Fish and Fish-Based Products for Nutrition and Health in the First 1000 Days: A Systematic Review of the Evidence from Low and Middle-Income Countries.

Fish provide essential nutrients for the critical window of growth and development in the first 1000 d of life and are thus an attractive option for inclusion in nutrition-sensitive and nutrition-specific programming. We conducted a systematic review of the evidence for fish and fish-based products for nutrition and health outcomes during the first 1000 d of life in low- and middle-income countries, searching the peer-reviewed and gray literature from 1999 to 2020. Databases included PubMed, Web of Science, Embase, ProQuest, and the Clinical Trials repository. Our search returned 1135 articles, 39 of which met the inclusion criteria. All studies were dual evaluated for risk of bias. Of the included studies, 18 measured maternal health and nutrition outcomes and 24 measured infant/child outcomes (3 measured both). Our search uncovered 10 impact evaluations, all of which measured consumption of fish or fish-based complementary food products in children aged 6-24 mo. We did not find strong evidence for fish consumption in children improving child growth from the impact evaluations; however, the studies were highly heterogeneous in their design and likely underpowered to detect an effect. Results from observational studies were mixed but provided evidence that adding fish to maternal and child diets is associated with improved nutrition outcomes, such as reducing the risk of anemia and improving vitamin D status. Given the nutrient richness of fish and the fact that production is often more environmentally friendly as compared with other animal source foods, more robust evidence is needed on the role of fish consumption in nutrition interventions to inform policy and programming recommendations in low- and middle-income countries.

Proximity to small-scale inland and coastal fisheries is associated with improved income and food security.

Poverty and food insecurity persist in sub-Saharan Africa. We conducted a secondary analysis of nationally representative data from three sub-Saharan Africa countries (Malawi, Tanzania, and Uganda) to investigate how both proximity to and engagement with small-scale fisheries are associated with household poverty and food insecurity. Results from the analysis suggest that households engaged in small-scale fisheries were 9 percentage points less likely to be poor than households engaged only in agriculture. Households living in proximity to small-scale fisheries (average distance 2.7 km) were 12.6 percentage points more likely to achieve adequate food security and were 15 percentage points less likely to be income poor, compared to the most distant households. Households distant from fishing grounds (>5 km) were 1.5 times more likely to consume dried fish compared to households living close. Conserving the flow of benefits from small-scale fisheries is important for meeting the Sustainable Development Goals in the region.

A randomised controlled trial to test the effects of fish aggregating devices (FADs) and SBC activities promoting fish consumption in Timor-Leste: A study protocol.

Timor-Leste is one of the world's most malnourished nations where micronutrient-deficient diets are a contributing factor to the prevalence of child stunting, currently estimated to be 45.6% of children under five. Fish are an important source of nutrients and one that may assist the country's predominantly rural population of agriculturalists to exit poverty and malnutrition. However, a small national fishing fleet producing low catch volumes places fish out of reach of most inland and upland populations where it is needed most. Fish consumption is very low in rural, inland areas compared to coastal, regional, and global averages. This study is a one-year, partially masked, cluster-randomized controlled trial among families living in rural, inland Timor-Leste. We aim to test and compare the effects of two treatments, alone and in combination, on the frequency and volume of household fish consumption in rural, inland areas as a proxy for improved dietary diversity and micronutrient intake. Treatment 1 is the installation of nearshore, moored fish aggregating devices (FADs) to improve catch rates with existing fishing gears. Treatment 2 is a social and behaviour change (SBC) activity to promote fish consumption. Villages in inland communities will be randomized to receive treatment 1, treatment 2, both treatments, or neither treatment. Data will be collected at baseline (prior to the rollout of the treatments) and endline. Our study will determine the impact of an improved supply of fish, along with nutrition-oriented SBC activities, on the fish purchasing and consumption practices of rural, inland households. Findings from this study are urgently needed by Small Island Developing States to guide policy and investment decisions on how best to improve households' diets using locally available, nutrient-dense foods such as fish. Investments such as these are needed to break the cycle of malnutrition. This trial is registered at clinicaltrials.gov (NCT04729829). Trial registration: Trial registered at clinicaltrials.gov Identifier: NCT04729829.

