Potential anti-Pythium insidiosum therapeutics identified through screening of agricultural fungicides.

Pythiosis is a life-threatening infectious disease caused by the oomycete Pythium insidiosum. Clinical manifestations of pythiosis include an eye, blood vessel, skin, or gastrointestinal tract infection. Pythiosis has been increasingly reported worldwide, with an overall mortality rate of 28%. Radical surgery is required to save patients' lives due to the limited efficacy of antimicrobial drugs. Effective medical treatments are urgently needed for pythiosis. This study aims to find anti-P. insidiosum agents by screening 17 agricultural fungicides that inhibit plant-pathogenic oomycetes and validating their efficacy and safety. Cyazofamid outperformed other fungicides as it can potently inhibit genetically diverse P. insidiosum isolates while exhibiting minimal cellular toxicities. The calculated therapeutic scores determined that the concentration of cyazofamid causing significant cellular toxicities was eight times greater than the concentration of the drug effectively inhibiting P. insidiosum. Furthermore, other studies showed that cyazofamid exhibits low-to-moderate toxicities in animals. The mechanism of cyazofamid action is likely the inhibition of cytochrome b, an essential component in ATP synthesis. Molecular docking and dynamic analyses depicted a stable binding of cyazofamid to the Qi site of the P. insidiosum's cytochrome b orthologous protein. In conclusion, our search for an effective anti-P. insidiosum drug indicated that cyazofamid is a promising candidate for treating pythiosis. With its high efficacy and low toxicity, cyazofamid is a potential chemical for treating pythiosis, reducing the need for radical surgeries, and improving recovery rates. Our findings could pave the way for the development of new and effective treatments for pythiosis.IMPORTANCEPythiosis is a severe infection caused by Pythium insidiosum. The disease is prevalent in tropical/subtropical regions. This infectious condition is challenging to treat with antifungal drugs and often requires surgical removal of the infected tissue. Pythiosis can be fatal if not treated promptly. There is a need for a new treatment that effectively inhibits P. insidiosum. This study screened 17 agricultural fungicides that target plant-pathogenic oomycetes and found that cyazofamid was the most potent in inhibiting P. insidiosum. Cyazofamid showed low toxicity to mammalian cells and high affinity to the P. insidiosum's cytochrome b, which is involved in energy production. Cyazofamid could be a promising candidate for the treatment of pythiosis, as it could reduce the need for surgery and improve the survival rate of patients. This study provides valuable insights into the biology and drug susceptibility of P. insidiosum and opens new avenues for developing effective therapies for pythiosis.

Dual use of antifungals in medicine and agriculture: How do we help prevent resistance developing in human pathogens?

Azole resistance in Aspergillus fumigatus is a One Health resistance threat, where azole fungicide exposure compromises the efficacy of medical azoles. The use of the recently authorized fungicide ipflufenoquin, which shares its mode-of-action with a new antifungal olorofim, underscores the need for risk assessment for dual use of antifungals.

New treatments to disinfect vine cuttings with Phaeomoniella chlamydospora and the reason for the control

Petri disease is a problem for vineyard caused mainly by the fungus Phaeomoniella chlamydospora. Contaminated seedlings are source of inoculum for the disease. Treatment to disinfect vine rootstock cuttings for seedling production is hot water treatment (HWT) by 50 °C for 30 min, but the efficiency is contested. To improve its efficacy, the study aimed to assess the combination of the following methods and the reason for the control: i) exposition of the fungus to five different temperatures in HWT bath for 30 min; ii and iii) exposition of the fungus and also plants infected with P. chlamydospora to different disinfection treatments (biofumigation = soil + cabbage at 40 °C; temperatures of 40 and 23 °C, all in microcosm), in different periods (7, 14 and 21 days), with and without additional HWT (51 °C for 30 min). The results showed that HWT with high temperatures (55­70 °C) for 30 min inactivated the fungus. Biofumigation technique at 40 °C and the temperature solely of 40 °C applied for up to 21 days and combined with HWT (51 °C for 30 min) inhibited mycelial growth and inactivated the fungus in vine plant tissues without compromising the rooting.

In vitro study on the potential fungicidal effects of atorvastatin in combination with some azole drugs against multidrug resistant Candida albicans.

