IgE and anaphylaxis specific to the carbohydrate alpha-gal depend on IL-4.

BACKGROUND: Alpha-gal (Galα1-3Galß1-4GlcNAc) is a carbohydrate with the potential to elicit fatal allergic reactions to mammalian meat and drugs of mammalian origin. This type of allergy is induced by tick bites, and therapeutic options for this skin-driven food allergy are limited to the avoidance of the allergen and treatment of symptoms. Thus, a better understanding of the immune mechanisms resulting in sensitization through the skin is crucial, especially in the case of a carbohydrate allergen for which underlying immune responses are poorly understood. OBJECTIVE: We aimed to establish a mouse model of alpha-gal allergy for in-depth immunologic analyses. METHODS: Alpha-galactosyltransferase 1-deficient mice devoid of alpha-gal glycosylations were sensitized with the alpha-gal-carrying self-protein mouse serum albumin by repetitive intracutaneous injections in combination with the adjuvant aluminum hydroxide. The role of basophils and IL-4 in sensitization was investigated by antibody-mediated depletion. RESULTS: Alpha-gal-sensitized mice displayed increased levels of alpha-gal-specific IgE and IgG1 and developed systemic anaphylaxis on challenge with both alpha-gal-containing glycoproteins and glycolipids. In accordance with alpha-gal-allergic patients, we detected elevated numbers of basophils at the site of sensitization as well as increased numbers of alpha-gal-specific B cells, germinal center B cells, and B cells of IgE and IgG1 isotypes in skin-draining lymph nodes. By depleting IL-4 during sensitization, we demonstrated for the first time that sensitization and elicitation of allergy to alpha-gal and correspondingly to a carbohydrate allergen is dependent on IL-4. CONCLUSION: These findings establish IL-4 as a potential target to interfere with alpha-gal allergy elicited by tick bites.

Basophil activation in insect venom allergy: comparison of an established test using liquid reagents with a test using 5-color tubes with dried antibody reagents.

BACKGROUND: Flow cytometry-based basophil activation tests (BAT) have been performed with various modifications, differing in the use of distinct identification and activation markers. Established tests use liquid reagents while a new development involves the use of tubes with dried antibody reagents. The aim of this pilot study was to compare these two techniques in patients with insect venom allergy. METHODS: Seventeen patients with an insect venom allergy were included in the study. The established "BAT 1" utilizes conventional antibody solutions of anti-CCR3 for basophil identification and anti-CD63 to assess basophil activation, whereas "BAT 2" uses dried anti-CD45, anti-CD3, anti-CRTH2, anti-203c and anti-CD63 for identification and activation measurement of basophils. Negative and positive controls as well as incubations with honey bee venom and yellow jacket venom at three concentrations were performed. RESULTS: Seven patients had to be excluded due to low basophil counts, high values in negative controls or negative positive controls. For the remaining 10 patients the overall mean (± SD) difference in activated basophils between the two tests was 0.2 (± 12.2) %P. In a Bland-Altman plot, the limit of agreement (LoA) ranged from 24.0 to -23.7. In the qualitative evaluation (value below/above cut-off) Cohen's kappa was 0.77 indicating substantial agreement. BAT 2 took longer to perform than BAT 1 and was more expensive. CONCLUSION: The BAT 2 technique represents an interesting innovation, however, it was found to be less suitable compared to an established BAT for the routine diagnosis of insect venom allergies.

Unmet Needs in Darier's Disease from a Patient's Perspective: Lessons Learnt from the German Registry.

The MDHHgermany registry was initiated to characterize the "real-life" situation of affected individuals with Darier's disease (DD; Morbus Darier, MD) and Hailey-Hailey disease (HH), including their treatment and healthcare. To gain deeper insights into medical care of patients with DD, various aspects such as demographics, subjective symptoms, patient satisfaction with medical care, past and current therapies were explored. Patients with diagnosed DD were included. Subjective symptoms such as itch, pain and burning sensation were assessed. Individual therapy goals were recorded and patients assessed previous/current therapies along with satisfaction of medical care and treatment. A total of 55 patients were recruited; 47 patients were eligible for the analysis. Pruritus was rated the most bothersome symptom. Some 42.6% had not received systemic treatment so far or systemic therapies were rated ineffective (32.6%). Most commonly oral retinoids were prescribed, followed by corticosteroids. Patient satisfaction with medical care and treatment proved to be mediocre. This "real-life" data show an alarming unmet need regarding patients' satisfaction with medical care and treatment, evidenced by the reported lack of disease control. Further studies and interventions are needed to improve the spectrum of available therapies. MDHHgermany provides a foundational platform for future clinical trials, epidemiological studies, and pathophysiological analyses.

