The major hemoglobinopathies: epidemiology, molecular pathology, and clinical phenotype.

<p>The human genome normally contains four copies of α-globin genes (in paired copies on chromosome 16: genotype αα/αα) and two copies of β-globin genes (on chromosome 11). Normal adult hemoglobin (HbAA) is a tetramer of two α-globin and two β-globin proteins.</p>a<p>Not technically a hemoglobinopathy but rather a normal hemoglobin variant of all newborns and infants.</p

Studies of <i>P. falciparum</i> invasion of and development in RBCs containing hemoglobin variants.

<p>Unless otherwise stated, assessments of RBC invasion and growth are relative to HbAA or non-thalassemic RBCs.</p><p>NR, not reported; HPFH, syndrome of hereditary persistence of fetal hemoglobin.</p

General mechanisms by which hemoglobinopathies may attenuate the pathogenesis of falciparum malaria.

<p>(A) Restriction of red blood cell (RBC) invasion or intraerythrocytic growth, thereby suppressing parasite densities <i>in vivo</i>; (B) interference with parasite-derived mediators of pathogenesis, including those involved in the binding of parasite-infected RBCs (iRBCs) to extracellular host receptors; (C) modulation of innate host defenses to favor protective, anti-inflammatory responses over those that drive pathogenic, pro-inflammatory responses; (D) enhancement of adaptive cell-mediated and humoral immune responses that clear iRBCs from the blood.</p

Geographic clusters from which households were selected for sampling.

<p>Geographic clusters from which households were selected for sampling.</p

Under-5 mortality and malaria endemicity.

<p>A. U5MR (deaths per 1000 live births) by survey cluster. B. Cluster U5MR by adult <i>P. falciparum</i> prevalence. Black dots represent actual U5MRs, weighted relative to the number of births in each cluster; black line represents trend line from an unadjusted linear regression model (R² = 0.0538; p<0.001) weighted for differences in numbers of births between clusters (gray area is 95% confidence interval). C. Cluster U5MR by malaria endemicity category. Boxes represent interquartile range, midline is median, individual dots are outliers. p = 0.001 for overall comparison of medians by Kruskal-Wallis analysis of variance.</p

Results of a multilevel model of cluster-level indicators on under-5 deaths.

<p>C.I.: confidence interval. Odds ratios are adjusted for other covariates. 1^st quartile are clusters with the lowest proportion of the indicated variable, 4^th quartile with the highest proportion of the indicated variable. All children born to female respondents in or since 2003 were included (n = 8290).</p>a<p>Proportion of adults in each cluster who were parasitemic with <i>P. falciparum</i> by real-time PCR testing.</p>b<p>Proportion children under 5 in each cluster who had ever received any vaccination for any disease (as reported by the child's mother).</p>c<p>Proportion of children under 5 in each cluster who had diarrhea, fever, or cough in the preceding two weeks, (as reported by the child's mother).</p

Spatial epidemiology of <i>P. falciparum</i>, <i>ovale</i>, and <i>malariae</i> parasitemias.

<p>Parasite prevalence within 300 survey clusters. (note difference in visual scales). A. <i>P. Falciparum</i>. B. <i>P. ovale</i>. C. <i>P. malariae.</i></p

Individual and cluster characteristics by malaria endemicity.

<p>Values are expressed as percentages unless otherwise indicated; those in parentheses are 95% confidence intervals. ITN, insecticide-treated bednet.</p>a<p>Quintiles of 1 (poorest) – 5 (wealthiest) based on household ownership of goods owned and lodging characteristics.</p>b<p>Includes mixed-species parasitemias.</p

Penetration of malaria control measures.

<p>(note difference in visual scales). A. Proportion of households with children under 5 years of age by cluster who reported owning an insecticide-treated net. B. Proportion of children under 5 years of age by cluster that were reported to have slept under an insecticide-treated net the night prior to the survey. C. Proportion of pregnant women by cluster who reported sleeping under an insecticide-treated net the night prior to the survey. D. Proportion of women by cluster who reported taking any antimalarial during their most recent pregnancy within the preceding 5 years.</p

Malaria indices from household survey.

<p>Proportions weighted to account for sampling design. ITN, insecticide-treated bednet. HIV, human immunodeficiency virus. ACT, artemisinin-combination therapy.</p