Identification of 2,4-Disubstituted Imidazopyridines as Hemozoin Formation Inhibitors with Fast-Killing Kinetics and In Vivo Efficacy in the Plasmodium falciparum NSG Mouse Model

A series of 2,4-disubstituted imidazopyridines, originating from a SoftFocus Kinase library, was identified from a high throughput phenotypic screen against the human malaria parasite Plasmodium falciparum. Hit compounds showed moderate asexual blood stage activity. During lead optimization, several issues were flagged such as cross-resistance against the multidrug-resistant K1 strain, in vitro cytotoxicity, and cardiotoxicity and were addressed through structure–activity and structure–property relationship studies. Pharmacokinetic properties were assessed in mice for compounds showing desirable in vitro activity, a selectivity window over cytotoxicity, and microsomal metabolic stability. Frontrunner compound 37 showed good exposure in mice combined with good in vitro activity against the malaria parasite, which translated into in vivo efficacy in the P. falciparum NOD-scid IL-2Rγnull (NSG) mouse model. Preliminary mechanistic studies suggest inhibition of hemozoin formation as a contributing mode of action

Analysis of risk factors for T. brucei rhodesiense sleeping sickness within villages in south-east Uganda

<p>Abstract</p> <p>Background</p> <p>Sleeping sickness (HAT) caused by <it>T.b. rhodesiense </it>is a major veterinary and human public health problem in Uganda. Previous studies have investigated spatial risk factors for <it>T.b. rhodesiense </it>at large geographic scales, but none have properly investigated such risk factors at small scales, i.e. within affected villages. In the present work, we use a case-control methodology to analyse both behavioural and spatial risk factors for HAT in an endemic area.</p> <p>Methods</p> <p>The present study investigates behavioural and occupational risk factors for infection with HAT within villages using a questionnaire-based case-control study conducted in 17 villages endemic for HAT in SE Uganda, and spatial risk factors in 4 high risk villages. For the spatial analysis, the location of homesteads with one or more cases of HAT up to three years prior to the beginning of the study was compared to all non-case homesteads. Analysing spatial associations with respect to irregularly shaped geographical objects required the development of a new approach to geographical analysis in combination with a logistic regression model.</p> <p>Results</p> <p>The study was able to identify, among other behavioural risk factors, having a family member with a history of HAT (p = 0.001) as well as proximity of a homestead to a nearby wetland area (p < 0.001) as strong risk factors for infection. The novel method of analysing complex spatial interactions used in the study can be applied to a range of other diseases.</p> <p>Conclusion</p> <p>Spatial risk factors for HAT are maintained across geographical scales; this consistency is useful in the design of decision support tools for intervention and prevention of the disease. Familial aggregation of cases was confirmed for <it>T. b. rhodesiense </it>HAT in the study and probably results from shared behavioural and spatial risk factors amongmembers of a household.</p

The Unknown Risk of Vertical Transmission in Sleeping Sickness—A Literature Review

Children with human African trypanosomiasis (HAT) present with a range of generally non-specific symptoms. Late diagnosis is frequent with often tragic outcomes. Trypanosomes can infect the foetus by crossing the placenta. Unequivocal cases of congenital infection that have been reported include newborn babies of infected mothers who were diagnosed with HAT in the first 5 days of life and children of infected mothers who had never entered an endemic country themselves

Civil conflict and sleeping sickness in Africa in general and Uganda in particular

Conflict and war have long been recognized as determinants of infectious disease risk. Re-emergence of epidemic sleeping sickness in sub-Saharan Africa since the 1970s has coincided with extensive civil conflict in affected regions. Sleeping sickness incidence has placed increasing pressure on the health resources of countries already burdened by malaria, HIV/AIDS, and tuberculosis. In areas of Sudan, the Democratic Republic of the Congo, and Angola, sleeping sickness occurs in epidemic proportions, and is the first or second greatest cause of mortality in some areas, ahead of HIV/AIDS. In Uganda, there is evidence of increasing spread and establishment of new foci in central districts. Conflict is an important determinant of sleeping sickness outbreaks, and has contributed to disease resurgence. This paper presents a review and characterization of the processes by which conflict has contributed to the occurrence of sleeping sickness in Africa. Conflict contributes to disease risk by affecting the transmission potential of sleeping sickness via economic impacts, degradation of health systems and services, internal displacement of populations, regional insecurity, and reduced access for humanitarian support. Particular focus is given to the case of sleeping sickness in south-eastern Uganda, where incidence increase is expected to continue. Disease intervention is constrained in regions with high insecurity; in these areas, political stabilization, localized deployment of health resources, increased administrative integration and national capacity are required to mitigate incidence. Conflict-related variables should be explicitly integrated into risk mapping and prioritization of targeted sleeping sickness research and mitigation initiatives

