Toxicity Potential of Nutraceuticals.

During the past few decades and especially during and after the COVID-19 pandemic, the use of nutraceuticals has become increasingly popular in both humans and animals due to their easy access, cost-effectiveness, and tolerability with a wide margin of safety. While some nutraceuticals are safe, others have an inherent toxic potential. For a large number of nutraceuticals, no toxicity/safety data are available due to a lack of pharmacological/toxicological studies. The safety of some nutraceuticals can be compromised via contamination with toxic plants, metals, mycotoxins, pesticides, fertilizers, drugs of abuse, etc. Knowledge of pharmacokinetic/toxicokinetic studies and biomarkers of exposure, effect, and susceptibility appears to play a pivotal role in the safety and toxicity assessment of nutraceuticals. Interaction studies are essential to determine efficacy, safety, and toxicity when nutraceuticals and therapeutic drugs are used concomitantly or when polypharmacy is involved. This chapter describes various aspects of nutraceuticals, particularly their toxic potential, and the factors that influence their safety.

HUC-MSC-derived exosomes repaired the damage induced by hydroquinone to 16HBE cells via miR-221/PTEN pathway.

Mesenchymal stem cell - originated exosomes (MSC-exo) are promising non-cellular treatment agents for various diseases. The present study aimed to explore whether human umbilical cord MSC - originated exosomes (HUC-MSC-exo) have the function of protecting human cells (16HBE) against the damage caused by HQ and the related mechanism. HUC-MSC-exo was isolated with differential gradient ultracentrifugation method and characterized by using transmission electron microscope (TEM). 16HBE cells were used as the tool cells and co-cultured with HUC-MSC-exo. Confocal laser scanning microscope was employed to confirm the ingestion of HUC-MSC-exo by 16HBE. Cell proliferation, migration, oxidative stress, DNA and chromosome damages of 16HBE were analyzed under HQ stress, and the role of miR-221/PTEN axis was investigated. Our data showed that under HQ stress, different groups of cells exhibited significantly decreased proliferation and migration abilities, and significant oxidative stress, DNA and chromosome damage effects. HUC-MSC-exo could alleviate the cytotoxic, oxidative stress and genotoxic damage effects of HQ on 16HBE cells. Mechanistically, HQ exposure up-regulated the level of miR-221 and down-regulated PTEN, while HUC-MSC-exo could significantly reduce the level of miR-221 and promote PTEN expression, which was involved in alleviating the toxic effects of HQ on 16HBE cells. Our data indicates that HUC-MSC-exo can alleviate the oxidative stress, cytotoxic and genotoxic effects of HQ on 16HBE cells via miR-221/PTEN pathway, and it may be a promising agent for protecting against the toxicity of HQ.

Contextualizing toxic elements in the diet: a case for integration of toxic element data into food databases.

Food composition data plays a key role in the practice of nutrition. However, nutrition professionals may currently lack the resources they need to integrate information about toxic elements - such as arsenic, cadmium, and lead - in food into the advice they give consumers. Geographic, sociocultural, and individual factors may impact not only the toxic element content of food, but also how the balance between potentially toxic and health-promoting components of food must be weighed. Better integration and contextualization of toxic element data into key food databases could allow for more nuanced, comprehensive nutrition guidance.

The role of Ni- and Cd-resistant rhizobacteria in promoting the growth of rice seedlings and alleviating the combined phytotoxicity of Ni and Cd.

The problem of potentially toxic metal pollution is increasingly acute with the development of human society. In this study, we investigated the remediation of nickel (Ni) and cadmium (Cd) co-contamination through inoculating rice with three new-isolated Ni- and Cd-resistant plant growth-promoting rhizobacteria (PGPR) Y3, Y4, and Y5. These three strains possessed growth-promoting properties, including 1-aminocyclopropane-1-carboxylic acid (ACC) deaminase activity, the ability of indoleacetic acid (IAA) production, phosphate solubilization, siderophores production, and exopolysaccharide (EPS) development. According to 16S rDNA sequence homology, strains Y3, Y4, and Y5 were identified as Pseudomonas sp., Chryseobacterium sp., and Enterobacter sp., respectively. Based on the results of rice germination experiments conducted under combined toxicity, we set the contamination concentrations for Ni2+ at 20 µg mL-1 and Cd2+ at 40 µg mL-1. Then we conducted potting experiments at these concentration levels to study the effects of strains Y3, Y4, and Y5 on rice growth under synergistic Ni and Cd stress. The results indicated that the inoculated strains Y3, Y4, and Y5 were effective in promoting the growth of rice seedlings under the combined stress of Ni and Cd, and conferring tolerance to Ni and Cd by increasing the antioxidant enzyme activities of the seedlings. Among them, strain Y3 exhibited stronger ACC deaminase activity, IAA production capacity, and EPS production capacity, showing the most pronounced growth-promoting effect on rice. It was demonstrated that after inoculation with strain Y3, the germination rate of rice seeds increased by 43 %, the fresh weight of stems improved by 35 %, and the chlorophyll content enhanced by 70 % and other growth-promoting phenomena. Additionally, under Ni and Cd stress, strain Y5 performed better than strain Y4 in terms of IAA production capacity and its influence on rice root growth, suggesting that IAA production might play a specifically essential role in root growth under Ni and Cd stress.

