Hyperferritinemic sepsis, macrophage activation syndrome, and mortality in a pediatric research network: a causal inference analysis.

BACKGROUND: One of five global deaths are attributable to sepsis. Hyperferritinemic sepsis (> 500 ng/mL) is associated with increased mortality in single-center studies. Our pediatric research network's objective was to obtain rationale for designing anti-inflammatory clinical trials targeting hyperferritinemic sepsis. METHODS: We assessed differences in 32 cytokines, immune depression (low whole blood ex vivo TNF response to endotoxin) and thrombotic microangiopathy (low ADAMTS13 activity) biomarkers, seven viral DNAemias, and macrophage activation syndrome (MAS) defined by combined hepatobiliary dysfunction and disseminated intravascular coagulation, and mortality in 117 children with hyperferritinemic sepsis (ferritin level > 500 ng/mL) compared to 280 children with sepsis without hyperferritinemia. Causal inference analysis of these 41 variables, MAS, and mortality was performed. RESULTS: Mortality was increased in children with hyperferritinemic sepsis (27/117, 23% vs 16/280, 5.7%; Odds Ratio = 4.85, 95% CI [2.55-9.60]; z = 4.728; P-value < 0.0001). Hyperferritinemic sepsis had higher C-reactive protein, sCD163, IL-22, IL-18, IL-18 binding protein, MIG/CXCL9, IL-1ß, IL-6, IL-8, IL-10, IL-17a, IFN-γ, IP10/CXCL10, MCP-1/CCL2, MIP-1α, MIP-1ß, TNF, MCP-3, IL-2RA (sCD25), IL-16, M-CSF, and SCF levels; lower ADAMTS13 activity, sFasL, whole blood ex vivo TNF response to endotoxin, and TRAIL levels; more Adenovirus, BK virus, and multiple virus DNAemias; and more MAS (P-value < 0.05). Among these variables, only MCP-1/CCL2 (the monocyte chemoattractant protein), MAS, and ferritin levels were directly causally associated with mortality. MCP-1/CCL2 and hyperferritinemia showed direct causal association with depressed ex vivo whole blood TNF response to endotoxin. MCP-1/CCL2 was a mediator of MAS. MCP-1/CCL2 and MAS were mediators of hyperferritinemia. CONCLUSIONS: These findings establish hyperferritinemic sepsis as a high-risk condition characterized by increased cytokinemia, viral DNAemia, thrombotic microangiopathy, immune depression, macrophage activation syndrome, and death. The causal analysis provides rationale for designing anti-inflammatory trials that reduce macrophage activation to improve survival and enhance infection clearance in pediatric hyperferritinemic sepsis.

Ameliorative effects of camel milk and silymarin upon aflatoxin B1 induced hepatic injury in rats.

Aflatoxin B1 (AFB1) poses a major risk to both human and animal health because it contaminates food, feed, and grains. These dangerous effects can be mitigated using natural components. The purpose of this study was to examine the ameliorative effects of camel milk and silymarin supplementation upon aflatoxin B1 induced hepatic injury in rats. This improvement was assessed by measuring leukocytic and deferential counts, serum biochemical parameters, and gene expression of Tumor Necrosis Factor (TNF-α), antioxidant gene (NAD(P)H quinone oxidoreductase 1 (NQO1)), and base excision repair genes (APE1 and OGG1) in the liver tissue, in addition to liver histopathology. Sixty mature males Wister white rats were used to perform the present study; the rats were distributed in six groups (ten rats/group). The control group (without any treatment) received saline by gavage. The camel milk group received 1 ml of camel milk/kg body weight. The silymarin group received 1 ml of silymarin suspension solution at a dose of 20 mg of silymarin/kg of b.wt. The aflatoxin group received an aflatoxin-contaminated diet at a dose of 1.4 mg of aflatoxin /kg of diet and received saline. The camel milk + aflatoxin group received the same previous oral doses of camel milk and an aflatoxin-contaminated diet at the same time. The silymarin + aflatoxin group received the same previous doses of silymarin orally and an aflatoxin-contaminated diet at the same time. The obtained data indicated the deleterious effect of aflatoxin B1 on the leukocytic count, activity of AST and ALT, serum proteins, ferritin, alpha-fetoprotein, carcinoembryonic antigen, liver pathology, and the expression of the studied genes. However, these deleterious effects were mitigated by camel milk and silymarin supplementation. Thus, we could conclude that the ingestion of camel milk and silymarin mitigated the negative effects of AFB1 on the hematology, activity of AST and ALT, serum proteins, ferritin, alpha-fetoprotein, carcinoembryonic antigen, liver pathology, and gene expression in the rat model.

Serum levels of tumor markers and their clinical significance in epithelial ovarian cancer. / ä¸Šçš®æ€§åµå·¢ç™Œè¡€æ¸ ä¸­è‚¿ç˜¤æ ‡å¿—ç‰©æ°´å¹³åŠå ¶ä¸´åºŠæ„ä¹‰ï¼ˆè‹±æ–‡ï¼‰.

