Causal agents of Stemphylium-induced foliar diseases of tomatoes and other Solanaceae hosts in Brazil.

AIM: An extensive survey was done to clarify the prevalent Stemphylium species on Solanaceae plants across Brazil, and their host ranges. METHODS AND RESULTS: Eighty nine (89) Stemphylium isolates were obtained from naturally infected tomatoes as well as S. paniculatum, potato, eggplant, scarlet eggplant (Solanum aethiopicum var. gilo), Physalis angulata, and Capsicum species. Phylogenetic analyses encompassing the ITS-5.8S rDNA and glyceraldehyde-3-phosphate dehydrogenase genomic regions placed the isolates into two distinct groupings with either Stemphylium lycopersici or S. solani. Isolates of S. lycopersici (n = 81) were obtained infecting tomato, potato, eggplant, S. paniculatum, and P. angulata. Isolates of S. solani (n = 8) were detected in natural association with scarlet eggplant and tomato. Two isolates of S. lycopersici displayed a wide experimental host range in greenhouse bioassays, infecting accessions of 12 out of 18 species. Ocimum basilicum (Lamiaceae) was the only experimental host outside the Solanaceae family.

Burden of atopic dermatitis in Europe: A population-centred approach leveraging web search data in 21 European countries.

BACKGROUND: The complexity, high prevalence, and substantial personal and socioeconomic burden collectively render atopic dermatitis (AD) a major public health concern. Using crowdsourced Internet data has the potential to provide unique insights into this concern, as demonstrated by several previous studies. However, a comprehensive comparison across European countries remains lacking. OBJECTIVES: The study aimed to investigate AD-related web searches across Europe to assess spatiotemporal variations and associations between disease-related and external factors. METHODS: AD-related web search data were extracted for 21 European countries between February 2019 and January 2023. Descriptive analysis and autocorrelation functions were performed to examine spatiotemporal patterns. Correlations (r) were used to evaluate the associations between web searches and disease-related, socioeconomic and meteorological data. RESULTS: Over 241 million AD-related web searches were identified, with search volume varying substantially among European countries (p < 0.001) and correlating with AD prevalence and disease burden (both r = 0.51, p = 0.019). Search volume increased between 2019 and 2023 in all countries and seasonally peaked in January and March. Negative correlations with median population age (r = -0.46, p = 0.039), number of general practitioners (r = -0.29, p = 0.226) and specialists (r = -0.27, p = 0.270) were observed. Moderate to strong correlations were found between search volume and cold, humid and windy weather with fewer sunshine hours, while higher online interest typically occurred 1-3 months after such weather conditions. CONCLUSION: The study highlights the great potential of online crowdsourced data analysis, for example, to investigate the impact of climate change or to identify unmet needs at a population level. Furthermore, the growing online interest in AD and the corresponding seasonal peaks emphasize the necessity of adapting treatment plans, intensifying public health campaigns, and disseminating reliable online information by governments and healthcare providers, especially during these periods.

Age affects drug survival rates of interleukin (IL)-17 and IL-23 inhibitors in patients with plaque psoriasis: Results from a retrospective, multicentric, multi-country, cohort study.

BACKGROUND: Scarce data related to the drug survival of biologic agents in psoriasis patients aged ≥65 years is available. OBJECTIVES: To evaluate the drug survival of interleukin (IL)-23 or the IL-17 inhibitors approved for the treatment of moderate-to-severe psoriasis in elderly patients (aged ≥65 years), compared with younger adult patients (aged <65 years), and to identify clinical predictors that can influence the drug survival. METHODS: This retrospective multicentric cohort study included adult patients with moderate-to-severe psoriasis, dissecting two-patient subcohorts based on age: elderly versus younger adults. Kaplan-Meier estimator and proportional hazard Cox regression models were used for drug survival analysis. RESULTS: We included 4178 patients and 4866 treatment courses; 934 were elderly (1072 treatment courses), and 3244 were younger patients (3794 treatment courses). Drug survival, considering all causes of interruption, was higher in patients aged <65 years than in elderly patients overall (log-rank p < 0.006). This difference was significant for treatment courses involving IL-23 inhibitors (p < 0.001) but not for those with IL-17 inhibitors (p = 0.2). According to both uni- and multi-variable models, elder age was associated with an increased risk of treatment discontinuation (univariable analysis: HR: 1.229, 95% CI 1.062-1.422; p < 0.006; multivariable analysis: HR: 1.199, 95% CI 1.010-1.422; p = 0.0377). Anti-IL-23 agents were associated with a reduced likelihood of treatment discontinuation after adjusting for other variables (HR: 0.520, 95% CI 0.368-0.735; p < 0.001). Being previously treated with IL-17 inhibitors increased the probability of discontinuation. CONCLUSIONS: Elderly patients with psoriasis have an increased risk of biologic treatment discontinuation compared with younger adult patients, particularly, if being treated with IL-23 inhibitors. However, in stratified analyses conducted in elderly patients, IL-23 inhibitors showed higher drug survival rates than IL-17 inhibitors.