The resistance of Candida albicans to azole drugs represents a great global challenge. This study investigates the potential fungicidal effects of atorvastatin (ATO) combinations with fluconazole (FLU), itraconazole (ITR), ketoconazole (KET) and voriconazole (VOR) against thirty-four multidrug-resistant (MDR) C. albicans using checkerboard and time-kill methods. Results showed that 94.12% of these isolates were MDR to ≥ two azole drugs, whereas 5.88% of them were susceptible to azole drugs. The tested isolates exhibited high resistance rates to FLU (58.82%), ITR (52.94%), VOR (47.06%) and KET (35.29%), whereas only three representative (8.82%) isolates were resistant to all tested azoles. Remarkably, the inhibition zones of these isolates were increased at least twofold with the presence of ATO, which interacted in a synergistic (FIC index ≤ 0.5) manner with tested azoles. In silico docking study of ATO and the four azole drugs were performed against the Lanosterol 14-alpha demethylase enzyme (ERG11) of C. albicans. Results showed that the mechanism of action of ATO against C. albicans is similar to that of azole compounds, with a docking score (-4.901) lower than azole drugs (≥5.0) due to the formation a single H-bond with Asp 225 and a pi-pi interaction with Thr 229. Importantly, ATO combinations with ITR, VOR and KET achieved fungicidal effects (≥ 3 Log10 cfu/ml reduction) against the representative isolates, whereas a fungistatic effect (≤ 3 Log10 cfu/ml reduction) was observed with FLU combination. Thus, the combination of ATO with azole drugs could be promising options for treating C. albicans infection.

Canthin-6-one ameliorates TNBS-induced colitis in rats by modulating inflammation and oxidative stress. An in vivo and in silico approach.

Canthin-6-one (Cant) is an indole alkaloid found in several botanical drugs used as medicines, reported to be gastroprotective, anti-inflammatory, anti-microbial, anti-diarrheal and anti-proliferative. We aimed to explore Cant in the management of colitis using a trinitrobenzenesulfonic acid (TNBS)-induced rat model. Cant (1, 5 and 25 mg/kg) was administered by oral gavage to Wistar rats followed by induction of colitis with TNBS. Macroscopic and histopathological scores, myeloperoxidase (MPO), malondialdehyde (MDA) and reduced glutathione (GSH) were assessed in colon tissues. Pro- (TNF-α, IL-1ß and IL-12p70) and anti-inflammatory (IL-10) cytokines, and vascular endothelial growth factor (VEGF) were also quantified. Mitogen-activated protein kinase 14 (MAPK14) and Toll-like receptor-8 (TLR8), as putative targets, were considered through in silico analysis. Cant (5 and 25 mg/kg) reduced macroscopic and histological colon damage scores in TNBS-treated rats. MPO and MDA were reduced by up to 61.69% and 92.45%, respectively, compared to TNBS-treated rats alone. Glutathione concentration was reduced in rats administered with TNBS alone (50.00% of sham group) but restored to 72.73% (of sham group) with Cant treatment. TNF-α, IL-1ß, IL-12p70 and VEGF were reduced, and anti-inflammatory IL-10 was increased following Cant administration compared to rats administered TNBS alone. Docking ligation results for MAPK14 (p38α) and TLR8 with Cant, confirmed that these proteins are feasible putative targets. Cant has an anti-inflammatory effect in the intestine by down-regulating molecular immune mediators and decreasing oxidative stress. Therefore, Cant could have therapeutic potential for the treatment of inflammatory bowel disease and related syndromes.

Micellization of coenzyme Q by the fungicide caspofungin allows for safe intravenous administration to reach extreme supraphysiological concentrations.

Coenzyme Q10 (CoQ10; also known as ubiquinone) is a vital, redox-active membrane component that functions as obligate electron transporter in the mitochondrial respiratory chain, as cofactor in other enzymatic processes and as antioxidant. CoQ10 supplementation has been widely investigated for treating a variety of acute and chronic conditions in which mitochondrial function or oxidative stress play a role. In addition, it is used as replacement therapy in patients with CoQ deficiency including inborn primary CoQ10 deficiency due to mutations in CoQ10-biosynthetic genes as well as secondary CoQ10 deficiency, which is frequently observed in patients with mitochondrial disease syndrome and in other conditions. However, despite many tests and some promising results, whether CoQ10 treatment is beneficial in any indication has remained inconclusive. Because CoQ10 is highly insoluble, it is only available in oral formulations, despite its very poor oral bioavailability. Using a novel model of CoQ-deficient cells, we screened a library of FDA-approved drugs for an activity that could increase the uptake of exogenous CoQ10 by the cell. We identified the fungicide caspofungin as capable of increasing the aqueous solubility of CoQ10 by several orders of magnitude. Caspofungin is a mild surfactant that solubilizes CoQ10 by forming nano-micelles with unique properties favoring stability and cellular uptake. Intravenous administration of the formulation in mice achieves unprecedented increases in CoQ10 plasma levels and in tissue uptake, with no observable toxicity. As it contains only two safe components (caspofungin and CoQ10), this injectable formulation presents a high potential for clinical safety and efficacy.

