Background: Hepatitis C virus infection affects more than 170 million people worldwide and is frequently associated with chronic liver disease and hepatocellular carcinoma. No protective vaccine is yet available and the current standard of care, consisting of pegylated interferon alpha and ribavirin, has limited efficacy. Ribavirin is a key component of any effective anti-HCV regimen. However, accumulation of ribavirin in the red cell compartment not only reduces drug efficacy as a result of diversion to extra-hepatic sites but also produces haemolytic anaemia which can lead to dose reduction or discontinuation of treatment. Lipid or polymer based nanoparticles can be used to deliver therapeutic agents, such as drugs or small interfering RNAs (siRNAs) directly to their site of action. We therefore elected to develop new antiviral strategies based on the targeted delivery of ribavirin to hepatocytes, coupled with the identification of new therapeutic targets. In order to inform the rational use of direct intracellular delivery of ribavirin, we enquired whether variation in expression of the ribavirin transporter may determine drug uptake and permit the identification of individuals who would benefit from these alternative approaches to treatment. Aims: The aims of this study were to: • identify host proteins involved in virus replication • demonstrate reduction of viral replication by modulation of host gene expression • develop and test a nanoparticle based system for the delivery of therapeutic molecules, including siRNAs either alone or in combination with ribavirin. • assess the relationship between ribavirin uptake by primary human hepatocytes and expression of ribavirin receptors Methods: A subgenomic HCV replicon system was established to study the virus-host relationship and identify host proteins supporting viral replication by using stealth siRNA. Viral RNAs were in vitro transcribed and transfected into Huh7 cells and expression assessed using engineered GFP as a reporter gene. siRNAs were co-transfected with viral RNAs using a nucleofector. Modulation of host gene expression was measured by both quantitative RT-PCR and protein blotting. Liposomal nanoparticles containing ApoB-100 duplexes were supplied by Lipoxen. Primary human hepatocytes were isolated by a modified two step collagenase perfusion method and cultured on collagen coated plates. HPLC and real time PCR conditions were used to measure and correlate drug uptake and receptor expression respectively. Equilibrative nucleoside transporter (ENT1) gene was analysed by direct sequencing. Results: A JFH1 (HCV genotype 2a) virus based subgenomic replicon system was successfully established. Using this model system, host proteins VAP-A and STAT3 were shown to positively regulate virus replication while ACTN1 had no effect. Liposomes failed to deliver either siRNA targeted at apoB-100 or ribavirin and this was found to be due to structural instability of the delivery vehicle. In contrast, fluorescently labelled liposomes were stable and could be taken up by human hepatocyte cell lines under optimised conditions. A protocol capable of efficient isolation and culture of hepatocytes from human donor was validated. Data from primary human hepatocytes show that ENT1 expression was highly variable in different sets of primary livers and correlated strongly with ribavirin uptake. Strikingly, Huh7 cells did not take up ribavirin despite expressing wild type ENT1. It was also found that interferon alpha does not modulate ENT1 expression and therefore ribavirin uptake, suggesting it to be a highly unlikely mode of synergism between the two drugs. Conclusion: Modulation of host proteins VAP-A and STAT3 inhibited viral replication, confirming that host genes can be used as a potential target to inhibit viral replication. Liposomes used in this study were, however, found to be ineffective vehicles for the delivery of ribavirin or siRNA, as the majority of drug leaked before cellular uptake. Polymer based nanoparticles are currently being assessed for antiviral drug delivery. Variation in ENT1 expression may account for differences in response rate in patients receiving anti-HCV therapy. Results in the Huh 7 cell line suggest that, while ENT1 is necessary, other factors are also required to mediate ribavirin uptake.

