Systems epidemiology of snail-borne diseases : from methodological to social-ecological considerations in the fight towards elimination

Background: Snail-borne trematode infections, including schistosomiasis and fascioliasis, affect an estimated 250 million and 2.4 million people worldwide, respectively. Health implications range from asymptomatic infections to severe morbidity, developmental and cognitive impairment, thus affecting the current and later life of infected individuals. Nonetheless, snail-borne trematodiasis in general, and fascioliasis in particular, remain among the most neglected of the neglected tropical diseases. The occurrence of these parasitic liver- and blood-fluke infections depend on a myriad of interrelating factors comprising a complex system of disease and health. A key feature pertains to the availability of suitable aquatic snail intermediate hosts from the family of the Lymnaeidae (for schistosomiasis) and Planorbidae (for fascioliasis). The distribution of these intermediate host snails, in turn, depends on ecological and environmental factors of their habitats, whereas these habitats are shaped by humans. The construction of dams, for example, extends the suitable habitats for intermediate host snail species and has been implicated with the spread and intensification of schistosomiasis. Furthermore, socio-economic and cultural factors as well as behaviour largely determine the extent of risky water contact including direct and indirect consumption and thus govern the risk of becoming infected with Schistosoma and Fasciola. Prevailing habits and social believes as well as knowledge and education likewise influence water contact patterns and health seeking behaviour. Individual immunology plays a role in acquiring infections and subsequent development of the disease for individuals exposed to these fluke infections. The nature of the interrelations in snail-borne trematode infections are complex and widespread. In order to eliminate snail-borne trematodiasis, especially schistosomiasis, efforts in the domains from innovation to application need to be increased covering all aspects of the whole system. Goal and specific objectives: The overarching goal of this PhD thesis was to obtain a systems overview of schistosomiasis and – to some extend – fascioliasis in the northern area of Côte d’Ivoire, placing particular emphasis of disease prevalence, social-ecological systems and methodological considerations. Specific objectives include: (i) to evaluate and improve currently existing tools for the assessment of infection within the communities ranging from household sampling to the validation of two rapid-diagnostic test within the setting; (ii) to elucidate prevailing water contact pattern and underlying reasons thereof alongside other factors leading to an increased risk of acquiring snail-borne trematodiasis for the local communities in northern Côte d’Ivoire; and (iii) to assess the distribution and ecological determinants of aquatic snail species serving as intermediate hosts for schistosomiasis and fascioliasis and relating it to the prevalence of infections within the human communities using these water sources. Methods: A literature review was performed to identify suitable household sampling methods for situations where sampling frames are not available. Identified and newly proposed sampling methods were simulated over 250 iterations to identify features or the resulting samplings and assessing the amount of oversampling, systematic household exclusion as well as clustering. For the studies involving fieldwork, a total of forty villages were randomly selected for participation. The study protocols received clearance from the ethics committees of Basel (EKBB, reference no. 64/13) and the national ethics committee in Côte d’Ivoire (reference no. 32-MSLS/CNERdkn). In Chad, research authorization including ethical approval was granted by the District, regional and local authorities, village chiefs, study participants and parents/guardians of individuals aged below 18 years were informed about the purpose, procedures and potential risks and benefits of the study. Written informed consent was obtained from all participants and the parents/guardians of minors. Parasitological examinations as well as questionnaire surveys, focus group discussions and direct observations were performed within the villages, nearby Peulh settlements and surrounding water bodies. Parasitological examinations included reagent strip testing with Hemastix®, (Bayer Diagnostics; Basingstoke, United Kingdom), urine filtration of 10 ml of urine, double Kato-Katz of a single stool sample, Baerman filtration and the point-of-care circulating cathodic antigen test. Snails and water parameters were collected from water sites indicated by the communities as the ones most frequently accessed by the population. Results: Our literature review revealed 21 methods for household sampling and/or the creation or update of sampling frames. Some methods describe variations of cluster sampling, some aiming at the creation/obtaining or improving of existing sampling frames and some pertaining to achieve sampling in the absence of a sampling frame. Three methods pertained to sampling with rather strict requirements in surveys. A preliminary computer simulation of several existing and newly proposed spatial methods for household sampling revealed that all sampling methods based on a spatial approach oversampled houses around the starting point. Additionally many also systematically excluded certain households. One newly proposed method which employs the simple to implement use of a pouch of numbered paper lots is an adaption of the method from the extended programme of immunization (EPI). Equally sized and shaped paper lots containing numbers ranging from 1 to 20 are put into the pouch. An additional 21st lot is included, indicating that a new walking direction will have to be chosen randomly by spinning a bottle. This method delivered the best sample in the simulations, whereas several methods developed to improve the original EPI methods actually had worse outcomes compared to the original EPI method. A decision frame for choosing an adequate household sampling method for researchers and other individuals conducting surveys is proposed in the respective chapter. The prevalence of schistosomiasis in the Tchologo region of northern Côte d’Ivoire was very low; Infections with S. haematobium and S. mansoni infections were found in 2.2% and 1.0%, respectively. No human Fasciola infection was found. With a prevalence of 13%, microhaematuria, as assessed with reagent strips, far surpassed the prevalence of S. haematobium determined with urine filtration in the study region. Our literature review revealed that in many published surveys, microhaematuria-positive test results that were not linked to positive urine filtration results occurred irrespective of the underlying S. haematobium prevalence assessed by urine filtration. These findings indicate either the occurrence of alternative causes for blood in urine in endemic settings or the gross underestimation of the true prevalence of S. haematobium in various settings. All individuals in our study villages had access to, and were using, safe water sources. Nevertheless, accessing and consuming unsafe water was very common and occurred in most instances during work on the fields or at the side of the road where it was unfeasible to transport needed quantities of drinking water and/or where water from the dams, rivers and small water collections was needed for the work. Additionally we could show that 38% of direct physical contact with unsafe water resulted from the fact that people who otherwise reported to only use safe water sources had to cross open water and thus increase the risk of acquiring schistosomiasis, albeit adequate water supply and sanitation facilities. Intermediate host snail species were present in the study area, with fascioliasis intermediate host snails from the family of the Lymnaeidae occurring mostly in the northern part of the region, whereas Schistosoma mansoni transmitting Biomphalaria snails occurred mostly in the southern region, while Bulinus (intermediate host of S. haematobium) were ubiquitous. Human and animal presence at the water sites strongly correlated with snail occurrence. Conclusions: The adoption of a systemic approach for the control and elimination of snail-borne trematodiases can be very helpful, as it allows inclusion and consideration of a myriad of factors, ranging from methodological to social-ecological issues. Furthermore, researchers and intervention programmes could benefit from an even greater collaboration between different scientific fields, including but not limited to epidemiology, parasitology, sociology, anthropology and social psychology. Indeed, understanding the factors which make humans act in a certain desired or undesired way can play a major role in the success of control or elimination efforts. Most notably, the largest potential benefit could arise from working together with social marketers and drawing upon their years of experience in adequately identifying and analysing target populations and designing ways to tailor implement and communicate public health programmes/messages in a way that maximises community interest and incentives to adopt and sustain the programmes

