Publications by authors named "Sant-Rayn Pasricha"

84 Publications

Benefits and Risks of Iron Interventions in Infants in Rural Bangladesh.

N Engl J Med 2021 09;385(11):982-995

From the Population Health and Immunity Division, Walter and Eliza Hall Institute of Medical Research (S.-R.P., S.B., L.M.L., A.B.), Diagnostic Haematology, Royal Melbourne Hospital (S.-R.P.), Clinical Haematology, Peter MacCallum Cancer Centre and Royal Melbourne Hospital (S.-R.P.), the Department of Medical Biology (S.-R.P., A.B.), the Departments of Medicine and Infectious Diseases, Peter Doherty Institute for Infection and Immunity (S.B., L.M.L., B.-A.B.), and the Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health (S.B., J.A.S.), University of Melbourne, and the Victorian Infectious Diseases Service, Royal Melbourne Hospital (B.-A.B.), Parkville, VIC, and the Department of Public Health and Preventive Medicine, Monash University, Melbourne, VIC (J.F.) - all in Australia; the International Center for Diarrheal Disease Research, Bangladesh, Dhaka, Bangladesh (M.I.H., S.M.M.U.T., S.J.H., S.S., M.S.A.B., F.T., J.D.H.); the Department of Health Promotion, Education and Behavior, Arnold School of Public Health, University of South Carolina, Columbia (L.M.L.); and the Institute of Child Health, University College London, London (S.G.-M.).

Background: Universal provision of iron supplements (drops or syrup) or multiple micronutrient powders to young children in low-to-middle-income countries where anemia is prevalent is recommended by the World Health Organization and widely implemented. The functional benefits and safety of these interventions are unclear.

Methods: We conducted a three-group, double-blind, double-dummy, individually randomized, placebo-controlled trial to assess the immediate and medium-term benefits and risks of 3 months of daily supplementation with iron syrup or iron-containing multiple micronutrient powders, as compared with placebo, in 8-month-old children in rural Bangladesh. The primary outcome was cognitive development, as assessed by the cognitive composite score on the Bayley Scales of Infant and Toddler Development, third edition, immediately after completion of the assigned 3-month regimen; scores range from 55 to 145, with higher scores indicating better cognitive performance. Secondary outcomes included the cognitive composite score at 9 months after completion of the assigned regimen; behavioral, language, and motor development, as well as growth and hematologic markers, immediately after completion and at 9 months after completion; and safety.

Results: We randomly assigned 3300 infants to receive iron syrup (1101 infants), multiple micronutrient powders (1099), or placebo (1100) daily. After completion of the assigned 3-month regimen, no apparent effect on the cognitive composite score was observed with iron syrup as compared with placebo (mean between-group difference in change in score from baseline, -0.30 points; 95% confidence interval [CI], -1.08 to 0.48) or with multiple micronutrient powders as compared with placebo (mean between-group difference in change in score from baseline, 0.23 points; 95% CI, -0.55 to 1.00). No apparent effect on any other developmental or growth outcome was observed immediately after completion of the assigned regimen or at 9 months after completion. At 9 months after completion of the assigned regimen, the prevalences of anemia, iron deficiency, and iron deficiency anemia increased in all three trial groups but remained lower among the children who received iron syrup or multiple micronutrient powders than among those who received placebo. The risk of serious adverse events and incidence of symptoms of infection were similar in the three trial groups.

Conclusions: In this trial involving infants in Bangladesh, 3 months of daily supplementation with iron syrup or multiple micronutrient powders did not appear to have an effect on child development or other functional outcomes as compared with placebo. (Funded by the National Health and Medical Research Council of Australia; BRISC Australian New Zealand Clinical Trials Registry number, ACTRN12617000660381.).
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http://dx.doi.org/10.1056/NEJMoa2034187DOI Listing
September 2021

Vaccine efficacy and iron deficiency: an intertwined pair?

Lancet Haematol 2021 Sep;8(9):e666-e669

MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK; Department of Health Sciences and Technology, ETH Zurich, Zurich, Switzerland.

Vaccines are the most effective measure to prevent deaths and illness from infectious diseases. Nevertheless, the efficacy of several paediatric vaccines is lower in low-income and middle-income countries (LMICs), where mortality from vaccine-preventable infections remains high. Vaccine efficacy can also be decreased in adults in the context of some common comorbidities. Identifying and correcting the specific causes of impaired vaccine efficacy is of substantial value to global health. Iron deficiency is the most common micronutrient deficiency worldwide, affecting more than 2 billion people, and its prevalence in LMICs could increase as food security is threatened by the COVID-19 pandemic. In this Viewpoint, we highlight evidence showing that iron deficiency limits adaptive immunity and responses to vaccines, representing an under-appreciated additional disadvantage to iron deficient populations. We propose a framework for urgent detailed studies of iron-vaccine interactions to investigate and clarify the issue. This framework includes retrospective analysis of newly available datasets derived from trials of COVID-19 and other vaccines, and prospective testing of whether nutritional iron interventions, commonly used worldwide to combat anaemia, improve vaccine performance.
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http://dx.doi.org/10.1016/S2352-3026(21)00201-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8384343PMC
September 2021

Preanalytic and analytic factors affecting the measurement of haemoglobin concentration: impact on global estimates of anaemia prevalence.

BMJ Glob Health 2021 07;6(7)

Population Health and Immunity Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia.

The accuracy of haemoglobin concentration measurements is crucial for deriving global anaemia prevalence estimates and monitoring anaemia reduction strategies. In this analysis, we examined and quantified the factors affecting preanalytic and analytic variation in haemoglobin concentrations. Using cross-sectional data from three field studies (in children, pregnant and nonpregnant women), we examined the difference in haemoglobin concentration between venous-drawn and capillary-drawn blood measured by HemoCue (ie, preanalytic) and modelled how the bias observed may affect anaemia prevalence estimates in population surveys and anaemia public health severity classification across countries. Using data from an international quality assurance programme, we examined differences due to instrumentation from 16 different haematology analyzers (ie, analytic). Results indicated that capillary and venous haemoglobin concentrations are not in agreement (bias +5.7 g/L (limits of agreement (LoA) -11.2, 22.6) in preschool age children; range from -28 g/L to +20 g/L in pregnant women; bias +8.8 g/L (LoA -5.2, 22.9) in non-pregnant women). The bias observed could introduce changes in population survey estimates of anaemia of up to -20.7 percentage points in children and -28.2 percentage points in non-pregnant women after venous adjustment. Analytic variation was minimal and unlikely to influence the diagnosis of anaemia. These findings suggest that global estimates of anaemia prevalence derived from capillary haemoglobin, as they often are, may be inaccurate and lead to erroneous public health severity classification, but that point-of-care, or other, instruments should not introduce variation if properly used.
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http://dx.doi.org/10.1136/bmjgh-2021-005756DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8327809PMC
July 2021

Finding ferritin in the plateaus and valleys of iron deficiency.