Nonadherence to systemic immune-modifying therapy in people with psoriasis during the COVID-19 pandemic: findings from a global cross-sectional survey.

BACKGROUND: Nonadherence to immune-modifying therapy is a complex behaviour which, before the COVID-19 pandemic, was shown to be associated with mental health disorders in people with immune-mediated diseases. The COVID-19 pandemic has led to a rise in the global prevalence of anxiety and depression, and limited data exist on the association between mental health and nonadherence to immune-modifying therapy during the pandemic. OBJECTIVES: To assess the extent of and reasons underlying nonadherence to systemic immune-modifying therapy during the COVID-19 pandemic in individuals with psoriasis, and the association between mental health and nonadherence. METHODS: Online self-report surveys (PsoProtectMe), including validated screens for anxiety and depression, were completed globally during the first year of the pandemic. We assessed the association between anxiety or depression and nonadherence to systemic immune-modifying therapy using binomial logistic regression, adjusting for potential cofounders (age, sex, ethnicity, comorbidity) and country of residence. RESULTS: Of 3980 participants from 77 countries, 1611 (40.5%) were prescribed a systemic immune-modifying therapy. Of these, 408 (25.3%) reported nonadherence during the pandemic, most commonly due to concerns about their immunity. In the unadjusted model, a positive anxiety screen was associated with nonadherence to systemic immune-modifying therapy [odds ratio (OR) 1.37, 95% confidence interval (CI) 1.07-1.76]. Specifically, anxiety was associated with nonadherence to targeted therapy (OR 1.41, 95% CI 1.01-1.96) but not standard systemic therapy (OR 1.16, 95% CI 0.81-1.67). In the adjusted model, although the directions of the effects remained, anxiety was not significantly associated with nonadherence to overall systemic (OR 1.20, 95% CI 0.92-1.56) or targeted (OR 1.33, 95% CI 0.94-1.89) immune-modifying therapy. A positive depression screen was not strongly associated with nonadherence to systemic immune-modifying therapy in the unadjusted (OR 1.22, 95% CI 0.94-1.57) or adjusted models (OR 1.14, 95% CI 0.87-1.49). CONCLUSIONS: These data indicate substantial nonadherence to immune-modifying therapy in people with psoriasis during the pandemic, with attenuation of the association with mental health after adjusting for confounders. Future research in larger populations should further explore pandemic-specific drivers of treatment nonadherence. Clear communication of the reassuring findings from population-based research regarding immune-modifying therapy-associated adverse COVID-19 risks to people with psoriasis is essential, to optimize adherence and disease outcomes.

Tapinarof for the treatment of psoriasis.

Although topical drugs are the mainstay of treatment for patients with mild-to-moderate psoriasis, the developments observed in this field in the last two decades have been limited. The most commonly used drugs are still vitamin D analogues and corticosteroids, both with several limitations. The aryl hydrocarbon receptor (AhR) plays a role in the pathogenesis of psoriasis, and tapinarof, a novel, first-in-class, small molecule topical therapeutic AhR-modulating agent has been recently approved by the FDA for the topical treatment of plaque psoriasis in adults. Two large, 12-week, phase III trials, PSOARING 1 and 2, showed that 35.4%-40.2% of patients in the tapinarof 1% cream arm achieved the primary endpoint (Physician's Global Assessment [PGA] score of 0 or 1 and a decrease of ≥2-5 points at week 12) compared with 6.0%-6.3% for vehicle arm, respectively. The most common adverse effects were folliculitis, contact dermatitis, headache and pruritus. In the open label, 40-week, extension trial, PSOARING 3, the efficacy and safety results were similar, with 40.9% of patients achieving a PGA = 0 at least one time during the trial and 58.2% of patients with PGA≥2 achieved PGA = 0/1 at least once during the trial, without tachyphylaxis. There were no new safety signals, with most frequent adverse events being folliculitis, contact dermatitis, and upper respiratory tract infection. Tapinarof 1% cream has shown to be effective and to have a favorable safety profile in the treatment of psoriatic patients, representing an alternative to the current therapeutic options, increasing our armamentarium in the topical treatment of psoriasis.