Smallholders' coping mechanisms with wheat rust epidemics: Lessons from Ethiopia.

Crops are variously susceptible to biotic stresses-something expected to increase under climate change. In the case of staple crops, this potentially undermines household and national food security. We examine recent wheat rust epidemics and smallholders' coping mechanisms in Ethiopia as a case study. Wheat is a major food crop in Ethiopia widely grown by smallholders. In 2010/11 a yellow rust epidemic affected over one-third of the national wheat area. Two waves of nationally representative household level panel data collected for the preceding wheat season (2009/10) and three years after (2013/14) the occurrence of the epidemic allow us to analyze the different coping mechanisms farmers used in response. Apart from using fungicides as ex-post coping mechanism, increasing wheat area under yellow rust resistant varieties, increasing diversity of wheat varieties grown, or a combination of these strategies were the main ex-ante coping mechanisms farmers had taken in reducing the potential effects of rust re-occurrence. Large-scale dis-adoption of highly susceptible varieties and replacement with new, rust resistant varieties was observed subsequent to the 2010/11 epidemic. Multinomial logistic regression models were used to identify the key factors associated with smallholder ex-ante coping strategies. Household characteristics, level of specialization in wheat and access to improved wheat seed were the major factors that explained observed choices. There was 29-41% yield advantage in increasing wheat area to the new, resistant varieties even under normal seasons with minimum rust occurrence in the field. Continuous varietal development in responding to emerging new rust races and supporting the deployment of newly released resistant varieties could help smallholders in dealing with rust challenges and maintaining improved yields in the rust-prone environments of Ethiopia. Given the global importance of both wheat and yellow rust and climate change dynamics study findings have relevance to other regions.

MYCOTIC DERMATITIS IN JUVENILE FRESHWATER CROCODILES (CROCODYLUS JOHNSTONI) CAUSED BY NANNIZZIOPSIS CROCODILI.

Nannizziopsis crocodili, a contagious, keratinophilic fungus, was identified from biopsied tissue in a captive juvenile freshwater crocodile during an outbreak of severe multifocal dermatitis affecting four of five crocodiles. Lesions progressed from superficial, well-demarcated ulceration of scales, to black pigmentation, localized edema, erythema, and flattening of the scales. Treatment with topical enilconazole provided clinical improvement in three of four crocodiles but all developed terminal gout. One crocodile did not develop clinical disease despite long-term exposure. This is the first report of N. crocodili in freshwater crocodiles and in a location remote to the index Australian case.

Dissipation kinetic studies of fenamidone and propamocarb in vegetables under greenhouse conditions using liquid and gas chromatography coupled to high-resolution mass spectrometry.

In this study, fenamidone, propamocarb and their transformation products were monitored in cherry tomato, cucumber, and courgette samples. A mixture of both compounds, which have different physico-chemical characteristics, are commercially available (Consento®). For analysis, ultra high-performance liquid chromatography coupled to Orbitrap mass spectrometry (UHPLC-Orbitrap-MS) and gas chromatography coupled to Q-Orbitrap mass spectrometry (GC-Q-Orbitrap-MS) were used. The dissipation of these active ingredients was monitored at two doses (normal and double dose) from 1 to 40 days after the application of the commercial product. Half-lives (DT50) were lower than 30 days for both compounds, which indicates low persistence. Metabolites of both compounds were also monitored due to in some cases these can be more dangerous for human health than the parent compounds. The metabolites monitored were RPA 410193 ((5S)-3-anilino-5-methyl-5-phenylimidazolidine-2,4-dione), acetophenone, 2-phenylpropionic acid, 5-methyl-5-phenylhydantoin and 5-methylhydantoin for fenamidone, and propamocarb hydrochloride (propyl 3-(dimethylamino)propylcarbamate hydrochloride), N-oxide propamocarb (propyl [3-(dimethylnitroryl)propyl]carbamate), oxazoline-2-one propamocarb (3-[3-(dimethylamino)propyl]-4-hydroxy-4-methyl-1,3-oxazolidin-2-one), 2-hydroxypropamocarb and n-desmethyl propamocarb (propyl [3-(methylamino)propyl]carbamate) for propamocarb. In addition, they were detected one day after the application of commercial product, being RPA 410193, the metabolite detected at the highest concentration in samples. Retrospective analysis of incurred samples allowed putative identification of four possible new metabolites of propamocarb and one of fenamidone.

