Steve M Taylor

Duke University Medical Center, Durham, North Carolina, United States

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Publications (39)273.43 Total impact

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    ABSTRACT: Malaria surveillance is critical for control efforts, but diagnostic methods frequently disagree. Here we compare microscopy, PCR, and a Rapid Diagnostic Test in 7,137 samples from children in the Democratic Republic of the Congo using Latent Class Analysis. PCR had the highest sensitivity (94.6%) and microscopy had the lowest (76.7%).
    No preview · Article · Jan 2016
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    ABSTRACT: Background: Monitoring the effectiveness of intermittent preventive therapy in pregnancy (IPTp) with sulfadoxine-pyrimethamine (SP) is crucial owing to increasing SP resistance in sub-Saharan Africa. Methods: Between 2009 and 2013, both the efficacy of IPTp-SP at clearing existing peripheral malaria infections and the effectiveness of IPTp-SP at reducing low birthweight (LBW) were assessed among HIV-negative participants in 8 sites in 6 countries. Sites were classified as high, medium or low resistance after measuring mutations conferring SP resistance. An individual-level prospective pooled analysis was conducted. Results: Among 1,222 parasitaemic pregnant women, overall PCR-uncorrected and -corrected failure rates by day 42 were 21.3% and 10.0%, respectively (39.7% and 21.1% in high-resistance areas; 4.9% and 1.1% in low-resistance areas). Median time to recurrence decreased with increasing prevalence of Pfdhps-K540E. Among 6,099 women at delivery, each incremental dose of IPTp-SP was associated with a 22% reduction in the risk of LBW (prevalence ratio [PR]=0.78 [95% CI 0.69-0.88], p<0.001). This association was not modified by insecticide-treated net use or gravidity, and remained significant in areas with SP resistance (PR=0.81 [0.67-0.97], p=0.02). Conclusions: The efficacy of SP to clear peripheral parasites and prevent new infections during pregnancy is compromised in areas with >90% prevalence of Pfdhps-K540E. Nevertheless, in these high resistance areas, IPTp-SP use remains associated with increases in birthweight and maternal haemoglobin. The effectiveness of IPTp in eastern and southern Africa is threatened by further increases in SP-resistance and reinforces the need to evaluate alternative drugs and strategies for the control of malaria in pregnancy.
    No preview · Article · Oct 2015 · Clinical Infectious Diseases
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    ABSTRACT: Pneumocystis jirovecii is a symbiotic respiratory fungus that presents in two clinical forms: pneumonia in immunocompromised patients or colonization, defined by the presence of the organism without associated clinical symptoms. Currently diagnosis requires invasive bronchoscopy, which may not be available in some settings and is inappropriate for detecting colonization in healthy individuals. Non-invasive diagnostic techniques and molecular strain typing tools that can be used on these samples are critical for conducting studies to better understand transmission. We evaluated two real-time PCR assays targeting dihydropteroate synthase and the major surface glycoprotein for detection in 77 oropharyngeal washes (OPWs) from symptomatic 43 HIV-infected patients who underwent bronchoscopy. We also evaluated the ability of a new microsatellite (MS) genotyping panel to strain type infections from these samples. Each PCR used individually provided a high sensitivity (>80%) for detection of pneumonia, but a modest specificity (<70%). When used in combination, specificity was increased to 100% with a drop in sensitivity (74%). Concentration of organisms by PCR in the OPW tended to be lower in colonized individuals compared to those with pneumonia, but differences in concentration could not clearly define colonization in symptomatic individuals. OPW samples were genotyped using six MS with ≥4 alleles successfully genotyped in the majority of colonized patients and ≥5 alleles in patients with pneumonia. The MS profile was consistent over time within patients with serial OPWs analyzed. MS genotyping on non-invasive samples may aid in studying the molecular epidemiology of this pathogen without requiring invasive diagnostic techniques.
