Effects of meteorological and land surface modeling uncertainty on errors in winegrape ET calculated with SIMS.

Characterization of model errors is important when applying satellite-driven evapotranspiration (ET) models to water resource management problems. This study examines how uncertainty in meteorological forcing data and land surface modeling propagate through to errors in final ET data calculated using the Satellite Irrigation Management Support (SIMS) model, a computationally efficient ET model driven with satellite surface reflectance values. The model is applied to three instrumented winegrape vineyards over the 2017-2020 time period and the spatial and temporal variation in errors are analyzed. We illustrate how meteorological data inputs can introduce biases that vary in space and at seasonal timescales, but that can persist from year to year. We also observe that errors in SIMS estimates of land surface conductance can have a particularly strong dependence on time of year. Overall, meteorological inputs introduced RMSE of 0.33-0.65 mm/day (7-27%) across sites, while SIMS introduced RMSE of 0.55-0.83 mm/day (19-24%). The relative error contribution from meteorological inputs versus SIMS varied across sites; errors from SIMS were larger at one site, errors from meteorological inputs were larger at a second site, and the error contributions were of equal magnitude at the third site. The similar magnitude of error contributions is significant given that many satellite-driven ET models differ in their approaches to estimating land surface conductance, but often rely on similar or identical meteorological forcing data. The finding is particularly notable given that SIMS makes assumptions about the land surface (no soil evaporation or plant water stress) that do not always hold in practice. The results of this study show that improving SIMS by eliminating these assumptions would result in meteorological inputs dominating the error budget of the model on the whole. This finding underscores the need for further work on characterizing spatial uncertainty in the meteorological forcing of ET. Supplementary Information: The online version contains supplementary material available at 10.1007/s00271-022-00808-9.

Adaptations to the current ECCO/ESPGHAN guidelines on the management of paediatric acute severe colitis in the context of the COVID-19 pandemic: a RAND appropriateness panel.

OBJECTIVE: Paediatric acute severe colitis (ASC) management during the novel SARS-CoV-2/COVID-19 pandemic is challenging due to reliance on immunosuppression and the potential for surgery. We aimed to provide COVID-19-specific guidance using the European Crohn's and Colitis Organisation/European Society for Paediatric Gastroenterology, Hepatology and Nutrition guidelines for comparison. DESIGN: We convened a RAND appropriateness panel comprising 14 paediatric gastroenterologists and paediatric experts in surgery, rheumatology, respiratory and infectious diseases. Panellists rated the appropriateness of interventions for ASC in the context of the COVID-19 pandemic. Results were discussed at a moderated meeting prior to a second survey. RESULTS: Panellists recommended patients with ASC have a SARS-CoV-2 swab and expedited biological screening on admission and should be isolated. A positive swab should trigger discussion with a COVID-19 specialist. Sigmoidoscopy was recommended prior to escalation to second-line therapy or colectomy. Methylprednisolone was considered appropriate first-line management in all, including those with symptomatic COVID-19. Thromboprophylaxis was also recommended in all. In patients requiring second-line therapy, infliximab was considered appropriate irrespective of SARS-CoV-2 status. Delaying colectomy due to SARS-CoV-2 infection was considered inappropriate. Corticosteroid tapering over 8-10 weeks was deemed appropriate for all. After successful corticosteroid rescue, thiopurine maintenance was rated appropriate in patients with negative SARS-CoV-2 swab and asymptomatic patients with positive swab but uncertain in symptomatic COVID-19. CONCLUSION: Our COVID-19-specific adaptations to paediatric ASC guidelines using a RAND panel generally support existing recommendations, particularly the use of corticosteroids and escalation to infliximab, irrespective of SARS-CoV-2 status. Consideration of routine prophylactic anticoagulation was recommended.

Service evaluation of diabetes management during pregnancy in a regional maternity hospital: potential scope for increased self-management and remote patient monitoring through mHealth solutions.