Lancet Haematol 2021 Aug;8(8):e539-e540

Department of Medical Biology, Parkville, VIC 3052, Australia; Population Health and Immunity Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia; Diagnostic Haematology, The Royal Melbourne Hospital, Melbourne, VIC, Australia; Clinical Haematology, The Peter MacCallum Cancer Centre and The Royal Melbourne Hospital, Parkville VIC 3050 Australia. Electronic address:

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http://dx.doi.org/10.1016/S2352-3026(21)00196-4DOI Listing
August 2021

Serum or plasma ferritin concentration as an index of iron deficiency and overload.

Cochrane Database Syst Rev 2021 05 24;5:CD011817. Epub 2021 May 24.

Department of Nutrition and Food Safety, World Health Organization, Geneva, Switzerland.

Background: Reference standard indices of iron deficiency and iron overload are generally invasive, expensive, and can be unpleasant or occasionally risky. Ferritin is an iron storage protein and its concentration in the plasma or serum reflects iron stores; low ferritin indicates iron deficiency, while elevated ferritin reflects risk of iron overload. However, ferritin is also an acute-phase protein and its levels are elevated in inflammation and infection. The use of ferritin as a diagnostic test of iron deficiency and overload is a common clinical practice.

Objectives: To determine the diagnostic accuracy of ferritin concentrations (serum or plasma) for detecting iron deficiency and risk of iron overload in primary and secondary iron-loading syndromes.

Search Methods: We searched the following databases (10 June 2020): DARE (Cochrane Library) Issue 2 of 4 2015, HTA (Cochrane Library) Issue 4 of 4 2016, CENTRAL (Cochrane Library) Issue 6 of 12 2020, MEDLINE (OVID) 1946 to 9 June 2020, Embase (OVID) 1947 to week 23 2020, CINAHL (Ebsco) 1982 to June 2020, Web of Science (ISI) SCI, SSCI, CPCI-exp & CPCI-SSH to June 2020, POPLINE 16/8/18, Open Grey (10/6/20), TRoPHI (10/6/20), Bibliomap (10/6/20), IBECS (10/6/20), SCIELO (10/6/20), Global Index Medicus (10/6/20) AIM, IMSEAR, WPRIM, IMEMR, LILACS (10/6/20), PAHO (10/6/20), WHOLIS 10/6/20, IndMED (16/8/18) and Native Health Research Database (10/6/20). We also searched two trials registers and contacted relevant organisations for unpublished studies.

Selection Criteria: We included all study designs seeking to evaluate serum or plasma ferritin concentrations measured by any current or previously available quantitative assay as an index of iron status in individuals of any age, sex, clinical and physiological status from any country.

Data Collection And Analysis: We followed standard Cochrane methods. We designed the data extraction form to record results for ferritin concentration as the index test, and bone marrow iron content for iron deficiency and liver iron content for iron overload as the reference standards. Two other authors further extracted and validated the number of true positive, true negative, false positive, false negative cases, and extracted or derived the sensitivity, specificity, positive and negative predictive values for each threshold presented for iron deficiency and iron overload in included studies. We assessed risk of bias and applicability using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS)-2 tool. We used GRADE assessment to enable the quality of evidence and hence strength of evidence for our conclusions.

Main Results: Our search was conducted initially in 2014 and updated in 2017, 2018 and 2020 (10 June). We identified 21,217 records and screened 14,244 records after duplicates were removed. We assessed 316 records in full text. We excluded 190 studies (193 records) with reasons and included 108 studies (111 records) in the qualitative and quantitative analysis. There were 11 studies (12 records) that we screened from the last search update and appeared eligible for a future analysis. We decided to enter these as awaiting classification. We stratified the analysis first by participant clinical status: apparently healthy and non-healthy populations. We then stratified by age and pregnancy status as: infants and children, adolescents, pregnant women, and adults. Iron deficiency We included 72 studies (75 records) involving 6059 participants. Apparently healthy populations Five studies screened for iron deficiency in people without apparent illness. In the general adult population, three studies reported sensitivities of 63% to 100% at the optimum cutoff for ferritin, with corresponding specificities of 92% to 98%, but the ferritin cutoffs varied between studies. One study in healthy children reported a sensitivity of 74% and a specificity of 77%. One study in pregnant women reported a sensitivity of 88% and a specificity of 100%. Overall confidence in these estimates was very low because of potential bias, indirectness, and sparse and heterogenous evidence. No studies screened for iron overload in apparently healthy people. People presenting for medical care There were 63 studies among adults presenting for medical care (5042 participants). For a sample of 1000 subjects with a 35% prevalence of iron deficiency (of the included studies in this category) and supposing a 85% specificity, there would be 315 iron-deficient subjects correctly classified as having iron deficiency and 35 iron-deficient subjects incorrectly classified as not having iron deficiency, leading to a 90% sensitivity. Thresholds proposed by the authors of the included studies ranged between 12 to 200 µg/L. The estimated diagnostic odds ratio was 50. Among non-healthy adults using a fixed threshold of 30 μg/L (nine studies, 512 participants, low-certainty evidence), the pooled estimate for sensitivity was 79% with a 95% confidence interval of (58%, 91%) and specificity of 98%, with a 95% confidence interval of (91%, 100%). The estimated diagnostic odds ratio was 140, a relatively highly informative test. Iron overload We included 36 studies (36 records) involving 1927 participants. All studies concerned non-healthy populations. There were no studies targeting either infants, children, or pregnant women. Among all populations (one threshold for males and females; 36 studies, 1927 participants, very low-certainty evidence): for a sample of 1000 subjects with a 42% prevalence of iron overload (of the included studies in this category) and supposing a 65% specificity, there would be 332 iron-overloaded subjects correctly classified as having iron overload and 85 iron-overloaded subjects incorrectly classified as not having iron overload, leading to a 80% sensitivity. The estimated diagnostic odds ratio was 8.

Authors' Conclusions: At a threshold of 30 micrograms/L, there is low-certainty evidence that blood ferritin concentration is reasonably sensitive and a very specific test for iron deficiency in people presenting for medical care. There is very low certainty that high concentrations of ferritin provide a sensitive test for iron overload in people where this condition is suspected. There is insufficient evidence to know whether ferritin concentration performs similarly when screening asymptomatic people for iron deficiency or overload.
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http://dx.doi.org/10.1002/14651858.CD011817.pub2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8142307PMC
May 2021

The Role of Nutrition in COVID-19 Susceptibility and Severity of Disease: A Systematic Review.

J Nutr 2021 07;151(7):1854-1878

Medical Research Council (MRC) Unit The Gambia at the London School of Hygiene & Tropical Medicine, Fajara, The Gambia.

Background: Many nutrients have powerful immunomodulatory actions with the potential to alter susceptibility to coronavirus disease 2019 (COVID-19) infection, progression to symptoms, likelihood of severe disease, and survival.

Objective: The aim was to review the latest evidence on how malnutrition across all its forms (under- and overnutrition and micronutrient status) may influence both susceptibility to, and progression of, COVID-19.