Pneumonia is a common diagnosis in general practice and is associated with significant morbidity and mortality. Current estimates of pneumonia incidence in the UK are based on studies more than a decade ago and little is known about longer term outcomes in pneumonia patients. Though much is known about the aetiology of pneumonia and predictors of mortality, an emerging area for research is the relationship between commonly prescribed drugs in general practice and pneumonia. The aims of this thesis were first, to determine overall incidence and mortality for pneumonia and how these vary by socio-demographic characteristics like age, sex, deprivation; and second, to investigate whether statins, angiotensin converting enzyme inhibitors (ACEIs) and gastric acid suppressants like proton pump inhibitors (PPIs) and histamine 2 receptor antagonists (H2RAs) modify the risk of acquiring pneumonia and its prognosis. This study used data from The Health Improvement Network (THIN) database, a longitudinal database of anonymised computerised medical patient records from 330 United Kingdom (UK) general practices at the time of data extraction in 2006. A cohort design was used to determine pneumonia incidence and mortality in the UK. Case-control, case-series and cohort study designs were used to investigate associations between the various drug exposures and pneumonia. The overall incidence of pneumonia was 237 per 100,000 person-years (95 % confidence interval (CI): 235 to 239) and this rate was stable between 1991 and 2003. Pneumonia was more common in men and in children under the age of four years and adults over the age of 65 years. There was an increased incidence of pneumonia with higher levels of socioeconomic disadvantage. Pneumonia cases showed much higher all-cause mortality as compared to the general population, both in the short and long-term and this increase was independent of underlying comorbidity. After adjusting for potential confounders, current prescriptions for statins and ACE inhibitors were associated with a significant reduction in the risk of acquiring pneumonia. Current prescriptions for PPIs were associated with an increased risk of pneumonia. With regards the impact on mortality: the use of statins was associated with a lower risk of short and long-term mortality following pneumonia whereas the use of ACEIs was associated with a decreased mortality risk only in the short-term. No relationship was observed between prescriptions for PPIs, H2RAs and pneumonia mortality. This study shows that caution must be exercised while prescribing proton pump inhibitors especially in patients known to be at high risk of pneumonia. There is also a potential role for statins in preventing pneumonia in at-risk patients and improving pneumonia outcomes but this will necessitate clinical trials to determine adequate dose, duration and safety profiles before any prescribing policy recommendations are made.

There are many surgical implanted devices in current use and all are prone to biomaterial-related infections (BRI) associated with staphylococcal biofilm formation. BRI are usually associated with S. epidermidis or S. Aureus and are characterized by treatment failure and chronicity resulting in reoperation, removal of the implant, and loss of function or death. Staphylococcal small colony variants (SCVs) may be generated by exposure to sublethal concentrations of antibiotics or nutrient limitation which may occur in biofilms. Although the characteristics of S. aureus SCVs have been well studied, little information on SCVs of S. epidermidis and their potential role in BRI is currently available. This study was designed to investigate the biochemical and phenotypic characteristics of S. epidermidis SCVs to further identify characteristics which may contribute to their ability to cause these increasingly important infections. Exposure to two to four times the gentamicin MIC led to the emergence of stable S. epidermidis SCVs, and the ability to produce SCVs was strain dependent. These variants were isogenic by PFGE and less immunogenic by western blotting, and SDS-PAGE analysis of whole cell preparations and cell wall fractions showed altered protein profiles when compared to wild type strains. S epidermidis SCVs were resistant to aminoglycosides such as amikacin and/or netilmicin and they were thiamine and/or menadione auxotrophs. Chemiluminescence assays showed a decreased ATP content reflecting the deficiency in electron transport systems which results in a growth rate – all characteristics similar to those of S. aureus SCVs. Analysis of virulence factor production indicated that S. epidermidis SCVs showed increased lipolytic and proteolytic activity when compared to those of S. aureus. Some S. epidermidis SCVs showed phase variation in exopolysaccharide production which enabled them to be more adherent to uncoated plastic -a property that may also be important for the later stages of development of biofilms. Invasion assays demonstrated that some S. epidermidis and S. aureus SCVs were internalised by HUVECs by a receptor-mediated mechanism which differed from that of the wild type strains. Interaction of staphylococci with HUVECs induced cytokine production but SCVs stimulated production of IL1, IL-6 and IL-8 at lower concentrations than their related wild type parents in the first 6 hours of co-incubation. SCVs were also less damaging to the HUVEC cell line after 24 hours when compared to wild type strains. This study supports the suggestion that a switch to the S. epidermidis SCV phenotype could be a mechanism exploited by the wild type strains to facilitate their survival inside the host. The chronicity and increased antibiotic resistance associated with BRI could in part, be explained by the characteristics of SCVs identified in this study. In particular the ability to survive intracellularly combined with reduced immunogenicity and resulting decreased cytokine production, may contribute to persistence of infection. Although SCVs are resistant to some antibiotics, surviving intracellularly may further protect staphylococci from other drugs which are unable to enter mammalian cells. Resistance may be further enhanced for some strains in biofilms where enhanced polysaccharide production may also limit antibiotic access.