Knowledge and Practices on the Prevention and management of diarrhea in children under-2 years among women dwelling in urban slums of Karachi, Pakistan

Background: Diarrhea is the second leading cause of death especially among children. The age-proportionate mortality of diarrheal disease in infants under 2 years is 72%, among children under 5 years of age. Children living in urban slums are more prone to develop diarrhea. Although the disease can be prevented by many simple cost-effective interventions, i.e. proper sanitation and hygiene, appropriate feeding, and timely vaccination, poverty and lack of basic life amenities often potentiate diarrhea mortality. Gadap town is the largest town of Karachi with a deprived health system. This study aims to assess pediatric diarrhea prevalence and related knowledge-practice gaps in the slums of Gadap Town, Karachi, Pakistan. Method: A community-based cross-sectional study was conducted from November 2016 to May 2017 among mothers of children under 2 years, who were residents of Gadap Town, Karachi, Pakistan. The participants were approached by a multistage sampling method. A validated dichotomous questionnaire, piloted on 40 participants, translated into local language Urdu was used for data collection and the data was analyzed by SPSS® version 20.0. Results: 51.8% (n = 199) of participants were aged between 25 and 34 years. Among all participants, 68% (n = 261) had primary level education or less, compared to 4.7% (n = 18) of women who had graduate-level education. The mean number of children per woman was 2.52 ± 1.62. Self-reported pediatric diarrhea incidence was 72.1% (n = 277). More than half (55.2% n = 149) of participants reported frequent diarrhea episodes during the 2nd year of their child\u27s life. In this survey, we found the knowledge of women regarding diarrhea management and how to reduce diarrhea morbidity to be inadequate (p \u3e 0.05). However, many women reported appropriate practices which can significantly reduce diarrhea morbidity (p \u3c 0.05). Conclusion: While the knowledge among women on preventive measures for pediatric diarrhea was insufficient, the translation of the right knowledge into appropriate practices showed promising outcomes for reducing diarrhea morbidity. An integrated approach for improving feeding, sanitation, and hygiene practices along with continuous health education could curtail the burden of diarrhea among infants living in urban slum