Small pelagic fish supply abundant and affordable micronutrients to low- and middle-income countries.

Wild-caught fish provide an irreplaceable source of essential nutrients in food-insecure places. Fishers catch thousands of species, yet the diversity of aquatic foods is often categorized homogeneously as 'fish', obscuring an understanding of which species supply affordable, nutritious and abundant food. Here, we use catch, economic and nutrient data on 2,348 species to identify the most affordable and nutritious fish in 39 low- and middle-income countries. We find that a 100 g portion of fish cost between 10 and 30% of the cheapest daily diet, with small pelagic fish (herring, sardine, anchovy) being the cheapest nutritious fish in 72% of countries. In sub-Saharan Africa, where nutrient deficiencies are rising, <20% of small pelagic catch would meet recommended dietary fish intakes for all children (6 months to 4 years old) living near to water bodies. Nutrition-sensitive policies that ensure local supplies and promote consumption of wild-caught fish could help address nutrient deficiencies in vulnerable populations.

Characteristics that modify the effect of small-quantity lipid-based nutrient supplementation on child anemia and micronutrient status: an individual participant data meta-analysis of randomized controlled trials.

BACKGROUND: Small-quantity lipid-based nutrient supplements (SQ-LNSs) have been shown to reduce the prevalence of child anemia and iron deficiency, but effects on other micronutrients are less well known. Identifying subgroups who benefit most from SQ-LNSs could support improved program design. OBJECTIVES: We aimed to identify study-level and individual-level modifiers of the effect of SQ-LNSs on child hemoglobin (Hb), anemia, and inflammation-adjusted micronutrient status outcomes. METHODS: We conducted a 2-stage meta-analysis of individual participant data from 13 randomized controlled trials of SQ-LNSs provided to children 6-24 mo of age (n = 15,946). We generated study-specific and subgroup estimates of SQ-LNSs compared with control, and pooled the estimates using fixed-effects models. We used random-effects meta-regression to examine potential study-level effect modifiers. RESULTS: SQ-LNS provision decreased the prevalence of anemia (Hb < 110 g/L) by 16% (relative reduction), iron deficiency (plasma ferritin < 12 µg/L) by 56%, and iron deficiency anemia (IDA; Hb < 110 g/L and plasma ferritin <12 µg/L) by 64%. We observed positive effects of SQ-LNSs on hematological and iron status outcomes within all subgroups of the study- and individual-level effect modifiers, but effects were larger in certain subgroups. For example, effects of SQ-LNSs on anemia and iron status were greater in trials that provided SQ-LNSs for >12 mo and provided 9 (as opposed to <9) mg Fe/d, and among later-born (than among first-born) children. There was no effect of SQ-LNSs on plasma zinc or retinol, but there was a 7% increase in plasma retinol-binding protein (RBP) and a 56% reduction in vitamin A deficiency (RBP < 0.70 µmol/L), with little evidence of effect modification by individual-level characteristics. CONCLUSIONS: SQ-LNSs can substantially reduce the prevalence of anemia, iron deficiency, and IDA among children across a range of individual, population, and study design characteristics. Policy-makers and program planners should consider SQ-LNSs within intervention packages to prevent anemia and iron deficiency.This trial was registered at www.crd.york.ac.uk/PROSPERO as CRD42020156663.

Making the invisible visible: Developing and evaluating an intervention to raise awareness and reduce lead exposure among children and their caregivers in rural Bangladesh.