Methods: We synthesized information on 13 nutrition-related components and their potential interactions with COVID-19: overweight, obesity, and diabetes; protein-energy malnutrition; anemia; vitamins A, C, D, and E; PUFAs; iron; selenium; zinc; antioxidants; and nutritional support. For each section we provide: 1) a landscape review of pertinent material; 2) a systematic search of the literature in PubMed and EMBASE databases, including a wide range of preprint servers; and 3) a screen of 6 clinical trial registries. All original research was considered, without restriction to study design, and included if it covered: 1) severe acute respiratory syndrome coronavirus (CoV) 2 (SARS-CoV-2), Middle East respiratory syndrome CoV (MERS-CoV), or SARS-CoV viruses and 2) disease susceptibility or 3) disease progression, and 4) the nutritional component of interest. Searches took place between 16 May and 11 August 2020.

Results: Across the 13 searches, 2732 articles from PubMed and EMBASE, 4164 articles from the preprint servers, and 433 trials were returned. In the final narrative synthesis, we include 22 published articles, 38 preprint articles, and 79 trials.

Conclusions: Currently there is limited evidence that high-dose supplements of micronutrients will either prevent severe disease or speed up recovery. However, results of clinical trials are eagerly awaited. Given the known impacts of all forms of malnutrition on the immune system, public health strategies to reduce micronutrient deficiencies and undernutrition remain of critical importance. Furthermore, there is strong evidence that prevention of obesity and type 2 diabetes will reduce the risk of serious COVID-19 outcomes. This review is registered at PROSPERO as CRD42020186194.
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http://dx.doi.org/10.1093/jn/nxab059DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8194602PMC
July 2021

Management of hydroxyurea resistant or intolerant polycythemia vera.

Leuk Lymphoma 2021 May 5:1-10. Epub 2021 May 5.

Molecular Oncology and Cancer Immunology, Epworth Healthcare, Melbourne, Australia.

Polycythemia vera is a Philadelphia negative myeloproliferative neoplasm characterized by erythrocytosis in which the major cause of morbidity and mortality is thrombosis. Aspirin and hematocrit reduction by venesection or cytoreductive therapy are at the cornerstone of management. First line cytoreductive therapy in high-risk patients is hydroxyurea; however, its use is associated with toxicities and resistance in a significant proportion of patients. In a disease with a long overall survival with appropriate treatment, it is imperative that other treatment options do not accelerate the risk of progression to acute leukemia. The following review will appraise the evidence of interferon, ruxolitinib, and other agents in management of hydroxyurea resistant or intolerant polycythemia vera.
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http://dx.doi.org/10.1080/10428194.2021.1901092DOI Listing
May 2021

Alectinib induces marked red cell spheroacanthocytosis in a near-ubiquitous fashion and is associated with reduced eosin-5-maleimide binding.

Pathology 2021 Aug 19;53(5):608-612. Epub 2021 Feb 19.

Diagnostic Haematology, The Royal Melbourne Hospital, Parkville, Vic, Australia; Department of Clinical Haematology, Peter MacCallum Cancer Centre, Royal Melbourne Hospital, Melbourne, Vic, Australia; Walter and Eliza Hall Institute, Parkville, Vic, Australia; Department of Medical Biology, University of Melbourne, Parkville, Vic, Australia.

We reviewed haematological investigations for 43 patients treated at a single centre with alectinib, an inhibitor of anaplastic lymphoma kinase (ALK) which is considered standard first-line treatment for patients with ALK-rearranged advanced non-small cell lung cancer. Ninety-five percent of patients developed marked acanthocytosis, echinocytosis and/or spheroacanthocytosis, not observable with prior treatment with other ALK-inhibitors. Anaemia developed in 73% of patients (38% <100 g/L, 8% <80 g/L), though definite new haemolysis was present in only 11%. Eosin-5-maleimide binding was reduced in all assessed patients, and increased membrane cholesterol was identified in one patient assessed with lattice light sheet microscopy. We have identified a previously undescribed phenomenon whereby alectinib induces red cell membrane abnormalities in nearly all patients through an unclear, but likely ALK-independent, mechanism, resulting in mild anaemia without universal haemolysis.
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http://dx.doi.org/10.1016/j.pathol.2020.10.023DOI Listing
August 2021

Safety of rapid injection of undiluted ferric carboxymaltose to patients with iron-deficiency anaemia: a Phase II single-arm study.

Intern Med J 2021 Aug;51(8):1304-1311

Department of Haematology, Monash Health, Melbourne, Victoria, Australia.

Background: Ferric carboxymaltose is increasingly utilised to treat iron deficiency and is usually diluted in saline and administered as an intravenous infusion over 15 min. Although this is highly convenient compared with older formulations, we hypothesised the drug could be administered, safely given as a rapid bolus injection.

Aims: To define the risk of serious adverse events following administration of an undiluted, rapid, high-dose ferric carboxymaltose injection. Secondary aims included all other adverse events, as well as longitudinal effects on haemoglobin, iron stores, phosphate and hepcidin.

Methods: In a single-arm, Phase II study in 121 patients with iron-deficiency anaemia, we administered up to 1000 mg of ferric carboxymaltose as a rapid undiluted bolus injection, and recorded adverse events and collected blood samples over the first hour, and again at 2 and 4 weeks post-treatment.

Results: No patient experienced a serious adverse event. Flushing during the injection was common, as was a transient headache in the subsequent weeks. One patient experienced Grade 3 chest tightness, necessitating emergency department assessment but not admission or treatment. Treatment produced an average 12.3 g/L improvement in haemoglobin within 2 weeks, but commonly caused reductions in serum phosphate (although none of these was clinically symptomatic). Parenteral iron caused elevations in hepcidin sustained to 4 weeks post-injection. Patients stated they would be prepared to receive the treatment again.

Conclusion: Rapid injection of undiluted ferric carboxymaltose is well tolerated and could provide an approach to treat patients in the ambulatory setting.
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http://dx.doi.org/10.1111/imj.15195DOI Listing
August 2021

AGA Clinical Practice Guidelines on the Gastrointestinal Evaluation of Iron Deficiency Anemia.

Gastroenterology 2021 Jun 30;160(7):2618-2620. Epub 2020 Dec 30.

Diagnostic Haematology, The Royal Melbourne Hospital and, Population Health and Immunity Division, The Walter and Eliza Hall Institute of Medical Research and, Clinical Haematology at the Peter MacCallum Cancer Centre and, The Royal Melbourne Hospital, Parkville, Victoria, Australia.

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http://dx.doi.org/10.1053/j.gastro.2020.10.062DOI Listing
June 2021

Iron deficiency.

Lancet 2021 01 4;397(10270):233-248. Epub 2020 Dec 4.

Translational Metabolic Laboratory, Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen, Netherlands.

Iron deficiency is one of the leading contributors to the global burden of disease, and particularly affects children, premenopausal women, and people in low-income and middle-income countries. Anaemia is one of many consequences of iron deficiency, and clinical and functional impairments can occur in the absence of anaemia. Iron deprivation from erythroblasts and other tissues occurs when total body stores of iron are low or when inflammation causes withholding of iron from the plasma, particularly through the action of hepcidin, the main regulator of systemic iron homoeostasis. Oral iron therapy is the first line of treatment in most cases. Hepcidin upregulation by oral iron supplementation limits the absorption efficiency of high-dose oral iron supplementation, and of oral iron during inflammation. Modern parenteral iron formulations have substantially altered iron treatment and enable rapid, safe total-dose iron replacement. An underlying cause should be sought in all patients presenting with iron deficiency: screening for coeliac disease should be considered routinely, and endoscopic investigation to exclude bleeding gastrointestinal lesions is warranted in men and postmenopausal women presenting with iron deficiency anaemia. Iron supplementation programmes in low-income countries comprise part of the solution to meeting WHO Global Nutrition Targets.
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http://dx.doi.org/10.1016/S0140-6736(20)32594-0DOI Listing
January 2021

Immediate impact of stay-at-home orders to control COVID-19 transmission on socioeconomic conditions, food insecurity, mental health, and intimate partner violence in Bangladeshi women and their families: an interrupted time series.