Downy Mildew: A Serious Disease Threat to Rose Health Worldwide.

Peronospora sparsa is a downy mildew-causing oomycete that can infect roses, blackberries, and other members of the rose family. During the last 70 years, this disease has become a serious problem for rose growers in the U.S. and worldwide. While much is known about the disease and its treatment, including significant research on molecular identification methods, as well as environmental conditions conducive to disease and the fungicides used to prevent it, significant knowledge gaps remain in our basic comprehension of the pathogen's biology. For example, the degree of genetic relatedness of pathogen isolates collected from rose, caneberries, and cherry laurel has never been examined, and the natural movement of genotypes from host to host is not known. Further work could be done to determine the differences in pathogen population structure over time (using herbarium specimens and fresh collections) or differences in pathogen population structure and pathogen environmental adaptation for specimens from different geographic regions. The oospore stage of the organism is poorly understood, both as to how it forms and whether it serves as an overwintering structure in nurseries and landscapes. In production greenhouses, the detection of the pathogen using infrared thermographic imaging and possible inhibition by ultraviolet light needs to be explored. Further work needs to be done on breeding using wild roses as new sources for resistance and using new methods such as marker assisted selection and RNAi technologies. As roses are one of the most economically important ornamental crops worldwide, a proper understanding of the disease cycle could allow for better use of cultural and chemical controls to manage rose downy mildew in landscapes and in greenhouse and nursery production areas.

Mucormycosis in hospitalized patients at a tertiary care center in Lebanon: a case series.

PURPOSE: Mucormycosis (MCM) is a rare fungal infection affecting people with impaired immunity. Data related to MCM from Lebanon are scarce. The aim of this study is to shed light on the epidemiology, incidence, and outcome of patients with MCM hospitalized at a tertiary care center in Lebanon. METHODS: We conducted a retrospective chart review between Jan 1, 2008 and Jan 10, 2018. All patients with proven or probable MCM were included. RESULTS: A total of 20 patients were included. Their median age was 49 years and the majority were males. Comorbidities included mainly hematologic malignancy and diabetes mellitus. Most common sites of involvement were rhino-orbital and pulmonary, respectively. The number of MCM cases/10.000 hospital admissions increased significantly between 2008 and 2017 (0.47 vs. 1.18; P < 0.05). A liposomal amphotericin B formulation alone or in combination with other antifungals was used as a first line agent in all patients. All-cause mortality was 60%; however, death was attributed to MCM in 20% of cases. CONCLUSION: The incidence of MCM has significantly increased over the past 10 years at our institution, most likely due to the increasing patient population at risk. Understanding the epidemiology of MCM in our setting would help guide antifungal therapy.

Effects of two strobilurins (azoxystrobin and picoxystrobin) on embryonic development and enzyme activities in juveniles and adult fish livers of zebrafish (Danio rerio).

Azoxystrobin and picoxystrobin are two primary strobilurin fungicides used worldwide. This study was conducted to test their effects on embryonic development and the activity of several enzyme in the zebrafish (Danio rerio). After fish eggs were separately exposed to azoxystrobin and picoxystrobin from 24 to 144 h post fertilization (hpf), the mortality, hatching, and teratogenetic rates were measured. Additionally, effects of azoxystrobin and picoxystrobin on activities of three important antioxidant enzymes [catalase (CAT), superoxide dismutase (SOD) and peroxidase (POD)] and two primary detoxification enzymes [carboxylesterase (CarE) and glutathione S-transferase (GST)] and malondialdehyde (MDA) content in zebrafish larvae (96 h) and livers of adult zebrafish of both sexes were also assessed for potential toxicity mechanisms. Based on the embryonic development test results, the mortality, hatching, and teratogenetic rates of eggs treated with azoxystrobin and picoxystrobin all showed significant dose- and time-dependent effects, and the 144-h LC50 values of azoxystrobin and picoxystrobin were 1174.9 and 213.8 µg L-1, respectively. In the larval zebrafish (96 h) test, activities of CAT, POD, CarE, and GST and MDA content in azoxystrobin and picoxystrobin-treated zebrafish larvae increased significantly with concentrations of the pesticides compared with those in the control. We further revealed that azoxystrobin and picoxystrobin exposure both caused significant oxidative stress in adult fish livers and the changes differed between the sexes. Our results indicated that picoxystrobin led to higher embryonic development toxicity and oxidative stress than azoxystrobin in zebrafish and the male zebrafish liver had stronger ability to detoxify than that of the females.

