identification of bacteria-binding domains on LamR is of particular interest for development of vaccines or therapeutic interventions that provide protection against the three major meningitis-causing bacteria. The aim of the current work was first to localise the domains of LamR responsible for binding with PorA and PilQ of N. meningitidis; CbpA and OmpP2 of S. pneumonia, and OmpP2 of H. influenzae. Also, previous studies have shown conspicuous homodimerisation of 37LRP and heterodimerisation with Gal-3. Our second aim was to identify of amino acid residues involved in 37LRP self-association and heterodimer formation with Gal-3. In current work, several regions of LamR were hypothesised to constitute the binding site for the bacterial ligands; these predictions were based on previous studies on LamR binding domains and the crystal structure of laminin receptor. Also, to investigate both homo and heterodimerisation of LamR, the involvement of several putative amino acid residues within 37LRP in LamR dimerisation was was hypothesised.

Homoeoprophylaxis (HP) is the use of homoeopathically prepared substances to prevent targeted infectious diseases in recipients. Its first use in an epidemic of Scarlet Fever was documented in 1801. It has been used throughout the world since then for both short-term and long-term preventative purposes. The effectiveness and safety of Golden�s long-term HP program using homoeopathically prepared substances to prevent targeted infectious diseases in recipients was tested through two research projects. The effectiveness of the program could not be established with statistical certainty given the limited sample size and the low probability of acquiring an infectious disease. However, a possible level of effectiveness of 90.3% was identified subject to specified limitations. Further research to confirm the effectiveness of the program is justified. Statistically significant results were obtained that confirmed the safety of the program both in absolute terms as well as compared to all other methods of disease prevention studied. It also appeared possible that a national immunisation system where both vaccination and HP were available to parents would increase the national coverage against targeted infectious diseases, and reduce the incidence of some chronic health conditions, especially asthma.

Thesis (Ph. D.)--UCLA, 2009. / Vita. Description based on print version record. Includes bibliographical references (leaves 232-267).

Infection with hepatitis C virus (HCV) is cleared spontaneously in only 20% of cases with the majority of individuals developing a chronic infection. This discrepancy in disease outcome is incompletely understood but current understanding of the immune response to HCV suggests that rapid induction of a broadly neutralising antibody (nAb) response leads to resolution of acute infection. The majority of nAb identified target the envelope glycoproteins, particularly E2, and most appear to inhibit binding of E2 to the cellular receptor CD81. Antibodies targeting other interactions, such as those with the receptor CLDN or the fusion determinant, are underrepresented in the repertoire of anti-HCV antibodies. However, the antibody discovery process may have been biased by the nature of the assays used. Therefore new assays are needed to enable the discovery and characterisation of antibodies in an unbiased manner. To facilitate this, a novel insect cell display library was developed for mapping antibody-binding epitopes. Cells expressing specific E2 mutants provided the necessary proof-of-principle that loss of antibody binding could be detected in this system before a library expressing randomly mutated E2 was developed. Sorting experiments demonstrated that single cells could be isolated and enriched based on loss of antibody binding. Secondly, a method for characterising the immunoglobulin (Ig) genes of HCV infected patients was developed; Ig genes were isolated from small numbers of B cells and the sequences analysed. Finally, a patient cohort was studied with a view to investigating the evolution of the antibody response during early infection. The unreliable nature of the samples prevented such analysis; however a DNA fingerprinting method of testing the origin and relatedness of serum samples was developed. This will improve the reliability of future studies. Together these methods provide a work model for the assessment of samples and the isolation and characterisation of antibodies.

This thesis is a study-of the contribution of public health administration to the control of Infectious diseases in Fife during the period c. 1855-1950. It is a local study in the social history of medicine which attempts to test the conflicting theories of Thomas McKeown and Simon Szreter about the role of social intervention in mortality decline during the period. It covers the period from the earliest date when civil registration data on mortality from specified causes are available for Fife. During this period mortality from the main infectious diseases in the county declined almost continuously and by 88% from a rate of 608 deaths per 100 000 inhabitants during the years 1855-60. Public health administration is here defined as measures for disease prevention and control administered by local government. Such measures include the provision of adequate water supplies and drainage, improvement of housing, port sanitation, immunisation and the provision of infectious diseases hospitals and child welfare services. The first three chapters of this study include an introduction, a description of the geographical, demographic and economic conditions in Fife during the period and a description of the development of a system of public health administration in the county. This is followed by studies of the main infectious diseases, including smallpox, typhus and typhoid, diarrhoeal disease, diphtheria, scarlet fever, measles and whooping cough, influenza and all forms of tuberculosis. The pattern of mortality from each disease in Fife is described. Then from the records of local authorities in the county, the role of public health administration in the attempted control of each disease is described and evaluated. The conclusion assesses the overall contribution of public health administration to the decline in mortality from the main infectious diseases in Fife and suggests the relative importance of different measures in the process of disease control.

Thesis (Ph. D.)--University of New South Wales, 1999. / Also available online.