OBJECTIVES: Tumor markers have been widely used clinically. Detection of serum CA125 is one of the commonly used clinical methods for early screening and early diagnosis of epithelial ovarian cancer, but it is difficult to diagnose epithelial ovarian cancer with a single specific tumor marker. In this study, the combinatorial tumor marker detection method was used to compare the value of each tumor marker alone and different combinations in the diagnosis of epithelial ovarian cancer. METHODS: The clinical data of patients with epithelial ovarian cancer (n=65) and ovarian benign disease (n=29) were collected. Multiple tumor marker protein chip was used to detect cancer antigen 125 (CA125), carbohydrate antigen 242 (CA242), alpha-fetoprotein (AFP), beta-human chorionic gonadotropin (ß-HCG), carcinoembryonic antigen (CEA), cancer antigen 199 (CA199), neuron-specific enolase (NSE), Ferritin, cancer antigen 153 (CA153), and human growth hormone (HGH) serum levels, and to compare the differences between the benign and malignant ovarian tumors. The correlation between tumor markers and clinicopathologic features for ovarian epithelial carcinoma was analyzed by χ2 test. Spearman rank analysis showed the correlation between CA125 expression level and other tumor markers in epithelial ovarian cancer and the correlation between age and the above 10 tumor markers. Sensitivity, specificity, positive predictive value, negative predictive value, Youden index, and diagnostic efficiency were used to evaluate the diagnostic value of single tumor marker and the combination of tumor markers. RESULTS: The levels of ß-HCG, NSE, CA153, and CA125 in the epithelial ovarian cancer group were higher than those in the ovarian benign disease group. The level of NSE in the serum of patients with epithelial ovarian cancer was related to the clinical stage of patients. In addition, the levels of CA242, ß-HCG, CEA, NSE, Ferritin, CA153 in the serum of patients with epithelial ovarian cancer were positively correlated with CA125 (rs=0.497, P<0.001; rs=0.612, P<0.001; rs=0.358, P=0.003; rs=0.680, P<0.001; rs=0.322, P=0.009; rs=0.609, P<0.001, respectively), and the levels of ß-HCG, Ferritin, CA153 were positively correlated with the patient's age (rs=0.256, P=0.040; rs=0.325, P=0.008; rs=0.249, P=0.046, respectively). In the diagnosis of epithelial ovarian cancer, the sensitivity, Youden index, and diagnostic efficiency of CA125 detection alone were higher than the results of the other 9 separate detections. When CA153, CA199, CA242, Ferritin, and CEA were combined with CA125, the sensitivity of the combined detection of different combinations was higher than that of CA125 alone. The combined detection sensitivities of CA125+CEA and CA125+Ferritin+CEA were 89.2% and 90.8%, respectively, and the diagnostic efficiencies were both 84.1%, which were higher than those of other combinations. The Youden index of CA125+CEA joint detection was 0.616, which was higher than those of other combinations. CONCLUSIONS: CA125 has a high diagnostic value in the diagnosis of epithelial ovarian cancer. The detection of combined tumor markers in serum has higher sensitivity and specificity in epithelial ovarian cancer.

Association of neck circumference-related indices with metabolic, atherogenic and liver function biomarkers in patients with non-alcoholic fatty liver disease: a cross-sectional study.

OBJECTIVE: The present study aimed to establish the association of neck circumference (NC)-related indices with metabolic, atherogenic and liver function biomarkers in patients with non-alcoholic fatty liver disease (NAFLD). DESIGN: Cross-sectional study. SETTING: Outpatient clinics of Tabriz University of Medical Sciences. PARTICIPANTS: A total of 175 adult patients with NAFLD diagnosed by abdominal ultrasonography were included in this study. Sociodemographic characteristics, anthropometric measures and metabolic, atherogenic and liver function biomarkers were assessed. RESULTS: Results on 107 women and 68 men with NAFLD showed that 52%, 45.1% and 2.9% of patients had mild, moderate and severe NAFLD, respectively. There were significant differences in most of the anthropometric indices, serum levels of ferritin, creatinine and uric acid as well as liver enzymes, and Aspartate Aminotransferase (AST) to Platelet Ratio Index (APRI) between the genders (p<0.01). However, no significant differences were found in the glycaemic, lipid profile and atherogenic biomarkers. Both NC and neck-to-height ratio (NHtR) were significantly associated with body mass index (BMI) (p=0.018, p<0.001, respectively), waist circumference (WC) (p<0.001, p=0.044, respectively) and waist-to-hip ratio (WHR) (p<0.001, p=0.026, respectively) while results showed only a significant relationship between neck-to-waist ratio (NWR) with BMI (p<0.001) and WC (p<0.001). Among metabolic factors, there were significant and positive correlations between NC and serum haemoglobin A1c (r=0.198, p<0.001), AST (r=0.300, p<0.001), alanine aminotransferase (ALT) (r=0.348, p<0.001), ferritin (r=0.403, p<0.001) and uric acid (r=0.347, p=0.003) while AST/ALT ratio was inversely related to NC (r=-0.226, p=0.003). APRI, Lipid Accumulation Product Index and also Hepatic Steatosis Index were significantly correlated with NC, NHtR and NWR (p<0.01). CONCLUSIONS AND RELEVANCE: NC-related indices, particularly NC and NHtR, were correlated with some metabolic and liver function biomarkers (apart from lipid profile and atherogenic factors) in patients with NAFLD.

Hereditary haemochromatosis discovered after COVID-19 hospitalisation.

COVID-19 infection and hereditary haemochromatosis (HH) have something in common; the disease course can be monitored with ferritin levels. Throughout the pandemic, physicians have looked for markers to help predict disease severity. Ferritin levels are commonly used to predict and monitor disease severity in hospitalised patients with COVID-19. While ferritin is elevated as part of the acute-phase reaction in response to infection, it can also be elevated due to iron overload. We report a case of undiagnosed, asymptomatic HH that was unveiled after COVID-19 infection via monitoring for resolution of ferritin levels that were found to be extremely elevated during a moderate COVID-19 infection. This diagnosis allowed the patient to initiate phlebotomy treatment before symptoms of HH arose.