Blad-containing oligomer: a novel fungicide used in crop protection as an alternative treatment for tinea pedis and tinea versicolor.

PURPOSE: The lack of novel antifungal drugs and the increasing incidence and severity of fungal infections are major concerns worldwide. Herein, we tested the activity of the Blad-containing oligomer (BCO), a new antifungal molecule already in use for agriculture, on Malassezia spp. and dermatophytes, the causal agents of human tinea versicolor and tinea pedis. Given the lack of a standard method for Malassezia susceptibility testing and the plethora of published methods, we also developed an improved method for this genus. METHODOLOGY: The efficacy of BCO was assessed in vitro and compared to that of the drugs currently utilized in the treatment of tinea versicolor (fluconazole and itraconazole) and tinea pedis (itraconazole and terbinafine). For dermatophytes, the standard microdilution broth-based method was used, with small adjustments, and several broth formulations and inocula sizes were tested to develop an improved susceptibility method for Malassezia spp. RESULTS: We successfully developed a microdilution broth-based method with considerable advantages over other available methods, and used it for all in vitro susceptibility tests of Malassezia spp. isolates. We report that, on a molar basis, BCO was more effective than fluconazole or itraconazole on most strains of Malassezia spp. isolated from clinical samples (n=29). By contrast, BCO was less effective than itraconazole or terbinafine on the common dermatophytes Trichophyton rubrum and Trichophyton interdigitale. CONCLUSION: These data place BCO as a promising drug for the treatment of Malassezia-associated skin diseases. Further in vivo studies are now required to ascertain its applicability in the clinical setting.

Cutaneous alternariosis in an immunocompromised dog successfully treated with cold plasma and cessation of immunosuppressive medication.

A cutaneous infection with Alternaria spp. was diagnosed in a 2-year-old male intact Irish setter dog, presenting with multifocal papules, plaques and ulcerations involving all four distal limbs, shoulder blades, scrotum, pinnae and nasal mucous membranes. The dog had been treated for inflammatory bowel disease and lymphangiectasia with immunosuppressive doses of cyclosporine and prednisolone for approximately 3 months. The diagnosis was based on clinical signs, the demonstration of fungal elements within skin biopsies, deep fungal culture and fungal PCR from a formalin-fixed tissue specimen. Complete clinical remission was achieved by tapering and cessation of the immunosuppressive medication, treatment with cold atmospheric-pressure plasma (CAPP) and topical enilconazole within 8 weeks.

The Evolution of Fungicide Resistance Resulting from Combinations of Foliar-Acting Systemic Seed Treatments and Foliar-Applied Fungicides: A Modeling Analysis.

For the treatment of foliar diseases of cereals, fungicides may be applied as foliar sprays or systemic seed treatments which are translocated to leaves. Little research has been done to assess the resistance risks associated with foliar-acting systemic seed treatments when used alone or in combination with foliar sprays, even though both types of treatment may share the same mode of action. It is therefore unknown to what extent adding a systemic seed treatment to a foliar spray programme poses an additional resistance risk and whether in the presence of a seed treatment additional resistance management strategies (such as limiting the total number of treatments) are necessary to limit the evolution of fungicide-resistance. A mathematical model was developed to simulate an epidemic and the resistance evolution of Zymoseptoria tritici on winter wheat, which was used to compare different combinations of seed and foliar treatments by calculating the fungicide effective life, i.e. the number of years before effective disease control is lost to resistance. A range of parameterizations for the seed treatment fungicide and different fungicide uptake models were compared. Despite the different parameterizations, the model consistently predicted the same trends in that i) similar levels of efficacy delivered either by a foliar-acting seed treatment, or a foliar application, resulted in broadly similar resistance selection, ii) adding a foliar-acting seed treatment to a foliar spray programme increased resistance selection and usually decreased effective life, and iii) splitting a given total dose-by adding a seed treatment to foliar treatments, but decreasing dose per treatment-gave effective lives that were the same as, or shorter than those given by the spray programme alone. For our chosen plant-pathogen-fungicide system, the model results suggest that to effectively manage selection for fungicide-resistance, foliar acting systemic seed treatments should be included as one of the maximum number of permitted fungicide applications.