A call for systems epidemiology to tackle the complexity of schistosomiasis, its control, and elimination

Ever since the first known written report of schistosomiasis in the mid-19th century, researchers have aimed to increase knowledge of the parasites, their hosts, and the mechanisms contributing to infection and disease. This knowledge generation has been paramount for the development of improved intervention strategies. Yet, despite a broad knowledge base of direct risk factors for schistosomiasis, there remains a paucity of information related to more complex, interconnected, and often hidden drivers of transmission that hamper intervention successes and sustainability. Such complex, multidirectional, non-linear, and synergistic interdependencies are best understood by looking at the integrated system as a whole. A research approach able to address this complexity and find previously neglected causal mechanisms for transmission, which include a wide variety of influencing factors, is needed. Systems epidemiology, as a holistic research approach, can integrate knowledge from classical epidemiology, with that of biology, ecology, social sciences, and other disciplines, and link this with informal, tacit knowledge from experts and affected populations. It can help to uncover wider-reaching but difficult-to-identify processes that directly or indirectly influence exposure, infection, transmission, and disease development, as well as how these interrelate and impact one another. Drawing on systems epidemiology to address persisting disease hotspots, failed intervention programmes, and systematically neglected population groups in mass drug administration programmes and research studies, can help overcome barriers in the progress towards schistosomiasis elimination. Generating a comprehensive view of the schistosomiasis system as a whole should thus be a priority research agenda towards the strategic goal of morbidity control and transmission elimination

Reporter emission multiplexing in digital PCRs (REM-dPCRs): direct quantification of multiple target sequences per detection channel by population specific reporters

Digital PCRs (dPCRs) are widely used methods for the detection and quantification of rare abundant sequences relevant to fields such as liquid biopsy or oncology. In order to increase the information content and save valuable sample materials, there is a significant need for digital multiplexing methods that are easy to establish, analyse, and interpret, and ideally allow the usage of existing lab equipment. Herein, we present a novel reporter emission multiplexing approach for the digital PCR method (REM-dPCR), which meets these requirements. It further increases the multiplexing capacity of commercial dPCR devices. For example, we present a stepwise increase in multiplexing degrees from a monochrome two-plex assay in one detection channel to a six-plex REM-dPCR assay in a three-color dPCR device for KRAS/BRAF single nucleotide polymorphism (SNP) target sequences. The guidelines for the REM-dPCR design are presented, and the process from duplex to six-plex assay establishment, taking into account the target sequence-dependent effects on assay performance, is discussed. Furthermore, the assay-specific, sensitive and precise quantification of different fractions of KRAS mutant and wild-type DNA sequences in different ratios is demonstrated. To increase the device capacitance and the degree of multiplexing, the REM-dPCR uses the advantage of n target-independent reporter molecules in combination with target sequence-specific mediator probes. Different reporter types are labelled with fluorophores of different signal intensities but not necessarily different emission spectra. This leads to the generation of n independent single-positive populations in the dataspace, created by k detection channels, whereby n > k and n ≥ 2. By usage of target-independent but population-specific reporter types, a fixed set of six optimized signalling molecules could be defined. This reporter set enables the robust generation and precise differentiation of multiple fluorescence signals in dPCRs and can be transferred to new target panels. The set which enables stable signal generation and differentiation in a specified device would allow easy transfer to new target panels

Distribution of bovine Fasciola gigantica (Cobbold, 1885) in the district des Savanes, northern Côte d'Ivoire

Fascioliasis, caused by an infection with liver flukes of the genus Fasciola, is an important disease of livestock in most parts of the world. However, little is known about the distribution of fascioliasis in sub-Saharan Africa. We report results of a cross-sectional study conducted in 2014 in the district des Savanes in the northern part of Cote d'Ivoire. We obtained 275 livers from bovine suspected with fascioliasis and 51 unsuspected livers from 24 slaughterhouses. Livers were dissected using a standard operating procedure and all Fasciola gigantica flukes were removed from the tissues of the liver and the biliary ducts. We found F. gigantica in 125 livers from bovines suspected with fascioliasis (45.5%) in 10 departments of the district des Savanes. Among the unsuspected livers, five were positive for F. gigantica (9.8%). The distribution of fascioliasis showed considerable spatial heterogeneity, both at regional (ranging from 18.0% to 52.3%) and departmental level (ranging from 14.3% to 64.0%). Poro region was the most affected (52.3%) with a relatively homogeneous distribution. The departments most affected by fascioliasis were M'Bengue (64.0%), Sinematiali (62.1%) and Ferkessedougou (52.9%). Our study confirms that fascioliasis is an important veterinary disease in the northern part of Cote d'Ivoire, and hence, high-risk areas need to be targeted for prevention and control measures