Lancet Glob Health 2020 11 25;8(11):e1380-e1389. Epub 2020 Aug 25.

Population Health and Immunity Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia; Department of Medical Biology, The University of Melbourne, Parkville, VIC, Australia; Diagnostic Haematology, Royal Melbourne Hospital, Parkville, VIC, Australia; Clinical Haematology at the Peter MacCallum Cancer Centre and Royal Melbourne Hospital, Parkville, VIC Australia. Electronic address:

Background: Stay-at-home orders (lockdowns) have been deployed globally to control COVID-19 transmission, and might impair economic conditions and mental health, and exacerbate risk of food insecurity and intimate partner violence. The effect of lockdowns in low-income and middle-income countries must be understood to ensure safe deployment of these interventions in less affluent settings. We aimed to determine the immediate impact of COVID-19 lockdown orders on women and their families in rural Bangladesh.

Methods: An interrupted time series was used to compare data collected from families in Rupganj upazila, rural Bangladesh (randomly selected from participants in a randomised controlled trial), on income, food security, and mental health a median of 1 year and 2 years before the COVID-19 pandemic to data collected during the lockdown. We also assessed women's experiences of intimate partner violence during the pandemic.

Results: Between May 19 and June 18, 2020, we randomly selected and invited the mothers of 3016 children to participate in the study, 2424 of whom provided consent. 2414 (99·9%, 95% CI 99·6-99·9) of 2417 mothers were aware of, and adhering to, the stay-at-home advice. 2321 (96·0%, 95·2-96·7) of 2417 mothers reported a reduction in paid work for the family. Median monthly family income fell from US$212 at baseline to $59 during lockdown, and the proportion of families earning less than $1·90 per day rose from five (0·2%, 0·0-0·5) of 2422 to 992 (47·3%, 45·2-49·5) of 2096 (p<0·0001 comparing baseline with lockdown period). Before the pandemic, 136 (5·6%, 4·7-6·6) of 2420 and 65 (2·7%, 2·1-3·4) of 2420 families experienced moderate and severe food insecurity, respectively. This increased to 881 (36·5%, 34·5-38·4) of 2417 and 371 (15·3%, 13·9-16·8) of 2417 during the lockdown; the number of families experiencing any level of food insecurity increased by 51·7% (48·1-55·4; p<0·0001). Mothers' depression and anxiety symptoms increased during the lockdown. Among women experiencing emotional or moderate physical violence, over half reported it had increased since the lockdown.

Interpretation: COVID-19 lockdowns present significant economic, psychosocial, and physical risks to the wellbeing of women and their families across economic strata in rural Bangladesh. Beyond supporting only the most socioeconomically deprived, support is needed for all affected families.

Funding: National Health and Medical Research Council, Australia.
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http://dx.doi.org/10.1016/S2214-109X(20)30366-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7447230PMC
November 2020

Net benefit and cost-effectiveness of universal iron-containing multiple micronutrient powders for young children in 78 countries: a microsimulation study.

Lancet Glob Health 2020 08;8(8):e1071-e1080

School of Mathematics, Queensland University of Technology, Brisbane, QLD, Australia.

Background: Universal home fortification of complementary foods with iron-containing multiple micronutrient powders (MNPs) is a key intervention to prevent anaemia in young children in low-income and middle-income countries. However, evidence that MNPs might promote infection raises uncertainty about whether MNPs give net health benefits and are cost-effective. We aimed to determined country-specific net benefit or harm and cost-effectiveness of universal provision of MNPs to children aged 6 months.

Methods: We developed a microsimulation model to estimate net country-specific disability-adjusted life-years (DALYs), years lived with disability (YLDs), and years of life lost (YLLs) due to anaemia, malaria, and diarrhoea averted (or increased) by provision of a 6-month course of MNPs to children aged 6 months, compared with no intervention, who would be followed up for an additional 6 months (ie, to age 18 months). Anaemia prevalence was derived from Demographic and Health Surveys or similar national surveys, and malaria and diarrhoea incidence were sourced from the Global Burden of Disease Study. Programme and health-care costs were modelled to determine cost per DALY averted (US$). Additionally, we explored the effects of reduced MNP coverage in a sensitivity analysis.

Findings: 78 countries (46 countries in Africa, 20 in Asia or the Middle East, and 12 in Latin America) were included in the analysis, and we simulated 5 million children per country. 6 months of universal distribution of daily MNPs, assuming 100% coverage, produced a net benefit (DALYs averted) in 54 countries (24 in Africa, 19 in Asia and the Middle East, 11 in Latin America) and net harm in 24 countries (22 in Africa, one in Asia, and one in Latin America). MNP intervention provided a benefit on YLDs associated with anaemia, but these gains were attenuated and sometimes reversed by increases in YLLs associated with malaria and diarrhoea, reducing the benefits seen for DALYs. In the 54 countries where MNP provision was beneficial, the median benefit was 28·1 DALYs averted per 10 000 children receiving MNPs (IQR 20·6-40·4), and median cost per DALY averted was $3576 (IQR 2474-4918). DALY effects positively correlated with moderate and severe anaemia prevalence in Asia, the Middle East, and Latin America, but correlated inversely in Africa. Suboptimal coverage markedly reduced DALYs averted and cost-effectiveness.

Interpretation: Net health benefits of MNPs vary between countries, are highest where prevalence of moderate and severe anaemia is greatest but infection prevalence is smallest, and are ameliorated when coverage of the intervention is poor. Our data provide country-specific guidance to national policy makers.

Funding: International Union of Nutrition Sciences.
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http://dx.doi.org/10.1016/S2214-109X(20)30240-0DOI Listing
August 2020

Anemia and water, sanitation, and hygiene (WASH)-is there really a link?

Am J Clin Nutr 2020 11;112(5):1145-1146

Population Health and Immunity, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.

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http://dx.doi.org/10.1093/ajcn/nqaa213DOI Listing
November 2020

Balancing Safety and Potential for Impact in Universal Iron Interventions.

Nestle Nutr Inst Workshop Ser 2020 28;93:51-62. Epub 2020 Jan 28.

