A novel view of ferritin in cancer.

Since its discovery more than 85 years ago, ferritin has principally been known as an iron storage protein. However, new roles, beyond iron storage, are being uncovered. Novel processes involving ferritin such as ferritinophagy and ferroptosis and as a cellular iron delivery protein not only expand our thinking on the range of contributions of this protein but present an opportunity to target these pathways in cancers. The key question we focus on within this review is whether ferritin modulation represents a useful approach for treating cancers. We discussed novel functions and processes of this protein in cancers. We are not limiting this review to cell intrinsic modulation of ferritin in cancers, but also focus on its utility in the trojan horse approach in cancer therapeutics. The novel functions of ferritin as discussed herein realize the multiple roles of ferritin in cell biology that can be probed for therapeutic opportunities and further research.

COVID-19 compromises iron homeostasis: Transferrin as a target of investigation.

IMPORTANCE: Since the beginning of the COVID-19 pandemic, numerous metabolic alterations have been observed in individuals with this disease. It is known that SARS-CoV-2 can mimic the action of hepcidin, altering intracellular iron metabolism, but gaps remain in the understanding of possible outcomes in other pathways involved in the iron cycle. OBJECTIVE: To profile iron, ferritin and hepcidin levels and transferrin receptor gene expression in patients diagnosed with COVID-19 between June 2020 and September 2020. DESIGN, SETTING AND PARTICIPANTS: Cross-sectional study that evaluated iron metabolism markers in 427 participants, 218 with COVID-19 and 209 without the disease. EXPOSURES: The primary exposure was positive diagnose to COVID-19 in general population of Santo André and São Bernardo cities. The positive and negative diagnose were determinate through RT-qPCR. MAIN OUTCOMES AND MEASURES: Devido a evidências de alterações do ciclo do ferro em pacientes diagnosticados com COVID-19 e devido a corregulação entre hepcidina e receptor de transferrina, uma análise da expressão gênica deste último, poderia trazer insights sobre o estado de ferro celular. A hipótese foi confirmada, mostrando aumento da expressão de receptor de transferrina concomitante com redução do nível de hepcidina circulante. RESULTS: Serum iron presented lower values in individuals diagnosed with COVID-19, whereas serum ferritin presented much higher values in infected patients. Elderly subjects had lower serum iron levels and higher ferritin levels, and men with COVID-19 had higher ferritin values than women. Serum hepcidin was lower in the COVID-19 patient group and transferrin receptor gene expression was higher in the infected patient group compared to controls. CONCLUSIONS AND RELEVANCE: COVID-19 causes changes in several iron cycle pathways, with iron and ferritin levels being markers that reflect the state and evolution of infection, as well as the prognosis of the disease. The increased expression of the transferrin receptor gene suggests increased iron internalization and the mimicry of hepcidin action by SARS-CoV-2, reduces iron export via ferroportin, which would explain the low circulating levels of iron by intracellular trapping.

[Antiviral and virucidal activity of sodium deoxyribonucleate and its complex with iron against viruses of different kingdoms and families].

INTRODUCTION: The urgent problem of modern medicine is the fight against acute respiratory viral infections (ARVI). To combat ARVI, drugs of wide antiviral potency are needed, as well as immunomodulating drugs. Such antiviral and immunomodulatory effects has sodium deoxyribonucleate (DNA-Na) and its complex with iron (DNA-Na-Fe) developed on the basis of double-stranded DNA of natural origin. AIM OF THE STUDY: To assess antiviral and virucidal activity of DNA-Na and DNA-Na-Fe against viruses of different kingdoms and families. MATERIALS AND METHODS: Antiviral and virucidal activity of DNA-Na and DNA-Na-Fe was assessed in cell cultures infected with viruses. RESULTS AND DISCUSSION: DNA-Na and DNA-Na-Fe had antiviral activity against adenovirus at concentrations of 2501000 mcg/ml. Antiviral effect of both drugs was not detected in case of poliovirus. DNA-Na and DNA-Na-Fe had antiviral activity against coronavirus in all administration schemes. EC50 for DNA-Na ~ 2500 mcg/ml, for DNA-Na-Fe ~ 1000 mcg/ml. In cells treated with DNA-Na-Fe, secretion of following proinflammatory cytokines was detected: Interleukin (IL) 1, IL-2, IL-6, IL-18, interferon- (IFN-), IFN-, as well as anti-inflammatory cytokines: IL-4, IL-10, antagonist of IL-1 receptor. Evidently, DNA-Na and DNA-Na-Fe have antiviral effect, but mechanism of action does not seem to be associated with specific effect on viral replication. Presence of virucidal activity of drugs against representatives of Coronaviridae, Adenoviridae, Picornaviridae, Retroviridae, Herpesviridae in vitro test in range of 1.03.0 lg TCID50 was identified. CONCLUSION: Presence of simultaneous antiviral and virucidal activity of DNA-Na and DNA-Na-Fe against adeno- and coronaviruses shows their prospects for prevention and treatment of ARVI.