    Preview · Article · Sep 2015 · Open Forum Infectious Diseases
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    ABSTRACT: Malaria and undernutrition frequently coexist, especially in pregnant women and young children. Nutrient supplementation of these vulnerable groups might reduce their susceptibility to malaria by improving immunity. Antibody immunity to antigens expressed by a placental-binding parasite isolate, a non-placental binding parasite isolate, merozoites and schizonts at enrolment (before 20 gestation weeks) and at 36 gestation weeks were measured in 1,009 Malawian pregnant women receiving a daily lipid-based nutrient supplement, multiple micronutrients or iron and folic acid, who were participants in a randomized clinical trial assessing the effects of nutrient supplementation on pregnancy outcomes and child development(registration ID: NCT01239693 ). Antibodies to placental-binding isolates significantly increased while antibodies to most merozoite antigens declined over pregnancy. Overall, after adjustment for covariates, the type of supplementation did not influence antibody levels at 36 gestation weeks or the rate of change in antibody levels from enrolment to 36 weeks. A negative association between maternal body mass index and opsonizing antibodies to placental-binding antigens (coefficient (95% CI) -1.04 (-1.84, -0.24), was observed. Similarly, women with higher socioeconomic status had significantly lower IgG and opsonizing antibodies to placental-binding antigens. Neither of these associations was significantly influenced by the supplementation type. In the current cohort nutrient supplementation did not affect anti-malarial antibody responses, but poor and undernourished mothers should be a priority group in future trials.
    Full-text · Article · May 2015 · Malaria Journal
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    ABSTRACT: Red blood cell (RBC) variants protect African children from severe Plasmodium falciparum malaria. Their individual and interactive impacts on mild disease and parasite density, and their modification by age-dependent immunity, are poorly understood. We conducted a 4-year, prospective cohort study of children aged 0.5-17 years in Maliin 2008-2011. Exposures were haemoglobin S (HbS), HbC, α-thalassaemia, ABO blood groups, and glucose-6-phosphate dehydrogenase (G6PD)deficiency encoded by the X-linked A- allele. Primary and secondary outcomes were malaria incidence and parasite density. Incidence rate ratios (IRRs) were modeled with quasi-Poisson regression; parasite densities were analyzed with Generalized Estimating Equations. We diagnosed 4091 malaria episodes in 1543 children over 2656 child-years of follow-up (cyfu). RBC variants were common: HbAS 14.2%, HbAC 6.7%, α-thalassaemia 28.4%, type O blood group 40.2%, and G6PD deficiency9.4% (boys) and 20.4% (girls). Malaria incidence was 1.54 episodes/cyfu, ranged from 2.78 at age 3 to 0.40 at age 16 years, was reduced 34% in HbAS vs HbAA children (adjusted IRR [aIRR] 0.66; 95% CI 0.59-0.75) and 49% in G6PD A-/A- vs A+/A+ girls (aIRR 0.51; 95% CI 0.29-0.90), but was increased 15% in HbAC children (aIRR 1.15; 95% CI 1.01-1.32). Parasite density was reduced in HbAS vs HbAA children (median 10,550 vs 15, 150 parasites/μL; p=0.0004). HbAS-associated reductions in malaria risk and parasite density were greatest in early childhood. Individual and interactive impacts of HbAS, HbAC, and G6PD A-/A-on malaria risk and parasite density define clinical and cellular correlates of protection. Further identification of the molecular mechanisms of these protective effects may uncover novel targets for intervention. Intramural Research Program, National Institute of Allergy and Infectious Diseases, National Institutes of Health.
