Rapid assembly of highly-functionalised difluorinated cyclooctenones via ring-closing metathesis

Building block methodology from trifluoroethanol and ringclosing metathesis using a Fürstner modification of Grubbs’ conditions allows the rapid synthesis of novel difluorinated cyclooctenones

The birds of Uaso Narok Forest Reserve, Central Kenya

The birds of the Uaso Narok Forest, Central Kenya, were surveyed between June 2008 and April 2009. We recorded 161 species representing 49 families in total. Of these species, 34 were representative of the Afrotropical Highland Biome, representing 51% of all Kenyan species of this biome; two species were representative of the Somali-Masai biome. In addition to the Lesser Kestrel Falco naumanni (listed as Vulnerable in the IUCN Red List), there were 27 species of regional conservation concern. Breeding activity was recorded for 39 species, while a new population of Black-billed Weaver Ploceus melanogaster was discovered here, thus extending the species’ known range. The main human activities recorded in this forest included firewood collection, illegal logging and charcoal burning. This survey revealed that Uaso Narok Forest is important for the conservation of Kenya’s montane forest avifauna and deserves immediate official protection, as well as further biological research

Crossing Cultures: Guides and Models for Development, Selection, and Application

Despite many calls for it, there has been little action toward an all-inclusive manuscript that is practical, empirically verified, and provides guidelines for becoming and remaining strategically culturally adaptive. Further, a tremendous number of current articles and books emphasize managing or leading in an era of globalization. To meet these calls to work, learn, and innovate across cultures, the goal must be to move from the mass of unrelated assertions to the weaving of co-created, manageable models that are useful in learning, teaching, and practice

The Dantu blood group prevents parasite growth in vivo: evidence from a controlled human malaria infection study

Background: The long co-evolution of Homo sapiens and Plasmodium falciparum has resulted in the selection of numerous human genetic variants that confer an advantage against severe malaria and death. One such variant is the Dantu blood group antigen, which is associated with 74% protection against severe and complicated P. falciparum malaria infections in homozygous individuals, similar to that provided by the sickle haemoglobin allele (HbS). Recent in vitro studies suggest that Dantu exerts this protection by increasing the surface tension of red blood cells, thereby impeding the ability of P. falciparum merozoites to invade them and reducing parasite multiplication. However, no studies have yet explored this hypothesis in vivo. Methods: We investigated the effect of Dantu on early phase P. falciparum (Pf) infections in a controlled human malaria infection (CHMI) study. 141 sickle-negative Kenyan adults were inoculated with 3.2 × 103 aseptic, purified, cryopreserved Pf sporozoites (PfSPZ Challenge) then monitored for blood-stage parasitaemia for 21 days by quantitative polymerase chain reaction (qPCR)analysis of the 18S ribosomal RNA P. falciparum gene. The primary endpoint was blood-stage P. falciparum parasitaemia of ≥500/μl while the secondary endpoint was the receipt of antimalarial treatment in the presence of parasitaemia of any density. On study completion, all participants were genotyped both for Dantu and for four other polymorphisms that are associated with protection against severe falciparum malaria: α+-thalassaemia, blood group O, G6PD deficiency, and the rs4951074 allele in the red cell calcium transporter ATP2B4. Results: The primary endpoint was reached in 25/111 (22.5%) non-Dantu subjects in comparison to 0/27 (0%) Dantu heterozygotes and 0/3 (0.0%) Dantu homozygotes (p=0.01). Similarly, 49/111 (44.1%) non-Dantu subjects reached the secondary endpoint in comparison to only 7/27 (25.9%) and 0/3 (0.0%) Dantu heterozygotes and homozygotes, respectively (p=0.021). No significant impacts on either outcome were seen for any of the other genetic variants under study. Conclusions: This study reveals, for the first time, that the Dantu blood group is associated with high-level protection against early, non-clinical, P. falciparum malaria infections in vivo. Learning more about the mechanisms involved could potentially lead to new approaches to the prevention or treatment of the disease. Our study illustrates the power of CHMI with PfSPZ Challenge for directly testing the protective impact of genotypes previously identified using other methods. Funding: The Kenya CHMI study was supported by an award from Wellcome (grant number 107499). SK was supported by a Training Fellowship (216444/Z/19/Z), TNW by a Senior Research Fellowship (202800/Z/16/Z), JCR by an Investigator Award (220266/Z/20/Z), and core support to the KEMRI-Wellcome Trust Research Programme in Kilifi, Kenya (203077), all from Wellcome. The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. For the purpose of Open Access, the authors have applied a CC BY public copyright license to any Author Accepted Manuscript version arising from this submission. Clinical trial number: NCT0273976