Toxic Epidermal Necrolysis Observed in a Patient With the HLA-B*1502 Treated With Levofloxacin.

PURPOSE: To determine the relationship between HLA-B gene mutations and levofloxacin-induced toxic epidermal necrolysis (TEN). METHODS: A 71-year-old Chinese woman developed TEN after oral administration of solifenacin (5 mg) and levofloxacin (0.5 g) for cystitis. HLA-B*5801 and HLA-B*1502 alleles were detected using real-time PCR. FINDINGS: After supportive therapy (antiallergic treatments, plasma exchange, etc) and withdrawal of the culprit medication levofloxacin, the patient was discharged with re-epithelialization of the exfoliated skin. The patient was HLA-B*1502 allele positive and HLA-B*5801 allele negative. IMPLICATIONS: This is the first report of levofloxacin-induced TEN suspected to be caused by mutations in the HLA-B*1502 allele.

Ecological, environmental risks and sources of arsenic and other elements in soils of Tuotuo River region, Qinghai-Tibet Plateau.

Against the backdrop of global warming, the pollutants that were once "temporarily stored" in the permafrost are gradually being released, posing significant impacts on the environment. This has become an internationally focused hot topic. In this study, the contents of 11 elements such as As, Ti, Cd, Cr, Co, Mn, Cu, Pb, Ni, Zn and V in soil samples from 128 sampling points in the freeze-thaw area of the Tuotuo River in the source region of the Yangtze River on the Qinghai-Tibet Plateau were determined to evaluate the possible sources, contamination status and ecological, environmental and health risks of these elements. The mean values of As, Cd, Pb and Zn were higher than the corresponding Tibet soil background values. Among fourteen PTEs, As, Cd and Pb had the highest average values of enrichment factor and pollution index, indicating that freeze-thaw area soils showed moderate enrichment and pollution with As, Cd and Pb. Mean ecological risk factor (ER) of Cd was 109 and other PTEs mean ER values < 40, whereas ecological risk index (RI) values of all PTEs ranged from 59.5 to 880 and mean RI values was 152, indicating moderate ecological risk in study area. Explanatory power q value of total S (TS) content was 0.217 by GeogDetector, indicating TS was the most significant contributing factor to RI. Correlation analysis and PCA analysis showed that Cr, Cu, Ni, Co, Mn, Ti, V were mainly originated from natural sources, Cd, Pb and Zn from traffic activity, As from long-distance migration-freeze-thaw.

Cadmium Minimization in Crops: A Trade-Off With Mineral Nutrients in Safe Breeding.

Cadmium (Cd) contamination poses a threat to global crop safety. To address this issue, researchers mainly focused on the Cd, explored mechanism of accumulation to low-Cd breeding technologies and created several low-Cd varieties over the past decades. However, new challenges have emerged, particularly the yield reduction due to disturbances in mineral nutrient balance. The goals of breeding have been transferred from a primary focus on 'low-Cd crops' to 'low-Cd/nutrient-balanced' crops, which means limiting Cd content while maintaining other nutrient elements like iron (Fe), manganese (Mn) and zinc (Zn) at a proper content, thus to meet the future agricultural demands. Here, on a multielement perspective, we reviewed the mechanisms of Cd and mineral nutrient transport system in crops and summarized the research advances in Cd minimization through artificial mutations, natural variations and genetic engineering. Furthermore, the challenge of disruption of mineral nutrients in low-Cd crops was discussed and two potential approaches designing Cd-mineral nutrient-optimized artificial transporters and pyramiding Cd-mineral nutrient-optimized variations were proposed. Aiming at addressing these challenges, these approaches represent promising advancements in the field and offer potential pathways for future research and development in the creation of safe and high-quality crops.