Iron as a therapeutic target in chronic liver disease.

It was clearly realized more than 50 years ago that iron deposition in the liver may be a critical factor in the development and progression of liver disease. The recent clarification of ferroptosis as a specific form of regulated hepatocyte death different from apoptosis and the description of ferritinophagy as a specific variation of autophagy prompted detailed investigations on the association of iron and the liver. In this review, we will present a brief discussion of iron absorption and handling by the liver with emphasis on the role of liver macrophages and the significance of the iron regulators hepcidin, transferrin, and ferritin in iron homeostasis. The regulation of ferroptosis by endogenous and exogenous mod-ulators will be examined. Furthermore, the involvement of iron and ferroptosis in various liver diseases including alcoholic and non-alcoholic liver disease, chronic hepatitis B and C, liver fibrosis, and hepatocellular carcinoma (HCC) will be analyzed. Finally, experimental and clinical results following interventions to reduce iron deposition and the promising manipulation of ferroptosis will be presented. Most liver diseases will be benefited by ferroptosis inhibition using exogenous inhibitors with the notable exception of HCC, where induction of ferroptosis is the desired effect. Current evidence mostly stems from in vitro and in vivo experimental studies and the need for well-designed future clinical trials is warranted.

Phosphate and IL-10 concentration as predictors of long-covid in hemodialysis patients: A Brazilian study.

Background: The global burden of persistent COVID-19 in hemodialysis (HD) patients is a worrisome scenario worth of investigation for the critical care of chronic kidney disease (CKD). We performed an exploratory post-hoc study from the trial U1111-1237-8231 with two specific aims: i) to investigate the prevalence of COVID-19 infection and long COVID symptoms from our Cohort of 178 Brazilians HD patients. ii) to identify whether baseline characteristics should predict long COVID in this sample. Methods: 247 community-dwelling older (>60 years) patients (Men and women) undergoing HD (glomerular filtration rate < 15 mL/min/1.73m2) with arteriovenous fistula volunteered for this study. All patients presented hypertension and diabetes. Patients were divided in two groups: without long-COVID and with long-COVID. Body composition, handgrip strength, functional performance, iron metabolism, phosphate, and inflammatory profile were assessed. Patients were screened for 11-months after COVID-19 infection. Results were considered significant at P < 0.05. Results: We found that more than 85% of the COVID-19 infected patients presented a severe condition during the infection. In our sample, the mortality rate over 11-month follow was relatively low (8.4%) when compared to worldwide (approximately 36%). Long COVID was highly prevalent in COVID-19 survivors representing more than 80% of all cases. Phosphate and IL-10 were higher in the long COVID group, but only phosphate higher than 5.35 mg/dL appears to present an increased prevalence of long COVID, dyspnea, and fatigue. Conclusion: There was a high prevalence of COVID-19 infection and long COVID in HD patients from the Brazilian trial 'U1111-1237-8231'. HD clinics should be aware with phosphate range in HD patients as a possible target for adverse post-COVID events.

Efficacy and safety of intravenous iron repletion in patients with heart failure: a systematic review and meta-analysis.