Division of Population Health and Immunity, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia,

Almost 300 million children under 5 years of age are anemic worldwide. International policymakers recommend universal distribution of iron-based interventions - either iron supplements or iron-containing multiple micronutrient powders - to alleviate the burden of anemia in young children. When considering whether to implement universal iron interventions, it is essential to balance the putative benefits with possible risks. The key rationale for deploying universal iron interventions to reduce anemia in young children is to improve development, growth, and well-being. While plausible, few randomized controlled trials (RCTs) of iron interventions have carefully assessed these outcomes and there is currently inadequate evidence to support the hypothesis that universal iron interventions provide benefits on functional child health outcomes. Conversely, several important RCTs have found that when iron interventions are given to all children in a population, they may increase infection risk. Other possible risks of iron interventions have not yet been extensively described but include a risk of iron overdose and long-term iron loading in high-risk individuals. Identifying whether these interventions provide a net benefit or harm to populations is challenging. Until the quality of evidence for benefits improves, implementation of universal iron interventions in young children should be undertaken with caution.
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http://dx.doi.org/10.1159/000503356DOI Listing
June 2021

Antibodies against the erythroferrone N-terminal domain prevent hepcidin suppression and ameliorate murine thalassemia.

Blood 2020 02;135(8):547-557

MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom.

Erythroferrone (ERFE) is produced by erythroblasts in response to erythropoietin (EPO) and acts in the liver to prevent hepcidin stimulation by BMP6. Hepcidin suppression allows for the mobilization of iron to the bone marrow for the production of red blood cells. Aberrantly high circulating ERFE in conditions of stress erythropoiesis, such as in patients with β-thalassemia, promotes the tissue iron accumulation that substantially contributes to morbidity in these patients. Here we developed antibodies against ERFE to prevent hepcidin suppression and to correct the iron loading phenotype in a mouse model of β-thalassemia [Hbb(th3/+) mice] and used these antibodies as tools to further characterize ERFE's mechanism of action. We show that ERFE binds to BMP6 with nanomolar affinity and binds BMP2 and BMP4 with somewhat weaker affinities. We found that BMP6 binds the N-terminal domain of ERFE, and a polypeptide derived from the N terminus of ERFE was sufficient to cause hepcidin suppression in Huh7 hepatoma cells and in wild-type mice. Anti-ERFE antibodies targeting the N-terminal domain prevented hepcidin suppression in ERFE-treated Huh7 cells and in EPO-treated mice. Finally, we observed a decrease in splenomegaly and serum and liver iron in anti-ERFE-treated Hbb(th3/+) mice, accompanied by an increase in red blood cells and hemoglobin and a decrease in reticulocyte counts. In summary, we show that ERFE binds BMP6 directly and with high affinity, and that antibodies targeting the N-terminal domain of ERFE that prevent ERFE-BMP6 interactions constitute a potential therapeutic tool for iron loading anemias.
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http://dx.doi.org/10.1182/blood.2019003140DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7046598PMC
February 2020

Hepcidin-guided screen-and-treat interventions against iron-deficiency anaemia in pregnancy: a randomised controlled trial in The Gambia.

Lancet Glob Health 2019 11;7(11):e1564-e1574

Medical Research Council (MRC) Unit The Gambia at London School of Hygiene & Tropical Medicine (LSHTM), Serrekunda, The Gambia; LSHTM, London, UK. Electronic address:

Background: WHO recommends daily iron supplementation for pregnant women, but adherence is poor because of side-effects, effectiveness is low, and there are concerns about possible harm. The iron-regulatory hormone hepcidin can signal when an individual is ready-and-safe to receive iron. We tested whether a hepcidin-guided screen-and-treat approach to combat iron-deficiency anaemia could achieve equivalent efficacy to universal administration, but with lower exposure to iron.

Methods: We did a three-arm, randomised, double-blind, non-inferiority trial in 19 rural communities in the Jarra West and Kiang East districts of The Gambia. Eligible participants were pregnant women aged 18-45 years at between 14 weeks and 22 weeks of gestation. We randomly allocated women to either WHO's recommended regimen (ie, a daily UN University, UNICEF, and WHO international multiple-micronutrient preparation [UNIMMAP] containing 60 mg iron), a 60 mg screen-and-treat approach (ie, daily UNIMMAP containing 60 mg iron for 7 days if weekly hepcidin was <2·5 μg/L or UNIMMAP without iron if hepcidin was ≥2·5 μg/L), or a 30 mg screen-and-treat approach (ie, daily UNIMMAP containing 30 mg iron for 7 days if weekly hepcidin was <2·5 μg/L or UNIMMAP without iron if hepcidin was ≥2·5 μg/L). We used a block design stratified by amount of haemoglobin at enrolment (above and below the median amount of haemoglobin on every enrolment day) and stage of gestation (14-18 weeks vs 19-22 weeks). Participants and investigators were unaware of the random allocation. The primary outcome was the amount of haemoglobin at day 84 and was measured as the difference in haemoglobin in each screen-and-treat group compared with WHO's recommended regimen; the non-inferiority margin was set at -5·0 g/L. The primary outcome was assessed in the per-protocol population, which comprised all women who completed the study. This trial is registered with the ISRCTN registry, number ISRCTN21955180.

Findings: Between June 16, 2014, and March 3, 2016, 498 participants were randomised, of whom 167 were allocated to WHO's recommended regimen, 166 were allocated to the 60 mg per day screen-and-treat approach, and 165 were allocated to the 30 mg per day screen-and-treat approach. 78 participants were withdrawn or lost to follow-up during the study; thus, the per-protocol population comprised 140 women assigned to WHO's recommended regimen, 133 allocated to the 60 mg screen-and-treat approach, and 147 allocated to the 30 mg screen-and-treat approach. The screen-and-treat approaches did not exceed the non-inferiority margin. Compared with WHO's recommended regimen, the difference in the amount of haemoglobin at day 84 was -2·2 g/L (95% CI -4·6 to 0·1) with the 60 mg screen-and-treat approach and -2·7 g/L (-5·0 to -0·5) with the 30 mg screen-and-treat approach. Adherence, reported side-effects, and adverse events were similar between the three groups. The most frequent side-effect was stomachache, which was similar in the 60 mg screen-and-treat group (82 cases per 1906 person-weeks) and with WHO's recommended regimen (81 cases per 1974 person-weeks; effect 1·0, 95% CI 0·7 to 1·6); in the 30 mg screen-and-treat group the frequency of stomachache was slightly lower than with WHO's recommended regimen (58 cases per 2009 person-weeks; effect 0·7, 95% CI 0·5 to 1·1). No participants died during the study.

Interpretation: The hepcidin-guided screen-and-treat approaches had no advantages over WHO's recommended regimen in terms of adherence, side-effects, or safety outcomes. Our results suggest that the current WHO policy for iron administration to pregnant women should remain unchanged while more effective approaches continue to be sought.

Funding: Bill & Melinda Gates Foundation and the UK Medical Research Council.
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http://dx.doi.org/10.1016/S2214-109X(19)30393-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7109523PMC
November 2019

Transcriptomic profiling of the myeloma bone-lining niche reveals BMP signalling inhibition to improve bone disease.

Nat Commun 2019 10 4;10(1):4533. Epub 2019 Oct 4.

NIHR Oxford Biomedical Research Centre Blood Theme, University of Oxford, Oxford, UK.

