Abstract This study investigates iron use and production at the Zhuoerkut site, an important frontier city associated with the Western Regions Protectorate of the Han dynasty in southern Xinjiang. Metallographic and compositional analyses were conducted on iron artifacts and slags excavated from the site. Most of the analyzed iron artifacts display characteristics of white cast iron, while one sample shows the feature of incompletely annealed malleable cast iron. Chemical analysis of this sample reveals unusually high phosphorus and sulphur contents, which may indicate the use of mineral fuel during smelting, a practice documented in Xinjiang but uncommon in inland Han China. The slag assemblage suggests the presence of multiple metallurgical activities. Some slags are consistent with smithing residues, while others are broadly compatible with bloomery smelting. Overall, the evidence indicates a technologically diverse iron assemblage shaped by regional supply networks, local production practices and frontier environmental conditions.

Redox gradients, often driven by changes in sediment moisture levels in porous, heterogeneous groundwater systems, create dynamic conditions that may promote the production and transport of colloids within natural waters. While much research has focused on the inorganic composition of colloids, the organic composition remains less well understood. Organic matter (OM) in colloids may associate with minerals, complex metal ions, and serve as an electron donor for microbial respiration; therefore, its composition is of high interest. We examined the composition of porewater OM along a redox gradient in a riparian soil located along the Slate River in Crested Butte, Colorado, USA as a function of depth (90, 130, 200, and 350 cm below ground surface). All depths were oxic to suboxic, except 200 cm, where the products of iron and sulfate reduction were observed concomitant with an increase in dissolved and/or colloidal OM, pH, alkalinity, and conductivity. We investigated the composition of porewater using correlated scanning transmission X-ray microscopy and transmission electron microscopy. We observed a change in the OM chemistry from carboxylate-rich at the 200 cm depth (where it was also enmeshed with non-crystalline iron) to phenol- and substituted-aromatic-rich at other depths. Radiocarbon dating revealed carbon in porewater at 200 cm was younger than depths above and below. Soil porewater can flow down into the underlaying gravel bed during baseflow conditions, thus we speculate whether riparian porewater could transport iron- and carboxylate-rich organic colloids into surrounding surface waters through the gravel bed conduit.

Amphibacillus xylanus is an aerotolerant anaerobe that consumes large amounts of oxygen and requires iron as an essential micronutrient during its aerobic growth. However, this bacterium lacks a typical respiratory chain; therefore, intracellular free flavins and their reductases are thought to participate in the reduction of molecular oxygen and ferric iron (Fe3+). This system can potentially generate hydroxyl radicals through the Fenton reaction, highlighting the importance of regulating the production of redox-active ferrous iron (Fe2+). In this study, we employed a strategy of abruptly switching the cell culture system from aerobic to anaerobic conditions to examine Fe2+ production via free flavins. Sudden anaerobization induced growth inhibition and a significant increase in intracellular labile Fe2+. Whole-cell 57Fe Mössbauer spectroscopy revealed that in aerobic cells, high-spin Fe3+ is the major chemical species, whereas in anaerobic conditions, the intracellular iron pool is completely converted into Fe2+ and consists of low- and high-spin Fe2+ species. Increased Fe2+ production was mimicked using cell-free extracts and the reductase activity promoted electron transfer from NADH to Fe3+ via physiological concentrations of free flavin adenine dinucleotide under anaerobic conditions. RNA sequencing showed that the electrons of NADH generated through glycolysis and the pyruvate metabolic pathway can flow into a flavoprotein with flavin reductase activity. These findings suggest that the production of labile Fe2+ via free flavin is regulated by molecular oxygen, allowing safe iron utilization during the aerobic growth of A. xylanus.

