PhD / Doctoral
Permanent URI for this collection
Browse
Recent Submissions
- ItemOpen AccessGenetic risk factors for overuse and acute musculoskeletal injuries(2024) Hill, Lee-Devlin; Collins, Malcolm; Posthumus, MichaelBoth acute and chronic tendon and ligament injuries are multifactorial that are the result of a combination of a poorly understood complex interaction of several intrinsic and extrinsic risk factors. There is a growing body of evidence suggesting that inherited genetic elements may predispose an individual to injury risk and should therefore be considered as important intrinsic risk factors. Previous studies have investigated the association several collagen gene (COL1A1, COL5A1, COL6A1, COL11A1, COL11A2 and COL12A1) variants with chronic lower limb tendinopathies, such as Achilles tendinopathy, and other exercise-associated phenotypes involving the musculoskeletal system. These genes encode for important structural components of both tendons and ligaments and have been proposed to influence the inter-individual variation in the biomechanical properties of these tissues. The association of these collagen gene variants with rotator cuff tendinopathy (RCT), more specifically supraspinatus tendinopathy (SST), has not been extensively investigated. Except for COL1A1 variants, the association of the remaining collagen gene variants with an acute injury, such as anterior cruciate ligament (ACL) ruptures, has also not been extensively investigated. AIMS Therefore, the primary aim of this thesis was to investigate the association of the COL1A1 rs1800012 (G/T), COL5A1 rs12722 (T/C), COL5A1 rs10628678 (AGGG/-), COL6A1 rs35796750 (T/C), COL11A1 rs3753841 (T/C), COL11A1 rs1676486 (C/T), COL11A2 rs1799907 (A/T) and COL12A1 rs970547 (G/A) gene variants with RCT in a South African cohort of swimmers (Chapter 4), as well as ACL rupture in a combined cohort of European ancestry (Swedish, South African, Polish and Australian) (Chapter 5) and a South African Mixed Ancestry cohort (Chapter 6) using a case-control genetic association study approach. A secondary aim of the thesis was to investigate hypothesis-driven collagen gene-gene interactions between the investigated variants in modulating the risk of injury in the different RCT (Chapter 4) and ACL (Chapters 5 and 6) cohorts. Finally, a systematic review of the risk factors associated with RCT in swimmers was also included in this thesis (Chapter 3). METHODS For chapter 4, 103 (49 females, 54 males) swimmers with clinically diagnosed rotator cuff tendinopathy (RCT group) were recruited of the 103 participants in the RCT group, 84.5% (n=87) were diagnosed with a supraspinatus tendinopathy (SST) and were analysed separately as a sub-group. In addition, 101 (55 females,46 males) apparently healthy swimmers with no previous history of shoulder pathology (including RCT, trauma, bursitis, or adhesive capsulitis) (CON group) were recruited. All participants were unrelated, of self-reported European ancestry and recruited between 2013 and 2016. For Chapter 5, 195 physically active and unrelated participants of self-reported European ancestry were recruited between 2011 and 2013 from the University Hospital in Umeå and orthopaedic clinics in Luleå, Sweden. These participants within this cohort comprised of 79 individuals who had clinically diagnosed ACL injuries with a non-contact mechanism of rupture (NON group) and 116 apparently healthy, asymptomatic individuals with no history of ACL injuries (CON group). The Swedish cohort was included in a larger combined analysis consisting of 661 participants with ACL rupture and 378 uninjured controls from previously published cohorts of self-reported European ancestry from South Africa, Poland, and Australia. For chapter 6, 209 unrelated participants with self-reported mixed ancestry participants were included in this study. The participants were previously recruited between January 2012 and May 2016 from Groote Schuur Hospital, Victoria Hospital, and the Sports Science Orthopaedic Clinic within the Cape Town, South Africa. Ninety-four participants (77 males and 17 females) were included in the ACL group, of which 51 had sustained their ACL rupture through a non contact mechanism of injury (NON sub-group. Furthermore, 100 (81 males and 19 females) apparently healthy, individuals with no history of ACL rupture or injury were recruited from gyms and local sports clubs within the Cape Town area of South Africa. All participants were genotyped for the following collagen gene polymorphisms: COL1A1 rs1800012 (G/T), COL5A1 rs12722 (T/C) and rs10628678 (AGGG/-), COL6A1 rs35796750 (T/C), COL11A1 rs3753841 (T/C) and rs1676486 (C/T), COL11A2 rs1799907 (A/T) and COL12A1 rs970547 (G/A). RESULTS As presented in a systematic review of non-genetic risk factors (Chapter 3), only four risk factors for shoulder injuries were determined to be of moderate certainty, with the remaining 25 risk factors being appraised as low