Sequestering Agent (Binders): Sequestering agents refer to non-absorbable materials capable of binding toxins in the gastrointestinal tract, thus reducing enterohepatic recirculation and ultimately the body burden of toxins. Impossible Burger vs Beef: Which is Healthier? The mycotoxins in human food that the FDA currently focuses on are aflatoxins, deoxynivalenol, fumonisins, patulin, and ochratoxin A. Aflatoxins are mycotoxins produced by certain Aspergillus molds. I would like to point out straight away that first off you HAVE to ensure you are no longer being exposed to mould. Renal biopsy in the woman who developed nonoliguric acute renal failure revealed lesions of acute tubular necrosis [31]. The toxin can accumulate in the organs of the animals that are fed with contaminated feed and thus, lead to substantial economic losses in terms of livestock. Ochratoxin A (OTA) remains the single most potent member of this group of mycotoxins. 2023 DOCTOR ROBERT KILTZ. OTA is one of the most studied mycotoxins and is of great interest due to its toxic effects on human and animals. A few examples of foods containing ochratoxins are listed in Table 2. Microorganisms and enzymes could be a practical way to reduce the concentrations and to avoid the toxic effects via bioremediation. There is no limit on how many lab reports you can upload. Possible OTA-induced acute renal failure was recently reported in Italy after a farmer and his wife worked eight hours in a granary closed for several months. Also, other family members tested positive for OTA in urine and nasal secretion samples, while the pet dog was positive for OTA in its urine and an ear mass! Recently Manderville and Pfohl-Leszkowicz [39] explained how oxidative pathway lead to OTA genotoxicity. Inclusion in an NLM database does not imply endorsement of, or agreement with, The fungi that produce mycotoxins generally grow during crop production and storage steps in the food supply chain that the FDA regulates and monitors to ensure the food available for you to buy is not contaminated. Di Paolo N., Guarnieri A., Loi F., Sacchi G., Mangiarotti A.M., Di. Whether by offering dozens of templates to choose from that pre-populate the most popular laboratory panels or by giving you instant feedback on the entered values. In this aptasensor, 4-[(Trimethylsilyl) ethynyl] aniline was employed as an anti . Krogh and others [16] found epidemics of mycotoxic porcine nephropathy, closely related to excessive climatic conditions, to occur in pigs in the season preceding harvest. There is thus the need for thorough co-occurrence studies on toxin incidence. High levels of this toxin occur when hot, dry weather is followed by a period of high humidity. Mycotoxins are naturally occurring toxins produced by certain moulds (fungi). Mycotoxins can also attack the mucosal lining of the intestines causing intestinal permeability i.e. An official website of the United States government, : Exposure to ochratoxins through diet can cause acute toxicity in mammalian kidneys. By using modern agricultural and processing techniques, companies can reduce the possibility of contamination in their products. After writing the master blog called The Ultimate Guide To Mycotoxins I thought I would write smaller blogs on each of the main mycotoxins. 10 devices per kit. Herein, a highly sensitive and specific aptasensor was developed for the anti-interference detection of Ochratoxin A (OTA). Ochratoxin A: What It Is, Symptoms, Testing & Treatment. The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely. The FDA has set an action level for patulin in apple juice and apple juice products. 1. The FDA monitors mycotoxins in food and conducts research on how to best detect and prevent mycotoxin contamination. The Scientific Committee on Food (SCF) adopted on 17 September 1998 an opinion that revised an earlier opinion of 22 September 1994 as regards toxicological safety of Ochratoxin A. South African wines tested (15 white and nine red) were found to contain detectable levels (>0.01 g/L) of OTA, with a mean of 0.16 g/L in the white wines and a mean of 0.24 g/L in the red wines [5]. http://creativecommons.org/licenses/by/3.0/, optimum temperature for ochratoxin production, minimum water activity for ochratoxin production. Foods with high percentages of mycotoxins include grains, nuts, dried fruits, alcohol, coffee beans, and dried spices. The likes of Dr. Jill Carnahan suggest that one possible reason for people responding so well to a paleo diet is the natural reduction in intake of mycotoxins from food. Recent studies suggest that as climate conditions change, the occurrence and geographical distribution of aflatoxins might