Laith Yakob

Managing the whole landscape: historical, hybrid, and novel ecosystems

The reality confronting ecosystem managers today is one of heterogeneous, rapidly transforming landscapes, particularly in the areas more affected by urban and agricultural development. A landscape management framework that incorporates all systems, across the spectrum of degrees of alteration, provides a fuller set of options for how and when to intervene, uses limited resources more effectively, and increases the chances of achieving management goals. That many ecosystems have departed so substantially from their historical trajectory that they defy conventional restoration is not in dispute. Acknowledging novel ecosystems need not constitute a threat to existing policy and management approaches. Rather, the development of an integrated approach to management interventions can provide options that are in tune with the current reality of rapid ecosystem change.

Zika virus outbreak in the Americas: the need for novel mosquito control methods

Local transmission of Zika virus (ZIKV) in the Americas was fi rst confi rmed in February, 2014, on Easter Island. In May, 2015, 16 patients from the Brazilian states of Bahia and Rio Grande do Norte were found to be ZIKV-positive. 22 countries and territories have subsequently identifi ed autochthonous transmission within the region (fi gure). Until recently, ZIKV infection was only associated with mild symptoms (headache, rash, joint pain, conjunctivitis) but a possible link between ZIKV infection during pregnancy and subsequent birth defects (most notably microcephaly) was identifi ed in November, 2015. Approaching 4000 cases of suspected ZIKV-related microcephaly have arisen in Brazil alone where initial fi gures suggest between 440 000 and 1·3 million people have been infected so far. Concern in the region is escalating, with public health authorities in Colombia, Ecuador, El Salvador, and Jamaica all issuing an unprecedented health notice warning their residents to avoid pregnancy until 2018. ZIKV is a fl avivirus related to dengue virus (DENV) and historically has been transmitted by the same mosquito species, Aedes aegypti (fi gure). There is no available treatment or vaccine so disease control is limited to the management of mosquitoes which currently relies on either insecticides or the destruction of larval breeding sites. In Brazil, ultra-low-volume space spraying is recommended only during dengue outbreaks. However, widespread insecticide resistance (including high pyreth roid resistance rates) and the impracticality of identifying and eliminating standing pools of water on a city-wide scale provide little hope for the containment of this disease. Vaccine development is anticipated to take several years; in the more immediate term, what options are left for the control of ZIKV? Two novel approaches that have shown considerable promise in recent years are the genetic control of A aegypti mosquitoes and the development of mosquitoes that are resistant to arbovirus infection. The fi rst fi eld-trialled genetic control strategy is known as RIDL (the Release of Insects carrying Dominant Lethal genes) and involves the mass rearing of A aegypti that have been genetically modifi ed to express a repressible lethal gene. During their rearing in insectaries, the mosquitoes are provided with a dietary supplement not present in nature (eg, tetracycline), and this supplement represses the lethal gene activation. Only male mosquitoes are released and these compete with wild males to mate with wild females. Off spring do not survive to the adult stage because they do not receive the dietary additive in the wild. Lines of RIDL males have been shown to have minimal fi tness costs (ie, they are competitive with wild males) and the recent fi eld release in Bahia, Brazil, reportedly achieved a 95% reduction in local mosquito populations. An alternative approach is the use of endosymbiotic bacteria to prevent arboviruses replicating within the mosquito. The Eliminate Dengue project has been able to demonstrate that Wolbachia bacteria from Drosophila fruit fl ies can prevent DENV transmission in A aegypti mosquitoes without signifi cant fi tness costs.

Indoor residual spray and insecticide-treated bednets for malaria control: theoretical synergisms and antagonisms

Indoor residual spray (IRS) of insecticides and insecticide-treated bednets (ITNs) are the two most important malaria vector control tools in the tropical world. Application of both tools in the same locations is being implemented for malaria control in endemic and epidemic Africa. The two tools are assumed to have synergistic benefits in reducing malaria transmission because they both act at multiple stages of the transmission cycle. However, this assumption has not been rigorously examined, empirically or theoretically. Using mathematical modelling, we obtained the conditions for which a combination strategy can be expected to improve upon single control tools. Specifically, spraying of dichlorodiphenyltrichloroethane (DDT) in all houses where residents are not using ITNs can reduce transmission of malaria (R0) by up to 10 times more than the reduction achieved through ITNs alone. Importantly, however, we also show how antagonism between control tools can arise via interference of their modes of action. Repellent IRS reduces the likelihood that ITNs are contacted within sprayed houses and ITNs reduce the rate at which blood-fed mosquitoes rest on sprayed walls. For example, 80 per cent coverage of ITNs and DDT used together at the household level resulted in an R0 of 11.1 when compared with an R0 of 0.1 achieved with 80 per cent ITN coverage without DDT. While this undesired effect can be avoided using low-repellence pyrethroid chemicals for IRS, the extent of the potential benefits is also attenuated. We discuss the impact that this result will likely have on future efforts in malaria control combination strategy.