certainty. Moderate level of certainty was determined in (i) previous history of pain and injury, (ii) internal/external rotation range of motion, (iii) clinical joint laxity and instability and (iv) internal/external rotation strength. Although previously associated in some studies investigating other overuse musculoskeletal soft tissue injuries, none of the investigated collagen variants were independently associated with rotator cuff tendinopathy (RCT) or supraspinatus tendinopathy (SST) risk (Chapter 4). A novel finding of this thesis was that the C-A-(-) inferred haplotype constructed from COL11A1 rs3753841(T/C), COL11A2 rs1799907 (A/T) and COL5A1 rs10628678 (AGGG/-) was found to be significantly over-represented in the CON group (6.0 %) compared to the SST (0.4 %) groups (p=0.034). However, none of the inferred haplotypes constructed from (i) the two COL5A1 variants, (ii) the two COL11A1 variants, (iii) the three COL11A1 and COL11A2 variants, as well as all (iv) the COL11A1, COL11A2 and COL5A1 variants were associated with RCT or SST risk. Similarly inferred haplotypes constructed from (i) COL5A1 and COL6A1, (ii) COL5A1 and COL12A1, as well as (iii) COL6A1 and COL12A1 were also not associated with RCT or SST. The COL1A1 rs1800012 TT genotype was found to be significantly (p=0.027) under represented in the ACL (GG 68.0%, GT 30.9%, TT 1.1%) group of European ancestry during the combined analysis compared to the CON group (GG 67.0%, GT 29.0%, TT 4.0 %). A novel finding of this thesis was that this association was only observed in female (p = 0.045, OR = 0.00, CI 0.00 – 0.71; ACL: GG 68.1%, GT 31.9%, TT 0.0%; CON: GG 68.3%, GT 27.0%, TT 4.8%) but not male (p =0.299; ACL: GG 68.0%, GT 39.5%, TT 1.5%; CON: GG 66.5%, GT 31.0%, TT 3.6%) ACL groups. Although independently associated with ACL rupture in European populations, the COL1A1 rs1800012 TT genotype was however not significantly associated with ACL rupture in the Mixed Ancestry cohort (ACL: 85.4% GG, 13.5% GT and 1.0% TT vs CON: 82.3% GG, 17.7% GT and 0.0% GG, p=0.204). An additional novel finding was that the COL12A1 rs970547 polymorphism was significantly associated with risk in a South African Mixed Ancestry ACL rupture cohort (NON: 34.9% AA, 44.2% GA and 20.9% GG vs CON: 34.4% AA, 60.2% AG and 5.4% GG, p=0.021). This variant was however not associated with ACL rupture in the European populations (ACL: AA 63.7%, GA 31.3%, GG 5.1%) compared to the combined CON group (CON: AA 60.4%, GA 35.3%, GG 4.3%, p=0.423). None of the other investigated collagen gene variants were independently associated with ACL rupture in the European or mixed ancestry cohorts. Within participants of European ancestry, the C-AGGG (31.2% ACL vs 20.6% CON, p=0.001) and T-(-) (14.4% ACL vs 5.7% CON, p=0.010) inferred haplotypes constructed from COL5A1 rs12722 (C/T) and rs10628678 (AGGG/-) were significantly over-represented in the ACL rupture group. On the other hand the T-AGGG inferred haplotype was significantly (p>0.001) over-represented in the CON group (50.5%) compared to the ACL group (36.6%). None of the COL5A1 inferred haplotypes were however significantly associated with ACL rupture in the South African mixed ancestry cohort. A further novel finding was a significant interaction between the COL6A1 rs35796750 and COL12A1 rs970547 variants, the T-A inferred haplotype was significantly (p=0.030) over represented in the ACL group (11.0%) compared to the CON group (7.1%) when the participants of European ancestry were analysed. The T-G inferred haplotype was significantly (p=0.010) over-represented in the male CON sub-group (33.7%) compared to the male ACL sub group (23.0%) in the participants of European ancestry. Within the South African mixed ancestry population, the C-G inferred haplotype constructed from the COL6A1 and COL12A1 variants was significantly (p=0.029) over-represented in the ACL group (37.2%) compared to the CON group (31.1%). This haplotype remained significantly (p=0.027) associated when only the participants with a non-contact mechanism of injury (34.3% NON sub-group) was analysed. Finally, the inferred T-A haplotype constructed from COL5A1 rs12722 and COL12A1 rs970547 was significantly (p=0.039) with ACL rupture (27.3% ACL vs 17.9% CON) in the combined European cohort associated with risk. CONCLUSION This thesis investigated collagen gene variants that have been previously associated with a number of injury phenotypes and other exercise-related conditions in three independent cohorts. Whilst only two variant were found to be independently associated with risk, several gene-gene interactions were observed, demonstrating the complex and multifactorial nature of the MSK injuries. These novel findings therefore draw attention to the possible important role that genetic factors in the aetiology of tendon and ligament pathologies. Furthermore, this thesis highlights the importance of conducting studies in non-European and genetically diverse populations.