Relationship of Iron Intake, Ferritin, and Hepcidin with the Transverse Relaxation Rate of Water Protons in the Pancreas.

(1) Background: There is a paucity of markers of iron metabolism in health and disease. The aim was to investigate the associations of iron metabolism with pancreas transverse water proton relaxation rate (R2water) in healthy individuals and people after an attack of pancreatitis. (2) Methods: All participants underwent a 3.0 T magnetic resonance imaging of the abdomen on the same scanner. High-speed T2-corrected multi-echo (HISTO) acquisition at single-voxel magnetic resonance spectroscopy and inline processing were used to quantify pancreas R2water. Habitual dietary intake of iron was determined using the EPIC-Norfolk food frequency questionnaire. Circulating levels of ferritin and hepcidin were measured. Generalised additive models were used, adjusting for age, sex, body mass index, and haemoglobin A1c. (3) Results: A total of 139 individuals (47 healthy individuals, 54 individuals after acute pancreatitis, and 38 individuals after chronic pancreatitis) were included. Total dietary intake of iron was significantly associated with pancreas R2water, consistently in healthy individuals (p < 0.001), individuals after acute pancreatitis (p < 0.001), and individuals after chronic pancreatitis (p < 0.001) across all the statistical models. Ferritin was significantly associated with pancreas R2water, consistently in healthy individuals (p < 0.001), individuals after acute pancreatitis (p < 0.001), and individuals after chronic pancreatitis (p = 0.01) across all adjusted models. Hepcidin was significantly associated with pancreas R2water in individuals after acute pancreatitis (p < 0.001) and individuals after chronic pancreatitis (p = 0.04) in the most adjusted model. (4) Conclusions: Pancreas R2water, corrected for T2, is related to iron metabolism in both health and pancreatitis. This non-invasive marker could be used for automated in vivo identification of intra-pancreatic iron deposition.

Ferrostatin-1 post-treatment attenuates acute kidney injury in mice by inhibiting ferritin production and regulating iron uptake-related proteins.

Background: Acute kidney injury (AKI) is a common and serious medical condition with high morbidity and mortality. Recent research has highlighted ferroptosis, a novel form of programmed cell death, as a potential therapeutic target in mitigating renal tubular injury in AKI. Ferrostatin-1, a specific ferroptosis inhibitor, has been demonstrated to prevent renal injury through ferroptosis inhibition. Methods: Utilizing a murine AKI model, we investigated the effects of Ferrostatin-1 by administering it post-injury. Through high-throughput sequencing and pathological analysis, we focused on the critical role of ferroptosis-related pathways in the treatment. Results: Ferrostatin-1 post-conditioning effectively mitigated oxidative damage and reduced iron content associated with AKI. Additionally, critical ferroptosis-related proteins, such as GPX4, SLC7A11, NRF2, and FTH1, exhibited increased expression levels. In vitro, Ferrostatin-1 treatment of HK-2 cells significantly diminished lipid peroxidation and iron accumulation. Furthermore, Ferrostatin-1 was found to downregulate the PI3K signalling pathway. Conclusion: Ferrostatin-1 acted as a potential ferroptosis inhibitor with the capacity to enhance antioxidant defences. This study suggests that Ferrostatin-1 could serve as a promising novel strategy for improving the treatment of AKI and promoting recovery from the condition.

The Ferritin, Hepcidin and Cytokines Link in the Diagnoses of Iron Deficiency Anaemia during Pregnancy: A Review.

Following a diagnosis of iron deficiency anaemia in pregnancy, iron supplements are prescribed using UK guidelines; however, despite this, the condition remains highly prevalent, affecting up to 30% of pregnant women in the UK. According to the World Health Organisation, it globally accounts for 45% in the most vulnerable groups of pregnant women and infants (<5 years old). Recently, the efficacy of iron replacement therapy and the effectiveness of current standard testing of iron parameters have been reviewed in order to evaluate whether a more accurate diagnosis can be made using alternative and/or supplementary markers. Furthermore, many questions remain about the mechanisms involved in iron metabolism during pregnancy. The most recent studies have shed more light on serum hepcidin and raised questions on the significance of pregnancy related inflammatory markers including cytokines in iron deficiency anaemia. However, research into this is still scarce, and this review aims to contribute to further understanding and elucidating these areas.

New iron export pathways acting via holo-ferritin secretion.

Ferritin is a spherical nanocage protein for iron storage, composed of 24 light- or heavy-polypeptide chain subunits. A single ferritin molecule can carry up to 4500 iron atoms in its core, which plays an important role in suppressing intracellular iron toxicity. Serum ferritin levels are used as a marker for the total amount of iron stored in the body. Most serum ferritin is iron-free (apo-ferritin) and it is unclear how ferritin is released from cells. Ferritin is secreted into serum via extracellular vesicles (EVs) or the secretory autophagy pathway but not via the classical endoplasmic reticulum (ER)-to-Golgi secretion pathway. We recently discovered that the level of tetraspanin CD63, a common EV marker, is post-transcriptionally regulated by the intracellular iron level and both CD63 and ferritin expression is induced by iron loading. Ferritin is incorporated into CD63(+)-EVs through the ferritin-specific autophagy adapter molecule, NCOA4, and then secreted from cells. EV production differs drastically depending on cell type and physiological conditions. Extracellular matrix detached cells express pentaspanin prominin 2 and prominin 2(+)-EVs secrete ferritin independently of NCOA4 trafficking. Ferritin is tightly bound to iron in EVs and functions as an iron-carrier protein in the extracellular environment. Cells can suppress ferroptosis by secreting holo-ferritin, which reduces intracellular iron concentration. However, this exposes the neighboring cells receiving the secreted holo-ferritin to a large excess of iron. This results in cellular toxicity through increased generation of reactive oxygen species (ROS). Here we review the machinery by which ferritin is incorporated into EVs and its role as an intercellular communication molecule.