Evidencing the clinical and economic burden of musculoskeletal disorders in Tanzania: Paving the way for urgent rheumatology service development

Since 1990, there has been a dramatic rise in noncommunicable diseases (NCDs) within low-and middleincome countries (LMICs); the burden of NCDs in LMICs rose from accounting for 39% of disability-adjusted life years in 1990 to 66% in 2019 [1]. In response to this growing burden, global, regional and national health institutions have become increasingly active in orchestrating a response to NCDs. The global response to NCDs has prioritized cardiovascular disease, cancer, chronic respiratory disease and diabetes, with the World Health Organization Regional Office in Africa adding region-specific NCD burdens, such as sickle cell disease, to broaden priorities [2]. Amidst this galvanization of efforts to tackle NCDs, musculoskeletal (MSK) conditions have been relatively overlooked and neglected, resulting in an urgent need for service development to respond to MSK conditions in LMICs [1]

Estimating the prevalence, quality of life, economic and societal impact of arthritis in Tanzania: protocol for a mixed methods study [Protocol]

Introduction: Musculoskeletal (MSK) disorders are one of the major causes of disability globally. A 2010 Global Burden of Disease study reported that MSK diseases account for 20% of all Years Lived with Disability (YLDs) in Low- and Middle-Income countries. This study will use mixed methods to generate new findings on the prevalence, quality of life, economic and societal impact of musculoskeletal disorders (including arthritis) in the Hai district in Tanzania. Methods and analysis: In this mixed-methods study funded by the UK’s National Institute for Health Research (NIHR) Global Health Research Units and Groups (Award no: 17/63/35) we will conduct quantitative, community-based (urban, peri - urban and rural) and hospital based prospective surveys, supported by rapid ethnographic assessments (REAs), in-depth interviews, focus group discussions (FGDs) and clinical diagnostic screening to estimate the prevalence, economic and societal impact of arthritis. A retrospective medical records baseline review at the Kilimanjaro Christian Medical Centre (KCMC) will also be conducted to assess prevailing documentation and management of arthritis. Ethics and dissemination: Ethical approval has been obtained through Kilimanjaro Christian Medical University College (KCMUCo) Research Ethics and Review committee (CRERC) in Moshi, National Health Research Ethics Committee (NatHREC) of the National Institute for Medical research (NIMR) in Tanzania and the Medical Veterinary and Life Sciences (MVLS) Ethics committee at the University of Glasgow, UK (MVLS ethics project number:20018010). We will disseminate the findings in clinical, epidemiological, and economic peer reviewed journals. Other dissemination modalities include professional conferences, short reports, community leaflets, policy briefs and dissemination events to communities and various stakeholders including the Ministry of health in Tanzania

Trends of frequency, mortality and risk factors among patients admitted with stroke from 2017 to 2019 to the medical ward at Kilimanjaro Christian Medical Centre hospital: a retrospective observational study

Objective The burden of stroke has increased in recent years worldwide, particularly in low-income and middle-income countries. In this study we aim to determine the number of stroke admissions, and associated comorbidities, at a referral hospital in Northern Tanzania. Design This was a retrospective observational study. Setting The study was conducted at a tertiary referral hospital, Kilimanjaro Christian Medical Centre (KCMC), in the orthern zone of Tanzania. Participants The study included adults aged 18 years and above, who were admitted to the medical wards from 2017 to 2019. Outcome The primary outcome was the proportion of patients who had a stroke admitted in the medical ward at KCMC and the secondary outcome was clinical outcome such as mortality. Methods We conducted a retrospective audit of medical records from 2017 to 2019 for adult patients admitted to the medical ward at KCMC. Data extracted included demographic characteristics, previous history of stroke and outcome of the admission. Factors associated with stroke were investigated using logistic regression. Results Among 7976 patients admitted between 2017 and 2019, 972 (12.2%) were patients who had a stroke. Trends show an increase in patients admitted with stroke over the 3 years with 222, 292 and 458 in 2017, 2018 and 2019, respectively. Of the patients who had a stroke, 568 (58.4%) had hypertension while 167 (17.2%) had diabetes mellitus. The proportion of admitted stroke patients aged 18–45 years, increased from 2017 (n=28, 3.4%) to 2019 (n=40, 4.3%). The in-hospital mortality related to stroke was 229 (23.6%) among 972 patients who had a stroke and female patients had 50% higher odds of death as compared with male patients (OR:1.5; CI 1.30 to 1.80). Conclusion The burden of stroke on individuals and health services is increasing over time, which reflects a lack of awareness on the cause of stroke and effective preventive measures. Prioritising interventions directed towards the reduction of non-communicable diseases and associated complications, such as stroke, is urgently needed