increase, posing significant health risks to the soil ecosystem, food crop production and human health.. Can mould and mycotoxins cause chronic fatigue syndrome? In addition to the pronounced nephrotoxicity, ochratoxin A also have hepatotoxic, teratogenic, carcinogenic and immunosuppressive characteristics. Ochratoxin A (OTA)-a toxin produced by Aspergillus carbonarius, Aspergillus ochraceus, and Penicillium verrucosum-is one of the most-abundant food-contaminating mycotoxins. Box 1334, Durban, 4000, South Africa, 2University of Western Australia, The Lung Institute of Western Australia, Ground Floor E Block, Sir Charles Gairdner Hospital, Nedlands WA, 6009, Australia; Email: ua.ten.tenii@aloohbforp. Microtiter plate with 96 wells (12 strips with 8 wells each). Fuchs R., Peraica M. Ochratoxin A in human kidney diseases. Walker R., Larsen J.C. Ochratoxin A: previous risk assessments and issues arising. Analysis of the activity suggested that these enzymes were sensitive indicators of OTA-induced porcine nephropathy. A qualitative screening card for detection of ochratoxin A at various levels in food and feed commodities. Welcome to my blog on Ochratoxin A where Ill discuss the whats, hows, whys and when of mycotoxin testing and treatment. The uptake carrier has been identified but less is known about the mechanism involved in the release into bile. The European Scientific Committee on Food indicates a lower tolerable intake, below 5 ng/kg bw per day [29]. To avoid confusion, the original version of the document has been . [23] demonstrated that OTA binds covalently with DNA in mice and also in rats [24]. Safflower is often ingested as toxic vegetable oil. The https:// ensures that you are connecting to the The best-known example is patulin in juice or cider made from apples. OTA has a long half-life in humans and is thus easily detected in serum. Aflatoxin M1 is also found in milk of cows that eat aflatoxin B1 contaminated crops. Avoiding mycotoxin symptoms is another reason why its best to choose. Agents such as oral cholestyramine, charcoal, and phenylalanine can help prevent the absorption of these toxins from food. identified when fungi in food were more fully investigated. RIDASCREEN ELISA tests and the OCHRACARD screening cards are available for the screening and quantification of ochratoxin A in different samples. Individuals in the endemic region of the Balkan countries exposed to OTA developed DNA adducts in renal tissue and tumours [15,34,35]. Ochratoxins occur primarily in cereals in northern Europe and Africa. The delayed excretion of the toxin in man may be due to reabsorption during enterohepatic circulation, reabsorption from the urine after tubular secretion or extensive protein binding [33]. Ochratoxins are secondary metabolites of Aspergillus and Penicillium, that are hazardous to health through contamination of dietary foods. Ochratoxin A (OTA) is a nephrotoxic, immunotoxic, and carcinogenic mycotoxin. Several agents have shown specific efficacy in lowering mycotoxin and endotoxin levels including cholestyramine (a medication), activated carbons (charcoal), and chlorella. Tissue distribution after exposure of animals to OTA has consistently revealed that the greatest concentration is in the kidneys followed by either liver or muscle and then fat, but tissues found to contain OTA also include the adrenal glands, skin, myocardium, gastric mucosa, and bone marrow. Karyomegaly could be due to an environmental toxin that interferes with DNA replication. Staple foods like corn, cereals and coffee beans can contain high levels of mycotoxins, such as aflatoxin and ochratoxin. Such systems are biological entrance gates that determine the elimination toxicokinetics of OTA and therefore have a major impact on half-life times and selective organ exposure [33]. - Buy grains and nuts as fresh as possible; that have been grown as close to home as possible, and which have not been transported over a long time, - Buy only reputable brands of nuts and nut butters moulds are not entirely killed by processing or roasting, so can show up in products e.g. RIDASCREEN Ochratoxin A 30/15 is a competitive enzyme immunoassay for the quantitative analysis of ochratoxin A in corn, wheat, barley, rye, rice and feed. Co-contamination of ochratoxin A and citrinin was found in varying number of households in two Balkan villages. The mycotoxin Ochratoxin A (also known as OTA) is formed by the mold fungi of theAspergillusandPenicilliumspecies. The mold toxin is extremely harmful to the health of humans and animals. Can mould and mycotoxins cause gut problems such as IBS? Produced by Aspergillus mold. Human sweat has found to contain mycotoxins! Studies have reported that the pathological changes produced by aristolochic acid are comparable to those produced by OTA [2]. . 