- ItemOpen AccessThe economic burden, patients' well-being, and social determinants related to diabetes in South Africa(2024) Hellebo, Assegid; Alaba, Olufunke Aduke; Kengne, Andre PascaBackground: The health systems in Sub-Saharan Africa (SSA) are confronted by a growing prevalence of diabetes mellitus, with an estimated 24 million adults affected in 2021, a number expected to more than double by 2045. This rise in diabetes not only increases the risk of premature death, but also significantly reduces the quality of life and work productivity. South Africa is leading the diabetes epidemic in SSA, with the incidence rate increasing both in urban and rural settings, equally affecting both genders. While diabetes imposes high levels of health, financial and economic burdens, there is a dearth of studies focusing on identifying and analysing the factors that predict or influence a patient's well-being and quantifying productivity loss in relation to diabetes, particularly in SSA. Objectives: This thesis aims to evaluate the economic and well-being burden of diabetes in South Africa, focusing on productivity impacts, associated social determinants on patient outcomes and predictors of quality of life. The specific objectives are: firstly, to use population life table modelling to estimate the impact of type 2 diabetes (T2D) on the South African population, particularly in terms of productivity-adjusted life of years (PALYs) metric; secondly, to review and synthesise information regarding the costs and cost-effectiveness of managing T2D in SSA to enhance awareness, optimise resource allocation, and support evidence-based decision-making; thirdly, to investigate the role of social determinants of health (SDoH) in diabetes self-care management practices, emphasising the importance of maintaining optimal glycemic control; and lastly, to assess health-related quality of life (HRQoL) and associated factors among people with diabetes in South Africa; lastly, to develop locally relevant utility score valuations for more accurate economic evaluations and healthcare decision-making in South Africa. Methods: The thesis combined diverse methodological approaches to investigate the impact of T2D in South Africa. Life table modelling was used to simulate the health trajectory of individuals aged 20 to 65 with T2D, comparing cohorts with and without diabetes in terms of excess deaths, years of life lost (YLL), and PALYs. These simulations included adjustments 2 for variables like Gross Domestic Product (GDP), productivity indices, labour force dropout, and mortality risks, using data from the International Diabetes Federation (IDF), Statistics South Africa (Stats SA), and other sources, with the World Health Organisation (WHO) 3% annual discount rate for YLL and PALYs applied. For the second objective, a comprehensive systematic literature review, encompassing databases like PubMed-Medline and Google Scholar from 2010 to 2022, analysed the economic aspects of T2D management. Costs were normalised to 2023 US dollars, considering inflation and exchange rates. The third and fourth objectives utilised cross-sectional data of 539 people living with diabetes (PLWD) from urban and rural primary healthcare (PHC) facilities in Western Cape, South Africa. The third objective focused on assessing HRQoL using the EuroQol-3 Dimensions Questionnaire (EQ-5D-3L). The EQ-5D-3L responses were meticulously converted into a unified summary index score employing the UK time trade-off value set. HRQoL was assessed using the ordinal logistic regression. Lastly, the fourth objective explored the influence of SDoH on people with diabetes. Self-care management and adherence to recommended activities were measured, ranging from '0' (never) to '7' (daily adherence). The study employed binary and multinomial logistic regression analyses to investigate the interplay between SDoH, self-management, self-care management and self-care guidelines. Results: In 2019, T2D affected 9.5% of the working-age population in South Africa, totalling 3.2 million individuals. Projections indicate that T2D will lead to 669,427 excess deaths, a loss of 6.2 million years of life (9.3%), and 13 million productivity-adjusted life years (PALYs, 30.6%) by the retirement age of this cohort. Economically, T2D's impact is significant, with the loss of PALYs estimated at US$223 billion or US$69,875 per person, based on 2019's GDP per full-time employee. In the systematic review, most studies assessed costs from the provider perspective (direct and outpatient costs) and reported T2D costs as enormous in SSA. The annual cost ranged from $337.50 for basic medical care of uncomplicated T2D to $2330.74 total provider cost per patient. The highest burden was among individuals in the low-income quantile. Furthermore, analysis utilising cross-sectional data of 539 participants older than 18 years receiving care from rural and urban clinics in the Western