On the Holocene evolution of the Ayeyawady megadelta

The Ayeyawady delta is the last Asian megadelta whose evolution has remained essentially unexplored so far. Unlike most other deltas across the world, the Ayeyawady has not yet been affected by dam construction, providing a unique view on largely natural deltaic processes benefiting from abundant sediment loads affected by tectonics and monsoon hydroclimate. To alleviate the information gap and provide a baseline for future work, here we provide a first model for the Holocene development of this megadelta based on drill core sediments collected in 2016 and 2017, dated with radiocarbon and optically stimulated luminescence, together with a reevaluation of published maps, charts and scientific literature. Altogether, these data indicate that Ayeyawady is a mud-dominated delta with tidal and wave influences. The sediment-rich Ayeyawady River built meander belt alluvial ridges with avulsive characters. A more advanced coast in the western half of the delta (i.e., the Pathein lobe) was probably favored by the more western location of the early course of the river. Radiogenic isotopic fingerprinting of the sediment suggests that the Pathein lobe coast does not receive significant sediment from neighboring rivers. However, the eastern region of the delta (i.e., Yangon lobe) is offset inland and extends east into the mudflats of the Sittaung estuary. Wave-built beach ridge construction during the late Holocene, similar to several other deltas across the Indian monsoon domain, suggests a common climatic control on monsoonal delta morphodynamics through variability in discharge, changes in wave climate or both. Correlation of the delta morphological and stratigraphic architecture information on land with the shelf bathymetry, as well as its tectonic, sedimentary and hydrodynamic characteristics, provides insight on the peculiar growth style of the Ayeyawady delta. The offset between the western Pathein lobe and the eastern deltaic coast appears to be driven by tectonic-hydrodynamic feedbacks as the extensionally lowered shelf block of the Gulf of Mottama amplifies tidal currents relative to the western part of the shelf. This situation probably activates a perennial shear front between the two regions that acts as a leaky energy fence. Just as importantly, the strong currents in the Gulf of Mottama act as an offshore-directed tidal pump that helps build the deep mid-shelf Mottama clinoform with mixed sediments from the Ayeyawady, Sittaung and Thanlwin rivers. The highly energetic tidal, wind and wave regime of the northern Andaman Sea thus exports most sediment offshore despite the large load of the Ayeyawady River

Mycoplasma genitalium: an organism commonly associated with cervicitis among west African sex workers

Objectives: To identify the contribution of Mycoplasma genitalium to the aetiology of cervicitis in sub-Saharan Africa and its relative importance in the overall burden of sexually transmitted infections among female sex workers (FSW). Methods: The study population consisted of FSW recruited in Ghana and Bénin during the initial visit of a randomised controlled trial. A questionnaire was administered, a pelvic examination carried out, and cervical samples obtained for detection of M genitalium, Neisseria gonorrhoeae, Chlamydia trachomatis, and Trichomonas vaginalis. Clinical signs potentially indicating cervicitis were cervical discharge, pus on the cervical swab, bleeding after sampling, and inflammatory cervix. Results: Among 826 FSW, 26.3% were infected with M genitalium. N gonorrhoeae was strongly and independently associated with each of the four signs of cervicitis (adjusted odds ratios (AOR): 4.1 to 6.0). The AOR for C trachomatis were intermediate (1.3–4.1) and the AOR for M genitalium were lower (between 1.6 and 1.8) but statistically significant (p⩽0.05) for each sign. Conclusions: M genitalium is weakly associated with signs of cervicitis in west African FSW but is highly prevalent

Twenty-five years of monitoring of green space pattern dynamics in response to urbanization in the municipalities of Lubumbashi City (Upper Katanga, DR Congo)

This study assessed the spatial-temporal dynamics of green spaces in response to urban growth for the seven municipalities of Lubumbashi city, Democratic Republic of the Congo between, 1989 and 2014. Pattern analysis revealed that since 1989, the built-up proportion has gradually increased in all municipalities at the expense of green space area as a result of rapid demographic pressure coupled with a lack of an appropriate program for their preservation. In terms of pattern dynamics, green space extent has been dominated by attrition, fragmentation and dissection processes. This is opposed to creation and aggregation which characterized built-up areas. Our observations emphasize the need for a sustainable management of green spaces that takes into account the socio- economic context of each municipality