Sublingual immunotherapy tablets in monosensitized and polysensitized adults with allergic rhinoconjunctivitis.

Background: Most patients with allergic rhinitis/conjunctivitis (AR/C) are sensitized to more than one allergen. An ongoing question is the efficacy of single-allergen immunotherapy in patients who are polysensitized. Objective: To evaluate the efficacy and safety of grass, ragweed, tree, and house-dust mite (HDM) sublingual immunotherapy (SLIT) tablets in adults with AR/C who are mono- or polysensitized. Methods: Data from adults (ages ≥ 18 years) with AR/C who participated in phase III double-blind, placebo controlled field trials (four grass, two ragweed, two HDM, one tree) were included in the post hoc analyses. Efficacy was assessed by the total combined score (TCS) (sum of AR/C daily symptom and medication scores) during the entire pollen season for grass and tree trials, and peak pollen season for ragweed trials versus placebo. Efficacy for the HDM SLIT-tablet was assessed by the total combined rhinitis score (TCRS) (sum of rhinitis daily symptom and medication scores) during the last 8 weeks of treatment versus placebo. Results: For the grass SLIT-tablet, TCS improved by 20% (mean difference 1.33 [95% confidence interval {CI}, 0.44-2.22]) in the subjects who were monosensitized (n = 442) and 20% (mean difference 1.28 [95% CI, 0.90-1.67]) in the subjects who were polysensitized (n = 1857). For the ragweed SLIT-tablet, TCS improved by 19% (mean difference 1.72 [95% CI, -0.20 to 3.63]) in the subjects who were monosensitized (n = 115) and 27% (mean difference 2.27 [95% CI, 1.28-3.27]) in the subjects who were polysensitized (n = 528). For the tree SLIT-tablet, TCS improved by 54% (mean difference 4.65 [95% CI, 2.48-6.82]) in the subjects who were monosensitized (n = 138) and 34% (mean difference 2.51 [95% CI, 1.34-3.69]) in the subjects who were polysensitized (n = 437). For the HDM SLIT-tablet, TCRS improved by 20% (mean difference 1.24 [95% CI, 0.48-1.99]) in the subjects who were monosensitized (n = 468) and 17% (mean difference 0.85 [95% CI, 0.43-1.28]) in the subjects who were polysensitized (n = 1294). The overall safety profile was not qualitatively different between the subjects who were monosensitized and the subjects who were polysensitized. Conclusion: Grass, ragweed, tree, or HDM SLIT-tablet treatment is effective for the specific allergen in question in adults with AR/C and who are monosensitized or polysensitized. Targeting one relevant allergen with SLIT-tablets induces a clinical effect for that allergen in patients who were polysensitized.

The neglected twin: Nummular eczema is a variant of atopic dermatitis with codominant TH2/TH17 immune response.

BACKGROUND: Nummular eczema (NE) is a common chronic inflammatory skin disease characterized by multiple, pruritic, discoid-shaped lesions. Since the underlying immune mechanisms are not fully understood, it is unclear whether NE should be regarded as variant of atopic dermatitis (AD) or a distinct disease. OBJECTIVE: We compared the clinical, histopathologic, and molecular signatures of NE with that of type 2 and type 3 skin diseases. METHODS: We performed bulk RNA sequencing as well as histologic and clinical studies in lesional and nonlesional skin biopsy specimens from NE (n = 50), AD (n = 47), and psoriasis (n = 90) patients. RESULTS: NE displayed typical hallmarks of AD, such as an impaired epidermal barrier, microbial colonization, spongiosis, and eosinophil infiltration, but also aspects of psoriasis, including increased epidermal thickness, number of Ki-67+ cells, and neutrophilic infiltration. At the gene expression level, neutrophil-attracting cytokines (IL19, CXCL8, CXCL5) were upregulated, whereas TH2-related cytokines (IL13, CCL17, CCL18, CCL26, CCL27) were similarly expressed in NE compared to AD. Principal component analysis of transcriptome data from lesional skin showed that AD and NE cluster together distinct of psoriasis. In line with this, an established molecular classifier identified NE as AD rather than psoriasis. Finally, we demonstrated clinical and molecular efficacy of dupilumab treatment in NE. CONCLUSION: NE shows overlapping type 2 and type 3 immune signatures, while type 2 immunity predominates and should be the primary target of specific therapeutic interventions. This supports the view of NE as a variant of AD.

