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.

Limited understanding of influenza transmission has been a frequent obstacle during the development of pandemic influenza infection prevention and mitigation strategies. The science is hotly debated, especially the relative importance of transmission via large droplets or aerosols. Clarification of the relative importance of different modes of transmission is critical for the refinement of evidence-based infection control advice and has been called for by the European Center for Disease Control (ECDC), the World Health Organization (WHO), and the US Institute of Medicine. The primary aims of this thesis were to investigate influenza transmission; i) by obtaining data concerning viral shedding and the presence of influenza virus in the near environment of infected individuals and ii) through the exploration of a human challenge model to study transmission. Two major clinical studies have been performed; • Shedding and environmental deposition of novel A (H1N1) pandemic influenza virus. The primary aims of the study were to correlate the amount of virus detected in a subject’s nose with that recovered from his/her immediate environment (on surfaces and in the air) and with symptom duration and severity. Adults and children, both in hospital and from the community, who had symptoms of influenza infection were enrolled. Information about symptoms was collected and samples were taken including nose swabs, swabs from surfaces and air samples. Forty two subjects infected with influenza A(H1N1)pdm09 were recruited and followed up. The mean duration of nasal viral shedding was 6.2 days (by PCR) and 4.6 days (by culture). Over 25% of cases remained potentially infectious for at least 5 days. Symptom scores and viral shedding were poorly correlated. From surface swabs collected in the vicinity of 40 subjects, 15 (38%) subject locations were contaminated with virus. Overall 36 of 662 (5.4%) surface swabs taken were positive for influenza, two (0.3%) yielded viable virus. Subjects yielding positive surface samples had significantly higher nasal viral loads on illness Day 3 and more prominent respiratory symptom scores. Room air was sampled in the vicinity of 12 subjects and PCR positive samples were obtained from five (42%). Particles small enough to reach the distal lung (≤4µm) were found to contain virus. • Use of a human influenza challenge model to assess person-to-person transmission: Proof-of-concept study. The primary aim of this study was to establish that an experimentally induced influenza infection is transmissible. Healthy subjects deemed sero-susceptible to influenza A/H3N2/Wisconsin/67/2005 were intranasally inoculated (Donors) and when symptoms began, further sero-susceptible subjects (Recipients) were exposed to Donors during an ‘Exposure Event’. Subjects were in close contact, e.g. playing games and eating meals together, for a total of 28 hours during a 2 day period. Samples were collected to confirm infection status. Among 24 healthy adult subjects, nine were randomised to the ‘Donor’ group and 15 to the ‘Recipient’ group. Following inoculation 5 out of 9 Donors (55%) developed illness and 7 out of 9 (78%) were proven to be infected. After exposure, 5 out of 15 Recipients developed symptoms and 3 out of 15 were proven to be infected. Three others were found to be non sero-susceptible prior to exposure. The overall attack rate in Recipients was 20% but was 25% after adjustment for pre-exposure immunity. The contact, droplet and aerosol routes of influenza transmission are all likely to have a role. This thesis shows that transmission of influenza via surfaces may be less important than current infection control policies and public guidance documents imply. Air sampling results add to the accumulating evidence that supports the potential for aerosol transmission of influenza. The human challenge model could be used to investigate routes of influenza transmission further and a study funded by the Centers for Disease Control (CDC) is planned.

N,N-Diethyl-m-toluamide (DEET) is one of the most effective and commonly used mosquito repellents. However, during laboratory trials a small proportion of mosquitoes are still attracted by human odours despite the presence of DEET. In this study behavioural assays identified Aedes aegypti females that were insensitive to DEET. The selection of either sensitive or insensitive groups of females with males of unknown sensitivity over several generations resulted in two populations with different proportions of insensitive females. Crossing experiments showed the ‘DEET-insensitivity’ trait to be dominant. In addition to the finding of heritable DEET-insensitivity, unselected culture mosquitoes were shown to change their sensitivity to DEET after brief pre-exposure to the repellent. Female mosquitoes that were sensitive to DEET when first tested became insensitive when retested. Electroantennography showed that mosquitoes that were insensitive to DEET had a reduced response to DEET compared with mosquitoes that were sensitive to it. This was the case both for culture mosquitoes displaying insensitivity to DEET after brief pre-exposure to it, and for the sensitive and insensitive lines selected for several generations. Single sensillum recordings of the selected lines identified DEET-sensitive sensilla in the sensitive line that did not respond to DEET in the insensitive line. This study suggests that behavioural insensitivity to DEET in Ae. aegypti is a genetically determined dominant trait, which can also be temporarily induced by pre-exposure, and resides in changes in sensillum function. These results highlight the necessity for careful monitoring of DEET-insensitivity in the field, and caution when designing laboratory methods for repellency assays.