To fulfil the goal, the methodological approach to the economic analysis of regions belonging of the river sub-basin – the Lower Dnipro sub-basin, was refined so as to base on computing the economic indicators reflecting the level of economic development (gross value added and gross output), as well as on reviewing the key water-use values broken down. The economic analysis by the economic sector for the main water users, specifically for the industry (type-specific), agriculture, housing and communal services, before and after the demolition of the Kakhovka Reservoir was conducted. The economic analysis findings indicate that the economy of regions of the Lower Dnipro sub-basin experienced substantial losses in 2023 compared to 2021, particularly in water-dependent sectors such as extractive and manufacturing industries and agriculture. Surface water abstraction declined sharply in 2024 compared to 2021, primarily in the agricultural sector, energy production, and water supply services as the share of groundwater abstraction in the overall structure of water was increasing. A positive trend towards a reduction in the volumes of wastewater discharge and polluted wastewater discharge emerged in 2023 relative to 2021. Meanwhile, all the economic sectors of regions of the sub-basin, except for housing and communal services, increased the amount of polluted wastewater per unit of output. The article features an economic model developed for assessing water use by the economic sectors of the regions of the Lower Dnipro sub-basin that provides a framework for determining their socio-economic impacts and for breaking them by categories according to their water-use performance. Taking into account the results of the economic analysis of the sub-basin, in particular the indicators of gross value added and gross output by sector, combined with the results obtained on the basis of the developed economic model for assessing water use, provided a scientific basis for categorizing water-dependent sectors of the economy. The study identifies four groups of sectors based on their level of dependence on water resources and their socio-economic significance: sectors of complete dependence (housing and communal services and fisheries), sectors of multiple dependence (food processing industry, irrigated agriculture, and energy production), sectors of special dependence (iron and steel production, chemical industry, machinery manufacturing and metalworking), and sectors of moderate dependence (transport and selected recreational activities).

Background: Iron deficiency and iron-deficiency anemia remain highly prevalent, particularly among women of reproductive age, pregnant women, and patients with chronic disease. Oral iron is first-line therapy in most settings, yet its performance is frequently constrained by gastrointestinal intolerance, variable absorption, and poor adherence. The specialized four-source system discussed here combines heme iron, ferrous bisglycinate, ferrous gluconate, ferrous lactate, and vitamin C-rich botanical extracts with the intention of broadening uptake pathways and improving formulation robustness. Objective: We evaluated the translational plausibility of this formulation by retaining the quantitative preclinical evidence from its technical dossier and integrating it with published human clinical trial data relevant to its component strategy. Methods: We extracted the dossier-reported data on vitamin C retention, dissolution, intestinal absorption, hemoglobin recovery, and ferritin recovery. We then reviewed publicly available randomized trials, meta-analyses, and practice updates through March 2026 focusing on heme iron polypeptide, ferrous bisglycinate, conventional oral iron salts, vitamin C coadministration, and oral iron dosing frequency. Results: The retained dossier data showed superior 6-month vitamin C retention (93.25% vs 65.17% in the synthetic control), higher 60-minute cumulative dissolution (98.26% vs 76.54%-96.18% in comparators), greater rat intestinal iron absorption (38.72% vs 8.64%-29.43%), and stronger recovery of hemoglobin and ferritin in the iron-deficiency model. In public human studies, ferrous bisglycinate repeatedly showed favorable tolerability and, in pregnancy-related settings, stronger or noninferior hematologic performance relative to conventional salts; a 2023 meta-analysis of 17 randomized trials reported higher hemoglobin in pregnant women and fewer gastrointestinal adverse events. By contrast, heme iron polypeptide did not consistently outperform conventional oral iron in chronic kidney disease or post-bariatric surgery settings. Routine vitamin C coadministration provided little clinically meaningful additional benefit over oral iron alone, whereas alternate-day or once-daily oral dosing appeared physiologically advantageous in some women. Conclusions: The four-source system has a coherent mechanistic and preclinical rationale, but current public human evidence supports some components more strongly than others. At present, the most defensible clinical proposition is improved tolerability and complementary absorption pathways rather than universal superiority over all oral iron products.

Abstract Utilizing hydrogen for iron ore reduction presents a promising route to significantly mitigate or even eliminate CO 2 emissions associated with traditional iron production, yet its behavior under realistic shaft furnace conditions remains complex. A shaft furnace operates as a dynamic packed bed reactor where temperature and gas composition vary significantly both axially and radially, which causes strong variations in the local chemical potential due to the evolving H 2 /H 2 O ratio. In this study, the reduction behavior of a single iron ore pellet was experimentally examined under non-isothermal and time-dependent gas compositions corresponding to three radial positions as near-wall, intermediate, and axis, derived from CFD simulations of shaft furnace. Thermogravimetric (TGA), X-ray diffraction (XRD), and scanning electron microscopy coupled with energy-dispersive spectroscopy (SEM–EDS) analyses were employed to characterize the reduction, phase evolution and morphology of the reduced samples. The results revealed after approximately 105 minutes, complete reduction (100 pct) near the wall, partial reduction (90 pct) in the intermediate region, and limited reduction (12 pct) in the axis due to high water vapor content and lower temperature. The influence of gas flow rate on reduction kinetics was also investigated. Kinetic modeling using the Coats–Redfern method indicated that, under high H 2 O concentrations, solid-state diffusion predominated as the controlling mechanism across most reduction stages.