8-Hydroxyquinoline ruthenium(II) complexes induce ferroptosis in HeLa cells by down-regulating GPX4 and ferritin.

Ruthenium complexes are one of the most promising anticancer drugs triggered extensive research. Here, the synthesis and characterization of two ruthenium(II) polypyridine complexes containing 8-hydroxylquinoline as ligand, [Ru(dip)2(8HQ)]PF6 (Ru1), [Ru(dpq)2(8HQ)]PF6 (Ru2) (8HQ = 8-hydroxylquinoline; dip = 4,7-diphenyl-1,10-phenanthroline; dpq = pyrazino[2,3-f][1,10]phenanthroline) were reported. On the basis of cytotoxicity tests, Ru1 (IC50 = 1.98 ± 0.02 µM) and Ru2 (IC50 = 10.02 ± 0.19 µM) both showed good anticancer activity in a panel of cell lines, especially in HeLa cells. Researches on mechanism indicated that Ru1 and Ru2 acted on mitochondria and nuclei and induced reactive oxygen species (ROS) accumulation, while the morphology of nuclei and cell cycle had no significant change. Western blot assay further proved that GPX4 and Ferritin were down-regulated, which eventually triggered ferroptosis in HeLa cells. In addition, the toxicity test of zebrafish embryos showed that the concentrations of Ru1 and Ru2 below 120 µM and 60 µM were safe and did not have obvious effect on the normal development of zebrafish embryos.

Non-invasive assessment of normal and impaired iron homeostasis in the brain.

Strict iron regulation is essential for normal brain function. The iron homeostasis, determined by the milieu of available iron compounds, is impaired in aging, neurodegenerative diseases and cancer. However, non-invasive assessment of different molecular iron environments implicating brain tissue's iron homeostasis remains a challenge. We present a magnetic resonance imaging (MRI) technology sensitive to the iron homeostasis of the living brain (the r1-r2* relaxivity). In vitro, our MRI approach reveals the distinct paramagnetic properties of ferritin, transferrin and ferrous iron ions. In the in vivo human brain, we validate our approach against ex vivo iron compounds quantification and gene expression. Our approach varies with the iron mobilization capacity across brain regions and in aging. It reveals brain tumors' iron homeostasis, and enhances the distinction between tumor tissue and non-pathological tissue without contrast agents. Therefore, our approach may allow for non-invasive research and diagnosis of iron homeostasis in living human brains.

Serum Ferritin and Non-alcoholic Fatty Liver Disease: A Meta-analysis and Systematic Review.

BACKGROUND/AIMS: Previous studies have shown that hyperferritinemia is a common phenomenon in non-alcoholic fatty liver dis- ease patients. We aim to further explore the relationship between serum ferritin levels and non-alcoholic fatty liver disease using a meta-analysis. MATERIALS AND METHODS: Four Library databases were electronically searched from inception until December 2021 to find prospective cohort or case-control studies examining the relationship between serum ferritin levels and non-alcoholic fatty liver disease, and all kinds of literature were screened according to the inclusion and exclusion criteria. The odds ratio and other related data were extracted, and a meta-analysis was performed. RESULTS: Eleven studies examining the relationship between serum ferritin levels and non-alcoholic fatty liver disease were included. The serum ferritin levels in the non-alcoholic fatty liver disease group were significantly higher than those without non-alcoholic fatty liver disease group (1.54 ng/mL, 95% CI: 0.85-2.23, P < .001). Serum ferritin levels were significantly associated with the risk of non-alcoholic fatty liver disease in both men and women (odds ratio = 2.36, 95% CI: 1.41-3.93, P = .001 and odds ratio = 2.93, 95% CI: 1.83-4.69, P < .001, respectively), and after adjusting for the parameters, the relationships were still shown to be significant in men and women (odds ratio = 2.24, 95% CI: 1.64-3.05, P < .001 and odds ratio = 3.30, 95% CI: 2.13-5.11, P < .001, respectively). CONCLUSION: Serum ferritin levels were higher in patients with non-alcoholic fatty liver disease than in those without non-alcoholic fatty liver disease and were associated with the risk of non-alcoholic fatty liver disease in both men and women.

Iron-deficiency anemia in relation to body mass index among Iraqi primigravida women.

Anemia affects approximately half a billion women of reproductive age worldwide, with 31% of pregnant women in Iraq aged 15-49 years experiencing anemia. This condition is associated with increased risks of maternal and fetal morbidity and mortality, including stillbirths, miscarriages, prematurity, and low birth weight. This study investigated the correlation between iron-deficiency anemia (IDA) and body mass index (BMI) among primigravidae in Iraq. One hundred primiparous women in their third trimester were recruited from Baghdad Medical City Teaching Hospital and Teaching Hospital of Obstetrics and Gynecology in Karbala. Participants were categorized into four groups based on BMI: underweight (BMI < 18.5 kg/m^2), normal weight (BMI 18.5-24.9 kg/m^2), overweight (BMI 25-29.9 kg/m^2), and obese (BMI ≥ 30 kg/m^2). Demographic and medical history data were collected from the participants, and hematological investigations were conducted to measure hemoglobin (Hb), packed cell volume (PCV), mean corpuscular volume (MCV), and serum ferritin levels. Statistical significance was determined at p<0.05. The study enrolled 100 primiparous women, including 10 underweight, 24 normal weight, 28 overweight, and 38 obese participants. Analysis revealed a significant decrease in Hb levels among obese individuals compared to the normal weight group. Moreover, a significant difference in serum ferritin levels was observed between the obese and the other three groups (underweight, normal weight, and overweight). The findings indicated an inverse correlation between high BMI and serum ferritin and Hb levels. The study concluded that anemia is more common in obese pregnant women compared to normal-weight women. Furthermore, it demonstrates varying trends of iron-deficiency anemia (IDA) in relation to the body mass index (BMI) of pregnant women.