1999). This study conducted by the Food and Environmental Hygiene Department aims to assess the levels of ochratoxin A in foods in Hong Kong and the levels of exposure in secondary school students to this substance. Lactobacillus rhamnosus GG and Lactobacillus casei have a significant hepatoprotective effect against aflatoxin B1. Retrospective studies, in the absence of previous exposure data, have been performed on renal biopsy material to determine the activity of two renal tubular enzymes, phosphoenolpyruvate carboxykinase and gamma-glutamyl transpeptidase. These toxins can then be passed on to humans who eat contaminated meat and dairy. Produced by Aspergillus and Penicillium. Therefore, karyomegaly could be a histological marker of interstitial nephritis due to OTA as outlined by Dietrich and Swenberg [37]. Treatment should be aimed at removing the source of exposure. Mycotoxin Testing Mycotoxins: The Bottom Line. We've put industry-leading security standards in place to help protect against the loss, misuse, or alteration of the information under our control. There are a number of commercial kits available that can test for mycotoxin exposure. Recently, a case has been reported of OTA being found in the umbilical cord and placental tissue of a newborn whose mother had been exposed from a water-damaged home. For the coffee lovers among you, I highly recommend checking out Exhale Coffee. EuroProxima Ochratoxin-A in roasted coffee flow-through assay, 10 cards containing 20 tests and controls. We use procedural, physical, and electronic security methods designed to prevent unauthorized people from getting access to this information. Online immunoaffinity cartridges used in conjunction with the CHRONECT Symbiosis RIDACREST system for the automated clean-up and analysis of ochratoxin A prior to HPLC or LC-MS/MS. Common mycotoxins cause neoplasia (cancer), while others cause kidney and neurological diseases. The mycotoxin theory has prevailed until now, based on the studies of nephrotoxic mycotoxin OTA that revealed higher frequency of OTA-positive food and blood samples in endemic than in non-endemic Balkan areas. Phosphatidylcholine: Dr. Crista says if there was one edit she could make to her book Break The Mold it would be to add phosphatidylcholine to her recommendations. In conclusion, it would be prudent for the medical commu- nity to pay closer attention to the possibility of ochratoxin toxicity in patients with symptoms of renal pathology. OTA causes kidney toxicity in different animal species and kidney tumours in rodents. They have selected coffee beans which are have confirmed in laboratory testing to be free of mycotoxins and other nasties such as pesticides and metals, as well as being the highest in the good stuff such as chlorogenic acid one of the most researched compounds in coffee that provides so many of its health benefits. Studies from Canada, Sweden, West Germany, and Yugoslavia detected ochratoxin in human blood and serum. These preliminary results suggest that a serum concentration of OTA greater than 1.5 nmol/L may be a biomarker for glomerular nephritis. Carcinogenesis: In female pigs exposed to alimentary ochratoxin A for two years, no renal cancer was observed. Based on the available data, the panel concluded that foods like preserved meat, ripened cheese and cereals are the main contributors to dietary exposure. Vasoconstriction, loss of extremities (ears, tail, fee, etc.). Embryotoxicity, teratogenicity and immunotoxicity occur only at doses higher than those causing nephrotoxicity [20]. To treat possible fungal infections caused by mold exposure patients can take pharmaceutical medications such as itraconazole or nystatin. OTA exerted its effect on gut via the reduction of nutrient absorption, disruption of intestinal permeability, cell apoptosis, and modulation of immune system. strain K-804 [2,3] isolated from . Bitters support bile flow, a kay aspect on optimal detoxification, and bile is anti-bacterial and thus protective against conditions such as small intestine bacterial overgrowth. We know that fumonisins can cause a variety of illnesses in animals, especially to their liver and kidneys, but more research is needed to know exactly how these toxins affect humans. Before Avoiding interference and realizing the precise detection of mycotoxins in complex food samples is still an urgent problem for surface-enhanced Raman spectroscopy (SERS) analysis technology. [14] recently detected OTA in food collected in the endemic areas and in blood and urine of their residents. Renal damage has been