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NMR experiments redefine the hemoglobin binding properties of bacterial NEAr-iron Transporter domains.
Macdonald, R, Mahoney, BJ, Ellis-Guardiola, K, Maresso, A, Clubb, RT
Protein science : a publication of the Protein Society. 2019;(8):1513-1523
Abstract
Iron is a versatile metal cofactor that is used in a wide range of essential cellular processes. During infections, many bacterial pathogens acquire iron from human hemoglobin (Hb), which contains the majority of the body's total iron content in the form of heme (iron protoporphyrin IX). Clinically important Gram-positive bacterial pathogens scavenge heme using an array of secreted and cell-wall-associated receptors that contain NEAr-iron Transporter (NEAT) domains. Experimentally defining the Hb binding properties of NEAT domains has been challenging, limiting our understanding of their function in heme uptake. Here we show that solution-state NMR spectroscopy is a powerful tool to define the Hb binding properties of NEAT domains. The utility of this method is demonstrated using the NEAT domains from Bacillus anthracis and Listeria monocytogenes. Our results are compatible with the existence of at least two types of NEAT domains that are capable of interacting with either Hb or heme. These binding properties can be predicted from their primary sequences, with Hb- and heme-binding NEAT domains being distinguished by the presence of (F/Y)YH(Y/F) and S/YXXXY motifs, respectively. The results of this work should enable the functions of a wide range of NEAT domain containing proteins in pathogenic bacteria to be reliably predicted.
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Maternal hemoglobin concentrations across pregnancy and maternal and child health: a systematic review and meta-analysis.
Young, MF, Oaks, BM, Tandon, S, Martorell, R, Dewey, KG, Wendt, AS
Annals of the New York Academy of Sciences. 2019;(1):47-68
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Abstract
Maternal anemia is a well-recognized global health problem; however, there remain questions on specific hemoglobin (Hb) thresholds that predict health risk or protection for mother and child. We conducted a systematic review and meta-analysis to examine the associations of maternal Hb concentrations with a range of maternal and infant health outcomes, accounting for the timing of measurement (preconception, and first, second, and third trimesters), etiology of anemia, and cutoff category. The systematic review included 272 studies and the meta-analysis included 95 studies. Low maternal Hb (<110 g/L) was associated with poor birth outcomes (low birth weight, preterm birth, small-for-gestational-age (SGA), stillbirth, and perinatal and neonatal mortality) and adverse maternal outcomes (postpartum hemorrhage, preeclampsia, and blood transfusion). High maternal Hb (>130 g/L) was associated with increased odds of SGA, stillbirth, preeclampsia, and gestational diabetes. Relationships varied by the timing of measurement and cutoff category (stronger associations with lower cutoffs); limited data were available on anemia etiology. There were insufficient data for other maternal outcomes and long-term child health outcomes. Current data are insufficient for determining if revisions to current Hb cutoffs are required. Pooled high-quality individual-level data analyses, as well as prospective cohort studies, would be valuable to inform the reevaluation of Hb cutoffs.
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The Role of Reticulocyte Hemoglobin Content for Diagnosis of Iron Deficiency and Iron Deficiency Anemia, and Monitoring of Iron Therapy: a Literature Review.