INTRODUCTION: AFFIRM-AHF and IRONMAN demonstrated lower rates of the combined endpoint recurrent heart failure (HF) hospitalizations and cardiovascular death (CVD) using intravenous (IV) ferric carboxymaltose (FCM) and ferric derisomaltose (FDI), respectively in patients with HF and iron deficiency (ID) utilizing prespecified COVID-19 analyses. MATERIAL AND METHODS: We meta-analyzed efficacy, between trial heterogeneity and data robustness for the primary endpoint and CVD in AFFIRM-AHF and IRONMAN. As sensitivity analysis, we analyzed data from all eligible exploratory trials investigating FCM/FDI in HF. RESULTS: FCM/FDI reduced the primary endpoint (RR = 0.81, 95% CI 0.69-0.95, p = 0.01, I2 = 0%), with the number needed to treat (NNT) being 7. Power was 73% and findings were robust with fragility index (FI) of 94 and fragility quotient (FQ) of 0.041. Effects of FCM/FDI were neutral concerning CVD (OR = 0.88, 95% CI 0.71-1.09, p = 0.24, I2 = 0%). Power was 21% while findings were fragile with reverse FI of 14 and reversed FQ of 0.006. The sensitivity analysis from all eligible trials (n = 3258) confirmed positive effects of FCM/FDI on the primary endpoint (RR = 0.77, 95% CI 0.66-0.90, p = 0.0008, I2 = 0%), with NNT being 6. Power was 91% while findings were robust (FI of 147 and FQ of 0.045). Effect on CVD was neutral (RR = 0.87, 95% CI 0.71-1.07, p = 0.18, I2 = 0%). Power was 10% while findings were fragile (reverse FI of 7 and reverse FQ of 0.002). Rate of infections (OR = 0.85, 95% CI 0.71-1.02, p = 0.09, I2 = 0%), vascular disorder (OR = 0.84, 95% CI 0.57-1.25, p = 0.34, I2 = 0%) and general or injection-site related disorders (OR = 1.39, 95% CI 0.88-1.29, p = 0.16, I2 = 30%) were comparable between groups. There was no relevant heterogeneity (I2 > 50%) between the trials for any of the analyzed outcomes. CONCLUSIONS: Use of FCM/FDI is safe and reduces the composite of recurrent HF hospitalizations and CVD, while effects on CVD alone are based on available level of data indeterminate. Findings concerning composite outcomes exhibit a high level of robustness without heterogeneity between trials with FCM and FDI.

In the SARS-CoV-2 Pandora Pandemic: Can the Stance of Premorbid Intestinal Innate Immune System as Measured by Fecal Adnab-9 Binding of p87:Blood Ferritin, Yielding the FERAD Ratio, Predict COVID-19 Susceptibility and Survival in a Prospective Population Database?

SARS-CoV-2 severity predictions are feasible, though individual susceptibility is not. The latter prediction allows for planning vaccination strategies and the quarantine of vulnerable targets. Ironically, the innate immune response (InImS) is both an antiviral defense and the potential cause of adverse immune outcomes. The competition for iron has been recognized between both the immune system and invading pathogens and expressed in a ratio of ferritin divided by p87 (as defined by the Adnab-9 ELISA stool-binding optical density, minus the background), known as the FERAD ratio. Associations with the FERAD ratio may allow predictive modeling for the susceptibility and severity of disease. We evaluated other potential COVID-19 biomarkers prospectively. Patients with PCR+ COVID-19 tests (Group 1; n = 28) were compared to three other groups. In Group 2 (n = 36), and 13 patients displayed COVID-19-like symptoms but had negative PCR or negative antibody tests. Group 3 (n = 90) had no symptoms and were negative when routinely PCR-tested before medical procedures. Group 4 (n = 2129) comprised a pool of patients who had stool tests and symptoms, but their COVID-19 diagnoses were unknown; therefore, they were chosen to represent the general population. Twenty percent of the Group 4 patients (n = 432) had sufficient data to calculate their FERAD ratios, which were inversely correlated with the risk of COVID-19 in the future. In a case report of a neonate, we studied three biomarkers implicated in COVID-19, including p87, Src (cellular-p60-sarcoma antigen), and Abl (ABL-proto-oncogene 2). The InImS of the first two were positively correlated. An inverse correlation was found between ferritin and lysozyme in serum (p < 0.05), suggesting that iron could have impaired an important innate immune system anti-viral effector and could partially explain future COVID-19 susceptibility.

Health worker perspectives on access to antenatal care in rural plains Nepal during the COVID-19 pandemic.