Characterization of High and Low IFNG-Expressing Subgroups in Atopic Dermatitis.

Atopic dermatitis (AD) is one of the most common chronic inflammatory skin diseases, with an increasing number of targeted therapies available. While biologics to treat AD exclusively target the key cytokines of type 2 immunity, Janus kinase inhibitors target a broad variety of cytokines, including IFN-γ. To better stratify patients for optimal treatment outcomes, the identification and characterization of subgroups, especially with regard to their IFNG expression, is of great relevance, as the role of IFNG in AD has not yet been fully clarified. This study aims to define AD subgroups based on their lesional IFNG expression and to characterize them based on their gene expression, T cell secretome and clinical attributes. RNA from the lesional and non-lesional biopsies of 48 AD patients was analyzed by RNA sequencing. Based on IFNG gene expression and the release of IFN-γ by lesional T cells, this cohort was categorized into three IFNG groups (high, medium, and low) using unsupervised clustering. The low IFNG group showed features of extrinsic AD with a higher prevalence of atopic comorbidities and impaired epidermal lipid synthesis. In contrast, patients in the high IFNG group had a higher average age and an activation of additional pro-inflammatory pathways. On the cellular level, higher amounts of M1 macrophages and natural killer cell signaling were detected in the high IFNG group compared to the low IFNG group by a deconvolution algorithm. However, both groups shared a common dupilumab response gene signature, indicating that type 2 immunity is the dominant immune shift in both subgroups. In summary, high and low IFNG subgroups correspond to intrinsic and extrinsic AD classifications and might be considered in the future for evaluating therapeutic efficacy or non-responders.

Detection of Sensitization Profiles with Cellular In Vitro Tests in Wheat Allergy Dependent on Augmentation Factors (WALDA).

Wheat allergy dependent on augmentation factors (WALDA) is the most common gluten allergy in adults. IgE-mediated sensitizations are directed towards ω5-gliadin but also to other wheat allergens. The value of the different in vitro cellular tests, namely the basophil activation test (BAT) and the active (aBHRA) and passive basophil histamine-release assays (pBHRA), in the detection of sensitization profiles beyond ω5-gliadin has not been compared. Therefore, 13 patients with challenge-confirmed, ω5-gliadin-positive WALDA and 11 healthy controls were enrolled. Specific IgE (sIgE), skin prick tests, BATs, aBHRA, and pBHRA were performed with allergen test solutions derived from wheat and other cereals, and results were analyzed and compared. This study reveals a distinct and highly individual reactivity of ω5-gliadin-positive WALDA patients to a range of wheat allergens beyond ω5-gliadin in cellular in vitro tests and SPT. In the BAT, for all tested allergens (gluten, high-molecular-weight glutenin subunits, α-amylase/trypsin inhibitors (ATIs), alcohol-free wheat beer, hydrolyzed wheat proteins (HWPs), rye gluten and secalins), basophil activation in patients was significantly higher than in controls (p = 0.004-p < 0.001). Similarly, significant histamine release was detected in the aBHRA for all test substances, exceeding the cut-off of 10 ng/mL in all tested allergens in 50% of patients. The dependency of tests on sIgE levels against ω5-gliadin differed; in the pBHRA, histamine release to any test substances could only be detected in patients with sIgE against ω5-gliadin ≥ 7.7 kU/L, whereas aBHRA also showed high reactivity in less sensitized patients. In most patients, reactivity to HWPs, ATIs, and rye allergens was observed. Additionally, alcohol-free wheat beer was first described as a promising test substance in ω5-gliadin-positive WALDA. Thus, BAT and aBHRA are valuable tools for the identification of sensitization profiles in WALDA.