Since discovery H. pylori has been one of the most intensively researched bacteria. Although the majority of those infected remain asymptomatic it can lead to serious diseases which carry significant morbidity and mortality. The most serious complication of H. pylori infection is gastric cancer and one of the most effective ways to reduce the associated mortality is to detect pre-malignant disease, as this develops in a step wise manner. Using advanced endoscopy is one way to detect pre-malignant conditions but due to the variety in endoscopic techniques and mucosal classifications the diagnosis is often dependent on histology. This work aimed to develop simple, accurate classification systems to detect H. pylori associated disease. The sensitivity and specificity of magnification Narrow Band Imaging for detecting H. pylori gastritis was 69% and 67%, intestinal metaplasia 87% and 97% and dysplasia 92% and 98% respectively. H. pylori is also associated with iron deficiency anaemia but the mechanisms remain unclear. In children it has been proposed that H. pylori disrupts iron regulatory mechanisms via the peptide hepcidin but this has not been extensively researched in adults. Serum hepcidin was significantly lower in H. pylori infected anaemic individuals and anaemic individuals without evidence of infection when compared to controls (9-fold, p=0.009 and 5-fold, p < 0.0001 respectively). These results are opposite to data from children, possibly explained by the presence of gastric atrophy. The cellular localisation of ferroportin was different in the H. pylori infected group which could be due to local cytokine production. Gaining a better understanding of this mechanism could aid the development of more targeted investigation and treatment. However, with regards to allergic and autoimmune conditions, there is growing evidence to suggest H. pylori is inversely associated. It is believed that any benefit associated with H. pylori is confined to childhood when the immune system is developing. A significant reduction was seen in IL10+ Tregs (p=0.0029) after successful eradication suggesting the removal of H. pylori may have systemic consequences on the immune system that are still not fully understood. This work has highlighted the use of endoscopic techniques to identify individuals at risk of disease. It has also described the effects of eradication on the immune system which potentially could have implications for individuals with allergic conditions with regards to eradication therapy.