A Mathematical Model of Chikungunya Dynamics and Control: The Major Epidemic on Réunion Island

Chikungunya is a re-emerging arboviral disease transmitted by Aedes spp. mosquitoes. Although principally endemic to Africa and Asia, recent outbreaks have occurred in Europe following introductions by returning travellers. A particularly large outbreak occurred on Réunion Island in 2006, the published data from which forms the basis of the current study. A simple, deterministic mathematical model of the transmission of the virus between humans and mosquitoes was constructed and parameterised with the up-to-date literature on infection biology. The model is fitted to the large Réunion epidemic, resulting in an estimate of 4.1 for the type reproduction number of chikungunya. Although simplistic, the model provided a close approximation of both the peak incidence of the outbreak and the final epidemic size. Sensitivity analysis using Monte Carlo simulation demonstrated the strong influence that both the latent period of infection in humans and the pre-patent period have on these two epidemiological outcomes. We show why separating these variables, which are epidemiologically distinct in chikungunya infections, is not only necessary for accurate model fitting but also important in informing control.

Land Use and Land Cover Changes and Spatiotemporal Dynamics of Anopheline Larval Habitats during a Four-Year Period in a Highland Community of Africa

Spatial and temporal variations in the distribution of anopheline larval habitats and land use and land cover (LULC) changes can influence malaria transmission intensity. This information is important for understanding the environmental determinants of malaria transmission heterogeneity, and it is critical to the study of the effects of environmental changes on malaria transmission. In this study, we investigated the spatial and temporal variations in the distribution of anopheline larval habitats and LULC changes in western Kenya highlands over a 4-year period. Anopheles gambiae complex larvae were mainly confined to valley bottoms during both the dry and wet seasons. Although An. gambiae larvae were located in man-made habitats where riparian forests and natural swamps had been cleared, Anopheles funestus larvae were mainly found in permanent habitats in pastures. The association between land cover type and occurrence of anopheline larvae was statistically significant. The distribution of anopheline positive habitats varied significantly between months, during the survey. In 2004, the mean density of An. gambiae was significantly higher during the month of May, whereas the density of An. funestus peaked significantly in February. Over the study period, major LULC changes occurred mostly in the valley bottoms. Overall, farmland increased by 3.9%, whereas both pastures and natural swamps decreased by 8.9% and 20.9%, respectively. The area under forest cover was decreased by 5.8%. Land-use changes in the study area are favorable to An. gambiae larval development, thereby risking a more widespread distribution of malaria vector habitats and potentially increasing malaria transmission in western Kenya highlands.

Asymptomatic Clostridium difficile colonization: epidemiology and clinical implications

BackgroundThe epidemiology of Clostridium difficile infection (CDI) has changed over the past decades with the emergence of highly virulent strains. The role of asymptomatic C. difficile colonization as part of the clinical spectrum of CDI is complex because many risk factors are common to both disease and asymptomatic states. In this article, we review the role of asymptomatic C. difficile colonization in the progression to symptomatic CDI, describe the epidemiology of asymptomatic C. difficile colonization, assess the effectiveness of screening and intensive infection control practices for patients at risk of asymptomatic C. difficile colonization, and discuss the implications for clinical practice.MethodsA narrative review was performed in PubMed for articles published from January 1980 to February 2015 using search terms ‘Clostridium difficile’ and ‘colonization’ or ‘colonisation’ or ‘carriage’.ResultsThere is no clear definition for asymptomatic CDI and the terms carriage and colonization are often used interchangeably. The prevalence of asymptomatic C. difficile colonization varies depending on a number of host, pathogen, and environmental factors; current estimates of asymptomatic colonization may be underestimated as stool culture is not practical in a clinical setting.ConclusionsAsymptomatic C. difficile colonization presents challenging concepts in the overall picture of this disease and its management. Individuals who are colonized by the organism may acquire protection from progression to disease, however they also have the potential to contribute to transmission in healthcare settings.

Climate change induces demographic resistance to disease in novel coral assemblages

Climate change is reshaping biological communities and has already generated novel ecosystems. The functioning of novel ecosystems could depart markedly from that of existing systems and therefore obscure the impacts of climate change. We illustrate this possibility for coral reefs, which are at the forefront of climatic stress. Disease has been a principal cause of reef degradation and is expected to worsen with increased future thermal stress. However, using a field-tested epizoological model, we show that high population turnover within novel ecosystems enhances coral resistance to epizootics. Thus, disease could become a less important driver of change in the future. We emphasize the need to move away from projections based on historic trends toward predictions that account for novel behavior of ecosystems under climate change.