    Full-text · Article · Mar 2015
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    ABSTRACT: In Kenya, > 10 million episodes of acute febrile illness are treated annually among children under 5 years. Most are clinically managed as malaria without parasitological confirmation. There is an unmet need to describe pathogen-specific etiologies of fever. We enrolled 370 febrile children and 184 healthy controls. We report demographic and clinical characteristics of patients with Plasmodium falciparum, group A streptococcal (GAS) pharyngitis, and respiratory viruses (influenza A and B, respiratory syncytial virus [RSV], parainfluenza [PIV] types 1-3, adenovirus, human metapneumovirus [hMPV]), as well as those with undifferentiated fever. Of febrile children, 79.7% were treated for malaria. However, P. falciparum was detected infrequently in both cases and controls (14/268 [5.2%] versus 3/133 [2.3%], P = 0.165), whereas 41% (117/282) febrile children had a respiratory viral infection, compared with 24.8% (29/117) controls (P = 0.002). Only 9/515(1.7%) children had streptococcal infection. Of febrile children, 22/269 (8.2%) were infected with > 1 pathogen, and 102/275(37.1%) had fevers of unknown etiology. Respiratory viruses were common in both groups, but only influenza or parainfluenza was more likely to be associated with symptomatic disease (attributable fraction [AF] 67.5% and 59%, respectively). Malaria was overdiagnosed and overtreated. Few children presented to the hospital with GAS pharyngitis. An enhanced understanding of carriage of common pathogens, improved diagnostic capacity, and better-informed clinical algorithms for febrile illness are needed. ©The American Society of Tropical Medicine and Hygiene.
    Full-text · Article · Mar 2015 · The American journal of tropical medicine and hygiene
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    ABSTRACT: Understanding how malaria parasites move between populations is important, particularly given the potential for malaria to be reintroduced into areas where it was previously eliminated. We examine the distribution of malaria genetics across seven sites within the Democratic Republic of Congo (DRC) and two nearby countries, Ghana and Kenya, in order to understand how the relatedness of malaria parasites varies across space, and whether there are barriers to the flow of malaria parasites within the DRC or across borders. Parasite DNA was retrieved from dried blood spots from 7 Demographic and Health Survey sample clusters in the DRC. Malaria genetic characteristics of parasites from Ghana and Kenya were also obtained. For each of 9 geographic sites (7 DRC, 1 Ghana and 1 Kenya), a pair-wise RST statistic was calculated, indicating the genetic distance between malaria parasites found in those locations. Mapping genetics across the spatial extent of the study area indicates a complex genetic landscape, where relatedness between two proximal sites may be relatively high (RST > 0.64) or low (RST < 0.05), and where distal sites also exhibit both high and low genetic similarity. Mantel's tests suggest that malaria genetics differ as geographic distances increase. Principal Coordinate Analysis suggests that genetically related samples are not co-located. Barrier analysis reveals no significant barriers to gene flow between locations. Malaria genetics in the DRC have a complex and fragmented landscape. Limited exchange of genes across space is reflected in greater genetic distance between malaria parasites isolated at greater geographic distances. There is, however, evidence for close genetic ties between distally located sample locations, indicating that movement of malaria parasites and flow of genes is being driven by factors other than distance decay. This research demonstrates the contributions that spatial disease ecology and landscape genetics can make to understanding the evolutionary dynamics of infectious diseases.
    Preview · Article · Oct 2014 · Social Science [?] Medicine
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    ABSTRACT: Plasmodium falciparum parasites that are resistant to artemisinins have been detected in Southeast Asia. Resistance is associated with several polymorphisms in the parasite's K13-propeller gene. The molecular epidemiology of these artemisinin-resistant genotypes in African parasite populations is unknown. We developed an assay to quantify rare polymorphisms in parasite populations using a pooled deep-sequencing approach to score allele frequencies, validated it using mixtures of laboratory parasite strains, and then employed it to screen over 1,100 African P. falciparum infections collected since 2002 from 14 sites across sub-Saharan Africa. We found no mutations in African parasite populations that are associated with artemisinin resistance in Southeast Asian parasites. However, we observed 15 coding mutations, including 12 novel mutations, and limited allele sharing between parasite populations, consistent with a large reservoir of naturally-occurring K13-propeller variation. Though polymorphisms associated with artemisinin resistance in P. falciparum in Southeast Asia are not prevalent in sub-Saharan Africa, numerous K13-propeller coding polymorphisms circulate in Africa. Although their distributions do not support a widespread selective sweep for an artemisinin resistant phenotype, the impact of these mutations on artemisinin susceptibility is unknown and will require further characterization. Rapid, scalable molecular surveillance offers a useful adjunct in tracking and containing artemisinin resistance.