In the human gastric mucosa, an inflammatory response stimulated by H. pylori infection can lead to gastric cancer and peptic ulcer disease. Expression of the i1 active variant of Vacuolating Cytotoxin A (VacA) by the colonising bacterial strain has been identified as an independent risk factor for disease. VacA skews the adaptive immune response towards a regulatory phenotype to promote persistent H. pylori colonisation. In H. pylori-infected individuals, regulatory T cells (Tregs), which suppress inflammation through mechanisms including interleukin-10 (IL-10) production, are thought to play a role in protection against extra-gastric diseases such as multiple sclerosis and oesophageal cancer. IL-10 is an immunomodulatory cytokine which is expressed by several immune cell types including regulatory B cells (Bregs), whose role in H. pylori infection is unclear. Blood was donated by uninfected and infected patients, and those who underwent successful eradication of their H. pylori infection. A flow cytometry antibody panel was developed to quantify the relative frequencies of peripheral blood Bregs and Tregs, and investigate differences according to H. pylori status. Mice were also infected with H. pylori to determine VacA i1 versus i2 differences in the induced regulatory B and T cell frequencies. Stool samples were collected from patients to develop a VacA i-region PCR-based diagnostic test. Results showed that compared to during H. pylori infection, the proportion of IL-10-producing Tregs in the peripheral blood of patients declined after successful eradication therapy. A pilot study in mice revealed B lymphocytes to be another important source of IL-10, and the population expanded after H. pylori infection. In a study of H. pylori-positive, H. pylori-negative and H. pylori-eradicated patients, there were no significant differences in peripheral blood Breg or IL-10+ Breg frequencies. Data from an expanded mouse study using blood and spleen showed that VacA variants in a colonising H. pylori strain did not induce differences in Breg or Treg frequencies 9 weeks after wildtype or mutant H. pylori SS1 infection. The H. pylori 16S gene was successfully detected in stool DNA samples and could be used to determine infection status, but the development of a vacA i-region PCR-based typing stool test was unsuccessful. Previous work in the research group has identified how Treg frequencies are associated with H. pylori infection and disease. While Bregs are capable of producing IL-10 after stimulation, their role in H. pylori infection in mice and humans appears to be limited. The consistency of peripheral blood Treg frequencies in patients from their infected state until two years post-eradication is a start to understanding whether H. pylori-induced extra-gastric protection may also be maintained after eradication. While stool remains a promising resource for non-invasively diagnosing H. pylori infection worldwide, there are strong concerns about contamination and reproducibility which are unlikely to be overcome for use in a clinical setting.

Background: After three decades, Human Immunodeficiency Virus (HIV) continues to pose significant threats globally. The efforts to curb the HIV epidemic have required investment in research, with clinical trials being a major focus, to develop HIV prevention, treatment, and cure interventions. A large portion of such research has been undertaken within low income settings, due to the high burden of HIV and the availability of willing volunteers within this setting. HIV research calls for the implementation of ethical research practice which is informed by policy guidelines. However, current policies are largely informed by inputs from high income countries, and lack the voices of those closely involved in research implementation. In order to contribute to ethics policy development in HIV research, it is essential to involve different stakeholders by exploring their experiences/views on the issue. Existing research in this field has mainly explored experience of recruitment and trial conduct, while very little has been done on trial closure, indicating a significant evidence gap worth exploring. This research therefore sought to illuminate, explore and understand the significant issues regarding the care of HIV positive drug trial participants during closure of HIV clinical trials, within a low income setting, specifically, Uganda. Study aim: The study aimed to explore how care is perceived and enacted in HIV drug trial closure in Uganda, by addressing the following specific objectives: 1. From the perspective of research participants and research staff, to explore the views, opinions and understandings of the ethical/legal/moral post-trial obligations in HIV drug trials. 2. From the perspective of research staff, to explore the experiences, practices and processes related to care for HIV drug post-trial participants in a low income setting. 3. From the perspective of research participants, to explore the experiences of care at trial closure. 