Patient journey and disease-related digital media usage: A cross-sectional study among dermatology patients across Germany.

BACKGROUND AND OBJECTIVES: This study aimed to fill the gap of evidence-based data by examining the impact of health-related digital media use's impact on the patient-physician relationship and patient journey, with the goal of driving positive changes in office-based dermatological practice. PATIENTS AND METHODS: German individuals with skin conditions completed a questionnaire assessing health-related digital media use, eHealth literacy, impact of digital media use on the patient-physician relationship and patient journey, and sociodemographic and health characteristics from June to November 2022, followed by descriptive analysis and linear regressions. RESULTS: Overall, 919 participants were analyzed (median age: 47.00, interquartile range [28.00; 61.00] years, female: 53.6%, health-related digital media users: 56.8%). Google and online encyclopedias were commonly used before and after dermatological consultations. Online self-help groups were used by 75% of non-treated participants. Digital media use had no impact on the patient-physician relationship and a positive impact on the patient journey. Positive impacts were associated with higher eHealth literacy, satisfaction with digital media quality, importance of digital media, rural residence, high education, and trust in dermatologists. CONCLUSIONS: The potential of health-related digital media in office-based dermatological care necessitates the drive of an evidence-based digital health platform to improve eHealth literacy and satisfaction with the quality of digital media among affected individuals.

S3 Guideline Atopic dermatitis: Part 1 - General aspects, topical and non-drug therapies, special patient groups.

This S3 guideline was created based on the European S3 guideline, with special consideration of the medical conditions in the German-speaking region and incorporating additions from the previous German-language version. The interdisciplinary guideline commission consisted of representatives from the German Dermatological Society, the Professional Association of German Dermatologists, the Austrian Society of Dermatology and Venereology, the Swiss Society of Dermatology and Venereology, the German Society for Allergology and Clinical Immunology, the German Society for Pediatric and Adolescent Medicine, the Professional Association of Pediatricians and Adolescent Medicine, the Society for Pediatric Allergology and Environmental Medicine, the German Society for Pediatric Rehabilitation and Prevention, the German Society for Psychosomatic Medicine and Medical Psychotherapy, the German Network for Health Services Research, the German Eczema Association and the German Allergy and Asthma Association. This first part of the guideline focuses on the definition and diagnostic aspects of atopic dermatitis (AD), addressing topical therapy as well as non-pharmacological treatment approaches such as UV therapy, psychoeducational therapy, dietary interventions for AD, allergen immunotherapy for AD, and complementary medicine. This part of the guideline also covers specific aspects of AD in children and adolescents, during pregnancy and lactation, and in the context of family planning. Additionally, it addresses occupational aspects of AD and highlights the perspective of the patients. The second part of the guideline, published separately, addresses the systemic therapy of AD.

S3 guideline Atopic dermatitis: Part 2 - Systemic treatment.

The present S3 guideline was created based on the European English-language S3 guideline, with special consideration given to the medical conditions in the German-speaking region, and with additions from the previous German-language version, in accordance with the criteria of the AWMF. This second part of the guideline addresses the systemic therapy of atopic dermatitis (AD). It covers topics such as the indication for systemic therapy in children, adolescents, and adult patients with AD. Furthermore, it addresses all medications approved for AD, such as the biologics dupilumab and tralokinumab, the Janus kinase inhibitors abrocitinib, baricitinib, and upadacitinib, as well as conventional immunosuppressive therapies with systemic glucocorticosteroids and ciclosporin. Additionally, it discusses systemic off-label therapies. The first part of the guideline, published separately, includes the definition and diagnostic aspects of AD, describes topical therapy, non-drug therapy approaches, and addresses aspects related to special patient groups.

Cutaneous innate immune sensing of Toll-like receptor 2-6 ligands suppresses T cell immunity by inducing myeloid-derived suppressor cells.

