Alan J. Magill

Bio: Alan J. Magill is an academic researcher from Bill & Melinda Gates Foundation. The author has contributed to research in topics: Malaria & Plasmodium falciparum. The author has an hindex of 45, co-authored 85 publications receiving 6599 citations. Previous affiliations of Alan J. Magill include Naval Medical Research Center & University of Maryland, Baltimore.

Genetic diversity and chloroquine selective sweeps in Plasmodium falciparum

Abstract: Widespread use of antimalarial agents can profoundly influence the evolution of the human malaria parasite Plasmodium falciparum. Recent selective sweeps for drug-resistant genotypes may have restricted the genetic diversity of this parasite, resembling effects attributed in current debates to a historic population bottleneck. Chloroquine-resistant (CQR) parasites were initially reported about 45 years ago from two foci in southeast Asia and South America, but the number of CQR founder mutations and the impact of chlorquine on parasite genomes worldwide have been difficult to evaluate. Using 342 highly polymorphic microsatellite markers from a genetic map, here we show that the level of genetic diversity varies substantially among different regions of the parasite genome, revealing extensive linkage disequilibrium surrounding the key CQR gene pfcrt and at least four CQR founder events. This disequilibrium and its decay rate in the pfcrt-flanking region are consistent with strong directional selective sweeps occurring over only approximately 20-80 sexual generations, especially a single resistant pfcrt haplotype spreading to very high frequencies throughout most of Asia and Africa. The presence of linkage disequilibrium provides a basis for mapping genes under drug selection in P. falciparum.

Update on Rapid Diagnostic Testing for Malaria

Abstract: To help mitigate the expanding global impact of malaria, with its associated increasing drug resistance, implementation of prompt and accurate diagnosis is needed. Malaria is diagnosed predominantly by using clinical criteria, with microscopy as the current gold standard for detecting parasitemia, even though it is clearly inadequate in many health care settings. Rapid diagnostic tests (RDTs) have been recognized as an ideal method for diagnosing infectious diseases, including malaria, in recent years. There have been a number of RDTs developed and evaluated widely for malaria diagnosis, but a number of issues related to these products have arisen. This review highlights RDTs, including challenges in assessing their performance, internationally available RDTs, their effectiveness in various health care settings, and the selection of RDTs for different health care systems.

Primaquine: report from cdc expert meeting on malaria chemoprophylaxis i

Abstract: Primaquine phosphate has been used for preventing relapse of Plasmodium vivax and P. ovale malaria since the early 1950s, based on its ability to kill latent (hypnozoite) and developing liver stages of these parasites. There are three uses for primaquine in malaria: radical cure of established infection with P. vivax or P. ovale malaria; presumptive anti-relapse therapy (PART; terminal prophylaxis) in persons with extensive exposure to these parasites; and primary prophylaxis against all malaria species. All persons for whom primaquine is being considered must have a glucose-6-phosphate dehydrogenase (G6PD) enzyme level checked before use, and persons who have a deficiency of G6PD must not take primaquine for prophylaxis or PART. The recommended adult dose for PART based on clinical trials and expert opinion is 30 mg base daily for 14 days, started on return from a malarious region and overlapping with a blood schizonticide. The adult dose for primary prophylaxis is 30 mg daily begun 1 day before travel and continued for 7 days after return. This review will examine the evidence for these recommendations.

A research agenda for malaria eradication: drugs.

Abstract: Antimalarial drugs will be essential tools at all stages of malaria elimination along the path towards eradication, including the early control or "attack" phase to drive down transmission and the later stages of maintaining interruption of transmission, preventing reintroduction of malaria, and eliminating the last residual foci of infection. Drugs will continue to be used to treat acute malaria illness and prevent complications in vulnerable groups, but better drugs are needed for elimination-specific indications such as mass treatment, curing asymptomatic infections, curing relapsing liver stages, and preventing transmission. The ideal malaria eradication drug is a coformulated drug combination suitable for mass administration that can be administered in a single encounter at infrequent intervals and that results in radical cure of all life cycle stages of all five malaria species infecting humans. Short of this optimal goal, highly desirable drugs might have limitations such as targeting only one or two parasite species, the priorities being Plasmodium falciparum and Plasmodium vivax. The malaria research agenda for eradication should include research aimed at developing such drugs and research to develop situation-specific strategies for using both current and future drugs to interrupt malaria transmission.

