Thesis (M.D.)--University of Hong Kong, 1992.

Thesis (M.D.)--University of Hong Kong, 1992. / Also available in print.

Thesis (Ph. D.)--University of Hong Kong, 2000. / Includes bibliographical references (leaves 149-168).

published_or_final_version / Medicine / Master / Doctor of Medicine

Background: Globally, the number of adolescents living with perinatally-acquired HIV continues to rise including in Malawi. To date, this group has received relatively less attention in the field of HIV care; yet they are increasingly surviving into adulthood. There is a growing need for the development of appropriate care and support services for this group; however their sexual and reproductive health (SRH) needs remain poorly addressed. Research Aim: This study aimed to explore perinatally-infected young women’s experiences of growing up with HIV in order to understand their SRH outcomes within their wider socio-cultural and structural context. Methods: A qualitative case study design was adopted whereby each ‘case’ comprised a female adolescent (15-19 years), a nominated caregiver and a service provider. Data was collected for 14 cases through in-depth interviews. The interviews with adolescents were based on an innovative visual method known as ‘my story book’. Results: The study found that young women endured multiple losses that negatively impacted upon their sense of self and belonging. Emotional, material and social support were essential in helping them to build a sense of identity, but their access to such resources was highly variable. Young women’s strategies to seek love, acceptance or support often led them to take sexual risks and left them with little control over their reproductive health. Both the service providers and caregivers often ‘turned a blind eye’ to young women’s sexual activities, leading to poor SRH outcomes. Lack of open discussion on SRH issues was related to cultural and religious norms hindering young women’s access to information and contraception. Conclusion: Addressing the complex needs of the young women poses a key challenge for Malawi’s HIV services. One way forward is to explore ways in which services could develop integrated models of care, offering a ‘one-stop shop’ to this vulnerable group.

Hepatitis C virus (HCV) causes acute and chronic liver diseases in humans. Its two envelope proteins, E1 and E2, are heavily glycosylated. They interact with host cell receptors and provide a target for host immune recognition. The host virus interactions determine the pathogenesis and outcome of HCV infection. L-ficolin is a soluble pattern recognition molecule of importance in innate immune defence against microorganisms. It activates the lectin complement pathway upon binding to carbohydrate recognition patterns on microorganisms. It was hypothesised that L-ficolin could interact with HCV glycoproteins. Both recombinant and serum derived L-ficolin were investigated for binding to the envelope glycoprotein E1E2 of HCV. Specific, dose-dependent binding of L-ficolin to HCV glycoprotein E1E2 was observed. The interaction between L-ficolin and HCV particles in infected sera was also demonstrated. Binding of L-ficolin to HCV pseudoparticles expressing E1E2 glycoproteins resulted in neutralisation of virus infectivity. The serum L-ficolin level was significantly higher in patients with mild HCV liver fibrosis compared to patients with severe HCV liver fibrosis. These results suggest a potential protective effect of L-ficolin, as an innate immune defence, against HCV infection. To study the role of anti-HCV E1 and E2 (anti-E1E2) in HCV disease, the levels of anti-E1E2 antibodies were evaluated in 230 sera of patients with chronic hepatitis C by enzyme-linked immunosorbent assay. The antigens used were recombinant HCV glycoproteins derived from genotype 1 (H77c) and genotype 3 (UKN3A1.28). Seroreactivity was greater when sera were tested against antigen derived from their homologous genotype than against heterologous antigen. The seroreactivity was inversely proportional to the viral load and to the degree of liver fibrosis. These results demonstrate that seroreactivity against E1E2 depends upon the genotypic origin of the E1E2 antigens and the infecting genotype, and suggest a possible protective effect of anti-E1E2 against disease progression.