4. From the perspective of research participants, to explore the experiences of transitioning from HIV research to care/community. Methodology: The study adopted an interpretive-constructivist approach, and employed a social constructivist grounded theory methodology. The study included a total of 21 trial participants and 22 research staff from three different HIV drug trials, in two Ugandan research institutions. In addition, relevant ethical documents were reviewed from two of the included trials. Data collection and analysis followed the principles of grounded theory, with data collection and preliminary analysis being undertaken concurrently, and earlier data informing subsequent data collection. Data collection strategies included individual interviews, focus group discussions, and key informant interviews. Data was collected over a period of 10 months, from October 2014 to August, 2015. NVivo10 software was used to manage the data. Ethical approval was received from the University of Nottingham UK and The AIDS Support Organization (TASO) Uganda, Research Ethics Committees (RECs). The study was registered with the Uganda National Council for Science and Technology (UNCST), as SS 3608. Permission to conduct the research was granted by the respective research institutions, and written informed consent was received from all respondents. Findings: The findings showed that trial closure was often stressful for HIV positive participants in Uganda, and often resulted in negative psychological, socio-economic and health impacts. The negative effects mainly resulted from being stopped from accessing research related health care, which was of a significantly higher quality, and the inability to find alternative care to match the research standards. The main concerns which arose during the transition process of participants from HIV drug trials to usual care facilities include: the loss of the quality care and valued relationships in research, the need to find and link to alternative care facilities, the need to meet the increased financial needs, and worries about the effects/outcomes of research participation. These concerns demanded a range of additional care and supportive strategies from researchers (and other stakeholders). A conceptual model, the model of ‘Facilitated Transition’ was developed, which summarises the findings of this research and provides a diagrammatic representation of the research findings, showing the links and relationships between the different elements. The research established that the transition of HIV positive trial participants from research to usual care facilities is a process, which appears to consist of three overlapping phases. These phases include: The pre-closure phase which represents events occurring before the actual trial closure but that underpin post-trial care, the trial closure phase which is the active phase of the closure, in which trial participants are prepared and exited from the trials, and the post-trial phase which represents the events occurring after trial participants have been linked to post-trial care facilities until 12 months later. These phases are demarcated by specific time points, which reflect how the transition process evolves, proceeds and concludes. At the various phases of the process, specific concerns (care needs) arise, being influenced by the participants’ previous care experiences and perceptions, plus their health and socio-economic positions. Specific actions are required to proactively facilitate trial participants during these phases. These actions are underpinned by the perceived ethical and moral responsibilities of the researchers, and are principally aimed at establishing a continuum of HIV care and treatment after trial closure, promoting positive care experiences for trial participants during the transition, and enabling the settlement and adaptation of trial participants to care in the public healthcare system. Conclusions: This is the first known study to investigate perspectives on post-trial care among HIV positive trial participants in a low income setting, from those closely engaged in the research process. This study has provided novel contributions in the area of HIV research ethics and post-trial care in general. The study has established that trial closure involving HIV positive participants raises significant ethical, moral and practical concerns in the Ugandan context. The findings further demonstrated that current post-trial care practice does not meet all the care needs of the HIV positive trial participants. Existing ethical recommendations on post-trial care place an emphasis on the need to ensure access to trial drugs and provision of trial results, where as less attention is given to other important aspects, as revealed in this research. To meet the post-trial care needs of HIV positive participants in Uganda, a comprehensive trial closure strategy is required. In addition to the already existing aspects of post-trial care, the new strategy should aim to: (i) address the financial needs of trial participants through financial assessment, support and empowerment, (ii) provide practical support during linkage to post-trial care, and (iii) offer post-trial follow-up to monitor and support the participants. Implementing these recommendations may require involvement of various stakeholders, including researchers, ethics authorities, research funders and donors, public healthcare workers, families, trial participants, and the community. Recommendations for future research: Further research is required to ascertain the rates of linkage to care, and to assess the health outcomes of post-trial participants following trial exit. In addition, a study to target the views of other stakeholders, such as the public healthcare facility workers, the family, and ethics authorities on post-trial care may be essential to understand better the ways in which to support HIV positive trial participants in Uganda. Furthermore, a longitudinal prospective study on a larger sample is required to test the model proposed in this research. And finally, there is need to deliberate more on the ethical and moral implications of financial benefits in HIV research involving HIV positive participants in a low income setting.