Cape, South Africa, revealed that healthcare utilisation was inversely related to diabetes self-care scores, indicating that patients with less frequent healthcare visits tended to have higher self-care scores. SDoH factors such as urban residency, education level, and obesity status were significant determinants of self-care guidelines. Specifically, urban residency (AOR=0.50; 95%CI= 0.29, 0.88; p=0.03), secondary education (AOR=1.13; 95%CI= 1.02, 2.03; p=0.05), and being obese 3 (AOR=0.43; 95%CI= 0.19, 1.00; p=0.03) were associated with varying levels of self-care. Additionally, food insecurity and long travel distances to healthcare facilities negatively impacted self-care adherence, while having a stable house was positively associated with higher self-care management. Regarding HRQoL, the study's participants had a mean utility score of 0.85. Males reported higher HRQoL compared to females (AOR=1.64; 95%CI= 0.96, 2.80; p= 0.07), and urban residents had lower HRQoL than rural (AOR= 0.41; 95%CI= 0.27, 0.63; p<0.01). Having at least primary education (AOR= 0.53; 95%CI= 0.36, 0.79; p<0.01) is associated with lower HRQoL, while higher AUDIT score correlated with increased HRQoL (AOR= 1.89; 95%CI= 1.13, 3.18; p= 0.02). Factors like higher self-efficacy and severe mental health issues were significantly associated with HRQoL, with the latter predicting very low HRQoL (AOR= 18.31; 95%CI= 2.21, 152.08; p= 0.01). Other factors, including body mass index (BMI), marital status, housing stability, and food security, showed no significant impact on HRQoL. Conclusions: This series of studies emphasises the multifaceted impact of diabetes in South Africa, spanning public health, economics, individual well-being, and Social Determinants of Health. The findings call for a multi-pronged strategy encompassing prevention, effective management, and a broader socio-economic approach to tackle the diabetes epidemic. By addressing these areas, it is possible to mitigate the escalating impact of diabetes in South Africa and improve overall health outcomes for individuals living with this chronic condition.
- ItemOpen AccessA life cycle-based investigation into the potential of a circular and low-carbon plastics economy in South Africa(2024) Goga, Taahira; von Blottnitz, Harro; Russo ValentinaPlastics are multi-functional materials that, while associated with numerous applications, are becoming strongly linked with the drawbacks of a primarily fossil fuel-based linear economy model. This results in the release of greenhouse gas emissions, low material recovery rates, and the environmental impacts associated with disposal and leakage. The circular economy approach is viewed as an alternative model that aims to improve environmental and economic performance, in the case of plastic systems by replacing conventional feedstock, reducing plastic litter, and creating value from waste through reuse and recovery. However, a transition from a linear to a circular model for the plastics sector remains poorly understood. Studies are generally restricted to the analysis of waste management systems with limited information available on the connection between material circularity and environmental impacts. Although several global studies have sought to explore this link using life cycle assessment methods, they do not consider national scale factors, such as the effect of a country's waste management landscape and its energy mix. This research study investigates potential future versions of a low-carbon and circular plastics economy in South Africa. The scenarios evaluated are based on local voluntary and regulatory objectives and include increased mechanical recycling, the shift from single-use consumption to reuse, and decarbonisation of the sector by integrating renewable energy into the electricity mix as well as replacement of the fossil fuel feedstock for monomer production. Furthermore, the combination of scenarios is modelled to demonstrate the potential benefit of implementing these strategies in concert. The industrial ecology tools Material Flow Analysis (MFA) and Life Cycle Assessment (LCA) are utilised to determine the degree of circularity and assess the impacts of these strategies along the plastics life cycle. The results are presented in terms of circularity and environmental indicators including but not limited to recycling rates, quantity of leakage, Global Warming Potential (GWP), and ecosystem quality. The results for the reference year (2018) demonstrate that South Africa had a per capita plastic consumption of 36 kg/capita/year, with a plastic sector input recycling rate of 40.3%, employment opportunities totalling 77 348, and a carbon footprint equivalent to 3.9% of the country's total annual emissions. Based on current practices and with no policy interventions or measures, the short-term forecast indicates that plastic production will increase by a rate of 1.7% annually between 