    Full-text · Article · Sep 2014 · The Journal of Infectious Diseases
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    ABSTRACT: Iron deficiency and malaria have similar global distributions, and frequently co-exist in pregnant women and young children. Where both conditions are prevalent, iron supplementation is complicated by observations that iron deficiency anaemia protects against falciparum malaria, and that iron supplements increase susceptibility to clinically significant malaria, but the mechanisms remain obscure. Here, using an in vitro parasite culture system with erythrocytes from iron-deficient and replete human donors, we demonstrate that Plasmodium falciparum infects iron-deficient erythrocytes less efficiently. In addition, owing to merozoite preference for young erythrocytes, iron supplementation of iron-deficient individuals reverses the protective effects of iron deficiency. Our results provide experimental validation of field observations reporting protective effects of iron deficiency and harmful effects of iron administration on human malaria susceptibility. Because recovery from anaemia requires transient reticulocytosis, our findings imply that in malarious regions iron supplementation should be accompanied by effective measures to prevent falciparum malaria.
    No preview · Article · Jul 2014 · Nature Communications
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    ABSTRACT: Sulfadoxine-resistant Plasmodium falciparum undermines malaria prevention with sulfadoxine/pyrimethamine. Parasites with a highly resistant mutant dihydropteroate synthase (dhps) haplotype have recently emerged in eastern Africa; they negated preventive benefits of sulfadoxine/pyrimethamine, and might exacerbate placental malaria. We explored emerging lineages of dhps mutant haplotypes in Malawi, the Democratic Republic of the Congo, and Tanzania by using analyses of genetic microsatellites flanking the dhps locus. In Malawi, a triple-mutant dhps SGEG (mutant amino acids are underlined) haplotype emerged in 2010 that was closely related to pre-existing double-mutant SGEA haplotypes, suggesting local origination in Malawi. When we compared mutant strains with parasites from the Democratic Republic of the Congo and Tanzania by multiple independent analyses, we found that SGEG parasites were partitioned into separate lineages by country. These findings support a model of local origination of SGEG dhps haplotypes, rather than geographic diffusion, and have implications for investigations of emergence and effects of parasite drug resistance.
    Full-text · Article · Jul 2014 · Emerging infectious diseases
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    ABSTRACT: Background Intermittent preventive treatment of malaria in pregnancy (IPTp) with sulphadoxine-pyrimethamine (SP) decreases adverse effects of malaria during pregnancy. Zambia implemented its IPTp-SP programme in 2003. Emergence of SP-resistant Plasmodium falciparum threatens this strategy. The quintuple mutant haplotype (substitutions in N51I, C59R, S108N in dhfr and A437G and K540E in dhps genes), is associated with SP treatment failure in non-pregnant patients with malaria. This study examined efficacy of IPTp-SP and presence of the quintuple mutant among pregnant women in Mansa, Zambia. Methods In Mansa, an area with high malaria transmission, HIV-negative pregnant women presenting to two antenatal clinics for the 1st dose of IPTp-SP with asymptomatic parasitaemia were enrolled and microscopy for parasitaemia was done weekly for five weeks. Outcomes were parasitological failure and adequate parasitological response (no parasitaemia during follow-up). Polymerase chain reaction assays were employed to distinguish recrudescence from reinfection, and identify molecular markers of SP resistance. Survival analysis included those who had reinfection and incomplete follow-up (missed at least one follow-up). Results Of the 109 women included in the study, 58 (53%) completed all follow-up, 34 (31%) had incomplete follow-up, and 17 (16%) were lost to follow-up after day 0. Of those who had complete follow-up, 15 (26%, 95% confidence interval [CI] [16–38]) had parasitological failure. For the 92 women included in the survival analysis, median age was 20 years (interquartile range [IQR] 18–22), median gestational age was 22 weeks (IQR range 20–24), and 57% were primigravid. There was no difference in time to failure in primigravid versus multigravid women. Of the 84 women with complete haplotype data for the aforementioned loci of the dhfr and dhps genes, 53 (63%, 95% CI [50–70]) had quintuple mutants (two with an additional mutation in A581G of dhps). Among women with complete follow-up and quintuple mutants, 22% had parasitological failure versus 0% without (p = 0.44). Conclusions While underpowered, this study found 26% failure rates of SP given the moderate prevalence of the quintuple mutant haplotype. Despite the presence of resistance, SP retained some efficacy in clearing parasites in pregnant women, and may remain a viable option for IPTp in Zambia.