Campylobacter jejuni, a leading foodborne pathogen in poultry, relies heavily on iron for survival and colonizes the gastrointestinal tract (GIT). Iron supplementation in poultry diets can inadvertently promote pathogen growth, particularly when excess or poorly absorbed iron accumulates in the lower GIT. Encapsulated iron products, such as SQM® Iron, offer a controlled-release mechanism that may mitigate this risk by reducing iron availability to microbes. This study evaluated the effects of free (FeSO4) versus polysaccharide-iron complex (PIC) on C. jejuni growth under iron-limited conditions, hypothesizing that encapsulated iron would support slower and more limited bacterial proliferation due to delayed iron release. Growth kinetics of C. jejuni ATCC 700819 were assessed in chelated Mueller-Hinton broth supplemented with three iron concentrations (10, 20, and 50 ppm) of FeSO4, PIC, or PIC matrix without iron. Optical density was measured every 20 min over 48 h under microaerophilic conditions. Maximum growth rate (µmax) and carrying capacity (K) were derived using non-linear curve modeling. ANOVA evaluated statistical significance with Tukey's HSD post hoc comparisons. Free iron (FeSO4) consistently supported the highest µmax and K values across both trials, indicating rapid and robust C. jejuni proliferation. The effect of encapsulated iron was variable: at higher concentrations (50 ppm) it approached FeSO4 performance, but at lower concentrations (10 ppm) its effect differed markedly between trials, sometimes supporting growth comparable to free iron and sometimes supporting substantially slower growth. The PIC matrix alone did not promote growth. These variable results indicate that the relationship between encapsulated iron and C. jejuni proliferation is complex and concentration-dependent. Free iron consistently promotes robust C. jejuni growth due to immediate bioavailability. The impact of encapsulated iron on C. jejuni proliferation is nuanced and variable, particularly at lower concentrations, suggesting its role in pathogen control is not straightforward and requires further investigation under controlled conditions. Furthermore, in vivo research is warranted to validate its utility in poultry pathogen management strategies.

Modulation of iron carbide phases and product distribution in Fischer-Tropsch to olefins via physical mixing of K-FeCx with zeolites

The aim of this article is to assess the production potential and resource availability of Ukrainian metallurgical enterprises and related industries and, based on this, to develop proposals for the further development of iron metallurgy in Ukraine. To achieve this aim, the following objectives were addressed: the current production capacities of enterprises producing crude iron were analyzed; the geological reserves and extraction of the main types of raw materials required for crude iron production were evaluated; and, based on a comparison of existing and potential production resources, the most promising path for the further development of iron metallurgy in Ukraine was identified. The study analyzed the current state, production trends from 2013 to 2025, and prospects for the further development of crude iron production and the raw and fuel materials required for it: iron ore and its beneficiation products, coking coal and blast furnace coke, refractories and raw materials for their production, as well as fluxes. A quantitative and qualitative assessment of the losses in the mining and metallurgical complex due to russian military aggression was carried out, which showed that the current state of coal industry enterprises and the mining and metallurgical complex cannot sustain pre-war production volumes that significantly contributed to the country’s GDP and had considerable export potential. A direction for the further development of iron metallurgy was proposed, namely – transitioning from blast furnace crude iron production to direct reduced iron production. This transition involves replacing the reducing agent – coke (a greenhouse gas emitter) – with a more environmentally friendly synthesis gas (a mixture of hydrogen and carbon monoxide). Low-metamorphic coal, which predominates in geological reserves and is currently mined in Ukraine, has been proposed as the raw material for producing synthesis gas through gasification. To reduce greenhouse gas emissions in the direct reduced iron production process, it has been proposed to combine gasification with water electrolysis, which produces hydrogen for direct reduction. The electricity required for electrolysis is proposed to be obtained by utilizing the heat from the gasification products.