Skin is constantly exposed to bacteria and antigens, and cutaneous innate immune sensing orchestrates adaptive immune responses. In its absence, skin pathogens can expand, entering deeper tissues and leading to life-threatening infectious diseases. To characterize skin-driven immunity better, we applied living bacteria, defined lipopeptides, and antigens cutaneously. We found suppression of immune responses due to cutaneous infection with Gram-positive S. aureus, which was based on bacterial lipopeptides. Skin exposure to Toll-like receptor (TLR)2-6-binding lipopeptides, but not TLR2-1-binding lipopeptides, potently suppressed immune responses through induction of Gr1(+)CD11b(+) myeloid-derived suppressor cells (MDSCs). Investigating human atopic dermatitis, in which Gram-positive bacteria accumulate, we detected high MDSC amounts in blood and skin. TLR2 activation in skin resident cells triggered interleukin-6 (IL-6), which induced suppressive MDSCs, which are then recruited to the skin suppressing T cell-mediated recall responses such as dermatitis. Thus, cutaneous bacteria can negatively regulate skin-driven immune responses by inducing MDSCs via TLR2-6 activation.

EAACI Molecular Allergology User's Guide 2.0.

Since the discovery of immunoglobulin E (IgE) as a mediator of allergic diseases in 1967, our knowledge about the immunological mechanisms of IgE-mediated allergies has remarkably increased. In addition to understanding the immune response and clinical symptoms, allergy diagnosis and management depend strongly on the precise identification of the elicitors of the IgE-mediated allergic reaction. In the past four decades, innovations in bioscience and technology have facilitated the identification and production of well-defined, highly pure molecules for component-resolved diagnosis (CRD), allowing a personalized diagnosis and management of the allergic disease for individual patients. The first edition of the "EAACI Molecular Allergology User's Guide" (MAUG) in 2016 rapidly became a key reference for clinicians, scientists, and interested readers with a background in allergology, immunology, biology, and medicine. Nevertheless, the field of molecular allergology is moving fast, and after 6 years, a new EAACI Taskforce was established to provide an updated document. The Molecular Allergology User's Guide 2.0 summarizes state-of-the-art information on allergen molecules, their clinical relevance, and their application in diagnostic algorithms for clinical practice. It is designed for both, clinicians and scientists, guiding health care professionals through the overwhelming list of different allergen molecules available for testing. Further, it provides diagnostic algorithms on the clinical relevance of allergenic molecules and gives an overview of their biology, the basic mechanisms of test formats, and the application of tests to measure allergen exposure.

Challenge-confirmed diagnosis restores quality of life in cofactor-dependent wheat allergy.

BACKGROUND: Food allergies including cofactor-dependent allergies such as cofactor-dependent wheat allergy (CDWA) decrease the quality of life (QOL) of patients. OBJECTIVE: To define the health-related QOL and fears in patients with CDWA and to evaluate the impact of diagnosis confirmation by oral challenge test (OCT). METHODS: Patients with CDWA diagnosed by clinical history, sensitization, and OCT were invited to participate. Clinical characteristics, patients' fears, self-perceived overall QOL, the Food Allergy Quality of Life Questionnaire-Adult Form score, and the risks and benefits of OCT were evaluated after the final diagnosis. RESULTS: A total of 22 adults with CDWA (13 male, 9 female; mean age 53.5 years; median 5 years until diagnosis) were included. Specific immunoglobulin E (IgE) levels for gluten proteins were inversely correlated with the reaction threshold (P < .05). Higher reaction severity in the patients' histories correlated with increased basal serum tryptase levels (P = .003) and gluten and gliadin specific IgE (P < .05), but not to QOL. After the first allergic reaction, patients reported a drop in QOL (P < .001). Challenge-confirmed diagnosis and medical consultation could restore the patients' QOL (P < .05) and reduce their fear of further reactions (P < .01). No severe reactions occurred during OCT, which was rated as not stressful and highly beneficial. Compared with patients with CDWA diagnosed without OCT in the literature, health-related QOL was less impaired (mean Food Allergy Quality of Life Questionnaire-Adult Form score 3.8), especially regarding the emotional impact (P < .001 vs existing literature). CONCLUSION: Until final diagnosis, patients with CDWA have a severe physical and psychological burden. OCT is a safe method to confirm the diagnosis, restore the patients' severely affected QOL, and reduce their fear of further reactions.