2018 and 2025 (Baseline scenario). This will lead to a projected increase in plastic use of 1 kg/capita and a subsequent rise in leakage of 11%. Furthermore, it is expected that the degree of environmental impact will increase between 10 and 18% with a further increase of 21% in the subsequent decade. In terms of normalised results, significant impacts across all scenarios were identified as human toxicity and ecotoxicity, fossil resource scarcity, and freshwater eutrophication. Additionally, the contribution analysis revealed that the major quantifiable environmental impacts are associated with upstream processes such as monomer and polymer production and product manufacturing with a combined share of 55- 85% of the total impacts at the endpoint level (Areas of Protection). This is primarily due to coal-based pathways for feedstock and energy production. Although all the mitigation strategies, particularly elevating recycled rates, and decarbonisation of the system, display a benefit relative to the Baseline scenario, the findings demonstrate that the greatest gain amongst materiality, circularity, and environmental indicators can be achieved under the Combination scenario in 2025 with an 11.2% increase in recycled content, 1 kg/capita reduction in leakage, and an average decrease of 16% in midpoint impacts. This benefit is further extended to an additional 40.1% increase in recycled content and a 55% average improvement in environmental effects in 2035 under the medium-term forecast with levels projected to decline below historical findings for 2018. A comparison of results with global targets shows the potential of combining scenarios beyond short-term local ambitions. Notwithstanding these significant benefits in circularity and environmental impacts, leakage to the environment would still be prevalent with an estimated 256 kt of plastic debris in 2035. Despite the identification of significant potential improvements from a material and environmental perspective through the combined application of the three modelled strategies, it is concluded that these would not transform the South African plastics sector to the extent that it could be classified as fully or even largely circular nor low-carbon in the short- to medium-term. Recommendations on the material aspects include designing for recyclability, investigating the potential for chemical recycling to complement mechanical recycling, and promoting reuse business models. From an emissions perspective, the transition to renewable energy needs to be accelerated, and the introduction of lower-carbon routes for the local polymer production process should be investigated. The findings also illustrate the need for increased coordination between upstream strategies centred around design and material innovation together with downstream processes focusing on end-of-life recycling and recovery to improve the environmental profile of the South African plastics system
- ItemOpen AccessIdentifying the characteristics of socially integrated mobile bully-victims using a mobile application(2024) Jokazi, Nombulelo; Kyobe, MichaelThe prevalence of mobile bully-victim behaviour is increasing on popular mobile social networks. Mobile bullying is a sub-type of cyberbullying committed using mobile technology. Mobile bully-victims are individuals who exhibit both bullying and victimisation behaviour. While there are different types of bully-victims, research on bullying has traditionally focused on marginalised bully-victims, rather than on socially integrated bully-victims, who appear to present a greater risk to young people. Socially integrated bully-victims form interpersonal relationships through social interactions, and in the process, are victimised, and bully their peers in retaliation. This bullying is becoming more prevalent, especially among university students in South Africa. This is worrisome as previous studies have linked this behaviour to negative outcomes, such as depression, anxiety, and suicidal tendencies. In addition, studies indicate that identifying socially integrated bully-victims can be challenging. Consequently, this group is not widely known, nor widely catered for by bullying prevention programmes. The objective of this study was to develop a mobile application that could be used to identify the characteristics of socially integrated bully-victims who use mobile technology. The focus on mobile technology and mobile technology users is important since this technology is utilised more by young people to conduct bullying, compared to other technologies. To achieve this goal, extensive literature reviews were conducted to identify the characteristics of socially integrated mobile bully-victims, and how these arise. This led to the development of an integrative framework using the five factor theory (FFT), and Bronfenbrenner's socio ecological model (SEM). The link between these theories is the developmental