Improvement of pig iron production technology by using the useful properties of the potential of secondary resources of raw materials and fuels

The present study introduces four novel compound binders CB1, CB2, CB3 and CB4, incorporated in cold-bonded briquettes (CBBs), by varying 3–6 wt.% and briquetted at briquetting pressures ranging from 200 to 400 MPa. Experimental analyses show that a minimum of 4 wt.% compound binder is required to fulfil blast furnace application requirements. CBBs with 4 wt.% CB1 and CB2 compound binders, briquetted at 200 MPa, achieved compressive loads of 3411 N and 2728 N. Reduction disintegration index (RDI) analysis revealed that CBBs prepared with 4 wt.% CB1 require 250 MPa briquetting pressure and those with 4 wt.% CB2 requires only 200 MPa. Reduction swelling index (RSI) analysis indicated that 4 wt.% of CB1 and CB2 performed well at 200 MPa briquetting pressure, resulting in 16.7% and 18.8% swelling, respectively. Economic assessments showed a reduction of 12% per ton as compared to conventional sinter and 17% per ton for pellet production, attributed to lower energy requirements.

Abstract Although the blast furnace process is the largest source of CO 2 emissions in the steel industry, it remains dominant due to its high productivity, cost-effectiveness, and flexibility in ore usage. Still, as CO 2 -reduction policies expand, the steel industry and consequently the blast furnace must evolve toward significantly lower emissions. For this purpose, Paul Wurth S.A. has unveiled EASyMelt, a stepwise solution to cut blast furnace CO 2 emissions by integrating multiple cutting-edge carbon-reduction technologies, such as reducing gas injection, top-gas recycling, gas reforming, and plasma heating. This study introduces the EASyMelt concept and provides a comprehensive techno-economic assessment of multiple implementation pathways, each using a different combination of energy vectors such as coke oven gas, natural gas, pure hydrogen, ammonia, and hot briquetted iron. Leveraging a multi-fluid numerical model, the analysis reveals that EASyMelt scenarios significantly impact the furnace’s thermal state, chemical behavior, and cohesive zone characteristics. Understanding these factors is critical to ensure successful and efficient implementation. EASyMelt deployment using natural gas and coke oven gas is found to reduce CO 2 emission of crude steel production by 47 pct while delivering operational expenditure savings at the current European carbon price of 72 €/t CO2 . Further integration of green energy vectors further enhances the environmental benefits: ammonia addition achieves a 63 pct reduction, hydrogen reaches 64 pct, and a combination of ammonia and hot briquetted iron push savings to 70 pct. While these advanced configurations require slightly higher carbon prices to maintain operational expenditure parity, such levels are likely to be reached shortly.

Coke, as an essential metallurgical raw material, is widely used in iron and steel production. To investigate the pyrolysis behavior and cross-linking reactions during the pyrolysis of coking coal, pyrolysis experiments were conducted in a quartz-tube fixed-bed reactor placed in an electric furnace. The yields and compositions of the pyrolysis products were systematically analyzed. Gaseous and tar components generated at different pyrolysis stages were characterized using gas chromatography (GC) and gas chromatography-mass spectrometry (GC-MS). The semi-coke was examined by X-ray photoelectron spectroscopy (XPS) and scanning electron microscopy (SEM). The results indicated that the yields of tar from coking coal pyrolysis have a notable impact on the cross-linking reactions occurring during the coal pyrolysis process. The structural differences between Malan coal (ML) and Tunlan coal (TL) coals underlie their distinct behaviors in cross-linking intensity, tar evolution profiles, and coke-forming properties. For high-volatile, highly fluid ML coal, the release of the aliphatic compounds in tar volatiles remains relatively low at the temperature of maximum fluidity, which is beneficial to the cross-linking reactions. In contrast, for TL coal with lower volatility and fluidity, substantial H2 emission during the early pyrolysis stage promotes cross-linking reactions. This study provides new insights into the temperature-dependent evolution of cross-linking reactions during coking coal pyrolysis.