    Full-text · Article · Jun 2014 · Malaria Journal
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    ABSTRACT: Imported malaria threatens control and elimination efforts in countries that have low rates of transmission. In 2010, an outbreak of Plasmodium falciparum malaria was reported among United Nations peacekeeping soldiers from Guatemala who had recently returned from the Democratic Republic of the Congo (DRC). Epidemiologic evidence suggested that the soldiers were infected in the DRC, but local transmission could not be ruled out in all cases. We used population genetic analyses of neutral microsatellites to determine the outbreak source. Genetic relatedness was compared among parasites found in samples from the soldiers and parasite populations collected in the DRC and Guatemala; parasites identified in the soldiers were more closely related to those from the DRC. A phylogenetic clustering analysis confirms this identification with >99.9% confidence. Thus, results support the hypothesis that the soldiers likely imported malaria from the DRC. This study demonstrates the utility of molecular genotyping in outbreak investigations.
    Preview · Article · Jun 2014 · Emerging infectious diseases
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    ABSTRACT: Malaria parasite infections that are only detectable by molecular methods are highly prevalent and represent a potential transmission reservoir. The methods used to detect these infections are not standardized and their operating characteristics are often unknown. We designed a proficiency panel of Plasmodium spp. in order to compare the accuracy of parasite detection of molecular protocols used by labs in a clinical trial consortium. Ten dried blood spots (DBS) were assembled containing P. falciparum, P. vivax, P. malariae, and P. ovale; DBS contained either a single species or a species mixed with P. falciparum. DBS panels were tested in 9 participating laboratories in masked fashion. Of 90 tests, 68 (75.6%) were correct; there were 20 false-negative results and 2 false-positives. The detection rate was 77.8% (49/63) for P. falciparum, 91.7% (11/12) for P. vivax, 83.3% (10/12) for P. malariae, and 70% (7/10) for P. ovale. Most false-negative P. falciparum results were from samples with estimated ≤ 5 parasites per μL blood. Between labs, accuracy ranged from 100% to 50%. In one lab, the inability to detect species in mixed-species infections prompted a re-design and improvement of the assay. Most PCR-based protocols were able to detect P. falciparum and P. vivax at higher densities but these assays may not reliably detect parasites in samples with low P. falciparum densities. Accordingly, formal quality assurance for PCR should be employed whenever this method is used for diagnosis or surveillance. Such efforts will be important if PCR is to be widely employed to assist malaria elimination efforts.
    Full-text · Article · Apr 2014 · Journal of clinical microbiology
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    ABSTRACT: In the Democratic Republic of the Congo (DRC), artesunate-amodiaquine is first-line therapy for falciparum malaria; little is known about the prevalence of molecular markers of parasite drug resistance. Across the DRC, we genotyped 166 parasites in Plasmodium falciparum chloroquine resistance transporter (pfcrt) using polymerase chain reaction (PCR) and sequencing. Of these parasites, 73 (44%) parasites were pure wild-type CVMNK, 55 (31%) parasites were chloroquine-resistant CVIET, 35 (21.1%) parasites were mixed CVMNK and CVIET, and 3 parasites were other genotypes. Ninety-two infections (55.4%) harbored the pfcrt K76T substitution that is highly correlated with chloroquine failure. The amodiaquine-resistant SVMNT haplotype was absent. Geographically, pfcrt haplotypes were not clearly clustered. Chloroquine accounted for 19.4% of antimalarial use, and amodiaquine accounted for 15.3% of antimalarial use; there were no associations between drug use and mutant haplotype prevalence. In the DRC, our molecular survey indicates that resistance to chloroquine is substantial but that resistance to amodiaquine is absent. These contrasting findings highlight the need for molecular surveillance of drug resistance to inform malaria control policies.