systems theory (DST), which explains the bi-directional relationship between individual characteristics and environmental influences. A conceptual model was derived from this integrative framework. This then guided the design, development, and assessment of the socially integrated mobile bully-victim (SIMBV) application. The researcher adopted pragmatism as her philosophical paradigm, and design science (DS) as her research strategy. DS provided the steps needed to develop a useful application. The SIMBV application was tested in two iterations involving undergraduate students at a university in the Western Cape province of South Africa. Forty-two out of 143 participants from the first iteration were found to possess the characteristics of socially integrated bully victims. These consisted predominantly of females and males between 18 and 19 years of age. The second iteration had 54 respondents, who possessed the characteristics of socially integrated mobile bully-victims. The findings from the cluster analysis indicate that individual characteristics and environmental factors shape the characteristics of socially integrated mobile bullying victims. The key characteristics of the studied SIMBVs in the South African context are retaliation, low agreeableness, openness, hostility, characteristic adoption, consciousness, popularity, prior victimisation and mobile bully-victim behaviour. The environmental factors on the other hand include peer norms, coercion by parents, exposure to violence and cultural expectations. In addition, SIMBVs were found to defend friends and others. This finding differs from earlier studies, which tend to report only negative characteristics of bully-victims. This study contributes to theory by developing a more comprehensive and integrated framework of socially integrated mobile bully-victims characteristics. This integrated framework and the conceptual model can be used to develop useful tools to mitigate bullying committed over mobile phones. Identifying and understanding SIMBVs is made easier for psychologists in higher education with the mobile application. SIMBVs felt free to share the depth of their experience since the mobile application features ensure anonymity, and the psychologist user can know the true characteristics of the SIMBV in real time. The application can enable the development of relevant policies and effective interventions for this group. The mobile app has educational material on mobile bullying that can be utilised by universities and schools to raise awareness about this phenomenon.
- ItemOpen AccessThe role of antibodies in tuberculosis(2024) Jacobs, Ashley; Wilkinson, RobertThe role of antibodies in tuberculosis (TB) has been debated for over a century. Antibodies against Mycobacterium tuberculosis (M.tb) are detectable in persons who appear to resist M.tb infection, and yet humoral immune activation is a consistent biomarker of TB disease progression. Antibody responses to TB could therefore be a dual-edged sword, whereby antibodies promote TB pathogenesis, but some people produce antibodies that contribute to immunity against M.tb. In this thesis, I have therefore investigated the role of antibodies in TB in multiple clinical cohorts. Firstly, I generated fully human monoclonal antibodies (mAbs) against M.tb from patients with ATB. I identify the antigen of one mAb as the secreted antigen GlnA1, and then show that this mAb promotes in vitro production of TNF-α, IL-6, and IL-1β in the absence of mycobacterial killing. Secondly, I investigated antibody responses against M.tb in persons who live with HIV (PLWH). PLWH fail to mount a significant increase in IgG levels against M.tb in ATB. M.tb-specific IgG responses are also detectable in different cohorts of PLWH with negative interferon gamma release assay (IGRA) tests. However, greater levels of M.tb-specific IgG associates with IGRA conversion. Thirdly, I showed the development of flow cytometric assays to study opsonization and antibody dependant cellular phagocytosis (ADCP) of live mycobacteria in BCG vaccinated adults. These methods show that BCG vaccination induces ADCP 28 days post-vaccination. Fourthly, I tested whether unswitched memory B cells, and specifically the marginal zone B cells (MZB) subset, are impacted by ATB. MZB respond to capsular pathogens and could thus recognize the M.tb cell wall. MZB are found to be depleted in ATB but are not enriched at the site of disease in PLWH with pericardial TB. The depletion of unswitched memory B cells in TB observed in this study resembles that reported in autoimmune disease. Taken together, I provide support to the notion that at least some antibodies against M.tb could contribute to immunopathology in TB. The fact that PLWH are at greater risk of disseminated TB, and mount less of an antibody response, however, supports a role for antibodies in preventing disseminated disease that remains to be studied.