The Prevalence of Previously Undiagnosed Leprosy in the General Population of Northwest Bangladesh

In order to estimate the level of leprosy in an area with many leprosy patients, we determined the prevalence of previously undiagnosed leprosy in the general population and compared this with the registered (or known) number of leprosy patients. We also compared it with the known prevalence of leprosy in contacts of leprosy patients. We examined 20 randomly selected geographical clusters of 1,000 persons each in two districts of Bangladesh, with over 4 million population. Physical examination was performed on all individuals. The number of newly found leprosy cases among 17,862 people above 5 years of age from the clusters was 27, giving a rate of previously undiagnosed leprosy of 15.1 per 10,000. This rate is six times higher than the registered prevalence, but three times lower than the rate in the most distant subgroup of contacts (neighbour of neighbour and social contacts) of leprosy patients in the same area. We conclude that in areas where leprosy is common, it may be preferable to do full village or neighbourhood surveys when a new leprosy patient is found, rather than to limit contact surveys to close contacts only, such as household members

Elucidating an immune metabolite pathway in sepsis

This thesis aimed to evaluate the role of the medium-chain-fatty-acid (MCFA)-GPR84 signalling axis in sepsis. Sepsis is a life-threatening condition where the dysregulated host response to an infection can lead to death by organ failure. Several bodily systems can be affected in sepsis, including metabolism on a cellular and physiological level. GPR84 is a receptor present on innate immune myeloid cells and is upregulated in response to inflammatory stimuli. In sepsis, GPR84 expression is strongly upregulated and is an integral biomarker member of a transcriptomic signature that has been shown to accurately predict sepsis in a neonatal sepsis study. The ligands that it binds comprise MCFAs with a chain length of 10 or 12 carbons. These lipids are currently understudied and their presence in relevant amounts in the human body has been doubted in the science community. Moreover, their presence in the inflammatory context, such as during infection or in sepsis, has not been studied previously. Furthermore, their potential origin, if present, remains to be elucidated as well. I hypothesize that the MCFA-GPR84 axis is a key regulated host response in sepsis. To address this hypothesis, it is pivotal to test whether MCFAs are present in the blood and whether their concentrations change in sepsis patients and if so, to determine their possible origin. To this end, I established a lipid quantification method using liquid-chromatography tandem mass spectrometry (LC-MS/MS) that was able to reliably measure MCFAs and a range of longer chain fatty acids and acylcarnitines. Employing this method on plasma samples from a sepsis cohort led to the measurement of C10:0 and C12:0, with C10:0 being significantly increased in sepsis and C12:0 significantly decreased in some types of sepsis compared to controls. Notably, the measured lipid levels were heterogeneous and only a subset of patients showed increased C10:0 levels. Furthermore, I found using transcriptomic data that oloeyl-acp-hydrolase (OLAH), the gene encoding an enzyme pivotal in cellular MCFA production, is upregulated in sepsis. OLAH’s cellular role has previously been established with regards to MCFA production by the mammary gland during lactation, upregulation of OLAH in sepsis is likely caused by cortisol. I found that a synthetic glucocorticoid (dexamethasone) lead to increased OLAH gene expression in immune cell lines in vitro, in addition, the glucocorticoid receptor was found as potential transcription factor regulating OLAH in an in silico approach. Also, peripheral blood mononuclear cells were found to be able to produce C10:0 in vitro. Further analyses were conducted in relation to a broader range of lipids and their levels in the plasma of sepsis patient to determine the plasma lipid profile associated with sepsis. In these investigations I found increased short-chain and medium-chain acylcarnitines and decreased poly-unsaturated fatty acids, namely arachidonic acid and eicosapentaenoic acid. An altered plasma lipid profile seems to be indicative of sepsis and was partially shown to be associated with mortality and severity. Finally, the transcriptional regulation of GPR84 and its temporal expression pattern was examined using an in silico approach and in vitro experiments. These results indicate that GPR84 is likely a secondary immune response gene, upregulated after around 2 hours of an inflammatory stimulus in myeloid cell types. Overall, it appears that the MCFA-GPR84 signalling axis is likely activated in a subset of sepsis patients, most likely those with increased cortisol and at a higher risk of complications and mortality. This tentatively indicates that C10:0-GPR84 signalling in sepsis is detrimental to survival. In conclusion, the data of my thesis supports the hypothesis that the MCFA-GPR84 signalling axis is a key regulated host response with the limitation that this is likely only the case in a subset of patients. In these patients though this signalling axis could likely be a mediator of the increased mortality observed in patients with strongly elevated cortisol

The spatial distribution of leprosy in four villages in Bangladesh: An observational study

BACKGROUND: There is a higher case-detection rate for leprosy among spatially proximate contacts such as household members and neighbors. Spatial information regarding the clustering of leprosy can be used to improve intervention strategies. Identifying high-risk areas within villages around known cases can be helpful in finding new cases. METHODS: Using geographic information systems, we created digital maps of four villages in a highly endemic area in northwest Bangladesh. The villages were surveyed three times over four years. The spatial pattern of the compounds--a small group of houses--was analyzed, and we looked for spatial clusters of leprosy cases. RESULTS: The four villages had a total population of 4,123. There were 14 previously treated patients and we identified 19 new leprosy patients during the observation period. However, we found no spatial clusters with a probability significantly different from the null hypothesis of random occurrence. CONCLUSION: Spatial analysis at the microlevel of villages in highly endemic areas does not appear to be useful for identifying clusters of patients. The search for clustering should be extended to a higher aggregation level, such as the subdistrict or regional level. Additionally, in highly endemic areas, it appears to be more effective to target complete villages for contact tracing, rather than narrowly defined contact groups such as households

A policymaker’s guide to understanding youth livelihood aspirations in Myanmar

The International Water Management Institute (IWMI) and WorldFish conducted a study with young people from a fishing community in the Ayeyarwady Delta of Myanmar. The study sought to understand the livelihood aspirations of these young people and how they were connected to eventual livelihood realities