Multiple myeloma is an incurable, bone marrow-dwelling malignancy that disrupts bone homeostasis causing skeletal damage and pain. Mechanisms underlying myeloma-induced bone destruction are poorly understood and current therapies do not restore lost bone mass. Using transcriptomic profiling of isolated bone lining cell subtypes from a murine myeloma model, we find that bone morphogenetic protein (BMP) signalling is upregulated in stromal progenitor cells. BMP signalling has not previously been reported to be dysregulated in myeloma bone disease. Inhibition of BMP signalling in vivo using either a small molecule BMP receptor antagonist or a solubilized BMPR1a-FC receptor ligand trap prevents trabecular and cortical bone volume loss caused by myeloma, without increasing tumour burden. BMP inhibition directly reduces osteoclastogenesis, increases osteoblasts and bone formation, and suppresses bone marrow sclerostin levels. In summary we describe a novel role for the BMP pathway in myeloma-induced bone disease that can be therapeutically targeted.
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http://dx.doi.org/10.1038/s41467-019-12296-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6778199PMC
October 2019

Changes in micronutrient and inflammation serum biomarker concentrations after a norovirus human challenge.

Am J Clin Nutr 2019 12;110(6):1456-1464

Hubert Department of Global Health, Emory University, Atlanta, GA, USA.

Background: To accurately assess micronutrient status, it is necessary to characterize the effects of inflammation and the acute-phase response on nutrient biomarkers.

Objective: Within a norovirus human challenge study, we aimed to model the inflammatory response of C-reactive protein (CRP) and α-1-acid glycoprotein (AGP) by infection status, model kinetics of micronutrient biomarkers by inflammation status, and evaluate associations between inflammation and micronutrient biomarkers from 0 to 35 d post-norovirus exposure.

Methods: Fifty-two healthy adults were enrolled into challenge studies in a hospital setting and followed longitudinally; all were exposed to norovirus, half were infected. Post hoc analysis of inflammatory and nutritional biomarkers was performed. Subjects were stratified by inflammation resulting from norovirus exposure. Smoothed regression models analyzed the kinetics of CRP and AGP by infection status, and nutritional biomarkers by inflammation. Linear mixed-effects models were used to analyze the independent relations between CRP, AGP, and biomarkers for iron, vitamin A, vitamin D, vitamin B-12, and folate from 0 to 35 d post-norovirus exposure.

Results: Norovirus-infected subjects had median (IQR) peak concentrations for CRP [16.0 (7.9-29.5) mg/L] and AGP [0.9 (0.8-1.2) g/L] on day 3 and day 4 postexposure, respectively. Nutritional biomarkers that differed (P < 0.05) from baseline within the inflamed group were ferritin (elevated day 3), hepcidin (elevated days 2, 3), serum iron (depressed days 2-4), transferrin saturation (depressed days 2-4), and retinol (depressed days 3, 4, and 7). Nutritional biomarker concentrations did not differ over time within the uninflamed group. In mixed models, CRP was associated with ferritin (positive) and serum iron and retinol (negative, P < 0.05).

Conclusion: Using an experimental infectious challenge model in healthy adults, norovirus infection elicited a time-limited inflammatory response associated with altered serum concentrations of certain iron and vitamin A biomarkers, confirming the need to consider adjustments of these biomarkers to account for inflammation when assessing nutritional status. These trials were registered at clinicaltrials.gov as NCT00313404 and NCT00674336.
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http://dx.doi.org/10.1093/ajcn/nqz201DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6885472PMC
December 2019

Nrf2 controls iron homeostasis in haemochromatosis and thalassaemia via Bmp6 and hepcidin.

Nat Metab 2019 05 13;1(5):519-531. Epub 2019 May 13.

MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DS, UK.

Iron is critical for life but toxic in excess because of iron-catalysed formation of pro-oxidants that cause tissue damage in a range of disorders. The Nrf2 transcription factor orchestrates cell-intrinsic protective antioxidant responses, and the peptide hormone hepcidin maintains systemic iron homeostasis, but is pathophysiologically decreased in haemochromatosis and beta-thalassaemia. Here, we show that Nrf2 is activated by iron-induced, mitochondria-derived pro-oxidants and drives Bmp6 expression in liver sinusoid endothelial cells, which in turn increases hepcidin synthesis by neighbouring hepatocytes. In Nrf2 knockout mice, the Bmp6-hepcidin response to oral and parenteral iron is impaired and iron accumulation and hepatic damage are increased. Pharmacological activation of Nrf2 stimulates the Bmp6-hepcidin axis, improving iron homeostasis in haemochromatosis and counteracting the inhibition of Bmp6 by erythroferrone in beta-thalassaemia. We propose that Nrf2 links cellular sensing of excess toxic iron to control of systemic iron homeostasis and antioxidant responses, and may be a therapeutic target for iron-associated disorders.
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http://dx.doi.org/10.1038/s42255-019-0063-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6609153PMC
May 2019

Use and interpretation of hemoglobin concentrations for assessing anemia status in individuals and populations: results from a WHO technical meeting.

Ann N Y Acad Sci 2019 08 21;1450(1):5-14. Epub 2019 Apr 21.

Evidence and Programme Guidance Unit, Department of Nutrition for Health and Development, World Health Organization, Geneva, Switzerland.

Anemia is an important public health problem that negatively affects health of individuals and economic potential of populations. An accurate case definition is critical for understanding burden and epidemiology of anemia, for planning public health interventions, and for clinical investigation and treatment of patients. The current threshold hemoglobin concentrations for diagnosis of anemia were proposed in 1968 and based on studies predominantly of Caucasian adult populations in Europe and North America. The World Health Organization is undertaking a project to review global guidelines for anemia. We describe the process of obtaining input from technical experts, researchers, blood bank experts, policy makers, and program implementers to identify key information or knowledge gaps for anemia diagnosis. From this scoping exercise, six priority areas were identified on diverse topics related to the use and interpretation of hemoglobin concentrations to diagnose anemia in individuals and populations. A call for authors was conducted to produce background, review, and research papers across priority topics. This paper summarizes the first technical meeting, which included commissioned papers as well as case studies, describes key data gaps identified, and describes the next steps in the guideline development process to assess available evidence and define knowledge gaps to improve anemia characterization.
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http://dx.doi.org/10.1111/nyas.14090DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6703163PMC
August 2019

Respiratory infections drive hepcidin-mediated blockade of iron absorption leading to iron deficiency anemia in African children.

Sci Adv 2019 03 27;5(3):eaav9020. Epub 2019 Mar 27.

MRC Unit The Gambia at LSHTM, Atlantic Road, Fajara, The Gambia.

Iron deficiency anemia (IDA) is the most prevalent nutritional condition worldwide. We studied the contribution of hepcidin-mediated iron blockade to IDA in African children. We measured hepcidin and hemoglobin weekly, and hematological, inflammatory, and iron biomarkers at baseline, 7 weeks, and 12 weeks in 407 anemic (hemoglobin < 11 g/dl), otherwise healthy Gambian children (6 to 27 months). Each child maintained remarkably constant hepcidin levels ( < 0.0001 for between-child variance), with half consistently maintaining levels that indicate physiological blockade of iron absorption. Hepcidin was strongly predicted by nurse-ascribed adverse events with dominant signals from respiratory infections and fevers (all < 0.0001). Diarrhea and fecal calprotectin were not associated with hepcidin. In multivariate analysis, C-reactive protein was the dominant predictor of hepcidin and contributed to iron blockade even at very low levels. We conclude that even low-grade inflammation, especially associated with respiratory infections, contributes to IDA in African children.
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http://dx.doi.org/10.1126/sciadv.aav9020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6436921PMC
March 2019

Rapid growth is a dominant predictor of hepcidin suppression and declining ferritin in Gambian infants.