Household socio-economic position and individual infectious disease risk in rural Kenya

The importance of household socio-economic position (SEP) in shaping individual infectious disease risk is increasingly recognised, particularly in low income settings. However, few studies have measured the extent to which this association is consistent for the range of pathogens that are typically endemic among the rural poor in the tropics. This cross-sectional study assessed the relationship between SEP and human infection within a single community in western Kenya using a set of pathogens with diverse transmission routes. The relationships between household SEP and individual infection with Plasmodium falciparum, hookworm (Ancylostoma duodenale and/or Necator americanus), Entamoeba histolytica/dispar, Mycobacterium tuberculosis, and HIV, and co-infections between hookworm, P. falciparum and E. histolytica/dispar, were assessed using multivariable logistic and multinomial regression. Individuals in households with the lowest SEP were at greatest risk of infection with P. falciparum, hookworm and E. histolytica/dispar, as well as co-infection with each pathogen. Infection with M. tuberculosis, by contrast, was most likely in individuals living in households with the highest SEP. There was no evidence of a relationship between individual HIV infection and household SEP. We demonstrate the existence of a household socio-economic gradient within a rural farming community in Kenya which impacts upon individual infectious disease risk. Structural adjustments that seek to reduce poverty, and therefore the socio-economic inequalities that exist in this community, would be expected to substantially reduce overall infectious disease burden. However, policy makers and researchers should be aware that heterogeneous relationships can exist between household SEP and infection risk for different pathogens in low income settings

Epidemiology of Theileria bicornis among black and white rhinoceros metapopulation in Kenya

[Background] A huge effort in rhinoceros conservation has focused on poaching and habitat loss as factors leading to the dramatic declines in the endangered eastern black rhinoceros (Diceros bicornis michaeli) and the southern white rhinoceros (Ceratotherium simum simum). Nevertheless, the role disease and parasite infections play in the mortality of protected populations has largely received limited attention. Infections with piroplasmosis caused by Babesia bicornis and Theileria bicornis has been shown to be fatal especially in small and isolated populations in Tanzania and South Africa. However, the occurrence and epidemiology of these parasites in Kenyan rhinoceros is not known.[Results] Utilizing 18S rRNA gene as genetic marker to detect rhinoceros infection with Babesia and Theileria, we examined blood samples collected from seven rhinoceros populations consisting of 114 individuals of black and white rhinoceros. The goal was to determine the prevalence in Kenyan populations, and to assess the association of Babesia and Theileria infection with host species, age, sex, location, season and population mix (only black rhinoceros comparing to black and white rhinoceros populations). We did not detect any infection with Babesia in the sequenced samples, while the prevalence of T. bicornis in the Kenyan rhinoceros population was 49.12% (56/114). White rhinoceros had significantly higher prevalence of infection (66%) compared to black rhinoceros (43%). The infection of rhinoceros with Theileria was not associated with animal age, sex or location. The risk of infection with Theileria was not higher in mixed species populations compared to populations of pure black rhinoceros.[Conclusion] In the rhinoceros studied, we did not detect the presence of Babesia bicornis, while Theileria bicornis was found to have a 49.12% prevalence with white rhinoceros showing a higher prevalence (66%) comparing with black rhinoceros (43%). Other factors such as age, sex, location, and population mix were not found to play a significant role.We acknowledge support by the CSIC Open Access Publication Initiative through its Unit of Information Resources for Research (URICI)Peer reviewe

Hepatosplenomegaly associated with chronic malaria exposure: evidence for a pro-inflammatory mechanism exacerbated by schistosomiasis