BACKGROUND: Pre-gestational and gestational diabetes mellitus are common complications in pregnancy affecting one in six pregnancies. The maternity services are under significant strain managing the increasing number of complex pregnancies. This has an impact on patients' experience of antenatal care. Therefore, there is a clear need to address pregnancy care. One possible solution is to use home-based digital technology to reduce clinic visits and improve clinical monitoring. METHODS: The aim of this study was to evaluate the antenatal services provided to pregnant women with diabetes who were monitored at the joint metabolic and obstetric clinic at the Southern Health and Social Care Trust in Northern Ireland. RESULTS: The questionnaires were completed by sixty-three women, most of whom had gestational diabetes mellitus. Most of the participants were between 25 and 35 years of age (69.8%), had one or more children (65.1%) and spent over 2 h attending the clinics (63.9%); 78% of women indicated that their travel time to and from the clinic appointment was over 15 min. Over 70% of women used smartphones for health-related purposes. However, only 8.8% used smartphones to manage their health or diabetes. Less than 25% of the women surveyed expressed concerns about using digital technology from home to monitor various aspects of their health in pregnancy. CONCLUSIONS: Overall, pregnant women who had or developed diabetes in pregnancy experience frequent hospital visits and long waiting times in the maternity clinics. Most of these pregnant women are willing to self-manage their condition from home and to be monitored remotely by the healthcare staff.

Hepcidin is the major predictor of erythrocyte iron incorporation in anemic African children.

Iron supplementation strategies in the developing world remain controversial because of fears of exacerbating prevalent infectious diseases. Understanding the conditions in which iron will be absorbed and incorporated into erythrocytes is therefore important. We studied Gambian children with either postmalarial or nonmalarial anemia, who were given oral iron supplements daily for 30 days. Supplements administered on days 1 and 15 contained the stable iron isotopes (57)Fe and (58)Fe, respectively, and erythrocyte incorporation was measured in blood samples drawn 14 days later. We investigated how the iron-regulatory hormone hepcidin and other inflammatory/iron-related indices, all measured on the day of isotope administration, correlated with erythrocyte iron incorporation. In univariate analyses, hepcidin, ferritin, C-reactive protein, and soluble transferrin receptor (sTfR) strongly predicted incorporation of (57)Fe given on day 1, while hepcidin, ferritin, and sTfR/log ferritin correlated with (58)Fe incorporation. In a final multivariate model, the most consistent predictor of erythrocyte isotope incorporation was hepcidin. We conclude that under conditions of competing signals (anemia, iron deficiency, and infection), hepcidin powerfully controls use of dietary iron. We suggest that low-cost point-of-care hepcidin assays would aid iron supplementation programs in the developing world.

Applying 3D Models of Giant Salamanders to Explore Form-Function Relationships in Early Digit-Bearing Tetrapods.

Extant salamanders are used as modern analogs of early digit-bearing tetrapods due to general similarities in morphology and ecology, but the study species have been primarily terrestrial and relatively smaller when the earliest digit-bearing tetrapods were aquatic and an order of magnitude larger. Thus, we created a 3D computational model of underwater walking in extant Japanese giant salamanders (Andrias japonicus) using 3D photogrammetry and open-access graphics software (Blender) to broaden the range of testable hypotheses about the incipient stages of terrestrial locomotion. Our 3D model and software protocol represent the initial stages of an open-access pipeline that could serve as a "one-stop-shop" for studying locomotor function, from creating 3D models to analyzing the mechanics of locomotor gaits. While other pipelines generally require multiple software programs to accomplish the different steps in creating and analyzing computational models of locomotion, our protocol is built entirely within Blender and fully customizable with its Python scripting so users can devote more time to creating and analyzing models instead of navigating the learning curves of several software programs. The main value of our approach is that key kinematic variables (e.g. speed, stride length, and elbow flexion) can be easily altered on the 3D model, allowing scientists to test hypotheses about locomotor function and conduct manipulative experiments (e.g. lengthening bones) that are difficult to perform in vivo. The accurate 3D meshes (and animations) generated through photogrammetry also provide exciting opportunities to expand the abundance and diversity of 3D digital animals available for researchers, educators, artists, conservation biologists, etc. to maximize societal impacts.

Paediatric Common Infections Pathways: improving antimicrobial stewardship and promoting ambulation for children presenting with common infections to hospitals in the UK and Ireland.