Estimating the prevalence, quality of life, economic and societal impact of arthritis in Tanzania: protocol for a mixed methods study [Protocol]

Introduction: Musculoskeletal (MSK) disorders are one of the major causes of disability globally. A 2010 Global Burden of Disease study reported that MSK diseases account for 20% of all Years Lived with Disability (YLDs) in Low- and Middle-Income countries. This study will use mixed methods to generate new findings on the prevalence, quality of life, economic and societal impact of musculoskeletal disorders (including arthritis) in the Hai district in Tanzania. Methods and analysis: In this mixed-methods study funded by the UK’s National Institute for Health Research (NIHR) Global Health Research Units and Groups (Award no: 17/63/35) we will conduct quantitative, community-based (urban, peri - urban and rural) and hospital based prospective surveys, supported by rapid ethnographic assessments (REAs), in-depth interviews, focus group discussions (FGDs) and clinical diagnostic screening to estimate the prevalence, economic and societal impact of arthritis. A retrospective medical records baseline review at the Kilimanjaro Christian Medical Centre (KCMC) will also be conducted to assess prevailing documentation and management of arthritis. Ethics and dissemination: Ethical approval has been obtained through Kilimanjaro Christian Medical University College (KCMUCo) Research Ethics and Review committee (CRERC) in Moshi, National Health Research Ethics Committee (NatHREC) of the National Institute for Medical research (NIMR) in Tanzania and the Medical Veterinary and Life Sciences (MVLS) Ethics committee at the University of Glasgow, UK (MVLS ethics project number:20018010). We will disseminate the findings in clinical, epidemiological, and economic peer reviewed journals. Other dissemination modalities include professional conferences, short reports, community leaflets, policy briefs and dissemination events to communities and various stakeholders including the Ministry of health in Tanzania

Association of latent class analysis-derived multimorbidity clusters with adverse health outcomes in patients with multiple long-term conditions: Comparative results across three UK cohorts

Background It remains unclear how to meaningfully classify people living with multimorbidity (multiple long-term conditions (MLTCs)), beyond counting the number of conditions. This paper aims to identify clusters of MLTCs in different age groups and associated risks of adverse health outcomes and service use. Methods Latent class analysis was used to identify MLTCs clusters in different age groups in three cohorts: Secure Anonymised Information Linkage Databank (SAIL) (n = 1,825,289), UK Biobank (n = 502,363), and the UK Household Longitudinal Study (UKHLS) (n = 49,186). Incidence rate ratios (IRR) for MLTC clusters were computed for: all-cause mortality, hospitalisations, and general practice (GP) use over 10 years, using <2 MLTCs as reference. Information on health outcomes and service use were extracted for a ten year follow up period (between 01st Jan 2010 and 31st Dec 2019 for UK Biobank and UKHLS, and between 01st Jan 2011 and 31st Dec 2020 for SAIL). Findings Clustering MLTCs produced largely similar results across different age groups and cohorts. MLTC clusters had distinct associations with health outcomes and service use after accounting for LTC counts, in fully adjusted models. The largest associations with mortality, hospitalisations and GP use in SAIL were observed for the “Pain+” cluster in the age-group 18–36 years (mortality IRR = 4.47, hospitalisation IRR = 1.84; GP use IRR = 2.87) and the “Hypertension, Diabetes & Heart disease” cluster in the age-group 37–54 years (mortality IRR = 4.52, hospitalisation IRR = 1.53, GP use IRR = 2.36). In UK Biobank, the “Cancer, Thyroid disease & Rheumatoid arthritis” cluster in the age group 37–54 years had the largest association with mortality (IRR = 2.47). Cardiometabolic clusters across all age groups, pain/mental health clusters in younger groups, and cancer and pulmonary related clusters in older age groups had higher risk for all outcomes. In UKHLS, MLTC clusters were not significantly associated with higher risk of adverse outcomes, except for the hospitalisation in the age-group 18–36 years. Interpretation Personalising care around MLTC clusters that have higher risk of adverse outcomes may have important implications for practice (in relation to secondary prevention), policy (with allocation of health care resources), and research (intervention development and targeting), for people living with MLTCs. Funding This study was funded by the National Institute for Health and Care Research (NIHR; Personalised Exercise-Rehabilitation FOR people with Multiple long-term conditions (multimorbidity)—NIHR202020)