In sub-Saharan Africa, chronic hepatosplenomegaly, with palpable firm/hard organ consistency, is common, particularly among school-aged children. This morbidity can be caused by long-term exposure to malaria, or by Schistosoma mansoni, and it is exacerbated when these two occur together. Although immunological mechanisms probably underlie the pathogenic process, these mechanisms have not been identified, nor is it known whether the two parasites augment the same mechanisms or induce unrelated processes that nonetheless have additive or synergistic effects. Kenyan primary schoolchildren, living in a malaria/schistosomiasis co-transmission area, participated in cross-sectional parasitological and clinical studies in which circulating immune modulator levels were also measured. Plasma IL-12p70, sTNF-RII, IL-10 and IL-13 levels correlated with relative exposure to malaria, and with hepatosplenomegaly. Soluble-TNF-RII and IL-10 were higher in children infected withS. mansoniHepatosplenomegaly caused by chronic exposure to malaria was clearly associated with increased circulating levels of pro-inflammatory mediators, with higher levels of regulatory modulators, and with tissue repair cytokines, perhaps being required to control the inflammatory response. The higher levels of regulatory modulators amongstS. mansoniinfected children, compared to those without detectableS. mansoni and malarial infections, but exposed to malaria, suggest thatS. mansoniinfection may augment the underlying inflammatory reaction

Human candidate gene polymorphisms and risk of severe malaria in children in Kilifi, Kenya: a case-control association study

Background: Human genetic factors are important determinants of malaria risk. We investigated associations between multiple candidate polymorphisms—many related to the structure or function of red blood cells—and risk for severe Plasmodium falciparum malaria and its specific phenotypes, including cerebral malaria, severe malaria anaemia, and respiratory distress. Methods: We did a case-control study in Kilifi County, Kenya. We recruited as cases children presenting with severe malaria to the high-dependency ward of Kilifi County Hospital. We included as controls infants born in the local community between Aug 1, 2006, and Sept 30, 2010, who were part of a genetics study. We tested for associations between a range of candidate malaria-protective genes and risk for severe malaria and its specific phenotypes. We used a permutation approach to account for multiple comparisons between polymorphisms and severe malaria. We judged p values less than 0·005 significant for the primary analysis of the association between candidate genes and severe malaria. Findings: Between June 11, 1995, and June 12, 2008, 2244 children with severe malaria were recruited to the study, and 3949 infants were included as controls. Overall, 263 (12%) of 2244 children with severe malaria died in hospital, including 196 (16%) of 1233 with cerebral malaria. We investigated 121 polymorphisms in 70 candidate severe malaria-associated genes. We found significant associations between risk for severe malaria overall and polymorphisms in 15 genes or locations, of which most were related to red blood cells: ABO, ATP2B4, ARL14, CD40LG, FREM3, INPP4B, G6PD, HBA (both HBA1 and HBA2), HBB, IL10, LPHN2 (also known as ADGRL2), LOC727982, RPS6KL1, CAND1, and GNAS. Combined, these genetic associations accounted for 5·2% of the variance in risk for developing severe malaria among individuals in the general population. We confirmed established associations between severe malaria and sickle-cell trait (odds ratio [OR] 0·15, 95% CI 0·11–0·20; p=2·61 × 10−58), blood group O (0·74, 0·66–0·82; p=6·26 × 10−8), and –α3·7-thalassaemia (0·83, 0·76–0·90; p=2·06 × 10−6). We also found strong associations between overall risk of severe malaria and polymorphisms in both ATP2B4 (OR 0·76, 95% CI 0·63–0·92; p=0·001) and FREM3 (0·64, 0·53–0·79; p=3·18 × 10−14). The association with FREM3 could be accounted for by linkage disequilibrium with a complex structural mutation within the glycophorin gene region (comprising GYPA, GYPB, and GYPE) that encodes for the rare Dantu blood group antigen. Heterozygosity for Dantu was associated with risk for severe malaria (OR 0·57, 95% CI 0·49–0·68; p=3·22 × 10−11), as was homozygosity (0·26, 0·11–0·62; p=0·002). Interpretation: Both ATP2B4 and the Dantu blood group antigen are associated with the structure and function of red blood cells. ATP2B4 codes for plasma membrane calcium-transporting ATPase 4 (the major calcium pump on red blood cells) and the glycophorins are ligands for parasites to invade red blood cells. Future work should aim at uncovering the mechanisms by which these polymorphisms can result in severe malaria protection and investigate the implications of these associations for wider health. Funding: Wellcome Trust, UK Medical Research Council, European Union, and Foundation for the National Institutes of Health as part of the Bill & Melinda Gates Grand Challenges in Global Health Initiative