Abstract inserted as part of Final MPH Thesis: Non-Communicable Diseases like diabetes, cardiovascular diseases, cancers and others, have become the major cause of premature death, morbidity and disability in many Pacific countries including Samoa. These are linked by common preventable risk factors like obesity, hypertension, smoking, unhealthy diets and physical inactivity. OBJECTIVES: To determine the trends and development of Non-Communicable diseases and its risk factors in Samoa over the last 24 years using the recently developed diagnostic criteria. RESEARCH DESIGN AND METHODS: This research thesis combines 3 large surveys that were done in 1978, 1991, and 2002, looking at the trends in the prevalence of diabetes, and the prevalence of the NCD risk factors such as blood pressure, obesity, cholesterol and smoking. The 3 survey samples were selected randomly from around similar regions (Urban Upolu, Rural Upolu, and Rural Savaii) of Samoa in 1978, 1991 and 2002, with a total of 5973 individuals (1978 survey = 1467; 1991 survey = 1778; 2002 survey = 2728) available for the thesis analysis. The 1978 and 1991 data sets were secured from Professor P Zimmet, and the 2002 STEPs survey data set was secured from the Samoa Ministry of Health. The 3 surveys methodologies, survey procedures, questionnaires and anthropometric measurements were similar though the diagnostic criteria used to measure obesity slightly differ between the surveys. The blood pressure measurements were similar though the diastolic blood pressure measure in 1978 was higher. The 1978 and 1991 surveys used fasting venous blood sampling to measure fasting plasma glucose, and cholesterol levels at the laboratory. OGTT was also used in 1978 and 1991, but not 2002. The 2002 survey used capillary sampling to measure fasting glucose using a glucometer, and cholesterol level using a cholesterol meter. The combined data was then cleaned, standardized and matched with each survey, to make analysis easier. The recent diagnostic criteria were then applied to all the surveys to diagnose diabetes (1999 WHO Diabetes Criteria), hypertension (WHO 1999, JNC-VII 2003, NHF 1999 Hypertension Criteria), obesity (BMI ≥30 kg/m??), and hypercholesterolaemia. The prevalences using the recent diagnostic criteria were then mapped out. RESULTS: The overall age-standardized prevalence of type 2 diabetes (known or previously unknown) utilizing the current 1999 WHO diagnostic criteria for men and women ≥20 years of age has increased from 5.4% (males 4.8%, females 5.9%) in 1978, to 12.0% (males 10.9%, females 13.5%) in 1991, and to 20.1% (males 17.2%, females 22.2%) in 2002. Among the individuals with diabetes in the 3 surveys, more than 60% had previously undiagnosed diabetes. Compared with the 1978 survey, the diabetes prevalence in 2002 represents a 4-fold increase over the 24 year period. This has occurred along with increasing obesity, urbanization and modernization, aging, cultural changes, and changes in physical activity. There is a high prevalence of non-communicable disease risk factors. The age-standardized prevalence of hypertension defined by the WHO 1999 and JNC-VII 2003 criteria was 47.2% in 1978, 22.5% in 1991, and 24.0% in 2002. The high prevalence of hypertension in 1978 was due to the method used for recording diastolic blood pressure. Hypertension was more common in the urban regions than rural regions in 1978 and 1991 while in 2002, there was no statistical difference between the rates of hypertension between the different regions due to the rise in the prevalence rate of hypertension in rural regions. There is a high prevalence of overweight and obesity in Samoa. Using the WHO classification for BMI, there was an increase in obesity (BMI ≥ 30kg/m??) prevalence in Samoa in the last decade, increasing steeply from 34.9% in 1978 to 51.3% in 1991, and slowing down to an increase to 57.4% in 2002. The prevalence of obesity is significantly higher in females compared with their male counterparts. The overweight prevalence (BMI 25-29.9kg/m??) was 34% in 1978, 31% in 1991 and 29% in 2002. The prevalence of obesity has increased by 65% from 1978 to 2002 with an increase of 47% from 1978 to 1991, and 12% from 1991 to 2002. Prevalence of obesity is increasing with age and is more of a problem in women than men. It is higher in the urban regions but there has been a faster rise in obesity prevalence in rural regions from 1978 to 2002 as the rural regions become urbanized. The prevalence of hypercholesterolaemia (total cholesterol ≥ 5.2 mmol/l) was 30.5% in 1978, and this increased to 51.1% in 1991. There was a marked decline of hypercholesterolaemia in 2002 (14.4%), which may be due to differences in the method of measurement. Although smoking prevalence remains high in Samoa it declined significantly from 42.4% 1978 to 35.3% 1991 but remained essentially steady at 38% in 2002. There was a significant gender difference in smoking with about 60% of men and 20% of women smoking regularly. CONCLUSION: Samoa is experiencing an increasing problem with Non-Communicable diseases like diabetes and some of its risk factors. Diabetes prevalence has dramatically increased by 4-fold in the last 24 years. The prevalence of hypertension has stabilized around 23% though there was a decrease from 1978. The prevalence of obesity has also increased. Smoking prevalence has slightly increased from 1991 to 2002 with a significant number of the population smoking. Hypercholesterolaemia is more common in 1991 with an apparent decrease in 2002. These findings have important implications for public health efforts and policy developments to contain the epidemic of Non-Communicable diseases in Samoa.