Paediatric common infection pathways have been developed in collaboration between the BSAC and national paediatric groups, addressing the management of cellulitis, lymphadenitis/lymph node abscess, pneumonia/pleural empyema, pyelonephritis, tonsillitis/peritonsillar abscess, otitis media/mastoiditis, pre-septal/post-septal (orbital) cellulitis, and meningitis. Guidance for the management of a child presenting with a petechial/purpuric rash and the infant under 3 months of age with fever is also provided. The aim of these pathways is to support the delivery of high-quality infection management in children presenting to a hospital. The pathways focus on diagnostic approaches, including the recognition of red flags suggesting complex or severe infection requiring urgent intervention, approaches to antimicrobial stewardship (AMS) principles and guidance on safe and timely ambulation aligned with good practice of outpatient parenteral antimicrobial therapy (OPAT).

Effectiveness of an early supplementation scheme of high-dose vitamin A versus standard WHO protocol in Gambian mothers and infants: a randomised controlled trial.

BACKGROUND: Most developing countries have adopted a standard WHO dosing schedule for vitamin A supplementation. However, in 2002 the International Vitamin A Consultative Group (IVACG) Annecy Accord recommended a new high-dose regimen for mothers and infants. Our aim was to test whether the new high-dose regimen of vitamin A supplementation would increase maternal and infant plasma vitamin A, reduce infant Helicobacter pylori infection and nasopharyngeal pneumococcal carriage, and improve infant gut epithelial integrity. METHODS: In an area of moderate vitamin A deficiency in rural Gambia, 220 mother-infant pairs were enrolled in a randomised double-blind trial between September, 2001, and October, 2004, that compared the IVACG high dose with the WHO dose. The primary endpoints were levels of maternal and infant plasma vitamin A, H pylori infection, pneumococcal carriage, and gut epithelial integrity. The trial is registered as ISRCTN 98554309. FINDINGS: 197 infants completed follow-up to 12 months (99 high dose and 98 WHO dose). There were no adverse events at dosing. No differences were found in the primary outcomes for high-dose versus WHO schedule: maternal vitamin A concentration at 2 months +0.02 micromol/L (95% CI -0.10 to 0.15); infant vitamin A at 5 months +0.01 micromol/L (-0.06 to 0.08); H pylori infection at 12 months -0.3% (-14.7 to 14.2); maternal pneumococcal carriage at 12 months -2.0% (-13.7 to 9.7); infant pneumococcal carriage at 12 months -4.1% (-15.8 to 7.6); infant gut mucosal damage at 12 months 5.2% (-8.7 to 19.2). There were more clinic attendances by the high-dose group in the first 6 months of life (p=0.018). INTERPRETATION: Our results do not lend support to the proposal to increase the existing WHO standard dosing schedule for vitamin A in areas of moderate vitamin A deficiency. Caution is urged for future studies because trials have shown possible adverse effects of higher doses of vitamin A, and potential negative interactions with the expanded programme on immunisation (EPI) vaccines.

Haptoglobin genotype, anaemia and malaria in Gambian children.

OBJECTIVE: To retest our previous finding that the haptoglobin (Hp) 22 genotype is associated with seasonal anaemia, and to investigate the role of malaria in this effect. METHODS: Haemoglobin (Hb) and peripheral parasitaemia were assessed at pre- and post-malarial season cross-sectional surveys in rural Gambian children aged 10-72 months. Between the surveys, active longitudinal surveillance was conducted to detect febrile episodes. RESULTS: Unlike previously, no overall reduction in Hb was observed (Hb = 106.1 vs. 107.2 g/l, P = 0.13, n = 545). However, multi-variable linear regression revealed differences in Hb over the season by Hp and Hb-sickle (HbS) genotype (-2.20 g/l per copy of the Hp2 allele, P = 0.043; HbAS vs. HbAA + 3.13 g/l, P = 0.11, n = 536). There was no effect of malarial episodes during follow-up; this suggests that when effective treatment is given, Hb levels recover. The A61-C Hp promoter SNP, associated with the Hp2 allele, had no effect. CONCLUSION: The effect of the Hp2 allele appears to be independent of effects on malaria incidence but may affect Hb levels through increased oxidant stress and red cell turnover. This may be supported by our previous observations that the effect of Hp22 was independent of markers of iron status and zinc protoporphyrin measured at the cross-sectional surveys and therefore also of iron availability for erythropoiesis.