The COVID-19 pandemic affected access to antenatal care in low and middle-income countries where anaemia in pregnancy is prevalent. We analyse how health workers provided antenatal care and the factors affecting access to antenatal care during the COVID-19 pandemic in Kapilvastu district in the western plains of Nepal. We used qualitative and quantitative methodologies, conducting eight semi-structured interviews with health workers who provided antenatal care during the pandemic, and a questionnaire containing open and closed questions with 52 female community health volunteers. Antenatal care was severely disrupted during the pandemic. Health workers had to find ways to provide care with insufficient personal protective equipment and guidance whilst facing extreme levels of stigmatisation which prevented them from providing outreach services. Pregnant women were fearful or unable to visit health institutions during the pandemic because of COVID-19 control measures. Pre-pandemic and during the pandemic health workers tried to contact pregnant and postpartum women and families over the phone, but this was challenging because of limited access to phones, and required pregnant women to make at least one antenatal care visit to give their phone number. The pandemic prevented new pregnancies from being registered, and therefore the possibilities to provide services over the phone for these pregnancies were limited. To reach the most marginalised during a pandemic or other health emergency, health volunteers and households need to exchange phone numbers, enabling proactive monitoring and care-seeking. Strengthening procurement and coordination between the municipal, provincial, and federal levels of government is needed to ensure adequacy of antenatal supplies, such as iron folic acid tablets, in health emergencies. Community engagement is important to ensure women and families are aware of the need to access antenatal care and iron folic acid, and to address stigmatisation of health workers.

Removal Performance and Mechanism of Emerging Pollutant Chloroquine Phosphate from Water by Iron and Magnesium Co-Modified Rape Straw Biochar.

Chloroquine phosphate (CQP) is effective in treating coronavirus disease 2019 (COVID-19); thus, its usage is rapidly increasing, which may pose a potential hazard to the environment and living organisms. However, there are limited findings on the removal of CQP in water. Herein, iron and magnesium co-modified rape straw biochar (Fe/Mg-RSB) was prepared to remove CQP from the aqueous solution. The results showed that Fe and Mg co-modification enhanced the adsorption efficiency of rape straw biochar (RSB) for CQP with the maximum adsorption capacity of 42.93 mg/g (at 308 K), which was about two times higher than that of RSB. The adsorption kinetics and isotherms analysis, as well as the physicochemical characterization analysis, demonstrated that the adsorption of CQP onto Fe/Mg-RSB was caused by the synergistic effect of pore filling, π-π interaction, hydrogen bonding, surface complexation, and electrostatic interaction. In addition, although solution pH and ionic strength affected the adsorption performance of CQP, Fe/Mg-RSB still had a high adsorption capability for CQP. Column adsorption experiments revealed that the Yoon-Nelson model better described the dynamic adsorption behavior of Fe/Mg-RSB. Furthermore, Fe/Mg-RSB had the potential for repeated use. Therefore, Fe and Mg co-modified biochar could be used for the remediation of CQP from contaminated water.

Iron Acquisition and Metabolism as a Promising Target for Antimicrobials (Bottlenecks and Opportunities): Where Do We Stand?

The emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) infections is one of the most crucial challenges currently faced by the scientific community. Developments in the fundamental understanding of their underlying mechanisms may open new perspectives in drug discovery. In this review, we conducted a systematic literature search in PubMed, Web of Science, and Scopus, to collect information on innovative strategies to hinder iron acquisition in bacteria. In detail, we discussed the most interesting targets from iron uptake and metabolism pathways, and examined the main chemical entities that exhibit anti-infective activities by interfering with their function. The mechanism of action of each drug candidate was also reviewed, together with its pharmacodynamic, pharmacokinetic, and toxicological properties. The comprehensive knowledge of such an impactful area of research will hopefully reflect in the discovery of newer antibiotics able to effectively tackle the antimicrobial resistance issue.

Indian food habit & food ingredients may have a role in lowering the severity & high death rate from COVID-19 in Indians: findings from the first nutrigenomic analysis.