Comorbidities, Exposure to Medications, and the Risk of Community-Acquired Clostridium difficile Infection: A Systematic Review and Meta-analysis

BACKGROUND Clostridium difficile infection (CDI) has been extensively described in healthcare settings; however, risk factors associated with community-acquired (CA) CDI remain uncertain. This study aimed to synthesize the current evidence for an association between commonly prescribed medications and comorbidities with CA-CDI. METHODS A systematic search was conducted in 5 electronic databases for epidemiologic studies that examined the association between the presence of comorbidities and exposure to medications with the risk of CA-CDI. Pooled odds ratios were estimated using 3 meta-analytic methods. Subgroup analyses by location of studies and by life stages were conducted. RESULTS Twelve publications (n=56,776 patients) met inclusion criteria. Antimicrobial (odds ratio, 6.18; 95% CI, 3.80-10.04) and corticosteroid (1.81; 1.15-2.84) exposure were associated with increased risk of CA-CDI. Among the comorbidities, inflammatory bowel disease (odds ratio, 3.72; 95% CI, 1.52-9.12), renal failure (2.64; 1.23-5.68), hematologic cancer (1.75; 1.02-5.68), and diabetes mellitus (1.15; 1.05-1.27) were associated with CA-CDI. By location, antimicrobial exposure was associated with a higher risk of CA-CDI in the United States, whereas proton-pump inhibitor exposure was associated with a higher risk in Europe. By life stages, the risk of CA-CDI associated with antimicrobial exposure greatly increased in adults older than 65 years. CONCLUSIONS Antimicrobial exposure was the strongest risk factor associated with CA-CDI. Further studies are required to investigate the risk of CA-CDI associated with medications commonly prescribed in the community. Patients with diarrhea who have inflammatory bowel disease, renal failure, hematologic cancer, or diabetes are appropriate populations for interventional studies of screening.

Modeling the Effects of Integrating Larval Habitat Source Reduction and Insecticide Treated Nets for Malaria Control

Integrated vector management for malaria control has received a lot of recent interest. Attacking multiple points in the transmission cycle is hoped to act synergistically and improve upon current single-tool interventions based on the use of insecticide-treated bed nets (ITNs). In the present study, we theoretically examined the application of larval habitat source reduction with ITNs in reducing malaria transmission. We selected this type of environmental management to complement ITNs because of a potential secondary mode of action that both control strategies share. In addition to increasing vector mortality, ITNs reduce the rate at which female mosquitoes locate human hosts for blood feeding, thereby extending their gonotrophic cycle. Similarly, while reducing adult vector emergence and abundance, source reduction of larval habitats may prolong the cycle duration by extending delays in locating oviposition sites. We found, however, that source reduction of larval habitats only operates through this secondary mode of action when habitat density is below a critical threshold. Hence, we illustrate how this strategy becomes increasingly effective when larval habitats are limited. We also demonstrate that habitat source reduction is better suited to human populations of higher density and in the presence of insecticide resistance or when the insecticidal properties of ITNs are depleted.

Identification of the first pyrimidine nucleobase transporter in Leishmania: similarities with the Trypanosoma brucei U1 transporter and antileishmanial activity of uracil analogues.

While purine transport has been widely studied in protozoa, almost nothing is known about their capacity to salvage pyrimidines. Here, we report a Leishmania major transporter with high affinity for uracil (Km=0.32+/-0.07 microM) which we designated LmU1. This transporter displayed a high degree of specificity, as it had virtually no affinity for cytosine, thymine or purine nucleobases, nor did it transport pyrimidine nucleosides. Highest affinity was for 5-fluorouracil. The results show that the permeant binding site of LmU1 interacts strongly with the keto groups of uracil, as shown by a low affinity for 2-thio- and 4-thiouracil. LmU1 appears to further bind uracil through a weak hydrogen bond with N(1)H of the pyrimidine ring in addition to a stronger H-bond with N(3)H. Substrate binding and selectivity were strikingly similar to that of the U1 transporter in the related kinetoplastid Trypanosoma brucei. Uracil analogues likely to be transported by LmU1 were also screened for antileishmanial activity, with 5-fluorouracil displaying strong activity against promastigotes and intracellular amastigotes. Overall, the results show that, like purine nucleobase transport, pyrimidine nucleobase transport function is very similar in L. major and T. brucei insect forms.