Gelaw, Y, Woldu, B, Melku, M
Clinical laboratory. 2019;(12)
Abstract
BACKGROUND The diagnosis of iron deficiency anemia is still complicated and most of the tests have drawbacks. Bone marrow examination, the gold standard for the diagnosis of iron deficiency and iron deficiency anemia, is a painful, invasive, and costly procedure. Other methods are also used to diagnose iron deficiency and iron deficiency anemia; soluble transferrin receptor, serum iron, serum ferritin, and transferrin saturation are most common biomarkers of iron status that are frequently affected by inflammation, chronic diseases, and in the normal aging process (except soluble transferrin receptor). All are less available compared to complete blood count with reticulocyte hemoglobin content (CHr). Reticulocytes have a normal life span of one or two days in the circulation. CHr is a good indication of iron availability and an early marker of iron deficient erythropoiesis which can be obtained readily using automated blood cell analyzers. Therefore, the main objective of the current review is to assess the role of CHr for diagnosis of iron deficiency, iron deficiency anemia, and monitoring of iron therapy. METHODS Studies published in English were searched using the National Library of Medicine, PubMed, and Google scholar databases. RESULTS According to this review, CHr has a moderate sensitivity and specificity for diagnosing iron deficiency, and is less affected by inflammation than serum iron, transferrin saturation, and ferritin and is an early predictor of treatment response. It is used in screening of iron deficiency, diagnosis of iron deficiency anemia, and diagnosis of functional iron deficiency anemia in acute or chronic diseases or inflammation. CHr is also important in treatment monitoring. It is useful for early measurement of response to iron therapy, increasing within days of the initiation of iron therapy. It helps monitoring of intravenous iron supplementation, recombinant human erythropoie¬tin therapy, and oral iron therapy in hemodialysis and non-hemodialysis patients, and children. CONCLUSIONS It is easy to analyze, less time consuming, and less expensive than bone iron examination and iron biochemical tests. However, there is no standardized cutoff point and different researchers use varying cutoff values which affects its accuracy in diagnosing iron deficiency and it should therefore be standardized. Moreover, since CHr can be affected with any conditions that cause iron restricted erythropoiesis, further analysis may be needed.
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The association of early linear growth and haemoglobin concentration with later cognitive, motor, and social-emotional development at preschool age in Ghana.
Ocansey, ME, Adu-Afarwuah, S, Kumordzie, SM, Okronipa, H, Young, RR, Tamakloe, SM, Oaks, BM, Arimond, M, Dewey, KG, Prado, EL
Maternal & child nutrition. 2019;(4):e12834
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Abstract
It is important to identify the periods during childhood when exposure to environmental risk factors results in long-term neurodevelopmental deficits. Stunting and anaemia may be sensitive indicators of exposure to such risks. In a prospective cohort enrolled before birth, we investigated the association of developmental scores at 4-6 years with (a) birth length and linear growth during three postnatal periods and (2) haemoglobin (Hb) concentration at three time points. Children were participants in a follow-up study of a randomized controlled trial of nutritional supplementation in Ghana. At 4-6 years, cognitive, motor, and social-emotional developments were assessed using standard tests adapted for this population. We estimated the associations of length-for-age z-score (LAZ) at birth and postnatal linear growth (n = 710) and Hb (n = 617) with developmental scores in regression models, using multistage least squares analysis to calculate uncorrelated residuals for postnatal growth. Cognitive development at 4-6 years was significantly associated with LAZ at birth (β = 0.12, 95% CI = 0.05, 0.19), ΔLAZ from 6 to 18 months (β = 0.16, 95% CI = 0.04, 0.28), and Hb at 18 months (β = 0.13, 95% CI = 0.06, 0.20), but not with ΔLAZ during 0-6 months, ΔLAZ from 18 months to 4-6 years, Hb at 6 months, or Hb at 4-6 years. No evidence of associations with motor or social-emotional development were found. These results suggest that in similar contexts, the earlier periods prior to birth and up to 18 months are more sensitive to risk factors for long-term cognitive development associated with LAZ and Hb compared with later childhood. This may inform the optimal timing of interventions targeting improved cognitive development.
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Patient Blood Management: Recommendations From the 2018 Frankfurt Consensus Conference.