The successful treatment with ixekizumab in a multi-failure psoriasis patient.

We report a patient with severe psoriasis who failed to respond to phototherapy, conventional systemic treatment and four biologic agents (etanercept, ustekinumab, adalimumab and secukinumab). Combination of a higher-dose secukinumab regimen with phototherapy had no success. Remarkably, ixekizumab, an IL-17A inhibitor, provided almost complete psoriasis clearance after 24 weeks of treatment. The reason for the success of ixekizumab after the failure to respond to a biologic with same mechanism of action is still unknown. Interestingly, failure of secukinumab does not preclude future therapeutic success with a second IL-17A-inhibitor.

Methyl-triclosan and triclosan impact embryonic development of Danio rerio and Paracentrotus lividus.

The presence of emerging pollutants in the environment is of major concern not only because of the potential negative impact in human health, but also due to the potential toxicity to non-target organisms. Within the personal and care products (PCPs), the disinfectant Triclosan (TCS) is one of the most concerning compounds. Once in the wastewater treatment plants (WWTPs), a small part of TCS can be biotransformed into a more persistent by-product: methyl-triclosan (M-TCS). Although several studies have focused on the occurrence of this compound in the water systems, the information on its toxicity to aquatic organisms is very limited. Here, we used embryo bioassays with two aquatic model animals to improve risk assessment of M-TCS; zebrafish (Danio rerio) embryo bioassays run up to 144 h post fertilization (hpf) and sea urchin (Paracentrotus lividus) up to 48 hpf, following established protocols. M-TCS and TCS exhibited similar toxicity to zebrafish with a NOEC of 160 µg/L. In contrast, M-TCS induced a delay in the development of the sea urchin larvae at all tested concentrations (1-1000 µg/L), whereas NOEC of TCS for P. lividus embryos was 40 µg/L. Overall, given the reported effects of M-TCS in the close range of environmentally relevant concentrations, and considering the low degradation rate and tendency to bioaccumulation (logKow: 5.2), further studies are warrant to better characterize the risk of this TCS metabolite to aquatic organisms.

Screening the Toxicity of Selected Personal Care Products Using Embryo Bioassays: 4-MBC, Propylparaben and Triclocarban.

Recently, several emerging pollutants, including Personal Care Products (PCPs), have been detected in aquatic ecosystems, in the ng/L or µg/L range. Available toxicological data is limited, and, for certain PCPs, evidence indicates a potential risk for the environment. Hence, there is an urgent need to gather ecotoxicological data on PCPs as a proxy to improve risk assessment. Here, the toxicity of three different PCPs (4-Methylbenzylidene Camphor (4-MBC), propylparaben and triclocarban) was tested using embryo bioassays with Danio rerio (zebrafish) and Paracentrotus lividus (sea urchin). The No Observed Effect Concentration (NOEC) for triclocarban was 0.256 µg/L for sea urchin and 100 µg/L for zebrafish, whereas NOEC for 4-MBC was 0.32 µg/L for sea urchin and 50 µg/L for zebrafish. Both PCPs impacted embryo development at environmentally relevant concentrations. In comparison with triclocarban and 4-MBC, propylparaben was less toxic for both sea urchin (NOEC = 160 µg/L) and zebrafish (NOEC = 1000 µg/L). Overall, this study further demonstrates the sensitivity of embryo bioassays as a high-throughput approach for testing the toxicity of emerging pollutants.

Effects of Tributyltin and Other Retinoid Receptor Agonists in Reproductive-Related Endpoints in the Zebrafish (Danio rerio).

Both field and experimental data examined the influence of exposure to environmental contaminant tributyltin (TBT) on marine organisms. Although most attention focused on the imposex phenomenon in gastropods, adverse effects were also observed in other taxonomic groups. It has been shown that imposex induction involves modulation of retinoid signaling in gastropods. Whether TBT influences similar pathways in fish is yet to be addressed. In this study, larvae of the model teleost Danio rerio were exposed to natural retinoids, all-trans-retinoic acid, 9-cis-retinoic acid, and all-trans-retinol, as well as to the RXR synthetic pan-agonist methoprene acid (MA) and to TBT. Larvae were exposed to TBT from 5 days post fertilization (dpf) to adulthood, and reproductive capacity was assessed and correlated with mode of action. TBT significantly decreased fecundity at environmentally relevant levels at 1 µg TBT Sn/g in diet. Interestingly, in contrast to previous reports, TBT altered zebrafish sex ratio toward females, whereas MA exposure biased sex toward males. Since fecundity was significantly altered in the TBT-exposed group with up to 62% decrease, the potentially affected pathways were investigated. Significant downregulation was observed in brain mRNA levels of aromatase b (CYP19a1b) in females and peroxisome proliferator activated receptor gamma (PPARg) in both males and females, suggesting an involvement of these pathways in reproductive impairment associated with TBT.