The production of high-quality iron concentrates suitable for the metallurgical industry from low-grade hematite ores is a challenging scientific and technical task. This paper presents the results of beneficiation of a low-grade hematite ore using a flowsheet based on hydrogen magnetizing roasting at 375 °C, followed by wet magnetic separation and reverse flotation. Furthermore, the effectiveness of using a vortex layer apparatus for grinding the magnetized ore is demonstrated. A concentrate with an iron content of 64.93 % and a recovery of 98 % was obtained. The proposed flowsheet can be used to produce high-quality iron concentrates via roasting-magnetic beneficiation from low-grade hematite ores and iron-rich wastes, aiming to reduce overall carbon dioxide emissions across the steel production chain.This research was funded by the Russian Science Foundation (project No. 24-29-00672).

Evaluation of the potential for iron recovery in mining tailings by magnetic separation

Iron, an essential trace element ubiquitously present in living organisms, is integral to various biological processes. Epidemiological studies have shown an elevated relative risk of lung cancer among male individuals with occupational exposure to high iron environments (such as those working near iron and steel production facilities). This suggests that respirable iron-containing particulate matters (RICPMs) may pose a potential carcinogenic risk; nevertheless, the underlying mechanisms remain poorly understood. The objective of this study is to explore the potential carcinogenic mechanisms of RICPM through integrative bioinformatics analyses combined with experimental validation. Sequencing data of a welding fume-exposed mouse model (GSE34056) were downloaded from the Gene Expression Omnibus (GEO) database. Ferroptosis-related genes were retrieved from The Cancer Genome Atlas-lung adenocarcinoma (TCGA-LUAD), Molecular Signatures Database (MSIGDB), and GeneCards® Human Gene Database (GENECARDS) databases. Key genes were screened and analyzed for expression profiles, single-gene pan-cancer relevance, single-gene Gene Set Enrichment Analysis (GSEA), and drug sensitivity. Experimental validations included measurements of reactive oxygen species (ROS), lipocalin-2 (LCN2) expression, ferroptosis-associated antioxidant genes [glutathione peroxidase 4 (GPX4), ferritin heavy chain 1 (FTH1)], and mitochondrial ultrastructure changes via transmission electron microscopy (TEM). Nano-Fe2O3 particles induced overexpression of LCN2 in bronchial epithelial cells, adenovirus 12-SV40 2B immortalized (BEAS-2B) cells, a phenomenon observed across multiple cancer types. The results indicate that RICPM may contribute to lung carcinogenesis through ROS-mediated chemical carcinogenesis pathway, upregulation of ferroptosis resistance mechanisms (e.g., GPX4 and FTH1 overexpression), inhibition of ferroptosis, and mitochondrial damage leading to impaired electron transport chain (ETC). Correlation analyses revealed significant associations between LCN2 and various pro-inflammatory cytokines. Drug sensitivity analyses suggested that high LCN2 expression may be linked to increased resistance to anticancer agents. The findings elucidate the potential carcinogenic pathways of RICPM and underscore LCN2 as a key mediator, which offer fresh perspectives on the pathogenesis of lung cancer in individuals exposed to high-iron environments and identify prospective therapeutic targets for the prevention and treatment of lung cancer.

This study examines iron horse-shaped Buckle excavated from the Hoseo region. Although such artifacts are rare, an analysis of their excavation contexts suggests that they were not exclusively owned by exceptional individuals. Based on typological classification and production techniques, these items appear to have emerged as a result of accepting cast iron production technology introduced during Baekje’s westward expansion in the 4th century. Furthermore, by approaching the issue from the perspective of the interaction between material and human agency, this study investigates the artisan groups who adopted the technology and the social value of iron horse-shaped Buckle. The findings indicate that the acceptance and production of this technology were carried out by indigenous artisan groups in the Mahan cultural sphere, and that iron horse-shaped Buckle did not fully replace their bronze counterparts in terms of social significance. Although the study is limited by the quantitative constraints of analyzing only two artifacts, it is hoped that this research will stimulate further studies on iron horse-shaped Buckle and other animal-shaped Buckle.