Background & objectives: During the COVID-19 pandemic, the death rate was reportedly 5-8 fold lower in India which is densely populated as compared to less populated western countries. The aim of this study was to investigate whether dietary habits were associated with the variations in COVID-19 severity and deaths between western and Indian population at the nutrigenomics level. Methods: In this study nutrigenomics approach was applied. Blood transcriptome of severe COVID-19 patients from three western countries (showing high fatality) and two datasets from Indian patients were used. Gene set enrichment analyses were performed for pathways, metabolites, nutrients, etc., and compared for western and Indian samples to identify the food- and nutrient-related factors, which may be associated with COVID-19 severity. Data on the daily consumption of twelve key food components across four countries were collected and a correlation between nutrigenomics analyses and per capita daily dietary intake was investigated. Results: Distinct dietary habits of Indians were observed, which may be associated with low death rate from COVID-19. Increased consumption of red meat, dairy products and processed foods by western populations may increase the severity and death rate by activating cytokine storm-related pathways, intussusceptive angiogenesis, hypercapnia and enhancing blood glucose levels due to high contents of sphingolipids, palmitic acid and byproducts such as CO2 and lipopolysaccharide (LPS). Palmitic acid also induces ACE2 expression and increases the infection rate. Coffee and alcohol that are highly consumed in western countries may increase the severity and death rates from COVID-19 by deregulating blood iron, zinc and triglyceride levels. The components of Indian diets maintain high iron and zinc concentrations in blood and rich fibre in their foods may prevent CO2 and LPS-mediated COVID-19 severity. Regular consumption of tea by Indians maintains high high-density lipoprotein (HDL) and low triglyceride in blood as catechins in tea act as natural atorvastatin. Importantly, regular consumption of turmeric in daily food by Indians maintains strong immunity and curcumin in turmeric may prevent pathways and mechanisms associated with SARS-CoV-2 infection and COVID-19 severity and lowered the death rate. Interpretation & conclusions: Our results suggest that Indian food components suppress cytokine storm and various other severity related pathways of COVID-19 and may have a role in lowering severity and death rates from COVID-19 in India as compared to western populations. However, large multi-centered case-control studies are required to support our current findings.

Chemistry and biology of ferritin.

Iron is an essential element required by cells and has been described as a key player in ferroptosis. Ferritin operates as a fundamental iron storage protein in cells forming multimeric assemblies with crystalline iron cores. We discuss the latest findings on ferritin structure and activity and its link to cell metabolism and ferroptosis. The chemistry of iron, including its oxidation states, is important for its biological functions, its reactivity, and the biology of ferritin. Ferritin can be localized in different cellular compartments and secreted by cells with a variety of functions depending on its spatial context. Here, we discuss how cellular ferritin localization is tightly linked to its function in a tissue-specific manner, and how impairment of iron homeostasis is implicated in diseases, including cancer and coronavirus disease 2019. Ferritin is a potential biomarker and we discuss latest research where it has been employed for imaging purposes and drug delivery.

Ironing Out Vaccine Efficacy.

Iron deficiency has been linked to impaired humoral immunity to vaccines. In this issue of Med, Frost et al. demonstrate the importance of serum iron levels for lymphocyte function during vaccination and infection, pointing to iron supplementation as a strategy to boost vaccine efficacy, including against COVID19.1.

Intravenous iron in patients with heart failure and iron deficiency: an updated meta-analysis.

AIMS: For patients with heart failure (HF) and iron deficiency (ID), randomized trials suggest that intravenous (IV) iron reduces hospitalizations for heart failure (HHF), but uncertainty exists about the effects in subgroups and the impact on mortality. We conducted a meta-analysis of randomized trials investigating the effect of IV iron on clinical outcomes in patients with HF. METHODS AND RESULTS: We identified randomized trials published between 1 January 2000 and 5 November 2022 investigating the effect of IV iron versus standard care/placebo in patients with HF and ID in any clinical setting, regardless of HF phenotype. Trials of oral iron or not in English were not included. The main outcomes of interest were a composite of HHF and cardiovascular death (CVD), on HHF alone and on cardiovascular and all-cause mortality. Ten trials were identified with 3373 participants, of whom 1759 were assigned to IV iron. IV iron reduced the composite of recurrent HHF and CVD (rate ratio 0.75, 95% confidence interval [CI] 0.61-0.93; p < 0.01) and first HHF or CVD (odds ratio [OR] 0.72, 95% CI 0.53-0.99; p = 0.04). Effects on cardiovascular (OR 0.86, 95% CI 0.70-1.05; p = 0.14) and all-cause mortality (OR 0.93, 95% CI 0.78-1.12; p = 0.47) were inconclusive. Results were similar in analyses confined to the first year of follow-up, which was less disrupted by the COVID-19 pandemic. Subgroup analyses found little evidence of heterogeneity for the effect on the primary endpoint, although patients with transferrin saturation <20% (OR 0.67, 95% CI 0.49-0.92) may have benefited more than those with values ≥20% (OR 0.99, 95% CI 0.74-1.30) (heterogeneity p = 0.07). CONCLUSION: In patients with HF and ID, this meta-analysis suggests that IV iron reduces the risk of HHF but whether this is associated with a reduction in cardiovascular or all-cause mortality remains inconclusive.