Thesis (M. Arch.)--University of Hong Kong, 1999. / Includes bibliographical references.

Background: The immunological as well as the psycho-social impact, of living with HIV/AIDS transform HIV/AIDS into a multidimensional process. Stigma and discrimination against people living with HIV/AIDS (PLWHA) are proposed as hostile scenarios increasing hopelessness and reducing perceived and real social support affecting people’s health status. Peer support strategies are proposed as key factors for dealing with this scenario; additionally, socio-cultural variables may determine the provision and perception of social support. Objectives: To enhance the understanding of the process of living with HIV/AIDS and the role played by social support and to suggest cooperative strategies for dealing with stigma and discrimination against PLWHA to improve people’s health. Sample and method: Five studies were conducted studying 37 HIV positive members and non-members of peer support organisations (PSOs) in Chile and England; nine healthcare professionals working with PLWHA; and three spokes persons from PSOs of PLWHA from Romania, England and Chile. Results: PSOs of PLWHA, which reflect a cooperative strategy used by PLWHA to deal with stigma and self-provide social support, appear to play an important and underexplored role in PLWHAs’ health status; this relationship is also affected by socio-cultural characteristics. A measure of PSS was developed and theoretical analysis lead to a linkage with Maslow’s hierarchy of needs. Personality characteristics were found critical for the success of PNI based interventions. Conclusions: Living with HIV/AIDS involves psychological and social complications. PSOs are a powerful cooperative strategy improving quality of life and general health; however, further research is needed to establish the real impact of PSOs over HIV+ people. Implications: The peer-support strategy of PSOs is a powerful but underused clinical strategy. Healthcare teams and PLWHA may benefit from including this strategy if cooperative work is carried out with PSOs.