Out-of-Pocket Costs in Alopecia Areata: A Cross-Sectional Study in German-speaking Countries.

Alopecia areata is a common skin disease which is associated with psychosocial and financial burden. No curative therapy exists and, hence, affected persons resort to self-financed cosmetic solutions. However, studies on the economic impact of alopecia areata on individuals are limited. To estimate annual individual out-of-pocket costs in persons with alopecia areata, a cross-sectional study using a standardized online questionnaire was performed in Germany, Austria and Switzerland. A total of 346 individuals (95.1% women, mean age: 38.5 ± 11.6 years) with alopecia areata participated between April and August 2020. Mean additional spending on everyday necessities was 1,248€ per person per year, which was significantly influenced by the duration of the illness, the treatment provider, and disease severity. Hair replacement products and cosmetics accounted for the highest monthly costs, followed by costs for physician visits, hospital treatments, and medication. Most participants (n = 255, 73.7%) were currently not undergoing treatment, due to lack of efficacy, side-effects, costs and acceptance of the disease. Sex differences in expenses were observed, with women having higher expenditures. Alopecia areata-related out-of-pocket costs place a considerable financial burden on affected individuals, are higher compared with those of other chronic diseases, and should be considered in economic assessments of the impact of this disease.

Happiness Behind the Scenes: Associations between Heuristic Happiness and Related Dimensions in Skin Diseases.

Positive health approaches, such as happiness, are largely unexplored in medicine, including dermatology. Taking into consideration the various happiness measures, the aims of this cross-sectional study were to assess this concept using a 1-item heuristic happiness question and its related dimensions (Satisfaction with Life, Positive and Negative Affect, Quality of Life, and Compound Psychological Capital) in outpatients with different skin diseases between December 2019 and June 2020, and to examine the link between these dimensions. Overall, 414 dermatological patients were included: 67 with psoriasis, 84 atopic eczema, 10 mastocytosis, 19 nummular eczema, 84 malignant melanoma and 150 keratinocyte carcinoma. Comparing the skin diseases, differences were observed for heuristic happiness, Positive Affect, and some domains of Quality of Life and Compound Psychological Capital. Analysing the relationship between heuristic happiness and other happiness measures, the data revealed moderate to strong correlations (r = 0.30-0.46, p< 0.001) and variations in the understanding of happiness between the skin diseases. Overall, the most important facet of happiness was Hope as a domain of Compound Psychological Capital. This study emphasizes the individual definition of heuristic happiness in patients with skin diseases. A 1-item heuristic approach may be a simple and practical method to assess the complexity and individuality of happiness.

The Treat-to-Target Project in Atopic Dermatitis: One Year On.

Atopic dermatitis is a chronic skin condition for which a range of systemic treatments have recently been approved. A treat-to-target strategy has been developed previously alongside an algorithm to guide the management of patients with atopic dermatitis. Here, we review the strategy and algorithm in the context of the evolving therapeutic landscape, and identify areas for further refinement and development.

Increasing incidence of Trichophyton tonsurans in Munich-A single-centre observation.

BACKGROUND: Tinea capitis and tinea corporis are highly prevalent fungal skin infections, which globally are mainly caused by Microsporum canis and Trichophyton rubrum, respectively. While in the United States and Great Britain Trichophyton tonsurans is widely prevalent as a causative pathogen, it so far only plays a minor role in Germany. OBJECTIVES: Since the frequency of pathogenic species varies regionally and temporally, this study assesses the proportion of Trichophyton tonsurans infections in the dermatology department of a large university hospital in Germany from 2019 to 2022 and thoroughly characterises the affected patient population. PATIENTS/METHODS: This retrospective study at the Technical University of Munich analyses mycological culture results regarding the identified dermatophyte and infection site. Detailed patient and disease-related information on Trichophyton tonsurans positive patients was obtained. RESULTS: In 2022, 23 patients of 111 dermatophyte culture-positive patients tested positive for Trichophyton tonsurans. This accounted for 20.7% and represented a tenfold increase from 2.1% in 2019. Contact sports were only practiced by 21.7% of patients, and no common hotspot or other linkage could be identified between the cases. Additionally, 47.8% of the patients received a systemic treatment, with 30.4% visiting the clinic more than three times. In 2022, 21.7% were diagnosed with a simultaneous infection of the capillitium and body, whereas this was only observed in 7.1% of cases in 2019 to 2021. CONCLUSIONS: This study suggests an increase of Trichophyton tonsurans infections via several routes of transmission.