Mueller, MM, Van Remoortel, H, Meybohm, P, Aranko, K, Aubron, C, Burger, R, Carson, JL, Cichutek, K, De Buck, E, Devine, D, et al
JAMA. 2019;(10):983-997
Abstract
IMPORTANCE Blood transfusion is one of the most frequently used therapies worldwide and is associated with benefits, risks, and costs. OBJECTIVE To develop a set of evidence-based recommendations for patient blood management (PBM) and for research. EVIDENCE REVIEW The scientific committee developed 17 Population/Intervention/Comparison/Outcome (PICO) questions for red blood cell (RBC) transfusion in adult patients in 3 areas: preoperative anemia (3 questions), RBC transfusion thresholds (11 questions), and implementation of PBM programs (3 questions). These questions guided the literature search in 4 biomedical databases (MEDLINE, EMBASE, Cochrane Library, Transfusion Evidence Library), searched from inception to January 2018. Meta-analyses were conducted with the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) methodology and the Evidence-to-Decision framework by 3 panels including clinical and scientific experts, nurses, patient representatives, and methodologists, to develop clinical recommendations during a consensus conference in Frankfurt/Main, Germany, in April 2018. FINDINGS From 17 607 literature citations associated with the 17 PICO questions, 145 studies, including 63 randomized clinical trials with 23 143 patients and 82 observational studies with more than 4 million patients, were analyzed. For preoperative anemia, 4 clinical and 3 research recommendations were developed, including the strong recommendation to detect and manage anemia sufficiently early before major elective surgery. For RBC transfusion thresholds, 4 clinical and 6 research recommendations were developed, including 2 strong clinical recommendations for critically ill but clinically stable intensive care patients with or without septic shock (recommended threshold for RBC transfusion, hemoglobin concentration <7 g/dL) as well as for patients undergoing cardiac surgery (recommended threshold for RBC transfusion, hemoglobin concentration <7.5 g/dL). For implementation of PBM programs, 2 clinical and 3 research recommendations were developed, including recommendations to implement comprehensive PBM programs and to use electronic decision support systems (both conditional recommendations) to improve appropriate RBC utilization. CONCLUSIONS AND RELEVANCE The 2018 PBM International Consensus Conference defined the current status of the PBM evidence base for practice and research purposes and established 10 clinical recommendations and 12 research recommendations for preoperative anemia, RBC transfusion thresholds for adults, and implementation of PBM programs. The relative paucity of strong evidence to answer many of the PICO questions supports the need for additional research and an international consensus for accepted definitions and hemoglobin thresholds, as well as clinically meaningful end points for multicenter trials.
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Effects of Ramadan fasting on athletes' hematological indices: a systematic review.
Trabelsi, K, Shephard, RJ, Boukhris, O, Ammar, A, El-Abed, K, Khanfir, S, Hakim, A, Bragazzi, NL
La Tunisie medicale. 2019;(10):1104-1113
Abstract
OBJECTIVE To evaluate the effects of Ramadan fasting on hematological data in athletes through a systematic appraisal of the literature. DESIGN Systematic review Data sources: The entire content of two databases, PubMed/MEDLINE and Web of Science Eligibility criteria for selecting studies: Ramadanrelated measurements of any hematological indices in athletes were considered. Both single-group pre-post with and without a control group studies conducted in athletes and published in English language before December 31, 2018 were included. Study appraisal: The methodological quality of the studies identified was assessed using 'QualSyst'. RESULTS Of nine selected articles, eight were of moderate quality and only one was of strong quality. The main problem to date has been a lack of appropriate controls. Compared to before Ramadan, hematocrit and hemoglobin values increased in three studies, decreased in one study and did not change in one study during Ramadan fasting. Another study reported increased hematocrit and a puzzling decrease of hemoglobin during as compared to before Ramadan fasting. In most studies, blood platelet counts and the limited number of immune function used to date remainedunchanged. CONCLUSIONS All reported changes in hematological indices remained within the normal reference range of the laboratory. Therefore, regular training can continue safely during Ramadan fasting from a hematological view point.
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Bayesian Methods for Exposure Misclassification Adjustment in a Mediation Analysis: Hemoglobin and Malnutrition in the Association Between Ascaris and IQ.