Frog hepatic health and metal pollution: An assemblage-level approach in a hotspot in southeastern Brazil.

Chemical pollutants include the harmful effects of various substances on soils, water bodies, and biodiversity. Amphibians are one of the most endangered groups of vertebrates and are impacted by chemical pollutants in various ways due to their complex life cycles. Since trace pollutant concentrations vary across environments, different frog ecomorphs (classified by their microhabitat use) may have different exposures. We aimed to determine the association between frog ecomorphs and the occurrence of histopathological hepatic lesions (HHLs) as an indicator of contaminant exposure. We focused on small forest streams near a large urban region in Brazil, heavily polluted in the 1980s. We examined 104 frog specimens from various families. All specimens exhibited HHLs, with melanomacrophages being the most common (n = 99). Arboreal frogs exhibited more vascular congestion, while terrestrial frogs showed structural hepatic damage. Higher cobalt levels were linked to increased liver necrosis in arboreal frogs and structural issues in both arboreal and terrestrial frogs. Cadmium was associated with hepatitis in terrestrial frogs. Although metal levels had no significant effects on rheophilic frogs, the prevalence of hepatitis and necrosis indicated complex exposure pathways. Iron and aluminum were linked to fewer lesions in rheophilic frogs, suggesting resilience. The high prevalence of HHLs signals an ongoing issue, with variations among ecomorphs suggesting differential exposure to pollutants and posing a complex challenge for community conservation.

Acute and chronic ocular outcomes in SJS/TEN patients treated with oral ciclosporin vs intravenous immunoglobulin.

Background/Aim: To evaluate differences in ocular complications of Stevens Johnson Syndrome (SJS)/Toxic Epidermal Necrolysis (TEN) patients receiving either systemic IVIG or Ciclosporin (CsA) as initial treatments. Methods: Retrospective review of consecutive patients admitted for SJS/TEN at the Singapore General Hospital (SGH) from 2011 to 2017 who received either IVIG or Ciclosporin at the onset of the disease and had ophthalmological follow-up of at least 6 months were included. Acute ocular severity of SJS/TEN was graded using the Gregory grading score; chronic ocular complications were graded using the Sotozono system. Results: A total of 18 subjects were included for analysis, with eight in the IVIG group and 10 in the CsA group. There were no significant differences in acute Gregory severity grading between the two groups. The CsA group had a trend towards worse overall chronic Sotozono grading scores compared to the IVIG group (median [IQR]: 2 [0-3] vs. 1 [0-6.5], p = 0.27), with a higher incidence of acute severe cornea involvement (60% vs. 25%, p = 0.93) and chronic corneal and eyelid involvement in the former than the latter. SJS/TEN patients with worse acute ocular involvement were more likely to have TEN and perianal mucosal involvement (50% vs. 0, p = 0.01). Conclusion: Compared to those who received IVIG, SJS/TEN patients who received CsA at the acute disease stage, seemed to have worse acute corneal and chronic corneal and eyelid complications. Larger studies are needed to confirm this finding.

Acute organic solvent toxic encephalopathy: A case report and literature review.

Organic solvents are a class of volatile, lipophilic substances that can easily enter the human body through skin and mucous membrane contact as well as air inhalation, and can lead to toxic encephalopathy (TE), especially after entering the lipid-rich nervous system. The present case reports a patient with acute organic solvent toxic encephalopathy (AOSTE), which may have been caused by occasional ink leakage from Xuzhou (Jiangsu, China). By summarizing the history the patient to exposure to organic solvents, clinical manifestations, radiology findings and relevant laboratory tests, we hypothesize that a history of ink exposure, brain magnetic resonance imaging findings and hippuric acid testing were indispensable factors in the diagnosis of AOSTE. After neurological treatment, the patient experienced notable improvement in symptoms. The present study reports on its clinical features, imaging features, treatment and follow-up, and review relevant literature to summarize its clinical experience, hoping to improve our understanding of AOSTE.

Fulminant Streptococcus suis Infection Causing Myocardial Damage and Toxic Shock-Like Syndrome: A Case Report.