    Preview · Article · Apr 2014 · The American journal of tropical medicine and hygiene
  • Steve M Taylor · Rick M Fairhurst
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    ABSTRACT: Multiple red cell variants are known to confer protection from malaria. Here, we review advances in identifying new variants that modulate malaria risk and in defining molecular mechanisms that mediate malaria protection. New red cell variants, including an innate variant in the red cell's major Ca pump and the acquired state of iron deficiency, have been associated with protection from clinical falciparum malaria. The polymorphisms hemoglobin C (HbC) and hemoglobin S (HbS) - known to protect carriers from severe falciparum malaria - enhance parasite passage to mosquitoes and may promote malaria transmission. At the molecular level, substantial advances have been made in understanding the impact of HbS and HbC upon the interactions between host microRNAs and Plasmodium falciparum protein translation; remodeling of red cell cytoskeletal components and transport of parasite proteins to the red cell surface; and chronic activation of the human innate immune system, which induces tolerance to blood-stage parasites. Several polymorphisms have now been associated with protection from clinical vivax malaria or reduced Plasmodium vivax density, including Southeast Asian ovalocytosis and two common forms of glucose-6-phosphate dehydrogenase deficiency. Red cell variants that modulate malaria risk can serve as models to identify clinically relevant mechanisms of pathogenesis, and thus define parasite and host targets for next-generation therapies.
    No preview · Article · Mar 2014 · Current opinion in hematology
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    Steve M Taylor · Jonathan J Juliano

    Preview · Article · Mar 2014 · The Journal of Infectious Diseases
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    ABSTRACT: Pneumocystis jirovecii is a symbiotic respiratory fungus that causes pneumonia (PcP) in immunosuppressed patients. Because P. jirovecii cannot be reliably cultured in vitro, it has proven difficult to study and gaps in our understanding of the organism persist. The release of a draft genome for the organism opens the door for the development of new genotyping approaches for studying its molecular epidemiology and global population structure. We identified and validated 8 putatively neutral microsatellite markers and 1 microsatellite marker linked to the dihydropteroate synthase gene (dhps), the enzymatic target of sulfa drugs used for PcP prevention and treatment. Using these tools, we analyzed P. jirovecii isolates from HIV-infected patients from three geographically distant populations: Uganda, the United States, and Spain. Among the 8 neutral markers, we observed high levels of allelic heterozygosity (average He, 0.586 to 0.842). Consistent with past reports, we observed limited global population structuring, with only the Ugandan isolates showing minor differentiation from the other two populations. In Ugandan isolates that harbored mutations in dhps, the microsatellite locus linked to dhps demonstrated a depressed He, consistent with positive directional selection for sulfa resistance mutations. Using a subset of these microsatellites, analyses of individual and paired samples from infections in San Francisco, CA, showed reliable typeability within a single infection and high discriminatory power between infections. These features suggest that this novel microsatellite typing approach will be an effective tool for molecular-epidemiological investigations into P. jirovecii population structure, transmission, and drug resistance.