Lead exposure is harmful at any time in life, but pre-natal and early childhood exposures are particularly detrimental to cognitive development. In Bangladesh, multiple household-level lead exposures pose risks, including turmeric adulterated with lead chromate and food storage in lead-soldered cans. We developed and evaluated an intervention to reduce lead exposure among children and their caregivers in rural Bangladesh. We conducted formative research to inform theory-based behavioral recommendations. Lead exposure was one of several topics covered in the multi-component intervention focused on early child development. Community health workers (CHWs) delivered the lead component of the intervention during group sessions with pregnant women and mother-child dyads (<15 months old) in a cluster-randomized trial. We administered household surveys at baseline (control n = 301; intervention n = 320) and 9 months later at endline (control n = 279; intervention n = 239) and calculated adjusted risk and mean differences for primary outcomes. We conducted two qualitative assessments, one after 3 months and a second after 9 months, to examine the feasibility and benefits of the intervention. At endline, the prevalence of lead awareness was 52 percentage points higher in the intervention arm compared to the control (adjusted risk difference: 0.52 [95% CI 0.46 to 0.61]). Safe turmeric consumption and food storage practices were more common in the intervention versus control arm at endline, with adjusted risk differences of 0.22 [0.10 to 0.32] and 0.13 [0.00 to 0.19], respectively. Semi-structured interviews conducted with a subset of participants after the intervention revealed that the perceived benefit of reducing lead exposure was high because of the long-term negative impacts that lead can have on child cognitive development. The study demonstrates that a group-based CHW-led intervention can effectively raise awareness about and motivate lead exposure prevention behaviors in rural Bangladesh. Future efforts should combine similar awareness-raising efforts with longer-term regulatory and structural changes to systematically and sustainably reduce lead exposure.

Dried small fish provide nutrient densities important for the first 1000 days.

Inadequate nutrient intakes are prevalent among many populations in sub-Saharan Africa and increasing fish consumption among pregnant/lactating women and children is one strategy to improve diets and address nutrient deficiencies. We report the nutrient content of two fish-based recipes-fish powder and fish chutney-that contain dried small fish available in local markets in Zambia. The contribution of a serving of each recipe to the recommended daily intakes of iron, zinc, calcium and docosahexaenoic acid (DHA) for pregnant/lactating women and children 6-24 months was calculated because these nutrients are commonly deficient in African diets. We found that one 10-g serving of fish powder provides 20% or more of the daily calcium recommendation and 37% or more of the daily DHA recommendation for both pregnant/lactating women and children. A 30-g serving of fish chutney provides over 40% of the daily calcium recommendation for pregnant women and over 50% for lactating women. Additionally, we investigated the nutrient density (nutrients per kilocalorie) of the fish powder and compared it with the nutrient density of a small-quantity lipid-based nutrient supplement plus (SQ-LNS-plus). SQ-LNS-plus is designed to enhance children's diets by providing micronutrients and DHA. Fish powder is similar to SQ-LNS-plus in iron and zinc density and even higher in calcium and DHA density. Consuming dried small fish as part of a daily meal can be a viable strategy for combatting nutrient deficiencies in the first 1000 days.

A holistic approach to promoting early child development: a cluster randomised trial of a group-based, multicomponent intervention in rural Bangladesh.

INTRODUCTION: In low- and middle-income countries, children experience multiple risks for delayed development. We evaluated a multicomponent, group-based early child development intervention including behavioural recommendations on responsive stimulation, nutrition, water, sanitation, hygiene, mental health and lead exposure prevention. METHODS: We conducted a 9-month, parallel, multiarm, cluster-randomised controlled trial in 31 rural villages in Kishoreganj District, Bangladesh. Villages were randomly allocated to: group sessions ('group'); alternating groups and home visits ('combined'); or a passive control arm. Sessions were delivered fortnightly by trained community members. The primary outcome was child stimulation (Family Care Indicators); the secondary outcome was child development (Ages and Stages Questionnaire Inventory, ASQi). Other outcomes included dietary diversity, latrine status, use of a child potty, handwashing infrastructure, caregiver mental health and knowledge of lead. Analyses were intention to treat. Data collectors were independent from implementers. RESULTS: In July-August 2017, 621 pregnant women and primary caregivers of children<15 months were enrolled (group n=160, combined n=160, control n=301). At endline, immediately following intervention completion (July-August 2018), 574 participants were assessed (group n=144, combined n=149, control n=281). Primary caregivers in both intervention arms participated in more play activities than control caregivers (age-adjusted means: group 4.22, 95% CI 3.97 to 4.47; combined 4.77, 4.60 to 4.96; control 3.24, 3.05 to 3.39), and provided a larger variety of play materials (age-adjusted means: group 3.63, 3.31 to 3.96; combined 3.81, 3.62 to 3.99; control 2.48, 2.34 to 2.59). Compared with the control arm, children in the group arm had higher total ASQi scores (adjusted mean difference in standardised scores: 0.39, 0.15 to 0.64), while in the combined arm scores were not significantly different from the control (0.25, -0.07 to 0.54). CONCLUSION: Our findings suggest that group-based, multicomponent interventions can be effective at improving child development outcomes in rural Bangladesh, and that they have the potential to be delivered at scale. TRIAL REGISTRATION NUMBER: The trial is registered in ISRCTN (ISRCTN16001234).