There have been no prior reports of direct myocardial damage caused by Streptococcus suis (S. suis), and understanding the clinical course of myocardial involvement is crucial for early diagnosis and initiation of treatment for this infection. A male pig farmer presented as an outpatient with a fever and sore throat, but within hours, his cardiac function declined, and his general condition deteriorated. Despite receiving comprehensive treatment, he succumbed to complications associated with toxic shock-like syndrome (TSLS). Blood cultures identified S. suis, and myocardial pathology revealed the presence of this bacterium in necrotic areas. This case marks the first reported instance of myocardial damage accompanied by TSLS due to S. suis, highlighting the significance of this infection.

Systematic assessment of source identification and ecological and probabilistic health risks of potentially toxic elements (PTEs) in soils of a typical coal mining area in Guanzhong region.

Mining activities may cause the accumulation of potentially toxic elements (PTEs) in surrounding soils, posing ecological threats and health dangers to the local population. Therefore, a comprehensive assessment using multiple indicators was used to quantify the level of risk in the region. The results showed that the mean values of the nine potentially toxic elements in the study area were lower than the background values only for Cr, and the lowest coefficient of variation was 17.1 % for As, and the spatial distribution characteristics of the elements indicate that they are enriched by different factors. The elements Hg and Cd, which have substantial cumulative features, are the key contributors to ecological risk in the study region, which is overall at moderate risk. APCS-MLR model parses out 4 possible sources: mixed industrial, mining and transportation sources (53.98 %), natural sources (24.56 %), atmospheric deposition sources (12.60 %), and agricultural production sources (8.76 %). The probabilistic health risks show that children are more susceptible to health risks than adults; among children, the safety criteria (HI < 1 and CR < 10-4) were surpassed by 29.29 % of THI and 8.58 % of TCR. According to source-orientated health hazards, the element Ni significantly increases the risk of cancer. Mixed sources from industry, mining, and transportation are important sources of health risks. The results of this research provide some scientific references for the management and decrease of regional ecological and health risks.

Necrotizing pneumonia secondary to Influenza A (H1N1) coinfection with Staphylococcus aureus: A case report.

Objective: This study aims to enhance understanding of necrotizing pneumonia and toxic shock syndrome by analyzing an adult case of community-acquired necrotizing pneumonia caused by co-infection of Influenza A (H1N1) and Staphylococcus aureus with LukS-PV and LukF-PV virulence factor genes. Method: The clinical data of one patient admitted to the intensive care unit (ICU) with co-infection of Influenza A (H1N1) and Staphylococcus aureus was retrospectively analyzed. Results: The patient exhibited typical clinical manifestations of viral and Staphylococcus aureus co-infection, including necrotizing pneumonia and toxic shock syndrome. The presence of LukS-PV and LukF-PV virulence factor genes of Staphylococcus aureus was detected in the patient's bronchoalveolar lavage fluid. Unfortunately，although antiviral agents (oseltamivir) and antibiotics (linezolid, imipenem-cilastatin) were timely administrated, as well as corticosteroids for anti-inflammatory purposes, the patient's condition was progressively deteriorated and eventually led to death. Conclusion: Clinical practitioners should be vigilant about the co-infection of Influenza virus and Staphylococcus aureus, particularly when the latter carries virulence factors. The presence of virulence factor genes of Staphylococcus aureus can lead to necrotizing pneumonia with a poor prognosis. This is a particular concern because both infections can be life threatening in young adults.

The Bioaccumulation of Heavy Metals in the Water and Tissues of Invasive Fish Carassius gibelio (Bloch, 1782) and Non-carcinogenic Health Risk Assessment from Meriç Delta Wetland, Türkiye.

Meriç Delta, which has a wide variety of ecosystems, is an A Class Wetland and the most significant natural stagnant freshwater ecosystem located in the south-western of Thrace Region of Türkiye. In this research, heavy metals (Cr, Ni, As, Cd, and Pb) were investigated in the surface water and Carassius gibelio (Bloch, 1782) obtained from Meriç Delta lakes (Gala, Pamuklu, Sigirci, and Dalyan), which are located on an important migration route of water birds. The heavy metals in surface water samples and fish tissues were determined by ICP-MS. Dissolved oxygen, oxygen saturation (%), pH, electrical conductivity, total dissolved solids, nitrite nitrogen, nitrate nitrogen, and total phosphorus parameters were measured in surface waters. High total phosphorus content was detected in the investigated region. The measured As, Cr, and Ni values in water samples were determined to be higher than Türkiye Regulation Standards criteria. Fish were taken from Gala and Sigirci Lake. The mean concentrations of measured heavy metals were found to be below permissible values in fish muscle and gill. The target hazard quotient (THQ) and total THQ values (HI) of all heavy metals did not exceed the limit value.