Zinc as an adjunct therapy in the management of severe pneumonia among Gambian children: randomized controlled trial.

BACKGROUND: The benefit of zinc as an adjunct therapy for severe pneumonia is not established. We assessed the benefit of adjunct zinc therapy for severe pneumonia in children and determined whether the study children were zinc deficient. METHODS: This was a randomized, parallel group, double-blind, placebo-controlled trial with an allocation ratio of 1:1 conducted in children with severe pneumonia to evaluate the efficacy of daily zinc as an adjunct treatment in preventing 'treatment failure' (presence of any sign of severe pneumonia) on day-5 and day-10 and in reducing the time to resolution of signs of severe pneumonia. Six hundred and four children 2-59 months of age presenting with severe pneumonia at six urban and rural health care facilities in The Gambia were individually randomised to receive placebo (n = 301) or zinc (n = 303) for seven days. To determine if the study children were zinc deficient, supplementation was continued in a randomly selected subgroup of 121 children from each arm for six months post-enrolment, and height-gain, nutritional status, plasma zinc concentrations, and immune competence were compared. RESULTS: Percentage of treatment failure were similar in placebo and zinc arms both on day 5 (14.0% vs 14.1%) and day 10 (5.2% vs 5.9%). The time to recovery from lower chest wall indrawing and sternal retraction was longer in the placebo compared to zinc arm (24.4 vs 23.0 hours; P = 0.011 and 18.7 vs 11.0 hours; P = 0.006 respectively). The time to resolution for all respiratory symptoms of severity was not significantly different between placebo and zinc arms (42.3 vs 30.9 hours respectively; P = 0.242). In the six months follow-up sub-group, there was no significant difference in height gain, height-for-age and weight-for-height Z-scores, mid upper arm circumference, plasma zinc concentrations, and anergy at six months post-enrolment. CONCLUSIONS: In this population, zinc given as an adjunct treatment for severe pneumonia showed no benefit in treatment failure rates, or clinically important benefit in time to recovery from respiratory symptoms and showed marginal benefit in rapidity of resolution of some signs of severity. This finding does not support routine use of zinc as an adjunct treatment in severe pneumonia in generally zinc replete children. TRIAL REGISTRATION: ISRCTN33548493.

Evaluation of 13C-urea breath test and fecal antigen immunoassay to detect Helicobacter pylori infection in Gambian infants.

Helicobacter pylori colonization was measured by [13C]-urea breath test in 198 Gambian infants and by fecal enzyme-linked immunosorbent assay in 52 of the 198 at ages 2, 5, and 12 months. By 12 months there was good concordance between tests; 33 of 44 (75%) test results were positive by enzyme-linked immunosorbent assay, and 29 of 44 (66%) test results were positive by urea breath test. H. pylori colonization is common among Gambian infants, and noninvasive tests can provide a reliable means of diagnosis.

Iron metabolism and malaria.

Recent evidence from a large, randomized, controlled trial has suggested that the universal administration of iron to children in malaria-endemic areas is associated with an increase in adverse health outcomes. The purpose of this paper is to summarize the available ecologic and intervention trials related to iron and malaria in children, and to set these against current knowledge of the biology of host-pathogen interactions involving iron metabolism. We conclude that, although not fully consistent, the balance of evidence confirms that administration of iron (usually in combination with folic acid) increases the incidence of malaria when given without prophylaxis and in the absence of universal access to treatment. The mechanisms by which additional iron can benefit the parasite are far from clear. There is evidence to suggest that the apparent detrimental effect of iron supplementation may vary according to levels of antecedent iron status, the presence of hemoglobinopathies and glucose-6-phosphate dehydrogenase (G6PD) deficiency, and other host genetic variants, such as variants in haptoglobin. The effects of malaria on host iron metabolism are also reviewed and reveal that the key cause of malaria-induced anemia is a maldistribution of iron and suppression of erythropoiesis rather than an exacerbation of gross iron deficiency. We tentatively conclude that, if it is to be recommended, universal iron supplementation in malarious areas should only be considered in conjunction with some form of prophylaxis (e.g., intermittent preventive therapy [IPT]) or in the context of good health services with ready access to facilities for malaria diagnosis and treatment. An alternative approach would be to screen for anemia and target supplementation only to anemic children. With regard to treatment, there is good evidence that iron supplementation should be withheld until the treatment schedule is complete, both because iron may inhibit treatment and because the absorption of oral iron is blocked by the inflammatory response.