Helicobacter pylori is regarded as the most important risk factor for peptic ulcer disease and gastric cancer. In Kurdistan region, northern Iraq, gastric cancer is rare (5/100,000). To investigate some possible reasons for this, the prevalence of H. pylori infection, gastric mucosal histopathological changes in H. pylori infected subjects, and virulence factor genotypes (especially dupA) of colonising strains were studied. The immune response to H. pylori infection, focusing on genes associated with T-helper (Th) and regulatory T-cell (Treg) cells, was also investigated. It was found that 79% of 163 adults and 37% of 120 children were seropositive for H. pylori (p<0.0001). For infected people, gastric lymphocyte infiltration was more prominent in the antrum (p=0.01). 71% of Iraqi H. pylori strains were positive for cagA and its presence was significantly associated with peptic ulcer disease (PUD) (p<0.01). cagA genes encoding four or more tyrosine phosphorylation motifs could not be found in any of the Iraqi strains. Isolates possessing the i1 form of vacA were significantly associated with GU (p<0.02). 32% of Iraqi H. pylori isolates were dupA-positive and presence of this gene was associated with PUD (p<0.01). The levels of IFNγ, IL-12 p35, IL-10, IL-4 and FOXP3 mRNA were found to be elevated in gastric mucosal samples from H. pylori-infected patients compared to those from H. pylori-negative patients (median increase 7-fold p=0.001; 17-fold p=0.002; 1320-fold p=0.001; 1184-fold p=0.001; and 3-fold p=0.01, respectively), indicating a predominant IL-4 and IL-10 (Th2) response. Interestingly, IFNγ mRNA levels were 16-fold higher in tissues taken from 17 infected smokers than found in tissues taken from 18 infected non-smokers (p=0.009). IL-4 mRNA levels in tissues from 20 infected females were 40-fold higher than in tissues from 15 males (p=0.005). Nucleotide sequencing of the dupA 3' region from 32 strains showed that dupA commonly had additional single base insertions or deletions that either truncated or extended the open reading frame (ORF). We have therefore classified dupA into two main groups: the common extended ORF within jhp0917-19 (dupA1), and dupA with an early stop codon to truncate the ORF (dupA2). ELISA performed on supernatants from H. pylori-infected gastric epithelial cell lines found no significant differences in IL-8 production between strains that possessed or lacked dupA. In comparison to wild-type H. pylori, disruption of dupA significantly reduced IL-12, IFNγ, TNFα and IL-8 production by peripheral blood mononuclear cells (PBMCs) in 2/4 strains. For the remaining 2 strains, where gene sequencing revealed a frame shift resulting in truncated dupA in the wild-type, the level of these cytokines was unchanged by dupA mutation. H. pylori infection is common in Kurdistan region and acquired at a young age. The low cancer rate may be partially explained by a predominant lymphocyte infiltration in the antrum rather than the corpus, which has been reported to be associated with reduced risk of gastric adenocarcinoma. An absence of the more toxic cagA genotype with four or more tyrosine phosphorylation motifs in the Iraqi strains, and the predominance of Th2 cytokine expression rather than a more pro-inflammatory Th1 response to H. pylori could also contribute to a reduced incidence of cancer. dupA1 appears to play an important role in promoting the inflammatory response of leukocytes to H. pylori.

<p>The prevalence of non-communicable diseases such as hypertension and diabetes including obesity has increased among the black population over the past few years. The increase in these diseases has been associated with increased urbanization and lifestyle changes. No studies have documented the experiences of people who have migrated to urban areas. Aim: To describe the type of lifestyle changes, reasons for the lifestyle changes and the barriers to adopting a healthy lifestyle among people who have migrated from rural areas to urban areas in the past 5 years and reside in Khayelitsha. Objectives: (1) To identify people who have moved from rural to urban areas in the past 2-5 years / (2) To explore reasons for moving to the city / (3) To explore experiences of respondents on moving to the city / (4) To identify the types of lifestyle changes related to chronic diseases among respondents on arrival to the city / (5) To identify reasons for the lifestyle changes among respondents / (6) To identify coping strategies that have been adopted by respondents / (7) To identify barriers to healthy lifestyle among respondents / (8) To make recommendations for development of appropriate interventions that will enable migrating populations to adjust better to city life.</p> <p>Rural-urban migration (urbanization) was associated with factors such as seeking employment, better life and working opportunities. On arrival in the city migrants face a number of challenges such as inability to secure employment and accommodation. Faced with these challenges, migrants change their lifestyle including buying fatty foods, increasing frequency in food consumption and decreasing in physical activity. In the city factors such as poverty, environment including lack of infrastructure, and lack of knowledge about nutrition, social pressures and family preferences were identified as hindrances to a healthy lifestyle. Conclusion: This study identified various factors that influence the decision to migrate from rural areas. Lifestyle changes in an urban setting are due to socio-economic, environmental and individual factors. Perceived benefits of moving to urban areas can pose challenges to health and this may have negative health-outcomes.</p>