Malaria is a cause of iron deficiency in African children.

Malaria and iron deficiency (ID) are common and interrelated public health problems in African children. Observational data suggest that interrupting malaria transmission reduces the prevalence of ID1. To test the hypothesis that malaria might cause ID, we used sickle cell trait (HbAS, rs334 ), a genetic variant that confers specific protection against malaria2, as an instrumental variable in Mendelian randomization analyses. HbAS was associated with a 30% reduction in ID among children living in malaria-endemic countries in Africa (n = 7,453), but not among individuals living in malaria-free areas (n = 3,818). Genetically predicted malaria risk was associated with an odds ratio of 2.65 for ID per unit increase in the log incidence rate of malaria. This suggests that an intervention that halves the risk of malaria episodes would reduce the prevalence of ID in African children by 49%.

Fish nutrient composition: a review of global data from poorly assessed inland and marine species.

OBJECTIVE: Our understanding of the nutrient contribution of fish and other aquatic species to human diets relies on nutrient composition data for a limited number of species. Yet particularly for nutritionally vulnerable aquatic food consumers, consumption includes a wide diversity of species whose nutrient composition data are disparate, poorly compiled or unknown. DESIGN: To address the gap in understanding fish and other aquatic species' nutrient composition data, we reviewed the literature with an emphasis on species of fish that are under-represented in global databases. We reviewed 164 articles containing 1370 entries of all available nutrient composition data (e.g. macronutrients, micronutrients and fatty acids) and heavy metals (e.g. Pb and Hg) for 515 species, including both inland and marine species of fish, as well as other aquatic species (e.g. crustaceans, molluscs, etc.) when those species were returned by our searches. RESULTS: We highlight aquatic species that are particularly high in nutrients of global importance, including Fe, Zn, Ca, vitamin A and docosahexaenoic acid (DHA), and demonstrate that, in many cases, a serving can fill critical nutrient needs for pregnant and lactating women and young children. CONCLUSIONS: By collating the available nutrient composition data on species of fish and other aquatic species, we provide a resource for fisheries and nutrition researchers, experts and practitioners to better understand these critical species and include them in fishery management as well as food-based programmes and policies.

Association between Malaria Infection and Early Childhood Development Mediated by Anemia in Rural Kenya.

Malaria is a leading cause of morbidity and mortality among children under five years of age, with most cases occurring in Sub-Saharan Africa. Children in this age group in Africa are at greatest risk worldwide for developmental deficits. There are research gaps in quantifying the risks of mild malaria cases, understanding the pathways linking malaria infection and poor child development, and evaluating the impact of malaria on the development of children under five years. We analyzed the association between malaria infection and gross motor, communication, and personal social development in 592 children age 24 months in rural, western Kenya as part of the WASH Benefits environmental enteric dysfunction sub-study. Eighteen percent of children had malaria, 20% were at risk for gross motor delay, 21% were at risk for communication delay, and 23% were at risk for personal social delay. Having a positive malaria test was associated with increased risk for gross motor, communication, and personal social delay while adjusting for child characteristics, household demographics, study cluster, and intervention treatment arm. Mediation analyses suggested that anemia was a significant mediator in the pathway between malaria infection and risk for gross motor, communication, and personal social development delays. The proportion of the total effect of malaria on the risk of developmental delay that is mediated by anemia across the subscales was small (ranging from 9% of the effect on gross motor development to 16% of the effect on communication development mediated by anemia). Overall, malaria may be associated with short-term developmental delays during a vulnerable period of early life. Therefore, preventative malaria measures and immediate treatment are imperative for children's optimal development, particularly in light of projections of continued high malaria transmission in Kenya and Africa.