Study protocol for a randomised controlled trial of a virtual antenatal intervention for improved diet and iron intake in Kapilvastu district, Nepal: VALID.

INTRODUCTION: Despite evidence that iron and folic acid (IFA) supplements can improve anaemia in pregnant women, uptake in Nepal is suboptimal. We hypothesised that providing virtual counselling twice in mid-pregnancy, would increase compliance to IFA tablets during the COVID-19 pandemic compared with antenatal care (ANC alone. METHODS AND ANALYSIS: This non-blinded individually randomised controlled trial in the plains of Nepal has two study arms: (1) control: routine ANC; and (2) 'Virtual' antenatal counselling plus routine ANC. Pregnant women are eligible to enrol if they are married, aged 13-49 years, able to respond to questions, 12-28 weeks' gestation, and plan to reside in Nepal for the next 5 weeks. The intervention comprises two virtual counselling sessions facilitated by auxiliary nurse midwives at least 2 weeks apart in mid-pregnancy. Virtual counselling uses a dialogical problem-solving approach with pregnant women and their families. We randomised 150 pregnant women to each arm, stratifying by primigravida/multigravida and IFA consumption at baseline, providing 80% power to detect a 15% absolute difference in primary outcome assuming 67% prevalence in control arm and 10% loss-to-follow-up. Outcomes are measured 49-70 days after enrolment, or up to delivery otherwise. PRIMARY OUTCOME: consumption of IFA on at least 80% of the previous 14 days. SECONDARY OUTCOMES: dietary diversity, consumption of intervention-promoted foods, practicing ways to enhance bioavailability and knowledge of iron-rich foods. Our mixed-methods process evaluation explores acceptability, fidelity, feasibility, coverage (equity and reach), sustainability and pathways to impact. We estimate costs and cost-effectiveness of the intervention from a provider perspective. Primary analysis is by intention-to-treat, using logistic regression. ETHICS AND DISSEMINATION: We obtained ethical approval from Nepal Health Research Council (570/2021) and UCL ethics committee (14301/001). We will disseminate findings in peer-reviewed journal articles and by engaging policymakers in Nepal. TRIAL REGISTRATION NUMBER: ISRCTN17842200.

Existing gaps and missed opportunities in delivering quality nutrition services in primary healthcare: a descriptive analysis of patient experience and provider competence in 11 low-income and middle-income countries.

OBJECTIVES: To assess the competence of primary healthcare (PHC) providers in delivering maternal and child nutrition services at the PHC level and patients' experience in receiving the recommended components of care. DESIGN: Observational cross-sectional analysis. SETTING: Healthcare facilities in low/middle-income countries (LMICs) with available service provision assessment surveys (Afghanistan (2018), Democratic Republic of Congo (2018), Haiti (2017), Kenya (2010), Malawi (2013-2014), Namibia (2009), Nepal (2015), Rwanda (2007), Senegal (2018), Tanzania (2015) and Uganda (2007). PARTICIPANTS: 18 644 antenatal visits and 23 262 sick child visits in 8458 facilities across 130 subnational areas in 11 LMICs from 2007 to 2019. OUTCOMES: (1) Provider competence assessed as the direct observations of actions performed during antenatal care (ANC) and sick child visits; and (2) patients' experience defined as the self-reported awareness of the nutrition services received during ANC and sick child visits and provider effectiveness in delivering these services. RESULTS: Except for DRC, all countries scored below 50% on patients' experience and provider competence. More than 70% of clients were advised on taking iron supplements during pregnancy; however, less than 32% of patients were advised on iron side effects in all the studied countries. Across all countries, providers commonly took anthropometric measurements of expectant mothers and children; however, such assessments were rarely followed up with advice or counselling about growth patterns. In addition, less than 20% of observed providers advised on early/immediate breast feeding in all countries with available data. CONCLUSION: The 11 assessed countries demonstrated the delivery of limited nutrition services; nonetheless, the apparent deficiency in the extent and depth of questions asked for the majority of tracer activities revealed significant opportunities for improving the quality of nutrition service delivery at the PHC level.

Ferritin - a multifaceted protein scaffold for biotherapeutics.