Fortification of condiments and seasonings with iron for preventing anaemia and improving health.

BACKGROUND: Anaemia affects approximately 1.8 billion people worldwide; over 60% of anaemia cases globally are due to iron deficiency (ID). Iron deficiency and anaemia contribute to the global burden of disease and affect physical and cognitive development in children, and work productivity and economic well-being in adults. Fortification of food with iron, alone or in combination with other nutrients, is an effective intervention to control ID. Condiments and seasonings are ideal food vehicles for iron fortification in countries where they are commonly used. OBJECTIVES: To determine the effects and safety of condiment and seasoning fortification with iron alone or iron plus other micronutrients on iron deficiency, anaemia, and health-related outcomes in the general population. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, CINAHL, and other databases up to 24 January 2023. We also searched the International clinical trials registry platform (ICTRP) for any ongoing trials. SELECTION CRITERIA: We included randomised controlled trials (RCTs) (randomisation at individual or cluster level), non-randomised controlled trials, interrupted time series with at least three measure points both before and after intervention, and controlled before-after studies. Participants were populations of any age (including pregnant women), from any country, excluding those with critical illness or severe co-morbidities. We included interventions in which condiments or seasonings have been fortified with any combination of iron and other vitamins and minerals, irrespective of the fortification technology used. DATA COLLECTION AND ANALYSIS: Two review authors independently screened and assessed the eligibility of studies. Disagreements were resolved through discussion or input from a third review author. Two review authors extracted the data and assessed the risk of bias in all the included studies. We followed the methods laid out by Cochrane and used GRADE criteria for assessing certainty of the evidence. MAIN RESULTS: Our search identified 15,902 records after removal of duplicates. We included 16 studies with 20,512 participants (18,410 participants after adjusting for clustering effects). They were all carried out in upper-middle- and lower-middle-income countries. Three studies were controlled before-after studies, one was non-randomised trial, and 12 were RCTs (including three cluster RCTs). Six studies took place in schools; seven in communities; and one each in a nursery/kindergarten, tea estate, and factory. Three studies involved only women, one study involved both women and their children, and all other studies focused on children and/or adolescents. Nine studies used salt as a vehicle for iron fortification, three used fish sauce, two used soy sauce, one used curry powder, and one a "seasoning powder". The dose of iron received by participants ranged from 4.4 mg to 55 mg/day. The sample sizes in the trials ranged from 123 to 14,398, and study durations ranged from three months to two years. Twelve RCTs contributed data for meta-analysis. Six trials compared iron-fortified condiments versus the unfortified condiment, and six trials provided data comparing iron fortification in combination with other micronutrients versus the same condiment with other micronutrients, but no added iron. In one trial, the fortificant contained micronutrients that may have affected the absorption of iron. Overall no studies were assessed as having a low risk of bias. All included studies were assessed to have a high overall risk of bias, with the most concerns being around allocation concealment, blinding, and random sequence generation. There was very high heterogeneity amongst studies in almost all examined outcomes. Condiments/seasonings fortified with iron versus unfortified condiments/seasonings We are uncertain about whether consuming condiments/seasonings fortified with iron in comparison to the same unfortified condiment reduces anaemia at the end of intervention (risk ratio (RR) 0.34, 95% confidence interval (CI) 0.18 to 0.65; 2328 participants; 4 studies; very low-certainty of evidence). We are uncertain about whether consuming iron-fortified condiments increases haemoglobin concentrations (mean difference (MD) 6.40 (g/L), 95% CI -0.62 to 13.41; 2808 participants; 5 studies; very low-certainty evidence). Fortification of condiments/seasonings with iron probably slightly reduces ID (RR 0.33, 95% CI 0.11 to 1.01; 391 participants; 2 studies; moderate-certainty evidence). We are uncertain about whether fortification with iron increases ferritin concentration (MD 14.81 (µg/L), 95% CI 5.14 to 24.48; 4459 participants; 6 studies; very low-certainty evidence). Condiments/seasonings fortified with iron plus other micronutrients versus condiments/seasonings fortified with other micronutrients except iron Consuming condiments/seasonings fortified with iron plus other micronutrients may reduce anaemia (RR 0.59, 95% CI 0.40 to 0.89; 1007 participants; 4 studies; low-certainty evidence). We are uncertain about whether fortification of condiments/seasonings with iron plus other micronutrients will improve haemoglobin concentration (MD 6.22 g/dL, 95% CI 1.60 to 10.83; 1270 participants; 5 studies; very low-certainty evidence). It may reduce ID (RR 0.36, 95% CI 0.19 to 0.69; 1154 participants; 4 studies; low-certainty evidence). We are uncertain about whether fortification with iron plus other micronutrients improves ferritin concentration (MD 10.63 µg/L, 95% CI 2.40 to 18.85; 1251 participants; 5 studies; very low -certainty evidence). Condiments/seasonings fortified with iron versus no intervention No trial reported data on this comparison. No studies reported adverse effects. Funding sources do not appear to have distorted the results in any of the assessed trials. AUTHORS' CONCLUSIONS: We are uncertain whether consuming iron-fortified condiments/seasonings reduces anaemia, improves haemoglobin concentration, or improves ferritin concentration. It may reduce ID. Findings about ferritin should be interpreted with caution since its concentrations increase during inflammation. Consuming condiments/seasonings fortified with iron plus other micronutrients may reduce anaemia, and we are uncertain whether this will improve haemoglobin concentration or ferritin concentration. More studies are needed to determine the true effect of iron-fortified condiments/seasonings on preventing anaemia and improving health. The effects of this intervention on other health outcomes like malaria incidence, growth and development are unclear.