Effects of single and integrated water, sanitation, handwashing, and nutrition interventions on child soil-transmitted helminth and Giardia infections: A cluster-randomized controlled trial in rural Kenya.

BACKGROUND: Helminth and protozoan infections affect more than 1 billion children globally. Improving water quality, sanitation, handwashing, and nutrition could be more sustainable control strategies for parasite infections than mass drug administration, while providing other quality of life benefits. METHODS AND FINDINGS: We enrolled geographic clusters of pregnant women in rural western Kenya into a cluster-randomized controlled trial (ClinicalTrials.gov NCT01704105) that tested 6 interventions: water treatment, improved sanitation, handwashing with soap, combined water treatment, sanitation, and handwashing (WSH), improved nutrition, and combined WSH and nutrition (WSHN). We assessed intervention effects on parasite infections by measuring Ascaris lumbricoides, Trichuris trichiura, hookworm, and Giardia duodenalis among children born to the enrolled pregnant women (index children) and their older siblings. After 2 years of intervention exposure, we collected stool specimens from 9,077 total children aged 2 to 15 years in 622 clusters, including 2,346 children in an active control group (received household visits but no interventions), 1,117 in the water treatment arm, 1,160 in the sanitation arm, 1,141 in the handwashing arm, 1,064 in the WSH arm, 1,072 in the nutrition arm, and 1,177 in the WSHN arm. In the control group, 23% of children were infected with A. lumbricoides, 1% with T. trichiura, 2% with hookworm, and 39% with G. duodenalis. The analysis included 4,928 index children (median age in years: 2) and 4,149 older siblings (median age in years: 5); study households had an average of 5 people, <10% had electricity access, and >90% had dirt floors. Compared to the control group, Ascaris infection prevalence was lower in the water treatment arm (prevalence ratio [PR]: 0.82 [95% CI 0.67, 1.00], p = 0.056), the WSH arm (PR: 0.78 [95% CI 0.63, 0.96], p = 0.021), and the WSHN arm (PR: 0.78 [95% CI 0.64, 0.96], p = 0.017). We did not observe differences in Ascaris infection prevalence between the control group and the arms with the individual interventions sanitation (PR: 0.89 [95% CI 0.73, 1.08], p = 0.228), handwashing (PR: 0.89 [95% CI 0.73, 1.09], p = 0.277), or nutrition (PR: 86 [95% CI 0.71, 1.05], p = 0.148). Integrating nutrition with WSH did not provide additional benefit. Trichuris and hookworm were rarely detected, resulting in imprecise effect estimates. No intervention reduced Giardia. Reanalysis of stool samples by quantitative polymerase chain reaction confirmed the reductions in Ascaris infections measured by microscopy in the WSH and WSHN groups. Trial limitations included imperfect uptake of targeted intervention behaviors, limited power to detect effects on rare parasite infections, and that it was not feasible to blind participants and sample collectors to treatment status. However, lab technicians and data analysts were blinded to treatment status. The trial was funded by the Bill & Melinda Gates Foundation and the United States Agency for International Development. CONCLUSIONS: Integration of improved water quality, sanitation, and handwashing could contribute to sustainable control strategies for Ascaris infections, particularly in similar settings with recent or ongoing deworming programs. Combining nutrition with WSH did not provide further benefits, and water treatment alone was similarly effective to integrated WSH. Our findings provide new evidence that drinking water should be given increased attention as a transmission pathway for Ascaris. TRIAL REGISTRATION: ClinicalTrials.gov NCT01704105.