Community-acquired pneumonia (CAP) is a leading cause of adult morbidity and mortality worldwide despite decades of effective antibiotics and vaccination initiatives. There have been no recent significant improvements in outcomes, including 30-day mortality. The bacterium Streptococcus pneumoniae is the most prevalent causative pathogen in CAP, being found in up to half of cases. In September 2006 a childhood pneumococcal vaccine (PCV-7) was introduced, leading to reductions in vaccine-type (VT) pneumococcal disease in infants, with possible additional benefits reported in adults. However, the effect that infant PCV-7 vaccination has on adult disease has to date been inadequately described in a small fraction of patients with invasive CAP, almost exclusively in populations in the US. These issues are explored fully in the literature review, encompassing chapters 1, 2 and 3. New strategies for CAP are therefore required. The outcome of CAP can be improved by a) preventing the disease by vaccination and herd immunity, and b) ameliorating the course of the disease after it has been acquired. This thesis presents a collection of studies that aim to acquire observational data to investigate these two issues. The majority of the included studies are drawn from a two year prospective cohort study of consecutive adults with CAP admitted to a large UK teaching hospital trust between September 2008 and September 2010. After obtaining informed consent, the presence of pneumococcal disease in each participant was established by testing urine samples for pneumococcal capsular polysaccharide, a test which has a high sensitivity and specificity. The urine samples were subsequently tested for pneumococcal serotype. A full record of care processes, investigations, and clinical outcomes was made, and child contact in the month preceding admission was assessed. These methods are described more fully in chapter 4. Chapter 5 presents the data on the pneumococcal serotypes found in the cohort over a two year period, and links them to epidemiological characteristics in the study population. The most prevalent serotypes were 14, 1, 8, 3 and 19A, with VT serotypes less frequent in the second year of the study. Chapter 6 examines the association that infecting serotype has with disease manifestation and patient characteristics. Infection with a serotype not contained within PCV-7 (NVT) was associated with younger and fitter patients, a higher rate of complications such as para-pneumonic effusion, and hypotension at admission. The effect of child contact on pneumococcal disease is reported in chapter 7. Prior contact with a child aged ≤8 years was particularly associated with pneumococcal aetiology, and contact with a PCV-7 vaccinated child independently associated with NVT CAP. The findings from these three chapters are unique in that they relate individual pneumococcal serotype to specific clinical disease patterns, epidemiology and transmission in both invasive and non-invasive pneumococcal CAP for the first time. They show a change in serotype distribution in adults following the introduction of PCV-7 in infants, which is important to inform future vaccine development for both adults and children. Furthermore, different serotypes are associated with different clinical disease patterns, which may have a significant impact on the disease that clinicians see at the “front door” given that the serotype distribution of pneumococcal CAP may be changing. Finally, the link between child vaccination and adult disease provides more direct evidence for the transmission of pneumococci from children to adults as a mechanism for the development of CAP in adults. The second part of this thesis looks at current care processes, and how these might be improved. Chapters 8, 9 and 10 relate to efforts to better predict prognosis, and chapters 11 and 12 with how patents with CAP may be better managed at the “front door”. Symptoms are clearly important to patients, but the role of symptoms in management and outcome is unclear. Chapter 8 presents a study validating a symptom score that has not yet entered routine use, but which is shown to correlate with clinical outcomes, and may be useful in assessing outcome in low severity CAP. The influence that oxygenation status at admission has on outcome is poorly understood. Chapter 9 describes a study showing that whilst hypoxaemia does positively predict adverse outcome, it is not as predictive as existing severity scores. The presence of hypoxaemia may however identify a subset of patients who are classified as low severity by existing severity scoring, but are nevertheless at increased risk of adverse outcome. Severity scoring is the cornerstone of management in adult CAP, and is explored in chapter 10. Current severity scores adequately predict mortality in CAP, but often generate a group of “moderate severity” where appropriate management is often unclear. This study looked at the effect of pre-admission functional status on outcome in conjunction with existing severity scores in this difficult group, and validated a novel severity score for predicting need for escalation of care, SMART-COP. Incorporation of functional status does marginally improve the performance of existing severity scores, but may be of more use as a post-severity score test to identify sub-groups of patients with moderate severity CAP who are at increased risk of death. Chapter 11 looks at the influence that making a prompt diagnosis (rather than prompt treatment with antibiotics, as has previously been studied) has on outcome, using the time between admission and first chest radiograph as a surrogate measure. Whilst an early chest radiograph was not associated with an improvement in mortality, it was associated with a shorter length of hospital stay, and may therefore be regarded as a marker of good quality care. There is current debate as to the role of the speciality physician in the front-door early assessment of patients, and whether early review of patients with CAP may improve outcome compared with management by a non-specialty physician. Chapter 12 looks at the effect that early specialist senior respiratory review has on outcome for adults with CAP, showing a clear benefit on length of hospital stay to early consultant review. In conclusion, this thesis provides an up-to-date picture of the circulating pneumococcal serotypes in non-invasive adult CAP, and correlates infecting serotype to clinical and epidemiological parameters. It also identifies five areas of clinical care where management processes could be improved. By addressing of these aspects the outcome of CAP may be improved in the future.