Haematologica 2019 08 7;104(8):1542-1553. Epub 2019 Feb 7.

WHO Collaborating Center for New Vaccines Surveillance, MRC Unit The Gambia at the London School of Hygiene and Tropical Medicine, Banjul, The Gambia, Africa

Iron deficiency and iron deficiency anemia are highly prevalent in low-income countries, especially among young children. Hepcidin is the major regulator of systemic iron homeostasis. It controls dietary iron absorption, dictates whether absorbed iron is made available in circulation for erythropoiesis and other iron-demanding processes, and predicts response to oral iron supplementation. Understanding how hepcidin is itself regulated is therefore important, especially in young children. We investigated how changes in iron-related parameters, inflammation and infection status, seasonality, and growth influenced plasma hepcidin and ferritin concentrations during infancy using longitudinal data from two birth cohorts of infants in rural Gambia (n=114 and n=193). This setting is characterized by extreme seasonality, prevalent childhood anemia, undernutrition, and frequent infection. Plasma was collected from infants at birth and at regular intervals, up to 12 months of age. Hepcidin, ferritin and plasma iron concentrations declined markedly during infancy, with reciprocal increases in soluble transferrin receptor and transferrin concentrations, indicating declining iron stores and increasing tissue iron demand. In cross-sectional analyses at 5 and 12 months of age, we identified expected relationships of hepcidin with iron and inflammatory markers, but also observed significant negative associations between hepcidin and antecedent weight gain. Correspondingly, longitudinal fixed effects modeling demonstrated weight gain to be the most notable dynamic predictor of decreasing hepcidin and ferritin through infancy across both cohorts. Infants who grow rapidly in this setting are at particular risk of depletion of iron stores, but since hepcidin concentrations decrease with weight gain, they may also be the most responsive to oral iron interventions.
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http://dx.doi.org/10.3324/haematol.2018.210146DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6669141PMC
August 2019

Fortification of maize flour with iron for controlling anaemia and iron deficiency in populations.

Cochrane Database Syst Rev 2018 12 22;12:CD010187. Epub 2018 Dec 22.

Evidence and Programme Guidance, Department of Nutrition for Health and Development, World Health Organization, Avenue Appia 20, Geneva, Geneva, Switzerland, 1211.

Background: Approximately 800 million women and children have anaemia, a condition thought to cause almost 9% of the global burden of years lived with disability. Around half this burden could be amenable to interventions that involve the provision of iron. Maize (corn) is one of the world's most important cereal grains and is cultivated across most of the globe. Several programmes around the world have fortified maize flour and other maize-derived foodstuffs with iron and other vitamins and minerals to combat anaemia and iron deficiency.

Objectives: To assess the effects of iron fortification of maize flour, corn meal and fortified maize flour products for anaemia and iron status in the general population.

Search Methods: We searched the following international and regional sources in December 2017 and January 2018: Cochrane Central Register of Controlled Trials (CENTRAL); MEDLINE; MEDLINE (R) In Process; Embase; Web of Science (both the Social Science Citation Index and the Science Citation Index); CINAHL Ebsco; POPLINE; AGRICOLA (agricola.nal.usda.gov); BIOSIS (ISI); Bibliomap and TRoPHI; IBECS; Scielo; Global Index Medicus - AFRO (includes African Index Medicus); EMRO (includes Index Medicus for the Eastern Mediterranean Region); LILACS; PAHO (Pan American Health Library); WHOLIS (WHO Library); WPRO (includes Western Pacific Region Index Medicus); IMSEAR, Index Medicus for the South-East Asian Region; IndMED, Indian medical journals; and the Native Health Research Database. We searched clinicaltrials.gov and the International Clinical Trials Registry Platform (ICTRP) for any ongoing or planned studies on 17 January 2018 and contacted authors of such studies to obtain further information or eligible data if available.For assistance in identifying ongoing or unpublished studies, we also contacted relevant international organisations and agencies working in food fortification on 9 August 2016.

Selection Criteria: We included cluster- or individually randomised controlled trials and observational studies. Interventions included (central/industrial) fortification of maize flour or corn meal with iron alone or with other vitamins and minerals and provided to individuals over 2 years of age (including pregnant and lactating women) from any country.

Data Collection And Analysis: Two review authors independently assessed the eligibility of studies for inclusion, extracted data from included studies and assessed the risk of bias of the included studies. Trial designs with a comparison group were included to assess the effects of interventions. Trial designs without a control or comparison group (uncontrolled before-and-after studies) were included for completeness but were not considered in assessments of the overall effectiveness of interventions or used to draw conclusions regarding the effects of interventions in the review.

Main Results: Our search yielded 4529 records. After initial screening of titles and abstracts, we reviewed the full text of 75 studies (80 records). We included 5 studies and excluded 70. All the included studies assessed the effects of providing maize products fortified with iron plus other vitamins and minerals versus unfortified maize flour. No studies compared this intervention to no intervention or looked at the relative effect of flour and products fortified with iron alone (without other vitamins and minerals). Three were randomised trials involving 2610 participants, and two were uncontrolled before-and-after studies involving 849 participants.Only three studies contributed data for the meta-analysis and included children aged 2 to 11.9 years and women. Compared to unfortified maize flour, it is uncertain whether fortifying maize flour or corn meal with iron and other vitamins and minerals has any effect on anaemia (risk ratio (RR) 0.90, 95% confidence interval (CI) 0.58 to 1.40; 2 studies; 1027 participants; very low-certainty evidence), or on the risk of iron deficiency (RR 0.75, 95% CI 0.49 to 1.15; 2 studies; 1102 participants; very low-certainty evidence), haemoglobin concentration (mean difference (MD) 1.25 g/L, 95% CI -2.36 to 4.86 g/L; 3 studies; 1144 participants; very low-certainty evidence) or ferritin concentrations (MD 0.48 µg/L, 95% CI -0.37 to 1.33 µg/L; 1 study; 584 participants; very low-certainty evidence).None of the studies reported on any adverse effects. We judged the certainty of the evidence to be very low based on GRADE, so we are uncertain whether the results reflect the true effect of the intervention. We downgraded evidence due to high risk of selection bias and unclear risk of performance bias in one of two included studies, high heterogeneity and wide CIs crossing the line of no effect for anaemia prevalence and haemoglobin concentration.

Authors' Conclusions: It is uncertain whether fortifying maize flour with iron and other vitamins and minerals reduces the risk of anaemia or iron deficiency in children aged over 2 years or in adults. Moreover, the evidence is too uncertain to conclude whether iron-fortified maize flour, corn meal or fortified maize flour products have any effect on reducing the risk of anaemia or on improving haemoglobin concentration in the population.We are uncertain whether fortification of maize flour with iron reduces anaemia among the general population, as the certainty of the evidence is very low. No studies reported on any adverse effects.Public organisations funded three of the five included studies, while the private sector gave grants to universities to perform the other two. The presence of industry funding for some of these trials did not appear to positively influence results from these studies.The reduced number of studies, including only two age groups (children and women of reproductive age), as well as the limited number of comparisons (only one out of the four planned) constitute the main limitations of this review.
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http://dx.doi.org/10.1002/14651858.CD010187.pub2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6517107PMC
December 2018

Are Current Serum and Plasma Ferritin Cut-offs for Iron Deficiency and Overload Accurate and Reflecting Iron Status? A Systematic Review.