Effects of lipid-based nutrient supplements and infant and young child feeding counseling with or without improved water, sanitation, and hygiene (WASH) on anemia and micronutrient status: results from 2 cluster-randomized trials in Kenya and Bangladesh.

Background: Anemia in young children is a global health problem. Risk factors include poor nutrient intake and poor water quality, sanitation, or hygiene. Objective: We evaluated the effects of water quality, sanitation, handwashing, and nutrition interventions on micronutrient status and anemia among children in rural Kenya and Bangladesh. Design: We nested substudies within 2 cluster-randomized controlled trials enrolling pregnant women and following their children for 2 y. These substudies included 4 groups: water, sanitation, and handwashing (WSH); nutrition (N), including lipid-based nutrient supplements (LNSs; ages 6-24 mo) and infant and young child feeding (IYCF) counseling; WSH+N; and control. Hemoglobin and micronutrient biomarkers were measured after 2 y of intervention and compared between groups using generalized linear models with robust SEs. Results: In Kenya, 699 children were assessed at a mean ± SD age of 22.1 ± 1.8 mo, and in Bangladesh 1470 participants were measured at a mean ± SD age of 28.0 ± 1.9 mo. The control group anemia prevalences were 48.8% in Kenya and 17.4% in Bangladesh. There was a lower prevalence of anemia in the 2 N intervention groups in both Kenya [N: 36.2%; prevalence ratio (PR): 0.74; 95% CI: 0.58, 0.94; WSH+N: 27.3%; PR: 0.56; 95% CI: 0.42, 0.75] and Bangladesh (N: 8.7%; PR: 0.50; 95% CI: 0.32, 0.78; WSH+N: 7.9%, PR: 0.46; 95% CI: 0.29, 0.73). In both trials, the 2 N groups also had significantly lower prevalences of iron deficiency, iron deficiency anemia, and low vitamin B-12 and, in Kenya, a lower prevalence of folate and vitamin A deficiencies. In Bangladesh, the WSH group had a lower prevalence of anemia (12.8%; PR: 0.74; 95% CI: 0.54, 1.00) than the control group, whereas in Kenya, the WSH+N group had a lower prevalence of anemia than did the N group (PR: 0.75; 95% CI: 0.53, 1.07), but this was not significant (P = 0.102). Conclusions: IYCF counseling with LNSs reduced the risks of anemia, iron deficiency, and low vitamin B-12. Effects on folate and vitamin A varied between studies. Improvements in WSH also reduced the risk of anemia in Bangladesh but did not provide added benefit over the nutrition-specific intervention. These trials were registered at clinicaltrials.gov as NCT01590095 (Bangladesh) and NCT01704105 (Kenya).

A behaviour change intervention with lipid-based nutrient supplements had little impact on young child feeding indicators in rural Kenya.

Poor infant and young child feeding (IYCF) practices are associated with linear growth faltering. Our objective was to evaluate the impact of a nutrition and water and sanitation for health intervention on three IYCF indicators-minimum dietary diversity (MDD), minimum meal frequency (MMF), and minimum acceptable diet (MAD) in Kenyan children. Households were randomized into one of eight groups: (a) active control; (b) passive control; (c) water quality (W); (d) sanitation (S); (e) handwashing (H); (f) combined Water, Sanitation, and Handwashing; (g) nutrition (N); and (h) combined WSH + N. In the N and WSH + N arms, community-based promoters counselled households on optimal IYCF practices, and small-quantity lipid-based nutrient supplements (SQ-LNS) were provided to children 6-24 months of age. Twelve months (Year 1) and 24 months (Year 2) after interventions began, enumerators surveyed mothers to ascertain IYCF practices. We made pairwise comparisons of each intervention arm versus the active control arm using log binomial models. In total, 3,652 caretakers were surveyed at Year 1 and 4,987 caretakers at Year 2. Compared with the active control, there were no differences in any of the arms in MDD, MMF, or MAD, aside from an increase in MDD at Year 1 in the nutrition only arm but not in the combined WSH + N arm (N: 68%; WSH + N: 61%; C: 61%; N arm prevalence ratio: 1.13 95% CI [1.01, 1.25]). In this setting, a nutrition behaviour change communication intervention had little impact on IYCF indicators. The provision of SQ-LNS was not detrimental to current IYCF indicators in the community.