Background: Allergic disease is uncommon in developing countries, especially in rural areas. A protective effect of helminth infection has been implicated as a potential explanation. Objectives: To determine whether reduced exposure to helminth infection is associated with a higher risk of allergen skin sensitisation and allergic disease, and whether such an association could be explained by a helminth-induced up-regulation of certain cytokines, in particular anti-inflammatory IL-10. Methods: We invited 1,742 rural Vietnamese schoolchildren to take part in a cross-sectional baseline survey followed by a randomised, double blind, placebo-controlled trial of anti-helminthic therapy at 0, 3, 6, and 9 months to compare the change in exercise-induced bronchospasm (primary outcome), wheeze, rhinitis, eczema, and allergen skin sensitisation (secondary outcomes) at 12 months. 244 secondary schoolchildren also had venous blood taken to measure helminth induced IL-10, IFN-gamma, IL-5, and IL-13. Out of these 244 children, 144 were infected with hookworm and had bloods taken again at 12 months. Results: Baseline survey 1,601 schoolchildren (92% of those eligible) in grades 1-9 aged 6-18 participated in the baseline survey. 0.4% (6/1601) of children had a fall in peak flow after exercise of at least 15%. Doctor-diagnosed asthma was equally rare (0.4%, 6/1601), while 5.0% (80/1601) of children had experienced wheezing over the past 12 months. 6.9% (110/1601) of parents reported that their children had suffered of hay fever in the past 12 months, and in 2.6% (41/1601) of cases this diagnosis was confirmed by a doctor. 5.6% of children (89/1601) reported an itchy rash over the past 12 months. 0.9% (14/1601) had a history of flexural involvement and on examination 0.5% (8/1601) proved to have flexural eczema on the day of the survey. Skin prick test positivity was commoner than allergic disease. 33.5% (537/1601) of children had at least one positive skin prick test (dustmites 14.4%, cockroach 27.6%). The cross-sectional analysis yielded only significant results for allergen skin sensitisation. In univariate analysis, sensitisation was less frequent in children with hookworm or Ascaris infection, and increased in those with better santitation, including flush toilets and piped drinking water. In multivariate analysis, the risk of allergen skin sensitisation to house dust mite was reduced in those with Ascaris lumbricoides infection (adjusted OR=0.28, 95% CI 0.10-0.78) and in children with higher hookworm burden (adjusted OR for 350+ versus no eggs per gram faeces=0.61, 0.39-0.96), and increased in those using flush toilets (adjusted OR for flush toilet versus none/bush/pit=2.51, 1.00-6.28). In contrast, sensitisation to cockroach was not independently related to helminth infection but was increased in those regularly drinking piped or well water rather than from a stream (adjusted OR=1.33, 1.02-1.75). Intervention study 1,566 children in grades 1-8 completed the baseline survey and all consented to be randomised to either anti-helminthic treatment or placebo. 1487 children (95%) completed the intervention study. There was no effect of therapy on the primary outcome, exercise-induced bronchoconstriction (within-participant mean % fall in peak flow from baseline after anti-helminthic treatment 2.25 (SD 7.3) vs placebo 2.19 (SD 7.8, mean difference 0.06 (95% CI -0.71-0.83), p=0.9), or on the prevalence of the secondary clinical outcomes questionnaire-reported wheeze (adjusted OR=1.16, 0.35-3.82), rhinitis (adjusted OR= 1.39, 0.89-2.15), or flexural eczema (adjusted OR=1.17, 0.39-3.49). However, anti-helmithic therapy was associated with a significant allergen skin sensitisation risk increase in the treatment compared to the placebo group (adjusted OR=1.31, 1.02-1.67). In post-hoc analysis this effect was particularly strong for children infected with Ascaris lumbricoides at baseline (adjusted OR=4.90, 1.48-16.19), the majority of whom were co-infected with hookworm. Cytokine profiles Hookworm-induced IL-10 was inversely related to allergen skin sensitisation (any positive skin prick test) at baseline, but this result missed conventional statistical significance (univariate OR=0.70, 0.48-1.03; adjusted OR=0.72, 0.44-1.18). No other cytokine response was associated with skin prick test positivity at baseline (univariate OR IFN-gamma=1.15, 0.71-1.85; univariate OR IL-5=0.84, 0.53-1.33). Similary, no significant changes in any of the cytokine profiles were observed following anti-helminthic therapy in the treatment compared to the placebo group (p=0.3 for all three cytokines). Conclusion The baseline study suggested that hookworm and Ascaris infection, sanitation and water supply independently reduce the risk of allergic sensitisation. The intervention study confirmed that helminth infection and allergic sensitisation are inversely related and that the effect of Ascaris and hookworm infections on skin prick test responses is additive. However, we found little evidence to suggest that this effect was mediated by IL-10. There was also insufficient evidence to suggest that loss of exposure to gut worms for 12 months results in an increase in clinical allergic disease. The effect of more prolonged de-worming warrants further research.