Arch Med Res 2018 08 17;49(6):405-417. Epub 2018 Dec 17.

Evidence and Programme Guidance, Department of Nutrition for Health and Development, World Health Organization, Geneva, Switzerland.

Background: Serum or plasma ferritin concentration is recommended by WHO as a biomarker to assess iron status in individuals and populations.

Methods: A systematic review was undertaken to summarise the evidence for ferritin reflecting iron status and to assess the cut-off points in different populations. Electronic databases were searched for studies evaluating ferritin concentrations compared against bone marrow aspirates for iron deficiency and to liver biopsies for risk of iron overload.

Results: From 18822 records, 298 studies were assessed in full-text, including 72 studies on iron deficiency and 36 on iron overload in the quantitative analysis. All studies were observational. For iron deficiency, the mean ferritin concentration in healthy individuals was 15.1 μg/L (9 studies, 390 participants) when bone marrow iron content was 0, and 70.4 μg/L (3 studies, 151 participants) when bone marrow iron was 1+ or higher. In non-healthy populations, mean ferritin concentrations were 82.43 μg/L for iron depletion (38 studies, 1023 participants) and 381.61 μg/L for iron sufficiency (38 studies, 1549 participants) with wide variations depending on the pathology. For iron overload the results point out to a cut-off close to 500 μg/L although the data was very limited.

Conclusion: Ferritin concentration is low in iron deficient individuals and high in iron-loaded individuals, regardless of confounding clinical conditions. Current WHO thresholds for healthy populations appear valid but the data is limited for different age groups or physiological conditions. For iron overload, ferritin concentration would only help in the presumptive diagnosis and guide the need for further assessment.
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http://dx.doi.org/10.1016/j.arcmed.2018.12.005DOI Listing
August 2018

Hemoglobinopathies in the Fetal Position.

N Engl J Med 2018 Oct;379(17):1675-1677

From the Walter and Eliza Hall Institute of Medical Research, the Department of Medical Biology, University of Melbourne, the Department of Diagnostic Haematology, Royal Melbourne Hospital, and Clinical Haematology at the Peter MacCallum Cancer Centre and the Royal Melbourne Hospital - all in Parkville, VIC, Australia (S.-R.P.); and the Weatherall Institute of Molecular Medicine, Medical Research Council Human Immunology Unit, and Haematology Theme, Oxford Biomedical Research Centre, University of Oxford, Oxford, United Kingdom (H.D.).

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http://dx.doi.org/10.1056/NEJMcibr1809628DOI Listing
October 2018

Erythroferrone inhibits the induction of hepcidin by BMP6.

Blood 2018 10 10;132(14):1473-1477. Epub 2018 Aug 10.

Medical Research Council (MRC) Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom.

Decreased hepcidin mobilizes iron, which facilitates erythropoiesis, but excess iron is pathogenic in β-thalassemia. Erythropoietin (EPO) enhances erythroferrone (ERFE) synthesis by erythroblasts, and ERFE suppresses hepatic hepcidin production through an unknown mechanism. The BMP/SMAD pathway in the liver is critical for hepcidin control, and we show that EPO suppressed hepcidin and other BMP target genes in vivo in a partially ERFE-dependent manner. Furthermore, recombinant ERFE suppressed the hepatic BMP/SMAD pathway independently of changes in serum and liver iron. In vitro, ERFE decreased SMAD1, SMAD5, and SMAD8 phosphorylation and inhibited expression of BMP target genes. ERFE specifically abrogated the induction of hepcidin by BMP5, BMP6, and BMP7 but had little or no effect on hepcidin induction by BMP2, BMP4, BMP9, or activin B. A neutralizing anti-ERFE antibody prevented ERFE from inhibiting hepcidin induction by BMP5, BMP6, and BMP7. Cell-free homogeneous time-resolved fluorescence assays showed that BMP5, BMP6, and BMP7 competed with anti-ERFE for binding to ERFE. We conclude that ERFE suppresses hepcidin by inhibiting hepatic BMP/SMAD signaling via preferentially impairing an evolutionarily closely related BMP subgroup of BMP5, BMP6, and BMP7. ERFE can act as a natural ligand trap generated by stimulated erythropoiesis to regulate the availability of iron.
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http://dx.doi.org/10.1182/blood-2018-06-857995DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6238155PMC
October 2018

Reducing anaemia in low income countries: control of infection is essential.

BMJ 2018 Aug 1;362:k3165. Epub 2018 Aug 1.

MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.

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http://dx.doi.org/10.1136/bmj.k3165DOI Listing
August 2018

Decreased Hepcidin Levels Are Associated with Low Steady-state Hemoglobin in Children With Sickle Cell Disease in Tanzania.

EBioMedicine 2018 Aug 25;34:158-164. Epub 2018 Jul 25.

School of Tropical Medicine & Global Health, Nagasaki University, Nagasaki, Japan; London School of Hygiene and Tropical Medicine, London, UK. Electronic address:

Background: The contribution of hepcidin as a regulator of iron metabolism & erythropoiesis on the severity of anemia in sickle cell disease (SCD) remains poorly characterized, especially in Sub-Saharan African populations. The aims of the study were to determine if hepcidin is associated with severity of steady-state anemia in SCD and to investigate factors associated with hepcidin and anemia in SCD.

Methods: Archived samples from 199 Tanzanian children, 56% boys aged 3-18 with laboratory-confirmed SCD were analysed based on recorded averaged steady-state hemoglobin (ASSH) quartiles (lowest vs. highest). Univariable and multivariable logistic regression was used to assess associations with ASSH quartiles.

Findings: In univariable analysis, hepcidin <5·5 ng/mL was associated with increased odds of being in the lowest ASSH quartile (OR 2·20; 95%CI 1·2-3·93) but which was limited to girls (OR 4·85, 95%CI 1·79-13·09, p = .046 for interaction). In multivariable analyses including either reticulocyte percentage or erythropoietin, lower hepcidin remained significantly associated with lowest ASSH quartile, although the hepcidin-sex interaction no longer reached statistical significance. No associations with ASSH quartile were observed for markers of inflammation, hemolysis or potential iron markers except for microcytosis, associated with higher ASSH, but which was confounded by reticulocyte percentage and alpha-thalassaemia status.

Interpretation: Hepcidin is lower in more severely anaemic children with SCD independent of inflammation or markers of erythropoiesis.

Funding: Funding sources include The Wellcome Trust (080025, 095009, 094780 & 070114), MRC-UK (MC-A760-5QX00), NIHR Oxford Biomedical Research Centre, and the Bill and Melinda Gates Foundation ("Hepcidin and Iron in Global Health", OPP1055865).
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http://dx.doi.org/10.1016/j.ebiom.2018.07.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6116423PMC
August 2018
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