Synthesis of ZIF-8/chitosan composites for Cu2+ removal from water.

In this work, a kind of novel Chitosan (Cs)-doped zeolite imidazole framework (ZIF-8@Cs) with a larger surface area and a smaller pore size was synthesised via a facial solvothermal approach and applied to remove Cu2+ from mine wastewater. Compared to nondoped ZIF-8, ZIF-8@Cs exhibited a stronger adsorption performance and removal efficiency. The reason was that ZIF-8@Cs doped by the Cs could suppress the aggregation and increase the monodispersity of ZIF-8. Using the high-performance ZIF-8@Cs, as a novel adsorbent, was successfully developed for the efficient removal of Cu2+ from mine wastewater. Various parameters, such as contact time, initial Cu2+ concentration, adsorbent dosage, and pH, were investigated. The results showed that a removal efficiency of 85% was obtained at 4 h contact time for a Cu2+ concentration of 30 mg/L at the optimum pH of 6.0. Equilibrium data were analysed using different isothermal models and kinetic models, analytic results indicated that the capture of Cu2+ by ZIF-8@Cs could favourably comply with the pseudo-first-order kinetic model and Langmuir isotherm model. The single-layer adsorption of Cu2+ on ZIF-8@Cs was dominated by diffusional mass transfer. Additionally, the results of the thermodynamic analysis indicated that the adsorption of Cu2+ by ZIF-8/Cs was a spontaneous, exothermic, and ordered process. Overall, the results reported herein indicated that ZIF-8/Cs with high adsorption efficiency are very attractive and imply a potential practical application for the removal of potentially toxic elements in wastewater.

Acute Toxic Cerebellar Leukoencephalopathy in an Eight-Year-Old Child Following Illicit Fentanyl and Cocaine Ingestion: A Case Report of Full Clinical Recovery.

During the current opioid epidemic, the number of children with illicit toxic ingestions is increasing. Children presenting with altered mental status and neurologic, particularly cerebellar symptoms of unclear etiology, should be considered to undergo brain imaging as well as toxicology screening to not miss the possible complication of acute toxic leukoencephalopathy. We report the case of an eight-year-old child who presented with somnolence and respiratory depression of unclear etiology, responding profoundly to naloxone, quickly raising concern for drug ingestion. The toxicology screen was positive for fentanyl, cocaine metabolites, caffeine, and diphenhydramine, but not available until day 3 of the hospital stay. In the interim, head CT and brain MRI findings revealed concerning bilateral cerebellar hypodensities, suggestive of opioid-induced leukoencephalopathy. This condition has been described as potentially malignant and fatal, but very few cases of this pathology have been described in children so far. Fortunately, all neurological symptoms in our patient, including altered mental status, respiratory depression, atactic gait, blurry vision, and lower extremity pain, completely resolved within five days of presentation and the patient seemingly underwent a full clinical recovery without residual symptoms. Awareness and prompt recognition of acute toxic leukoencephalopathy in children presenting with altered mental status or neurological symptoms of unclear etiology is of utmost importance to prevent deterioration and optimize treatment, especially during times of a worsening opioid epidemic in our country.

Assessment of potentially toxic element contents in chickens and poultry feeds from Bangladesh markets: Implications for human health risk.

Chicken (Gallus domesticus) is a significant source of animal protein for the people of Bangladesh. However, anthropogenic activity may contaminate chicken meat with potentially toxic elements (PTEs) despite the nutritional benefits. Current work aims to determine the accumulated content of PTEs (Pb, Cd, Cr, As, and Hg) in chickens and poultry feeds commercially sold in Bangladesh markets and compare with WHO, FAO, EU, EC, FSANZ standards. Three different chicken varieties, native (local variety, freehand raised), poultry (raised for meat only), and layer chicken (commercially raised for eggs and later used for meat), were investigated, and commercial poultry feeds were used to raise the latter two varieties. The Pb, Cd, Cr, As, and Hg contents (mg kg-1 fresh weight (f.w.) were 0.481-1.067, 0.025-0.118, 0.069-0.319, 0.007-0.071, 0.002-0.019, respectively. In addition, associated health risks due to the PTEs in different varieties of chicken organs, e.g., meat, liver, and kidney, were evaluated. The study suggests that the poultry feeds should be carefully monitored regarding PTEs content to avoid potential human health risks due to chicken consumption in Bangladesh.