Sickle Cell and α+-Thalassemia Traits Influence the Association between Ferritin and Hepcidin in Rural Kenyan Children Aged 14-26 Months.

Background: The relation between subclinical hemoglobinopathies and concentrations of the iron-regulatory hormone hepcidin is not well characterized. Objective: We investigated the relation of hepcidin concentration with hemoglobinopathies among young children in Kenya. Methods: We quantified serum hepcidin and ferritin in 435 Kenyan children aged 14-20 mo in a subsample of the Water, Sanitation, and Handwashing (WASH) Benefits Trial. Blood samples were genotyped for α+-thalassemia and for sickle cell disorder. Hepcidin was compared across sickle cell and α+-thalassemia genotypes separately by using generalized linear models, and children who were normozygous for both conditions were also compared with those who had either of these conditions. In the association between hepcidin and ferritin, we assessed effect modification by genotype. Results: In this population, we found that 16.2% had sickle cell trait and 0.2% had sickle cell disorder, whereas 40.0% were heterozygous for α+-thalassemia and 8.2% were homozygous. Hepcidin concentration did not differ by genotype, but effect modification was found by genotype in the association between hepcidin and ferritin (P < 0.1). Among normozygous sickle cell children (HbAA), there was an association between hepcidin and ferritin (ß = 0.92; 95% CI: 0.72, 1.10). However, among those with sickle cell trait (HbAS), the association was no longer significant (ß = 0.31; 95% CI: -0.04, 0.66). Similarly, among children who were normozygous (αα/αα) or heterozygous (-α/αα) for α+-thalassemia, hepcidin and ferritin were significantly associated [ß = 0.94 (95% CI: 0.68, 1.20) and ß = 0.77 (95% CI: 0.51, 1.03), respectively]; however, in children who were homozygous for α+-thalassemia (-α/-α), there was no longer a significant association (ß = 0.45; 95% CI: -0.10, 1.00). Conclusion: Hepcidin was not associated with hemoglobin genotype, but there may be a difference in the way hepcidin responds to iron status among those with either sickle cell trait or homozygous α+-thalassemia in young Kenyan children. This trial was registered at clinicaltrials.gov as NCT01704105.

Fine tuning the cell cycle: activation of the Cdk1 inhibitory phosphorylation pathway during mitotic exit.

Inactivation of cyclin-dependent kinase (Cdk) 1 promotes exit from mitosis and establishes G1. Proteolysis of cyclin B is the major known mechanism that turns off Cdk1 during mitotic exit. Here, we show that mitotic exit also activates pathways that catalyze inhibitory phosphorylation of Cdk1, a mechanism previously known to repress Cdk1 only during S and G2 phases of the cell cycle. We present evidence that down-regulation of Cdk1 activates Wee1 and Myt1 kinases and inhibits Cdc25 phosphatase during the M to G1 transition. If cyclin B/Cdk1 complex is present in G1, the inhibitory sites on Cdk1 become phosphorylated. Exit from mitosis induced by chemical Cdk inhibition can be reversed if cyclin B is preserved. However, this reversibility decreases with time after mitotic exit despite the continued presence of the cyclin. We show that this G1 block is due to phosphorylation of Cdk1 on inhibitory residues T14 and Y15. Chemical inhibition of Wee1 and Myt1 or expression of Cdk1 phosphorylation site mutants allows reversal to M phase even from late G1. This late Cdk1 reactivation often results in caspase-dependent cell death. Thus, in G1, the Cdk inhibitory phosphorylation pathway is functional and can lock Cdk1 in the inactive state.