Expression of the iron hormone hepcidin distinguishes different types of anemia in African children.

Childhood anemia is a major global health problem resulting from multiple causes. Iron supplementation addresses iron deficiency anemia but is undesirable for other types of anemia and may exacerbate infections. The peptide hormone hepcidin governs iron absorption; hepcidin transcription is mediated by iron, inflammation, and erythropoietic signals. However, the behavior of hepcidin in populations where anemia is prevalent is not well established. We show that hepcidin measurements in 1313 African children from The Gambia and Tanzania (samples taken in 2001 and 2008, respectively) could be used to identify iron deficiency anemia. A retrospective secondary analysis of published data from 25 Gambian children with either postmalarial or nonmalarial anemia demonstrated that hepcidin measurements identified individuals who incorporated >20% oral iron into their erythrocytes. Modeling showed that this sensitivity of hepcidin expression at the population level could potentially enable simple groupings of individuals with anemia into iron-responsive and non-iron-responsive subtypes and hence could guide iron supplementation for those who would most benefit.

Randomised controlled trial of weekly chloroquine to re-establish normal erythron iron flux and haemoglobin recovery in postmalarial anaemia.

OBJECTIVE: To determine if low-dose weekly chloroquine (CQ) therapy improves recovery from malaria-associated anaemia. DESIGN: Proof of concept randomised clinical trial. SETTING: West Kiang District, Lower River Region, The Gambia. PARTICIPANTS: Children resident in participating communities, aged 12-72 months, with uncomplicated malaria identified using active case detection over two consecutive malaria transmission seasons. INTERVENTIONS: In 2007, eligible children were randomised to chloroquine-sulfadoxine/pyrimethamine (CQ-SP) or co-artemether (ACT) antimalarial therapy, and after parasite clearance on day 3 were subsequently re-randomised (double-blind) to weekly low-dose CQ (5 mg/kg) or placebo. In 2008, all eligible children were treated with ACT and subsequently randomised to CQ or placebo. OUTCOME MEASURES: The primary outcome was a change in haemoglobin from baseline (day 3 of antimalarial treatment) to day 90 in the CQ and placebo treatment arms. Secondary outcomes were changes in urinary neopterin as a marker of macrophage activation, markers of erythropoietic response and prevalence of submicroscopic parasitaemia. Change in haemoglobin in the placebo arm by initial antimalarial treatment was also assessed. RESULTS: In 2007, 101 children with uncomplicated malaria were randomised to antimalarial treatment with CQ-SP or ACT and 65 were subsequently randomised to weekly CQ or placebo. In 2008, all children received ACT antimalarial treatment and 31 were subsequently randomised to receive weekly CQ or placebo. Follow-up to day 90 was 96%. There was no effect of weekly CQ vs placebo on change in haemoglobin at day 90 (CQ+10.04 g/L (95% CI 6.66 to 13.42) vs placebo +7.61 g/L (95% CI 2.88 to 12.35)). There was no effect on the secondary outcomes assessed, or effect of initial antimalarial therapy on haemoglobin recovery. Higher day 90 haemoglobin correlated independently with older age, not being stunted, higher haemoglobin at day 0 and adequate iron status at day 3. CONCLUSIONS: Weekly low-dose CQ after effective antimalarial treatment is not effective in improving recovery from postmalarial anaemia. TRIAL REGISTRATION: The clinical trial registration number is NCT00473837 (ClinicalTrials.gov).

FGF23 is correlated with iron status but not with inflammation and decreases after iron supplementation: a supplementation study.