induced by alimentary exposure to ochratoxin A in all single-stomach animals tested so far, including rodents, dogs, pigs and birds, and even in young ruminants still functioning as single-stomach animals. The kidney is the main target organ for ochratoxin A. Pasteurization wont get rid of patulin. The World Health Organisation advise the consumer to: However, this is not considering the mycotoxins that might be produced from water-damaged buildings really the most common cause of mould illness. Analysis of ochratoxin A in serum and urine of inhabitants from an area with Balkan Endemic Nephropathy: A one month follow up study. However, it has also been detected in animal products such as pork kidneys and liver. Shephard S., Fabiani A., Stockenstrm S., Mshicileli N., Sewram V. Quantitation of ochratoxin A in South African wines. Amendment: On page 75, before Figure 7, and on page 150, we have added text clarifying that the occurrence data for OTA on 73,891 food samples is available at the Zenodo link mentioned under the Annex section. A strain of Aspergillus ochraceus producing OTA was isolated from the wheat. Aristolochic acids are phytotoxins belonging to the Aristolochiaceae family of plants and have been suspected to induce similar nephrotoxic effects in humans and animals [2]. Stoev S.D., Paskalev M., MacDonald S., Mantle P.G. Our data entry forms are an easy, fast, and convenient way to enter the reports yourself. Ochratoxin A (OTA) was purified and characterized from Aspergillus ochraceus Wilh. EFSA has published a scientific opinion on public health risks related to the presence of ochratoxin A (OTA) in food - a mycotoxin naturally produced by moulds that can be found in a variety of foodstuffs including cereals, preserved meats, fresh and dried fruit, and cheese. The FAO/WHO Joint Expert Committee on Food Additives indicate a provisional tolerable intake of 14.3 ng/kg bw per day, based on the LOEL for renal effects in pigs [29]. Mycotoxic porcine nephropathy is recognized as an endemic disease entity also in several northern and central European countries. Go with certified toxin-free coffee: This is the only way to guarantee protection from mycotoxins in coffee. Listen and learn from my interview with Vivien Allred as she shares her recovery story: Check out my article Ochratoxin A Toxicity: Antioxidants To The Rescue!. Never disregard professional medical advice or delay in seeking it because of something you have read on this website. Reduced weight gain, abortion, poor survivability. This is in agreement with other studies carried out in the same region [4,13]. Most people are familiar with mycotoxins in the context of contaminated coffee beans. If you eat something containing high levels of those mycotoxins, you can get sick. Some studies have hypothesized that OTA may contribute to the development of neurodegenerative diseases such as Alzheimers and Parkinsons. Microbiome testing mycotoxins can cause significant disruption to the gut function. But with climate change mycotoxin contamination is spreading to new regions of the globe. and transmitted securely. Ochratoxin is known for contaminating grapes and wines. Balkan endemic nephropathy, a chronic tubulointerstitial renal disease, could be due to OTA. Food commodities intoxicated with ochratoxins. Chronic nephrotoxicity due to OTA is probably more usual and makes the diagnosis more difficult. 8600 Rockville Pike Even though the main objective of the food and feed chain processors and distributors is to avoid the extended contamination of plant-derived foods and animal feeds with mycotoxins, until now, complete OTA removal from foods and feedstuffs is not feasible. (Letter), Learn how and when to remove this template message, "Ochratoxin A: An overview on toxicity and carcinogenicity in animals and humans", Extensive information about mycotoxins and animal feed, https://en.wikipedia.org/w/index.php?title=Ochratoxin&oldid=1144917154, This page was last edited on 16 March 2023, at 08:16. The .gov means its official.Federal government websites often end in .gov or .mil. Krogh [17] states that most information on ochratoxin-induced nephropathy has been obtained in pigs during experimental studies comprising structural as well as functional changes. Krogh P., Elling F., Friis C., Hald B., Larsen A.E., Lillehj E.B., Madsen A., Mortensen H.P., Rasmussen F., Ravnskov U. Porcine nephropathy induced by long-term ingestion of ochratoxin A. Krogh P. Role of ochratoxin in disease causation. Aflatoxin is a type of mold that is considered a human carcinogen. Pfohl-Leszkowicz A. Ochratoxin A and aristolochic acid involvement in nephropathies and associated urothelial tract tumours. Found