The ferritin nanocage is an endogenous protein that exists in almost all mammals. Its hollow spherical structure that naturally stores iron ions has been diversely exploited by researchers in biotherapeutics. Ferritin has excellent biosafety profiles, and the nanosized particles exhibit rapid dispersion and controlled/sustained release pharmacokinetics. Moreover, the large surface-to-volume ratio and the disassembly/reassembly behavior of the 24 monomer subunits into a sphere allow diverse modifications by chemical and genetic methods on the surface and inner cage of ferritin. Here, we critically review ferritin and its applications. We (i) introduce the application of ferritin in drug delivery; (ii) present an overview of the use of ferritin in imaging and diagnosis for biomedical purposes; (iii) discuss ferritin-based vaccines; and (iv) review ferritin-based agents currently in clinical trials. Although there are no currently approved drugs based on ferritin, this multifunctional protein scaffold shows immense potential in drug development in diverse categories, and ferritin-based drugs have recently entered phase I clinical trials. This golden shortlist of recent developments will be of immediate benefit and interest to researchers studying ferritin and other protein-based biotherapeutics.

Ferric carboxymaltose and SARS-CoV-2 vaccination-induced immunogenicity in kidney transplant recipients with iron deficiency: The COVAC-EFFECT randomized controlled trial.

Background: Kidney transplant recipients (KTRs) have an impaired immune response after vaccination against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Iron deficiency (ID) may adversely affect immunity and vaccine efficacy. We aimed to investigate whether ferric carboxymaltose (FCM) treatment improves humoral and cellular responses after SARS-CoV-2 vaccination in iron-deficient KTRs. Methods: We randomly assigned 48 iron-deficient KTRs to intravenous FCM (1-4 doses of 500mg with six-week intervals) or placebo. Co-primary endpoints were SARS-CoV-2-specific anti-Receptor Binding Domain (RBD) Immunoglobulin G (IgG) titers and T-lymphocyte reactivity against SARS-CoV-2 at four weeks after the second vaccination with mRNA-1273 or mRNA-BNT162b2. Results: At four weeks after the second vaccination, patients receiving FCM had higher plasma ferritin and transferrin saturation (P<0.001 vs. placebo) and iron (P=0.02). However, SARS-CoV-2-specific anti-RBD IgG titers (FCM: 66.51 [12.02-517.59] BAU/mL; placebo: 115.97 [68.86-974.67] BAU/mL, P=0.07) and SARS-CoV-2-specific T-lymphocyte activation (FCM: 93.3 [0.85-342.5] IFN-É£ spots per 106 peripheral blood mononuclear cells (PBMCs), placebo: 138.3 [0.0-391.7] IFN-É£ spots per 106 PBMCs, P=0.83) were not significantly different among both arms. After the third vaccination, SARS-CoV-2-specific anti-RBD IgG titers remained similar between treatment groups (P=0.99). Conclusions: Intravenous iron supplementation efficiently restored iron status but did not improve the humoral or cellular immune response against SARS-CoV-2 after three vaccinations.

Hepcidin and ferritin levels as markers of immune cell activation during septic shock, severe COVID-19 and sterile inflammation.

Introduction: Major clinically relevant inflammatory events such as septic shock and severe COVID-19 trigger dynamic changes in the host immune system, presenting promising candidates for new biomarkers to improve precision diagnostics and patient stratification. Hepcidin, a master regulator of iron metabolism, has been intensively studied in many pathologies associated with immune system activation, however these data have never been compared to other clinical settings. Thus, we aimed to reveal the dynamics of iron regulation in various clinical settings and to determine the suitability of hepcidin and/or ferritin levels as biomarkers of inflammatory disease severity. Cohorts: To investigate the overall predictive ability of hepcidin and ferritin, we enrolled the patients suffering with three different diagnoses - in detail 40 patients with COVID-19, 29 patients in septic shock and eight orthopedic patients who were compared to nine healthy donors and all cohorts to each other. Results: We showed that increased hepcidin levels reflect overall immune cell activation driven by intrinsic stimuli, without requiring direct involvement of infection vectors. Contrary to hepcidin, ferritin levels were more strongly boosted by pathogen-induced inflammation - in septic shock more than four-fold and in COVID-19 six-fold in comparison to sterile inflammation. We also defined the predictive capacity of hepcidin-to-ferritin ratio with AUC=0.79 and P = 0.03. Discussion: Our findings confirm that hepcidin is a potent marker of septic shock and other acute inflammation-associated pathologies and demonstrate the utility of the hepcidin-to-ferritin ratio as a predictor of mortality in septic shock, but not in COVID-19.