The epidemiology and natural history of Hepatitis C has been studied in a large geographically determined population (Trent HCV study). It has previously been suggested that patients with Hepatitis C and a persistently normal Alanine aminotransferase (PNALT) represent a group of patients with mild disease and at low risk of disease progression. Patients with PNALT were, therefore, compared to those with an elevated ALT. The majority of patients initially fulfilling the definition of a PNALT had an abnormal ALT within 3 years of follow-up. They also demonstrated similar rates of fibrosis progression as a sub-group of HCV infected patients with an elevated ALT who were re-biopsied prior to any institution of therapy. They, therefore, warrant the same consideration with regard to treatment. The morbidity and mortality associated with Hepatitis C with severe fibrosis was assessed in a group of patients with a liver biopsy demonstrating Ishak fibrosis stage  4. A worse prognosis than previously reported was observed for this patient population. Once decompensation develops, HCV infection is associated with a high mortality rate. Indicators of poor synthetic liver function and hypergammaglobulinaemia were important prognostic factors for mortality, while combination antiviral therapy was associated with improved survival. The majority of HCV infected patients (75%) diagnosed with hepatocellular carcinoma (HCC) were known to have cirrhosis at least 6 months prior to diagnosis of HCC and were, therefore, amenable to surveillance. There was a variable application of surveillance, however, and no significant improvement in survival was demonstrated. Age, duration of infection and immunoglobulin G levels were associated with an increased risk of HCC in cirrhotic patients in the univariate analysis. Achieving an SVR was associated with a reduced risk. No variable in cirrhotic patients was shown to be independently associated with HCC in the multivariate analysis. A comparison of disease progression and treatment outcome in White and Asian (Indian subcontinent) patients was made. Asian patients generally presented at an older age and with more severe disease on biopsy. The patient’s ethnic group was not associated with the likelihood of either an SVR or completion of therapy. Instead cirrhosis and a raised GGT were associated with a failure to achieve SVR in the multivariate analysis. The platelet count is a surrogate marker for the severity of liver fibrosis and correlates with the Ishak fibrosis stage. An analysis of factors associated with an SVR was performed. In the multivariate model, age at start of treatment was the only independent predictor of SVR in Genotype 1, while estimated duration of infection and Ishak stage were predictors in genotype 2/3 patients. The platelet count was not an independent predictor of SVR or completion of therapy.