in wheat, corn, barley, oats, rice, rye, and safflower seeds. This is another reason why its best to avoid, Cereal Grains, peanuts, soybeans, and other foods. Multi-mycotoxin immunoaffinity columns for simultaneous detection of aflatoxins B1, B2, G1, G2 and ochratoxin A in a wide range of commodities in conjunction with HPLC or LC-MS/MS. Most people havent heard of mycotoxins, but nearly everyone has been exposed to them. Mycotoxins to Watch For. I have had clients sleep in tents in the garden, when levels of mould were significant, because they were aware of how they felt on entering their home. In this review we have outlined the current knowledge on ochratoxins. Pfohl-Leszkowicz A., Petkova-Bocharova T., Chernozemsky I.N., Castegnaro M. Balkan endemic nephropathy and the associated urinary tract tumours: review on etiological causes, potential role of mycotoxins. Vrabcheva T., Usleber E., Dietrich R., Mrtlbauer E. Co-occurrence of ochratoxin A and citrinin in cereals from Bulgarian villages with a history of Balkan endemic nephropathy. Learn what it is, what foods are high in ochratoxin A, symptoms, testing for mycotoxins, and treatment mycotoxins including detoxification. (primarily) Aflatoxins B1, B2, G1, and G2 (B2a, G2a, M1, and M2 are metabolites and seldom present in grain; M1 and M2 are important contaminants in milk), hemorrhagic enteritis; suppression of natural immunity to infection; decreased production of meat, milk and eggs, pulmonary mycotoxicosis, poor feed conversion, reduced growth rate, reduced immunity to infection, edema toxic to kidneys; possibly carcinogenic, Factor, (Vomitoxin) Deoxynivalenol or DON, (T-2, HT-2, Monoacetoxyscripenol or MAS, Diactoxyscripenol or DAS), F. acuminatum, F. sambucinum and F. sporotrichoides, hemorrhage; edema; vomiting And diarrhea; infertility; degeneration of bone marrow; death; reduced weight gain; slow growth; sterility, abortion, pulmonary edema in swine, neural tube defects and esophageal cancer in humans. Ochratoxin A (OTA) is secondary metabolite naturally produced in food and feed by toxigenic fungi, especially some Aspergillus species and Penicillium verucosum. Understand and improve your laboratory results with our health dashboard. Mycotoxins can also attack the mucosal lining of the intestines causing intestinal permeability i.e, leaky gut. Even small doses of mycotoxins can lead to serious diseases and even death. There are other tests that can be considered to have a more complete understanding of an individuals health. Major Mycotoxins and Toxin-Producing Fungi from Corn, Cereal, Soybeans, Peanuts, and Other Products and Some of their Effects on Animals. What the above quote means is we need to focus on your unique case. Their growth promoting conditions are delineated in Table 1. Renal Carcinogenesis. All data is backed up multiple times a day and encrypted using SSL certificates. Navigate to MycoTOX Profile (Mold Exposure). The role of ochratoxin A as a possible cause of Balkan endemic nephropathy and its risk evaluation. OTA was detected in 87% of all samples. Hepatotoxin; carcinogenic; reduced growth rate; Aspergillus alutaceaus var. Careers, Unable to load your collection due to an error. Carefully inspect whole grains and nuts for evidence of mould, and discard any that look mouldy, discoloured, or shriveled. Samples were collected from: (a) 20 households of Balkan endemic nephropathy villages (n = 8), and 16 households of Balkan endemic nephropathy-free households (within-village household controls) and (b) 22 Balkan endemic nephropathy-free households of Balkan endemic nephropathy-free villages and 22 households between-village controls. Some foodssuch as grains, dried beans, dried fruits, and coffeeare susceptible to fungus or mold that produce toxins known as mycotoxins. Common food sources include corn, wheat, barley, oats, rice, rye and safflower seeds. To limit your exposure to mycotoxins in coffee there are three steps you can take: Mycotoxins can be found growing on the surface of products and can also penetrate deep into foods. Dietrich D.R., Swenberg J.A. The foods most susceptible to aflatoxins include peanuts, corn, tree nuts such as Brazil nuts and pistachios, and some small grains such as rice. Found in coffee beans and grains, including corn and wheat. Toxins found in food infected by certain molds or fungi. In doing so, the respective mycotoxin is concentrated in order to achieve highly-sensitive and exact test results. Ochratoxin A a toxin produced by different Aspergillus and Penicillium species is one of the most-abundant food-contaminating mycotoxins. At HealthMatters, we're committed to maintaining the security and confidentiality of your