ANTECEDENTES: La anemia afecta aproximadamente a 1800 millones de personas en todo el mundo; más del 60% de los casos de anemia en el mundo se deben a la deficiencia de hierro (DH). La deficiencia de hierro y la anemia contribuyen a la carga mundial de morbilidad y afectan al desarrollo físico y cognitivo de los niños, así como a la productividad laboral y el bienestar económico de los adultos. El enriquecimiento de los alimentos con hierro, solo o en combinación con otros nutrientes, es una intervención eficaz para controlar la DH. Los condimentos y sazonadores son vehículos alimentarios ideales para el enriquecimiento con hierro en los países donde se utilizan habitualmente. OBJETIVOS: Determinar los efectos y la seguridad del enriquecimiento de condimentos y aderezos con hierro solo o hierro más otros micronutrientes sobre la deficiencia de hierro, la anemia y los desenlaces relacionados con la salud en la población general. MÉTODOS DE BÚSQUEDA: Se realizaron búsquedas en CENTRAL, MEDLINE, Embase, CINAHL y otras bases de datos hasta el 24 de enero de 2023. También se realizaron búsquedas de ensayos en curso en la Plataforma de registros internacionales de ensayos clínicos (ICTRP). CRITERIOS DE SELECCIÓN: Se incluyeron ensayos controlados aleatorizados (ECA) (asignación aleatoria a nivel individual o grupal), ensayos controlados no aleatorizados, series temporales interrumpidas con al menos tres puntos de medición tanto antes como después de la intervención, y estudios controlados del tipo antes­después. Los participantes fueron poblaciones de cualquier edad (incluidas mujeres embarazadas), de cualquier país, excluidos aquellos con enfermedades críticas o comorbilidades graves. Se incluyeron las intervenciones en las que los condimentos o sazonadores se han enriquecido con cualquier combinación de hierro y otras vitaminas y minerales, independientemente de la tecnología de enriquecimiento utilizada. OBTENCIÓN Y ANÁLISIS DE LOS DATOS: Dos autores de la revisión seleccionaron y evaluaron de forma independiente la elegibilidad de los estudios. Los desacuerdos se resolvieron mediante debate o aporte de material de un tercer autor de la revisión. Dos autores de la revisión extrajeron los datos y evaluaron el riesgo de sesgo en todos los estudios incluidos. Se siguieron los métodos establecidos por Cochrane y se utilizó el método GRADE para evaluar la certeza de la evidencia. RESULTADOS PRINCIPALES: La búsqueda identificó 15 902 registros tras eliminar los duplicados. Se incluyeron 16 estudios con 20 512 participantes (18 410 participantes después de ajustar los efectos del conglomerado). Todos ellos se llevaron a cabo en países de ingresos medios­bajos y medios­altos. Tres estudios fueron controlados del tipo antes­después, uno fue un ensayo no aleatorio y 12 fueron ECA (incluidos tres ECA grupales). Seis estudios tuvieron lugar en escuelas, siete en comunidades y uno en una guardería, uno en una plantación de té y uno en una fábrica. En tres estudios participaron solo mujeres, en un estudio participaron tanto mujeres como sus hijos, y todos los demás estudios se centraron en niños y/o adolescentes. Nueve estudios utilizaron la sal como vehículo para el enriquecimiento con hierro, tres la salsa de pescado, dos la salsa de soja, uno el curry en polvo y otro un "sazonador en polvo". La dosis de hierro recibida por los participantes osciló entre 4,4 mg y 55 mg/día. El tamaño muestral de los ensayos osciló entre 123 y 14 398, y la duración de los estudios, entre tres meses y dos años. Doce ECA aportaron datos para el metanálisis. Seis ensayos compararon condimentos enriquecidos con hierro versus el condimento no enriquecido, y seis ensayos proporcionaron datos que comparaban el enriquecimiento con hierro en combinación con otros micronutrientes versus el mismo condimento con otros micronutrientes, pero sin hierro agregado. En un ensayo, el fortificante contenía micronutrientes que podrían haber afectado la absorción del hierro. En general, no se evaluó ningún estudio como de riesgo de sesgo bajo. Se evaluó que todos los estudios incluidos tenían un riesgo de sesgo general alto, y las mayores preocupaciones se centraron en la ocultación de la asignación, el cegamiento y la generación de secuencias al azar. Hubo una heterogeneidad muy alta entre los estudios en casi todos los desenlaces examinados. Condimentos/sazonadores enriquecidos con hierro versus condimentos/sazonadores no enriquecidos Es incierto si el consumo de condimentos/sazonadores enriquecidos con hierro en comparación con el mismo condimento no enriquecido reduce la anemia al finalizar la intervención (razón de riesgos [RR] 0,34; intervalo de confianza [IC] del 95%: 0,18 a 0,65; 2328 participantes; cuatro estudios; evidencia de certeza muy baja). Es incierto si el consumo de condimentos enriquecidos con hierro aumenta las concentraciones de hemoglobina (diferencia de medias [DM] 6,40 g/l; IC del 95%: ­0,62 a 13,41; 2808 participantes; cinco estudios; evidencia de certeza muy baja). El enriquecimiento de condimentos/sazonadores con hierro probablemente reduce ligeramente la DH (RR 0,33; IC del 95%: 0,11 a 1,01; 391 participantes; dos estudios; evidencia de certeza moderada). Es incierto si el enriquecimiento con hierro aumenta la concentración de ferritina (DM 14,81 µg/L; IC del 95%: 5,14 a 24,48; 4459 participantes; seis estudios; evidencia de certeza muy baja). Condimentos/sazonadores enriquecidos con hierro y otros micronutrientes versus condimentos/sazonadores enriquecidos con otros micronutrientes excepto hierro El consumo de condimentos/sazonadores enriquecidos con hierro más otros micronutrientes podría reducir la anemia (RR 0,59; IC del 95%: 0,40 a 0,89; 1007 participantes; cuatro estudios; evidencia de certeza baja). Es incierto si el enriquecimiento de condimentos/sazonadores con hierro más otros micronutrientes mejorará la concentración de hemoglobina (DM 6,22 g/dL; IC del 95%: 1,60 a 10,83; 1270 participantes; cinco estudios; evidencia de certeza muy baja). Podría reducir la DH (RR 0,36; IC del 95%: 0,19 a 0,69; 1154 participantes; cuatro estudios; evidencia de certeza baja). Es incierto si el enriquecimiento con hierro más otros micronutrientes mejora la concentración de ferritina (DM 10,63 µg/L; IC del 95%: 2,40 a 18,85; 1251 participantes; cinco estudios; evidencia de certeza muy baja). Condimentos/sazonadores enriquecidos con hierro versus ninguna intervención Ningún ensayo informó datos sobre esta comparación. Ningún estudio informó efectos adversos. Las fuentes de financiación no parecen haber distorsionado los resultados en ninguno de los ensayos evaluados. CONCLUSIONES DE LOS AUTORES: Es incierto si el consumo de condimentos/sazonadores enriquecidos con hierro reduce la anemia, mejora la concentración de hemoglobina o mejora la concentración de ferritina. Podría reducir la DH. Los resultados sobre la ferritina deben interpretarse con cautela, ya que sus concentraciones aumentan durante la inflamación. El consumo de condimentos/sazonadores enriquecidos con hierro más otros micronutrientes podría reducir la anemia, y no se sabe con certeza si mejorará la concentración de hemoglobina o de ferritina. Se necesitan más estudios para determinar el verdadero efecto de los condimentos/sazonadores enriquecidos con hierro en la prevención de la anemia y la mejora de la salud. Los efectos de esta intervención en otros desenlaces sanitarios como la incidencia del paludismo, el crecimiento y el desarrollo son inciertos.