Blouin, B, Casapia, M, Kaufman, JS, Joseph, L, Larson, C, Gyorkos, TW
Epidemiology (Cambridge, Mass.). 2019;(5):659-668
Abstract
BACKGROUND Soil-transmitted helminth infections have been found to be associated with child development. The objective was to investigate hemoglobin levels and malnutrition as mediators of the association between Ascaris infection and intelligence quotient (IQ) scores in children. METHODS We conducted a longitudinal cohort study in Iquitos, Peru, between September 2011 and July 2016. A total of 1760 children were recruited at 1 year of age and followed up annually to 5 years. We measured Ascaris infection and malnutrition at each study visit, and hemoglobin levels were measured as of age 3. The exposure was defined as the number of detected Ascaris infections between age 1 and 5. We measured IQ scores at age 5 and used Bayesian models to correct exposure misclassification. RESULTS We included a sample of 781 children in the analysis. In results adjusted for Ascaris misclassification, mean hemoglobin levels mediated the association between Ascaris infection and IQ scores. The natural direct effects (not mediated by hemoglobin) (95% CrI) and natural indirect effects (mediated by hemoglobin) (95% CrI) were compared with no or one infection: -0.9 (-4.6, 2.8) and -4.3 (-6.9, -1.6) for the effect of two infections; -1.4 (-3.8, 1.0) and -1.2 (-2.0, -0.4) for three infections; and -0.4 (-3.2, 2.4) and -2.7 (-4.3, -1.0) for four or five infections. CONCLUSION Our results are consistent with the hypothesis that hemoglobin levels mediate the association between Ascaris infection and IQ scores. Additional research investigating the effect of including iron supplements in STH control programs is warranted.
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Effects of increased hemoglobin on child growth, development, and disease: a systematic review and meta-analysis.
Larson, LM, Kubes, JN, Ramírez-Luzuriaga, MJ, Khishen, S, H Shankar, A, Prado, EL
Annals of the New York Academy of Sciences. 2019;(1):83-104
Abstract
In children under 5, a hemoglobin (Hb) cutoff of 11 g/dL is recommended by the World Health Organization to define anemia, yet few studies have examined whether this cut point accurately coincides with negative functional consequences. This systematic review and meta-analysis of iron intervention and observational studies aimed to clarify the consequences of low Hb concentration in children under age 5 years on growth, development, and chronic disease (functional outcomes) across the full range of Hb values. A literature search returned 5049 studies; of these, 56 intervention and 20 observational studies fit the inclusion criteria. Among iron supplementation trials, a metaregression indicated significant associations between intervention effects on Hb and their effects on motor and mental development. For each 1 standard deviation (SD) increase in Hb, motor scores increased by 0.28 SD and mental scores increased by 0.24 SD. Iron supplementation trials among children with lower Hb concentrations at baseline showed stronger associations between their effects on Hb and their effects on mental development (P-interaction = 0.008). Heterogeneity among observational studies precluded calculation of pooled associations between Hb and functional outcomes. Available evidence was not able to establish an inflection point at which decreasing Hb begins to be associated with negative functional outcomes. Future research is needed to examine associations of Hb with growth and development in populations with varying levels of Hb, inflammation, and in different ages and settings.
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Luspatercept improves hemoglobin levels and blood transfusion requirements in a study of patients with β-thalassemia.