BACKGROUND: Recent studies have described relationships between iron status and fibroblast growth factor-23 (FGF23) but the possible confounding effects of inflammation on iron status have not been considered. The aims of this study were a) to consider a relationship between FGF23 and inflammation b) to identify relationships between iron status and FGF23 whilst correcting for inflammation and c) to assess the relationship between changes in FGF23 and iron status after supplementation. STUDY DESIGN AND METHODOLOGY: Blood samples from an iron supplementation study in children (n=79) were collected at baseline and after 3 months supplementation with iron sulphate. The children were from a rural Gambian population where rates of iron deficiency and infection/inflammation are high. This study identified cross-sectional and longitudinal relationships between FGF23, inflammation (C-reactive protein (CRP)) and iron status (ferritin, haemoglobin, and zinc protoporphyrin). CRP ≥ 5 mg/dL was used to indicate inflammation and FGF23 ≥ 125 RU/mL was considered elevated. RESULTS: FGF23 was not significantly correlated with CRP. At baseline, all markers of iron status were significantly correlated with FGF23. Ferritin was the strongest independent inverse predictor of FGF23 in subjects with and without elevated CRP (coefficient (SE)): All subjects=-0.57 (0.12), R2=22.3%, P≤0.0001; subjects with CRP < 5 mg/dL=-0.89 (0.14), R2=38.9%, P≤0.0001. FGF23 was elevated in 28% of children at baseline and 16% post supplementation (P=0.1). Improved iron status was associated with a decrease in FGF23 concentration in univariate (ferritin =-0.41 (0.11), R2=14.1%, P=0.0004; haemoglobin=-2.22 (0.64), R2=12.5%, P=0.0008; zinc protoporphyrin=1.12 (0.26), R2=18.6%, P≤0.0001) and multivariate analysis (R2=33.1%; ferritin=-0.36 (0.10), P=0.0007, haemoglobin = -1.83 (0.61), P=0.004, zinc protoporphyrin=0.62 (0.26), P=0.02). CONCLUSIONS: Iron status rather than inflammation is a negative predictor of plasma FGF23 concentration. Improvements in iron status following iron supplementation are associated with a significant decrease in FGF23 concentration.

Iron delocalisation in the pathogenesis of malarial anaemia.

There is consensus that the pathophysiology of malaria-associated anaemia is multifactorial, but the precise mechanisms behind many of the haematological changes during malaria remain unclear. In this review, we attempt to build a composite picture of the pathophysiology of malarial anaemia using evidence from experimental, human and animal studies. We propose that cytokine- and hepcidin-mediated iron delocalisation, a principal mechanism in the anaemia of inflammation, plays an important role in the aetiology of malarial anaemia, and can explain some of the clinical and laboratory findings. These mechanisms interact with other aetiological determinants, such as dietary iron and micronutrient supply, helminth load, other infections and genetic variation, in determining the severity and associated features of anaemia. We suggest that iron delocalisation as a mechanism for malarial anaemia could be exploited for the development of alternative therapeutic strategies for post-malaria anaemia.

Haptoglobin and sickle cell polymorphisms and risk of active trachoma in Gambian children.

BACKGROUND: Susceptibility and resistance to trachoma, the leading infectious cause of blindness, have been associated with a range of host genetic factors. In vitro studies of the causative organism, Chlamydia trachomatis, demonstrate that iron availability regulates its growth, suggesting that host genes involved in regulating iron status and/or availability may modulate the risk of trachoma. The objective was to investigate whether haptoglobin (Hp) haplotypes constructed from the functional polymorphism (Hp1/Hp2) plus the functional promoter SNPs -61A-C (rs5471) and -101C-G (rs5470), or sickle cell trait (HbAS, rs334) were associated with risk of active trachoma when stratified by age and sex, in rural Gambian children. METHODOLOGY AND PRINCIPAL FINDINGS: In two cross sectional surveys of children aged 6-78 months (n = 836), the prevalence of the clinical signs of active trachoma was 21.4%. Within boys, haplotype E (-101G, -61A, Hp1), containing the variant allele of the -101C-G promoter SNP, was associated with a two-fold increased risk of active trachoma (OR = 2.0 [1.17-3.44]). Within girls, an opposite association was non-significant (OR = 0.58 [0.32-1.04]; P = 0.07) and the interaction by sex was statistically significant (P = 0.001). There was no association between trachoma and HbAS. CONCLUSIONS: These data indicate that genetic variation in Hp may affect susceptibility to active trachoma differentially by sex in The Gambia.

Iron incorporation and post-malaria anaemia.