An Overview of Heavy Chain Ferritin in Cancer.

As a spherical protein that acts as a repository for intracellular iron, Ferritin is the most important iron storage form and is known to influence tumor immunity. Unbound ferritin is composed of 24 subunits, made up of ferritin light chain (FTL) and ferritin heavy chain (FTH). Ferritin can be automatically put together to form hollow nanocages that measure 12 nm around the outside and 8 nm around the inside. Cancer causes the second-most deaths worldwide, effective elimination of tumor cells while protecting normal cells is the foundation of modern tumor therapy. To this end, the innate tumor-targeting activity of human FTH1, first identified ten years ago, is highly appealing. Unmodified human FTH1 binds to its receptor, transferrin receptor 1 (TfR1), which is frequently overexpressed in cancer cells. FTH1-TfR1 binding permits improved drug efficacy by promoting ferritin-mediated targeted delivery. In addition, FTH is also associated with the prognosis of multiple typies of cancer. The level of FTH1 is significantly and positively correlated with the infiltration of tumor-associated macrophages. FTH1 also plays an important role in regulating the tumor immunity of solid cancer. As such, FTH1 has been extensively applied in the targeted delivery of anticancer drugs, diagnostic molecules (e.g., radioisotopes and fluorophones), and inorganic nanoparticles (NPs) to tumors.This article reviews the role of FTH in cancer and its potential as a therapeutic target.

Predicting acute pulmonary embolism in COVID-19.

Acute pulmonary embolism (PE) is a life-threatening condition in patients with Coronavirus disease-2019 (COVID-19). Computed tomography pulmonary angiography is the preferred test to confirm the diagnosis. However, computed tomography pulmonary angiography is expensive and is not available in every clinic. This study aimed to determine whether clinical findings, symptoms, and parameters that are cost-effective and available in many clinics such as C-reactive protein (CRP) lymphocyte ratio (CLR), and ferritin CRP ratio (FCR) can be used in the diagnosis of PE in patients with COVID-19. Out of the reviewed files, 127 patients were diagnosed with PE, whereas 105 patients had no PE. At the first admission, laboratory parameters, complaints, respiratory rate, and percent oxygen saturation in the blood (SpO2) with a pulse oximeter were recorded for each patient. Eosinophil levels remained lower, whereas ferritin lymphocyte ratio and CLR were higher in the PE group. Patients with more elevated ferritin, CRP, and CLR had an increased mortality risk. Shortness of breath and tiredness was more common in the PE group. A decrease in eosinophil levels, whereas an increase in CLR, D-dimer, and CRP may predict PE. Elevated CLR is highly predictive of PE and is associated with increased mortality risk. COVID-19 patients with a CLR level above 81 should be investigated for PE.