Toxicity screening of diclofenac, propranolol, sertraline and simvastatin using Danio rerio and Paracentrotus lividus embryo bioassays.

Early life-stage bioassays have been used as an alternative to short-term adult toxicity tests since they are cost-effective. A single couple can produce hundreds or thousands of embryos and hence can be used as a simple high-throughput approach in toxicity studies. In the present study, zebrafish and sea urchin embryo bioassays were used to test the toxicity of four pharmaceuticals belonging to different therapeutic classes: diclofenac, propranolol, simvastatin and sertraline. Simvastatin was the most toxic tested compound for zebrafish embryo, followed by diclofenac. Sertraline was the most toxic drug to sea urchin embryos, inducing development abnormalities at the ng/L range. Overall, our results highlight the potential of sea urchin embryo bioassay as a promising and sensitive approach for the high-throughput methods to test the toxicity of new chemicals, including pharmaceuticals, and identify several drugs that should go through more detailed toxicity assays.

Small Molecules in the Treatment of Psoriasis.

Preclinical Research Psoriasis is an inflammatory systemic skin disease that affects various parts of the body requiring long-term management due to its chronic nature. Available treatment options include topical, systemic or biological therapies, which have long-term limitations associated to toxicity, tolerability and risk for adverse effects requiring its intermittent use and close monitoring. Small molecules modulate proinflammatory cytokines, selectively inhibit signaling pathways and showing potential to treat inflammatory diseases in patients not responding to conventional treatments. Presently, small molecules available are phosphodiesterase 4 inhibitors or Janus kinase inhibitors. Other small molecules under development for psoriasis include fumaric acid esters, amygdalin analogs, protein kinase C inhibitors, mitogen-activated protein kinase inhibitors, spleen protein kinase inhibitors, other tyrosine kinase inhibitors, sphingosine 1-phosphate receptor agonists, and A3 adenosine receptor agonists. These new treatment options represent important advances in the development of specific drugs to respond to the goals of treatment and improve patient quality of life.

Ustekinumab: The "New Kid on the Block" in the Treatment of Psoriatic Arthritis.

Psoriatic arthritis (PsA) is a chronic inflammatory seronegative spondyloarthritis associated with psoriasis. While TNF-α inhibitors have revolutionized the treatment of rheumatic diseases, including PsA, not all patients respond to these agents while others are unsuitable or intolerant to them. Thus, there is a need for additional treatment modalities with a novel mechanism of action. In the past years, the IL-23/Th17 axis has emerged as an important mechanism in the pathogenesis of PsA. Ustekinumab, a fully human IgG1κ monoclonal antibody that targets the common subunit p40 of IL-12 and IL-23, has been shown in clinical trials, to be well-tolerated and effective in patients with active PsA. It improved signs and symptoms of PsA, inhibited radiographic progression and was effective in dactylitis, enthesitis, and skin disease, with a safety profile consistent with the one observed in patients with psoriasis. Moreover, it was to be effective in anti-TNF-α experienced patients, definitely fulfilling an unmet need in the management of PsA.

Safety of Anti-TNF Therapies in Immune-Mediated Inflammatory Diseases: Focus on Infections and Malignancy.

Preclinical Research The efficacy of anti-TNF agents in the treatment of multiple immune-mediated inflammatory diseases (IMIDs) has increased their daily use. However, concerns remain regarding their long-term safety profile. Using a literature-based review of the infectious and malignant complications of anti-TNF biologics in IMIDs including psoriasis, Rheumatoid Arthritis, and inflammatory bowel disease, this review presents current evidence relative to the safety of anti-TNF agents in the context infections and malignancy in adults with IMIDs. Treatment with anti-TNF biologics is an effective treatment option with known risks that can be mitigated by appreciating the safety aspects and via a thorough screening and continuous monitoring of the patient.