In order to cope with the challenge of large-scale integration of renewable energy to the balance of power supply and demand, and give full play to the potential of flexible regulation of iron and steel enterprises, a source load coordination optimization scheduling model considering the flexible coordination of iron and steel production and energy storage is proposed. Firstly, the multi-unit coupling adjustable capacity model of electric arc furnace (EAF), air separation unit (ASU), rolling mill and captive power plant is established, and the regulation characteristics and coupling relationship between different production units are clarified. Secondly, a day-ahead and intra-day two-stage scheduling framework is proposed. In the intra-day stage, the energy storage system is introduced to mitigate the fluctuation in wind power, and the mixed integer linear programming method is adopted to minimize the total operating cost of the system. Finally, an example is given to verify the effectiveness of the model. Case studies demonstrate that the proposed approach effectively reduces load variability and enhances operational stability. After the introduction of energy storage, the power standard deviation of EAFs and ASUs decreases by 29.6% and 28%, respectively, and the operational continuity of the rolling process is improved. Although the initial wind curtailment level in the test system is relatively low, the proposed strategy further mitigates peak curtailment and improves renewable accommodation capability. In addition, moderate operational cost savings are achieved.

What Is the Issue? Iron deficiency is a common comorbidity in patients with heart failure. Decision-makers are interested in understanding the clinical efficacy and safety of ferric derisomaltose in the treatment of patients with heart failure and iron deficiency. What Did We Do? We searched key resources, including journal citation databases, and conducted a focused internet search for relevant evidence published since 2020. What Did We Find? Clinical evidence suggests that ferric derisomaltose results in limited improvement in health-related quality of life in the short-term, without any effect on mortality, hospitalization, or exercise capacity compared to usual care. There was a reduction in the frequency of cardiovascular death or hospitalization for stroke, myocardial infarction, or heart failure in patients who received ferric derisomaltose compared to patients who received usual care, but the evidence was uncertain due to imprecision and risk of bias. Safety outcomes were similar in both groups of patients. An evidence-based guideline suggests that clinicians may consider 1 of 3 IV iron products, including ferric derisomaltose, for the treatment of patients with heart failure with reduced ejection fraction and iron deficiency, despite a lack of sufficient evidence to support a strong recommendation for IV iron therapy. We did not identify any evidence on the comparative clinical efficacy and safety of ferric derisomaltose compared to ferric carboxymaltose or other IV iron products in adult patients with heart failure and iron deficiency. What Does It Mean? There was insufficient evidence to strongly support the use of IV ferric derisomaltose for the treatment of patients with heart failure with reduced ejection fraction and iron deficiency. It is not known how well ferric derisomaltose works or how safe it is compared with ferric carboxymaltose or other IV iron treatments in adults with heart failure and iron deficiency. Additional evidence is necessary to inform decision-making regarding the use of ferric derisomaltose for the treatment of adults with heart failure and iron deficiency.

Data comparing clinical outcomes of different intravenous iron products is limited. The purpose of this study was to compare the efficacy and safety of iron sucrose (IS) and ferric carboxymaltose (FCM) on hemoglobin levels. This retrospective study was conducted at our quaternary care hospital between May 2015 and June 2019. Adults who received either of the study drugs were included in the analysis. Only the first encounter was used for patients who received multiple iron courses. Wilcoxon signed-rank test was used to compare outcomes versus baseline medians in each group separately, while Mann-Whitney U test was used to compare the change between baseline and outcome medians between both groups. A total of 643 patients were included in the analysis, with 311 receiving iron sucrose (IS) and 332 receiving ferric carboxymaltose (FCM). The median Charlson Comorbidity Index (CCI) was 1 (0-5) for IS and 4 (0-7) for FCM (P < .001). Both iron products significantly increased hemoglobin levels by the end of the study compared to baseline, from 93 (84-105) to 114 (99-127) g/L (P < .001) in the IS group and from 92 (81-103) to 103 (87-117) g/L (P < .001) in the FCM group. Additionally, the change in hemoglobin was significantly more pronounced with IS 16.5 (5-29) g/L versus 6.5 (-1 to 21) g/L for FCM (P < .001). Stepwise multivariable linear regression analysis revealed that baseline hemoglobin [β = 0.52 (0.4-0.6); P < .001], erythrocyte stimulating agents use [β = -7.4 (-11 to -3.8); P < .001], total iron product dose [β = 0.01 (0.01-0.02); P < .001], blood transfusion [β = -9.5 (-12 to -6.6); P < .001], CCI [β = -0.6 (-1 to -0.12); P = .013], and FCM [β = -9.5 (-12 to -6.6); P < .001] were the main predictors of hemoglobin level at the end of the study. Multiple factors were shown to affect hemoglobin levels, which need to be considered when managing anemia, including the type of iron formulation used. Our findings need to be verified in larger prospective studies.