Magnitude and factors associated with nonadherence to antiepileptic drug treatment in Africa: A cross-sectional multisite study

Objectives: The epilepsy treatment gap is large in low- and middle-income countries, but the reasons behind nonadherence to treatment with antiepileptic drugs (AEDs) across African countries remain unclear. We investigated the extent to which AEDs are not taken and associated factors in people with active convulsive epilepsy (ACE) identified in cross-sectional studies conducted in five African countries. Methods: We approached 2,192 people with a confirmed diagnosis of ACE for consent to give blood voluntarily. Participants were asked if they were taking AEDs, and plasma drug concentrations were measured using a fluorescence polarization immunoassay analyzer. Information about possible risk factors was collected using questionnaire-based clinical interviews. We determined factors associated with nonadherence to AED treatment in children and adults, as measured by detectable and optimal levels, using multilevel logistic regression. Results: In 1,303 samples assayed (43.7% were children), AEDs were detected in 482, but only 287 had optimal levels. Of the 1,303 samples, 532 (40.8%) were from people who had reported they were on AEDs. The overall prevalence of nonadherence to treatment was 63.1% (95% confidence interval [CI] 60.5–65.6%) as measured by detectable AED levels and 79.1% (95% CI 73.3–84.3%) as measured by optimal AED levels; self-reported nonadherence was 65.1% (95% CI 45.0–79.5%). Nonadherence was significantly (p < 0.001) more common among the children than among adults for optimal and detectable levels of AEDs, as was the self-reported nonadherence. In children, lack of previous hospitalization and learning difficulties were independently associated with nonadherence to treatment. In adults, history of delivery at home, absence of burn marks, and not seeking traditional medicine were independently associated with the nonadherence to AED treatment. Significance: Only about 20% of people with epilepsy benefit fully from antiepileptic drugs in sub-Saharan Africa, according to optimum AEDs levels. Children taking AEDs should be supervised to promote compliance

Clinical features, proximate causes, and consequences of active convulsive epilepsy in Africa

Purpose: Epilepsy is common in sub-Saharan Africa (SSA), but the clinical features and consequences are poorly characterized. Most studies are hospital-based, and few studies have compared different ecological sites in SSA. We described active convulsive epilepsy (ACE) identified in cross-sectional community-based surveys in SSA, to understand the proximate causes, features, and consequences. Methods: We performed a detailed clinical and neurophysiologic description of ACE cases identified from a community survey of 584,586 people using medical history, neurologic examination, and electroencephalography (EEG) data from five sites in Africa: South Africa; Tanzania; Uganda; Kenya; and Ghana. The cases were examined by clinicians to discover risk factors, clinical features, and consequences of epilepsy. We used logistic regression to determine the epilepsy factors associated with medical comorbidities. Key Findings: Half (51%) of the 2,170 people with ACE were children and 69% of seizures began in childhood. Focal features (EEG, seizure types, and neurologic deficits) were present in 58% of ACE cases, and these varied significantly with site. Status epilepticus occurred in 25% of people with ACE. Only 36% received antiepileptic drugs (phenobarbital was the most common drug [95%]), and the proportion varied significantly with the site. Proximate causes of ACE were adverse perinatal events (11%) for onset of seizures before 18 years; and acute encephalopathy (10%) and head injury prior to seizure onset (3%). Important comorbidities were malnutrition (15%), cognitive impairment (23%), and neurologic deficits (15%). The consequences of ACE were burns (16%), head injuries (postseizure) (1%), lack of education (43%), and being unmarried (67%) or unemployed (57%) in adults, all significantly more common than in those without epilepsy. Significance: There were significant differences in the comorbidities across sites. Focal features are common in ACE, suggesting identifiable and preventable causes. Malnutrition and cognitive and neurologic deficits are common in people with ACE and should be integrated into the management of epilepsy in this region. Consequences of epilepsy such as burns, lack of education, poor marriage prospects, and unemployment need to be addressed