    No preview · Article · Feb 2014 · Journal of clinical microbiology
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    ABSTRACT: Anemia is common in women of child-bearing age in the Democratic Republic of the Congo (DRC). As part of the 2007 DRC Demographic and Health Survey (DHS), 4638 women of childbearing age (including 526 pregnant women) were tested for HIV and had the hemoglobin content of their blood recorded. We used the leftover dried blood spots to assess malaria prevalence using PCR assays. The DHS provided extensive information on individuals, as well as the geographic coordinates of household clusters which enabled us to derive several variables that characterize the spatial context of these clusters. Multilevel analyses were conducted to determine individual and contextual risk factors for anemia. Prevalence varied geographically; the odds of anemia were associated with both one's ethnic group and the amount and type of nearby agriculture. The odds were not affected by HIV or malaria status.
    No preview · Article · Aug 2013 · Health & Place
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    ABSTRACT: Molecular surveillance for drug-resistant malaria parasites requires reliable, timely, and scalable methods. These data may be efficiently produced by genotyping parasite populations using second-generation sequencing (SGS). We designed and validated a SGS protocol to quantify mutant allele frequencies in the Plasmodium falciparum genes dhfr and dhps in mixed isolates. We applied this new protocol to field isolates from children and compared it to standard genotyping using Sanger sequencing. The SGS protocol accurately quantified dhfr and dhps allele frequencies in a mixture of parasite strains. Using SGS of DNA that was extracted and then pooled from individual isolates, we estimated mutant allele frequencies that were closely correlated to those estimated by Sanger sequencing (correlations, >0.98). The SGS protocol obviated most molecular steps in conventional methods and is cost saving for parasite populations >50. This SGS genotyping method efficiently and reproducibly estimates parasite allele frequencies within populations of P. falciparum for molecular epidemiologic studies.
    Full-text · Article · Aug 2013 · The Journal of Infectious Diseases
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    Steve M Taylor · Carla Cerami · Rick M Fairhurst
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    ABSTRACT: Plasmodium falciparum malaria kills over 500,000 children every year and has been a scourge of humans for millennia. Owing to the co-evolution of humans and P. falciparum parasites, the human genome is imprinted with polymorphisms that not only confer innate resistance to falciparum malaria, but also cause hemoglobinopathies. These genetic traits-including hemoglobin S (HbS), hemoglobin C (HbC), and α-thalassemia-are the most common monogenic human disorders and can confer remarkable degrees of protection from severe, life-threatening falciparum malaria in African children: the risk is reduced 70% by homozygous HbC and 90% by heterozygous HbS (sickle-cell trait). Importantly, this protection is principally present for severe disease and largely absent for P. falciparum infection, suggesting that these hemoglobinopathies specifically neutralize the parasite's in vivo mechanisms of pathogenesis. These hemoglobin variants thus represent a "natural experiment" to identify the cellular and molecular mechanisms by which P. falciparum produces clinical morbidity, which remain partially obscured due to the complexity of interactions between this parasite and its human host. Multiple lines of evidence support a restriction of parasite growth by various hemoglobinopathies, and recent data suggest this phenomenon may result from host microRNA interference with parasite metabolism. Multiple hemoglobinopathies mitigate the pathogenic potential of parasites by interfering with the export of P. falciparum erythrocyte membrane protein 1 (PfEMP1) to the surface of the host red blood cell. Few studies have investigated their effects upon the activation of the innate and adaptive immune systems, although recent murine studies suggest a role for heme oxygenase-1 in protection. Ultimately, the identification of mechanisms of protection and pathogenesis can inform future therapeutics and preventive measures. Hemoglobinopathies slice the "Gordian knot" of host and parasite interactions to confer malaria protection, and offer a translational model to identify the most critical mechanisms of P. falciparum pathogenesis.
    Full-text · Article · May 2013 · PLoS Pathogens

Publication Stats

638 Citations
273.43 Total Impact Points

Institutions

  • 2013-2016
    • Duke University Medical Center
      Durham, North Carolina, United States
    • University of California, San Francisco
      San Francisco, California, United States
  • 2009-2015
    • Duke University
      Durham, North Carolina, United States
  • 2012-2014
    • University of North Carolina at Chapel Hill
      • Department of Epidemiology
      North Carolina, United States