Association between serum ferritin and liver stiffness in adults aged ≥20 years: A cross-sectional study based on NHANES.

The importance of serum ferritin has been demonstrated in many liver diseases, but its relationship with liver stiffness remains unclear. The objective of this study was to investigate the association between serum ferritin levels and participants' liver stiffness measurement (LSM) in the United States population. We conducted a screening of participants from National Health and Nutrition Examination Survey (NHANES) 2017.1 to 2020.3 to ensure that participants included in this study had complete serum ferritin and LSM information. Association between the independent variable (serum ferritin) and the dependent variable (LSM) was investigated by multiple linear regression and subgroup analysis was performed to identify sensitive individuals, and we subsequently assessed whether there was a non-linear relationship between the 2 using smoothed curve fitting and threshold effect models. The final 7143 participants were included in this study. There was a positive association between participants' serum ferritin concentration and LSM, with an effect value of (ß = 0.0007, 95% confidence interval (CI): 0.0002-0.0011) in the all-adjusted model. The smoothing curve and threshold effect models indicated a non-linear positive correlation between serum ferritin and LSM, which was more pronounced when serum ferritin concentration exceeded 440 ng/mL. Subsequent subgroup analysis showed that this positive correlation was more pronounced in males (ß = 0.0007, 95% CI: 0.0001-0.0012), age >60 years (ß = 0.00015, 95% CI: 0.0007-0.0023), black participants (ß = 0.00018, 95% CI: 0.0009-0.0026), and participants with body mass index (BMI) <25 kg/m2 (ß = 0.00012, 95% CI: 0.0005-0.0020). In U.S. adults, there was a positive correlation between serum ferritin levels and liver stiffness, which was more pronounced when serum ferritin exceeded 440 ng/mL. Our study suggested that regular serum ferritin testing would be beneficial in monitoring changes in liver stiffness. Male, age >60 years, black participants, and those with a BMI < 25 kg/m2 should be of greater consideration.

Independent risk factors for COVID-19-associated coagulopathy.

OBJECTIVE: Past three years since the beginning of the outbreak, we have obtained satisfactory data on COVID-19. However, data on risk factors of COVID-19-associated coagulopathy (CAC) are extremely limited. Prediction of CAC might be a game changer since it is related to poor prognosis. Seeking independent risk factors for CAC was the main aim of the study. PATIENTS AND METHODS: 510 hospitalized COVID-19 patients were retrospectively screened. Forty-eight of them were excluded due to irrelevant D-dimer or ferritin elevation. The remaining patients were stratified into three groups as overt coagulopathy, significant pulmonary microthrombosis, and patients without coagulopathy. The overt coagulopathy group included cases with macrothrombosis or disseminated intravascular coagulation (DIC). The significant pulmonary microthrombosis group covered the cases that had clinical deterioration with simultaneous marked D-dimer elevation. The group of patients without coagulopathy included the asymptomatic patients with normal or elevated D-dimer levels. RESULTS: Overt coagulopathy developed in 3.2% and significant pulmonary microthrombosis in 10.1% of the patients. In the multivariate analysis, not receiving low molecular weight heparin (LMWH) (p=0.002), a level of D-dimer >15,000 U/ml (p=0.013) were associated with overt coagulopathy. In addition, levels of initial LDH >480 IU/L (p=0.022) and initial ferritin >1,000 ng/ml (p=0.036) were associated with significant pulmonary microthrombosis. Not receiving LMWH (p=0.001) was also associated with significant pulmonary microthrombosis, when multivariate analysis was performed by the parameters with a p-value <0.1 in the univariate analysis. Furthermore, all cases with DIC had Gram-negative bacterial sepsis. CONCLUSIONS: Not receiving LMWH, high levels of D-dimer, initial LDH, and initial ferritin are independent risk factors for CAC. DIC does not appear to develop based on COVID-19.

Phytoferritin functions in two interface-loading of natural pigment betanin and caffeic acid with enhanced color stability and the sustained release of betanin.

Betanin, a natural red pigment, is sensitive and prone to fading and discoloration, affecting its stability and bioavailability. Phytoferritin is a nano-diameter protein with unique interior-/exterior-interfaces. By the unique interfaces and pH-induced self-assembly of ferritin, a ferritin-betanin complex (FB) with an encapsulation efficiency of 17.66 ± 1.24% was prepared. The caffeic acid-FB (CFB) was further fabricated by attaching ferritin with caffeic acid, and the binding number n of caffeic acid was 88.47 ± 9.49, with a binding constant K of (1.63 ± 0.33) × 104 M-1. Fluorescence and Fourier transform infrared analysis indicated that the encapsulation of betanin and the binding of caffeic acid influenced the ferritin structure. The interaction between caffeic acid and ferritin was mainly through van der Waals forces and hydrogen bonds. TEM and DLS showed that the globular structure and diameter (12 nm) remained in CFB. Furthermore, the ferritin and caffeic acid exhibited a synergistic effect in enhancing thermal, light, and ferric ion stabilities, and controlled the betanin release in a more sustained manner in the simulated gastrointestinal tract. In addition, the antioxidant capacity of CFB was enhanced compared with free betanin. This study promotes the bioavailability of betanin by two interface-loading of ferritin, and guides the use of ferritin nanoparticles as a nanocarrier for pigment stabilization.