Properties and environmental quality of the overburden and tailings of manganese mining in the Eastern Amazon.

Knowledge about the characteristics of overburden and tailings from manganese (Mn) mining is essential for defining their levels of potentially toxic elements (PTEs) and appropriate environmental management. This study aimed to assess the total and bioavailable contents of PTEs in Mn mining areas in the Eastern Amazon, as well as the associated environmental risks. The samples were collected in areas of overburden and tailings deposition, in addition to forest soils in the Azul mine, Carajás Mineral Province, Brazil. These samples were characterized in terms of fertility, granulometry, and total and bioavailable PTE contents. The pH values of the forest soil were more acidic than those of the overburden and tailings, and the organic matter contents were considerably higher in the forest soil. All PTEs, especially Mn, Ba, Cu, Zn, and Pb, presented higher contents in the overburden and tailings. However, chemical fractionation revealed that PTEs were predominantly in the residual fraction, with percentage contents above 60% of the total content. These results suggest a low risk of environmental contamination. The findings of this study may support more efficient environmental rehabilitation in Mn mining areas in the Amazon.

Biodegradation of monocrotophos, cypermethrin & fipronil by Proteus myxofaciens VITVJ1: A plant - microbe based remediation.

Current study was focused on the degradation of pesticides such as Monocrotophos, Cypermethrin & Fipronil (M, C & F) using phyto and rhizoremediation strategies. The isolate Proteus myxofaciens (VITVJ1) obtained from agricultural soil was capable of degrading M, C & F. The bacteria exhibited resistance to all the pesticides (M, C & F) up to 1500 ppm and was also capable of forming biofilms. The degraded products identified using Gas Chromatography-Mass Spectroscopy (GC-MS) and FTIR was further used for deriving the degradation pathway. The end product of M, C & F was acetic acid and 3-phenoxy benzoic acid which was confirmed by the presence of functional groups such as C=O and OH. Seed germination assay revealed the non-toxic nature of the degraded products with increased germination index in the treatments augmented with degraded products. The candidate genes such as opdA gene, Est gene and MnP1gene was amplified with the amplicon size of 700bp, 1200bp and 500bp respectively. P. myxofaciens not only degraded M, C & F, but was also found to be a plant growth promoting rhizobacteria. Since, it was capable of producing Indole Acetic acid (IAA), siderophore and was able to solubilize insoluble phosphate. Therefore, VITVJ1 upon augmentation to the rhizoremediation setup aided the degradation of pesticides with increase in plant growth as compared to that of the phytoremediation setup. To our knowledge this is the first study where P. myxofaciens has been effectively used for the degradation of three different classes of pesticides, which could also enhance the growth of plants and simultaneously degrade M, C & F.

S3 guideline: Diagnosis and treatment of epidermal necrolysis (Stevens-Johnson syndrome and toxic epidermal necrolysis) - Part 1: Diagnosis, initial management, and immunomodulating systemic therapy.

Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) are rare, predominantly drug-induced, acute, life-threatening diseases of skin and mucosae. SJS and TEN are nowadays considered variants of one disease entity with varying degrees of severity called epidermal necrolysis (EN). EN is associated with high morbidity and mortality and constitutes a major disease burden for affected patients. The guideline "Diagnosis and treatment of epidermal necrolysis (Stevens-Johnson syndrome and toxic epidermal necrolysis)" was developed under systematic consideration of existing scientific literature and in a formal consensus process according to regulations issued by the Association of Scientific Medical Societies in Germany (AWMF) to establish an evidence-based framework to support clinical decision-making. The interdisciplinary guideline commission consisted of representatives from various specialist societies and patient representatives. The guideline is aimed at specialists in the fields of dermatology, ophthalmology, plastic surgery, intensive care, and pediatrics in hospitals and offices, as well as other medical speciallved in the diagnosis and treatment of EN. The guideline is also aimed at patients, their relatives, insurance funds, and policymakers. This first part focuses on the diagnostic aspects, the initial management as well as the immunomodulating systemic therapy.