BACKGROUND: Iron supplementation is employed to treat post-malarial anaemia in environments where iron deficiency is common. Malaria induces an intense inflammatory reaction that stalls reticulo-endothelial macrophagal iron recycling from haemolysed red blood cells and inhibits oral iron absorption, but the magnitude and duration of these effects are unclear. METHODOLOGY/PRINCIPAL FINDINGS: We examined the red blood cell incorporation of oral administered stable isotopes of iron and compared incorporation between age matched 18 to 36 months old children with either anaemia post-malaria (n = 37) or presumed iron deficiency anaemia alone (n = 36). All children were supplemented for 30 days with 2 mg/kg elemental iron as liquid iron sulphate and administered (57)Fe and (58)Fe on days 1 and 15 of supplementation respectively. (57)Fe and(58)Fe incorporation were significantly reduced (8% vs. 28%: p<0.001 and 14% vs. 26%: p = 0.045) in the malaria vs. non-malaria groups. There was a significantly greater haemoglobin response in the malaria group at both day 15 (p = 0.001) and 30 (p<0.000) with a regression analysis estimated greater change in haemoglobin of 7.2 g/l (s.e. 2.0) and 10.1 g/l (s.e. 2.5) respectively. CONCLUSION/SIGNIFICANCE: Post-malaria anaemia is associated with a better haemoglobin recovery despite a significant depressant effect on oral iron incorporation which may indicate that early erythropoetic iron need is met by iron recycling rather than oral iron. Supplemental iron administration is of questionable utility within 2 weeks of clinical malaria in children with mild or moderate anaemia.

Host-pathogen interactions: the role of iron.

Iron is essential for both host and pathogen, and complex systems of acquisition and utilization have evolved in competition. Our increasing knowledge of the basic mechanisms of homeostasis and their adaptation during deficiency, overload, and infection indicate that iron is a key regulator of host pathogen interactions. This review concentrated on the clinical and public health aspects of the interaction between the iron acquisition mechanisms of select pathogens of public health importance with host iron homeostasis. Knowledge of these interactions is essential in assessing likely morbidity responses to supplementation.

Haplotype association between haptoglobin (Hp2) and Hp promoter SNP (A-61C) may explain previous controversy of haptoglobin and malaria protection.

BACKGROUND: Malaria is one of the strongest recent selective pressures on the human genome, as evidenced by the high levels of varying haemoglobinopathies in human populations-despite the increased risk of mortality in the homozygous states. Previously, functional polymorphisms of Hp, coded by the co-dominant alleles Hp1 and Hp2, have been variously associated with several infectious diseases, including malaria susceptibility. METHODOLOGY/PRINCIPAL FINDINGS: Risk of a clinical malarial episode over the course of a malarial transmission season was assessed using active surveillance in a cohort of Gambian children aged 10-72 months. We report for the first time that the major haplotype for the A-61C mutant allele in the promoter of haptoglobin (Hp)-an acute phase protein that clears haemoglobin released from haemolysis of red cells-is associated with protection from malarial infection in older children, (children aged >or=36 months, >500 parasites/ul and temperature >37.5 degrees C; OR = 0.42; [95% CI 0.24-0.73] p = 0.002) (lr test for interaction, <36 vs >or=36 months, p = 0.014). Protection was also observed using two other definitions, including temperature >37.5 degrees C, dipstick positive, plus clinical judgement of malaria blinded to dipstick result (all ages, OR = 0.48, [95% CI 0.30-0.78] p = 0.003; >or=36 months, OR = 0.31, [95% CI 0.15-0.62] p = 0.001). A similar level of protection was observed for the known protective genetic variant, sickle cell trait (HbAS). CONCLUSIONS/SIGNIFICANCE: We propose that previous conflicting results between Hp phenotypes/genotypes and malaria susceptibility may be explained by differing prevalence of the A-61C SNP in the populations studied, which we found to be highly associated with the Hp2 allele. We report the -61C allele to be associated with decreased Hp protein levels (independent of Hp phenotype), confirming in vitro studies. Decreased Hp expression may lead to increased oxidant stress and increased red cell turnover, and facilitate the development of acquired immunity, similar to a mechanism suggested for sickle cell trait.