personal information. . Regularly eating foods with aflatoxins can increase your risk of liver cancer, cause birth defects, and lead to kidney and immune system problems. One test, available from Genova, looks at lipid peroxides which was mentioned earlier can be elevated as a consequence of ochratoxin exposure. OTA is a recognized renal carcinogen in the mouse and rat [1,21,22]. Mantle P., Faucet-Marquis V., Manderville R., Sciqualli B., Pfohl-Leszkowicz A. A recentstudy showed Ochratoxin A triggered autism via epigenetic mechanism (Mezzelani et al., 2016). peanut butter, - Make sure that foods are stored properly and are not kept for extended periods of time before being used. Growth conditions for ochratoxin production. This disease occurs in the rural population of geographically limited areas of Bulgaria, Bosnia and Herzegovina, Croatia, Romania, and Serbia, and a number of theories have been proposed about its aetiology. Liver elimination of OTA is maintained by protein carriers that shuffle the toxin from its protein-bound form in blood into the hepatocyte and subsequently secrete the toxin into bile. Mycotoxins are poisonous compounds produced by mold and fungi found commonly in grains, fruits, and coffee. Produced by various molds, including Fusarium and Stachybotrys (black mold). Another avenue through which mycotoxins can harm us is by disrupting our gut microbiota. There are numerous things that may require support ranging from small intestine bacterial overgrowth, to bile support, histamine issues and mast cell activation syndrome to fibromyalgia. Omega 3 Fats: Omega 3 fats are helpful at diluting the toxins which build up in the fatty parts of our mitochondria, cells, organs and body. Environmental factors such as temperature, humidity, and the amount of rain affect whether mold will grow on food while it is growing, being harvested, and/or stored. Mycotoxin: Its Impact on Gut Health and Microbiota, A Review of the Mechanism of Injury and Treatment Approaches for Illness Resulting From Exposure to Water-Damaged Buildings, Mold, and Mycotoxins, Deficient Glutathione in the Pathophysiology of Mycotoxin-Related Illness, Role of Mycotoxins in the Pathobiology of Autism: A First Evidence, Mycotoxins and human disease: a largely ignored global health issue, Ochratoxin A and human health risk: A review of the evidence, A Review of the Diagnosis and Treat of Ochratoxin A Inhalational Exposure Associated with Human Illness and Kidney Disease including Focal Segmental Glomerulosclerosis, Milievi, D. R., krinjar, M., and Balti, T. (2010). Purpose The relation between plasma OTA levels, dietary habits, and specific disease risk biomarkers (body mass index (BMI), C-reactive protein (CRP), and cardiovascular . Found in cereals, spices, dried fruit, coffee, grape juice. Nutrient deficiencies may impact on many aspects of health including detoxification capacity which is essential to optimise when wanting to heal from mould illness. Immunoaffinity columns such as OCHRAPREP are used in conjunction with HPLC in order to purify complex and strongly-colored food samples, including spices. We include products in articles we think are useful for our readers. It may possibly cause cancer in humans, but more research is needed to know exactly how this toxin affects humans. Ochratoxin-producing fungi may contaminate agricultural products in the field (preharvest spoilage), during storage (postharvest spoilage), or during processing. Symptoms include malaise and agitation, abdominal distress, diarrhea, and vomiting. control OTA are preventive in order to avoid fungal growth and OTA production. Upload your lab reports and get your interpretation today. Nephropathy: In humans, ochratoxins cause endemic nephropathy, which has been described in several studies in North Eastern Europe as reported by Walker and Larsen [27,28,29,30]. Minimal exposure can occur through contaminated foods such as cereals, grape juices, dairy, spices, wine, dried vine fruit, and coffee. According to Simon [32] epidemiologic studies showed that in areas where high OTA levels are reached in food and in the blood of the population, there is a high incidence of nephropathy and renal tumours. You can test for mycotoxins in the urine. Guidance Document: Guidance for Industry. The following moulds produce Ochratoxin A: Aspergillus ochraceus, Aspergilluscarbonarius, Aspergillusniger and Penicillium verrucosum. A certification looks like the chart below. OTA and probably other mycotoxins could be major environmental factors in the occurrence of renal disease especially in developing countries according to Tatu and co-workers [40].
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