Background: Although antiretroviral treatment is expanding in sub-Saharan Africa, the World Health Organization advocates for integration of palliative care with HAAR T because pain, other distressing symptoms and complex psychosocial challenges persist throughout the HIV trajectory. Palliative care improves the outcome for patients with HIV and may complement antiretroviral treatment by increasing adherence through better management of side effects from the treatment, providing patient and family-centred holistic care, and giving end-of-life care when necessary. However, integrating what have become two disciplines is challenging. Aim: To study the implications for palliative care provision in the context of changing policy to universal access to HAART for people living with advanced AIDS (PLWA) in Uganda. Research questions addressed in the study included: 1. How do patients with advanced AIDS (stage III and IV) and with palliative care needs and their families experience care delivery and receipt over a period of 8 weeks? 2. How is the morphine roll-out programme among advanced AIDS patients operationalized in Uganda? 3. What are the challenges faced by health care workers involved in delivery and implementation of integrated palliative care for patients with advanced AIDS? 4. What are the views of key opinion leaders on development of palliative care policies in Uganda? Methods: A mixed methods approach was employed. The study comprised of three phases. In phase one, a consecutive sample of 30 newly enrolled patients advanced AIDS (stage III & IV) and their carers were recruited at Hospice Africa Uganda and followed up for 8 weeks. Qualitative interviews were conducted with patients and their carers at one time point and an outcome measure using African Palliative Care Association-Palliative Outcome Scale (APCA-POS) was used to assess changes in their experiences over 8 weeks, following access to palliative care. In phase two, 10 palliative care staff members participated in individual interviews and one focus group to explore the challenges they faced in delivering services to patients. Phase three explored, by the use of interviews with 7 key stakeholders, the broader context of palliative care policy development and opinions about key priorities for the future. Findings: Out of 30 patients, 14 were male and 16 were female. They ranged in age from 18-60 years. The majority of patients were bed-ridden and experienced distressing symptoms related to advanced AIDS and AIDS-defining cancers which necessitated timely palliative care intervention. The key findings of the study relate to the range of physical symptoms experienced by patients and the psychosocial challenges of disclosure and stigma encountered by patients and their families against a backdrop of profound poverty. Palliative care staff indicated two categories which broadly covered the challenges of palliative care delivery to PLWA in Uganda: service-linked and provider-linked challenges. Palliative health care staff and key stakeholders identified strategies to respond to palliative care needs for PLWA across four dimensions: a) partnerships or networking together with stakeholders; b) improving palliative care education; c) raising awareness of palliative care among communities and health care workers; d) advocacy and policies which support and strengthen initiation and expansion of palliative care services to PLWA, including the availability of morphine. Conclusion: The study shows the paramount importance of drawing on patients' and carers' experiences and concerns to shape models of African palliative care. Both palliative care staff and key informants' perspectives highlight successes, barriers and important lessons for palliative care service delivery in Uganda. These lessons have several implications across the dimensions of practice, education, policy and research. Palliative care staff need to work with several key players or stakeholders to address the many psychosocial issues affecting PLWA including support during treatment. The study indicates the need to translate government policies on palliative care into action.

This thesis aims to examine the effectiveness of a mobile phone based SMS game as a learning intervention for the Peer Educators of the Males having Sex with Males (MSM) groups in Kolkata, India. MSM groups are marginalised and are at higher risk of HIV/AIDS, falling under the core groups for the National AIDS Control and Prevention programmes in India. Peer to peer education for behaviour change in HIV/AIDS prevention projects is a bottom up approach to reach out to this marginalised population for HIV prevention. Training is in place for MSM peer educators but research shows gaps in their support and learning needs. This project developed a mobile game based learning tool to address the peer educators’ learning and support needs. Using a participatory research approach a multiplayer SMS based simulation game was developed, deployed and evaluated, using an existing game engine called ‘Day of the Figurines’. In an effort to enhance experience sharing and peer learning the real life experiences of the peer educators were captured and incorporated through a participatory and iterative process as scenarios of the game. A SMS game on mobile phones was chosen to be in keeping with the marginalised, secretive nature of the MSM identity of the peer educators as well as be in keeping with the mobile nature of their work. The SMS game was piloted in Nottingham and Kolkata and the final intervention was deployed and evaluated in Kolkata with a group of sixteen peer educators from MANAS Bangla, a network of community based MSM organisations in Kolkata, India. Evaluation of the game showed it to be useable, relevant to peer education, interesting and entertaining but in some cases slow, uninteresting and confusing. The game play was affected by technical faults but players still exchanged SMS messages with the game and communicated between players using the ‘chat’ feature of the game. Playing the game enabled players to acquire better communication skills and increased confidence, it gave them a feeling of self-efficacy and influenced their work practices. The intervention was instrumental in increasing the peer educators’ critical consciousness, it created a space to address the practical barriers faced by the peer educators by providing dialogic methods for developing knowledge, encouraging and facilitating collaboration, developing communication skills and increasing access to learning opportunities. This research contributes an exploration of peer educators’ problems, evaluation of mobile game based learning and account of participants’ experiences in a mobile-health development context in resource constrained settings.