Detecting recent positive selection in the human genome from haplotype structure

Abstract: The ability to detect recent natural selection in the human population would have profound implications for the study of human history and for medicine. Here, we introduce a framework for detecting the genetic imprint of recent positive selection by analysing long-range haplotypes in human populations. We first identify haplotypes at a locus of interest (core haplotypes). We then assess the age of each core haplotype by the decay of its association to alleles at various distances from the locus, as measured by extended haplotype homozygosity (EHH). Core haplotypes that have unusually high EHH and a high population frequency indicate the presence of a mutation that rose to prominence in the human gene pool faster than expected under neutral evolution. We applied this approach to investigate selection at two genes carrying common variants implicated in resistance to malaria: G6PD and CD40 ligand. At both loci, the core haplotypes carrying the proposed protective mutation stand out and show significant evidence of selection. More generally, the method could be used to scan the entire genome for evidence of recent positive selection.

Adaptation from standing genetic variation

Abstract: Populations adapt to novel environments in two distinct ways: selection on pre-existing genetic variation and selection on new mutations. These alternative sources of beneficial alleles can result in different evolutionary dynamics and distinct genetic outcomes. Compared with new mutations, adaptation from standing genetic variation is likely to lead to faster evolution, the fixation of more alleles of small effect and the spread of more recessive alleles. There is potential to distinguish between adaptation from standing variation and that from new mutations by differences in the genomic signature of selection. Here we review these approaches and possible examples of adaptation from standing variation in natural populations. Understanding how the source of genetic variation affects adaptation will be integral for predicting how populations will respond to changing environments.

A molecular marker of artemisinin-resistant Plasmodium falciparum malaria

Abstract: Plasmodium falciparum resistance to artemisinin derivatives in southeast Asia threatens malaria control and elimination activities worldwide. To monitor the spread of artemisinin resistance, a molecular marker is urgently needed. Here, using whole-genome sequencing of an artemisinin-resistant parasite line from Africa and clinical parasite isolates from Cambodia, we associate mutations in the PF3D7_1343700 kelch propeller domain ('K13-propeller') with artemisinin resistance in vitro and in vivo. Mutant K13-propeller alleles cluster in Cambodian provinces where resistance is prevalent, and the increasing frequency of a dominant mutant K13-propeller allele correlates with the recent spread of resistance in western Cambodia. Strong correlations between the presence of a mutant allele, in vitro parasite survival rates and in vivo parasite clearance rates indicate that K13-propeller mutations are important determinants of artemisinin resistance. K13-propeller polymorphism constitutes a useful molecular marker for large-scale surveillance efforts to contain artemisinin resistance in the Greater Mekong Subregion and prevent its global spread.

Guidelines for prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: recommendations from CDC, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America.

Abstract: This report updates and combines earlier versions of guidelines for the prevention and treatment of opportunistic infections (OIs) in HIV-infected adults (i.e., persons aged >/=18 years) and adolescents (i.e., persons aged 13--17 years), last published in 2002 and 2004, respectively. It has been prepared by the Centers for Disease Control and Prevention (CDC), the National Institutes of Health (NIH), and the HIV Medicine Association (HIVMA) of the Infectious Diseases Society of America (IDSA). The guidelines are intended for use by clinicians and other health-care providers, HIV-infected patients, and policy makers in the United States. These guidelines address several OIs that occur in the United States and five OIs that might be acquired during international travel. Topic areas covered for each OI include epidemiology, clinical manifestations, diagnosis, prevention of exposure; prevention of disease by chemoprophylaxis and vaccination; discontinuation of primary prophylaxis after immune reconstitution; treatment of disease; monitoring for adverse effects during treatment; management of treatment failure; prevention of disease recurrence; discontinuation of secondary prophylaxis after immune reconstitution; and special considerations during pregnancy. These guidelines were developed by a panel of specialists from the United States government and academic institutions. For each OI, a small group of specialists with content-matter expertise reviewed the literature for new information since the guidelines were last published; they then proposed revised recommendations at a meeting held at NIH in June 2007. After these presentations and discussion, the revised guidelines were further reviewed by the co-editors; by the Office of AIDS Research, NIH; by specialists at CDC; and by HIVMA of IDSA before final approval and publication. The recommendations are rated by a letter that indicates the strength of the recommendation and a Roman numeral that indicates the quality of evidence supporting the recommendation, so that readers can ascertain how best to apply the recommendations in their practice environments. Major changes in the guidelines include 1) greater emphasis on the importance of antiretroviral therapy for the prevention and treatment of OIs, especially those OIs for which no specific therapy exists; 2) information regarding the diagnosis and management of immune reconstitution inflammatory syndromes; 3) information regarding the use of interferon-gamma release assays for the diagnosis of latent Mycobacterium tuberculosis (TB) infection; 4) updated information concerning drug interactions that affect the use of rifamycin drugs for prevention and treatment of TB; 5) the addition of a section on hepatitis B virus infection; and 6) the addition of malaria to the list of OIs that might be acquired during international travel. This report includes eleven tables pertinent to the prevention and treatment of OIs, a figure that pertains to the diagnois of tuberculosis, a figure that describes immunization recommendations, and an appendix that summarizes recommendations for prevention of exposure to opportunistic pathogens.