Piga, A, Perrotta, S, Gamberini, MR, Voskaridou, E, Melpignano, A, Filosa, A, Caruso, V, Pietrangelo, A, Longo, F, Tartaglione, I, et al
Blood. 2019;(12):1279-1289
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Abstract
β-thalassemia is a hereditary disorder with limited approved treatment options; patients experience anemia and its complications, including iron overload. The study aim was to determine whether luspatercept could improve anemia and disease complications in patients with β-thalassemia. This open-label, nonrandomized, uncontrolled study consisted of a 24-week dose-finding and expansion stage (initial stage) and a 5-year extension stage, currently ongoing. Sixty-four patients were enrolled; 33 were non-transfusion dependent (mean hemoglobin, <10.0 g/dL; <4 red blood cell [RBC] units transfused per 8 weeks), and 31 were transfusion dependent (≥4 RBC units per 8 weeks). Patients received 0.2 to 1.25 mg/kg luspatercept subcutaneously every 21 days for ≥5 cycles (dose-finding stage) and 0.8 to 1.25 mg/kg (expansion cohort and 5-year extension). The primary end point was erythroid response, defined as hemoglobin increase of ≥1.5 g/dL from baseline for ≥14 consecutive days (without RBC transfusions) for non-transfusion-dependent patients or RBC transfusion burden reduction ≥20% over a 12-week period vs the 12 weeks before treatment for transfusion-dependent patients. Eighteen non-transfusion-dependent patients (58%) receiving higher dose levels of luspatercept (0.6-1.25 mg/kg) achieved mean hemoglobin increase ≥1.5 g/dL over ≥14 days vs baseline. Twenty-six (81%) transfusion-dependent patients achieved ≥20% reduction in RBC transfusion burden. The most common grade 1 to 2 adverse events were bone pain, headache, and myalgia. As of the cutoff, 33 patients remain on study. In this study, a high percentage of β-thalassemia patients receiving luspatercept had hemoglobin or transfusion burden improvements. These findings support a randomized clinical trial to assess efficacy and safety. This study was registered at www.clinicaltrials.gov as #NCT01749540 and #NCT02268409.
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Roxadustat for Anemia in Patients with Kidney Disease Not Receiving Dialysis.
Chen, N, Hao, C, Peng, X, Lin, H, Yin, A, Hao, L, Tao, Y, Liang, X, Liu, Z, Xing, C, et al
The New England journal of medicine. 2019;(11):1001-1010
Abstract
BACKGROUND Roxadustat (FG-4592) is an oral inhibitor of hypoxia-inducible factor (HIF) prolyl hydroxylase that stimulates erythropoiesis and regulates iron metabolism. In phase 2 studies involving patients with chronic kidney disease, roxadustat increased levels of endogenous erythropoietin to within or near the physiologic range, along with increasing hemoglobin levels and improving iron homeostasis. Additional data are needed regarding the efficacy and safety of roxadustat for the treatment of anemia in patients with chronic kidney disease who are not undergoing dialysis. METHODS In this phase 3 trial conducted at 29 sites in China, we randomly assigned 154 patients with chronic kidney disease in a 2:1 ratio to receive roxadustat or placebo three times a week for 8 weeks in a double-blind manner. All the patients had a hemoglobin level of 7.0 to 10.0 g per deciliter at baseline. The randomized phase of the trial was followed by an 18-week open-label period in which all the patients received roxadustat; parenteral iron was withheld. The primary end point was the mean change from baseline in the hemoglobin level, averaged over weeks 7 through 9. RESULTS During the primary-analysis period, the mean (±SD) change from baseline in the hemoglobin level was an increase of 1.9±1.2 g per deciliter in the roxadustat group and a decrease of 0.4±0.8 g per deciliter in the placebo group (P<0.001). The mean reduction from baseline in the hepcidin level (associated with greater iron availability) was 56.14±63.40 ng per milliliter in the roxadustat group and 15.10±48.06 ng per milliliter in the placebo group. The reduction from baseline in the total cholesterol level was 40.6 mg per deciliter in the roxadustat group and 7.7 mg per deciliter in the placebo group. Hyperkalemia and metabolic acidosis occurred more frequently in the roxadustat group than in the placebo group. The efficacy of roxadustat in hemoglobin correction and maintenance was maintained during the 18-week open-label period. CONCLUSIONS In Chinese patients with chronic kidney disease who were not undergoing dialysis, those in the roxadustat group had a higher mean hemoglobin level than those in the placebo group after 8 weeks. During the 18-week open-label phase of the trial, roxadustat was associated with continued efficacy. (Funded by FibroGen and FibroGen [China] Medical Technology Development; ClinicalTrials.gov number, NCT02652819.).