Influence of the use of fungicides on the volatile composition of Monastrell red wines obtained from inoculated fermentation.

The influence of six fungicides (famoxadone, fenhexamid, fluquinconazole, kresoxim-methyl, quinoxyfen and trifloxystrobin) on the volatile composition of red wines obtained from inoculated fermentation was studied. Although treatments were carried out under critical agricultural practices (CAP), the residues in the wines were below their maximum residue limit (MRL). Ethyl decanoate was the compound most influenced by these fungicides, while diethyl succinate, decanoic acid, ß-ionone, and citronellol concentration were not changed with any of the treatments. The treatment of grapes with trifloxystrobin induced changes in only one volatile compound, and the variation in volatile composition of wines from grapes treated with fenhexamid, fluquinconazole and quinoxyfen compared to control wines was almost negligible invaluable. The treatment with famoxadone influenced more volatile compounds than the other ones, except for wine from grapes treated with kresoxim-methyl, which was the only wine that showed a big change in its aromatic composition.

Fluoride enhances the activity of fungicides that destabilize cell membranes.

Fluoride has long been known to inhibit bacterial and fungal cell growth most likely by blocking the functions of key metabolic enzymes. In this study, we demonstrate that antifungal compounds that disrupt cell membrane integrity exhibit improved ability to inhibit cell growth when used with millimolar concentrations of fluoride. Specifically, antifungal compounds of the polyene class and an antifungal peptide exhibit synergy with fluoride to inhibit the growth of various fungal species, including Candida albicans. Our results demonstrate that certain compounds can be found that increase the cellular uptake of fluoride, and provide new opportunities for creating antimicrobial compounds whose functions are enhanced when combined with otherwise sub-inhibitory concentrations of small ions.

Proteomic analysis of blood cells in fish exposed to chemotherapeutics: evidence for long term effects.

Proteomics technology are increasingly used in ecotoxicological studies to characterize and monitor biomarkers of exposure. The present study aims at identifying long term effects of malachite green (MG) exposure on the proteome of peripheral blood mononuclear cells (PBMC) from the Asian catfish, Pangasianodon hypophthalmus. A common (0.1 ppm) concentration for therapeutic treatment was applied twice with a 72 h interval. PBMC were collected directly at the end of the second bath of MG (T1) and after 1 month of decontamination (T2). Analytical 2D-DIGE gels were run and a total of 2551±364 spots were matched. Among them, MG induced significant changes in abundance of 116 spots with no recovery after one month of decontamination. Using LC-MS/MS and considering single identification per spot, we could identify 25 different proteins. Additionally, MG residues were measured in muscle and in blood indicating that leuco-MG has almost totally disappeared after one month of decontamination. This work highlights long term effects of MG treatment on the PBMC proteome from fish intended for human consumption.

The area under the disease progress stairs: calculation, advantage, and application.

The area under the disease progress curve (AUDPC) is frequently used to combine multiple observations of disease progress into a single value. However, our analysis shows that this approach severely underestimates the effect of the first and last observation. To get a better estimate of disease progress, we have developed a new formula termed the area under the disease progress stairs (AUDPS). The AUDPS approach improves the estimation of disease progress by giving a weight closer to optimal to the first and last observations. Analysis of real data indicates that AUDPS outperforms AUDPC in most of the tested trials and may be less precise than AUDPC only when assessments in the first or last observations have a comparatively large variance. We propose using AUDPS and its standardized (sAUDPS) and relative (rAUDPS) forms when combining multiple observations from disease progress experiments into a single value.

Contact dermatitis caused by dimethylfumarate in Argentina.

For the first time in Argentina, we describe an outbreak of contact dermatitis. New pairs of shoes caused intense pruritus, pain, and eruption, followed by edema, blisters, and a severe negative impact on the epidermal barrier of the feet. We identify dimethylfumarate as the causal agent and suggest an analytical method for its fast identification.