Evaluating public interest in herpes zoster in Germany by leveraging the internet: a retrospective search data analysis.

BACKGROUND: Herpes zoster (HZ) and its complication postherpetic neuralgia (PHN), whose incidence are both expected to increase with an ageing population, have demonstrated high costs on healthcare systems and burden on individual quality of life. Previous studies have shown the possibility of assessing public interest in a disease and factors that influence search behaviour using internet search data. The aim of this study was to analyze internet search data for HZ in Germany to evaluate public interest in the disease and relevant influential temporal and geographic factors that modify search behavior. METHODS: Google Ads Keyword Planner was used to generate a list of HZ-related keywords including their search volume for Germany as a whole and its sixteen federal states from October 2016 to September 2020. All keywords were qualitatively categorized, and changes over time and correlations with population density, physician density, and vaccination rates were assessed using Welch's ANOVA, Bonferroni correction for post-hoc analyses, and Pearson's correlation. RESULTS: A total of 1,651 relevant keywords with a search volume of 20,816,210 searches were identified. Overall, national search volume increased each year of the study period with a peak in August 2020. More than half of the total search volume related to general queries (55.1%). The highest average monthly search volumes were observed in the states of Hamburg, Saarland, and Bremen. Average monthly search volume showed strong positive correlations with population density (r = .512, p = .043) and a strong negative correlation with the number of inhabitants per working physician (r = -.689, p = .003). CONCLUSIONS: The study demonstrated that evaluating internet search data is a viable method for assessing public interest in HZ, thereby identifying areas of unmet need to support targeted public health campaigns.

Outlier detection in dermatology: Performance of different convolutional neural networks for binary classification of inflammatory skin diseases.

BACKGROUND: Artificial intelligence (AI) and convolutional neural networks (CNNs) represent rising trends in modern medicine. However, comprehensive data on the performance of AI practices in clinical dermatologic images are non-existent. Furthermore, the role of professional data selection for training remains unknown. OBJECTIVES: The aims of this study were to develop AI applications for outlier detection of dermatological pathologies, to evaluate CNN architectures' performance on dermatological images and to investigate the role of professional pre-processing of the training data, serving as one of the first anchor points regarding data selection criteria in dermatological AI-based binary classification tasks of non-melanoma pathologies. METHODS: Six state-of-the-art CNN architectures were evaluated for their accuracy, sensitivity and specificity for five dermatological diseases and using five data subsets, including data selected by two dermatologists, one with 5 and the other with 11 years of clinical experience. RESULTS: Overall, 150 CNNs were evaluated on up to 4051 clinical images. The best accuracy was reached for onychomycosis (accuracy = 1.000), followed by bullous pemphigoid (accuracy = 0.951) and lupus erythematosus (accuracy = 0.912). The CNNs InceptionV3, Xception and ResNet50 achieved the best accuracy in 9, 8 and 6 out of 25 data sets, respectively (36.0%, 32.0% and 24.0%). On average, the data set provided by the senior physician and the data set provided in accordance with both dermatologists performed the best (accuracy = 0.910). CONCLUSIONS: This AI approach for the detection of outliers in dermatological diagnoses represents one of the first studies to evaluate the performance of different CNNs for binary decisions in clinical non-dermatoscopic images of a variety of dermatological diseases other than melanoma. The selection of images by an experienced dermatologist during pre-processing had substantial benefits for the performance of the CNNs. These comparative results might guide future AI approaches to dermatology diagnostics, and the evaluated CNNs might be applicable for the future training of dermatology residents.

Histology-based classifier to distinguish early mycosis fungoides from atopic dermatitis.

BACKGROUND: Histopathological differentiation of early mycosis fungoides (MF) from benign chronic inflammatory dermatoses remains difficult and often impossible, despite the inclusion of all available diagnostic parameters. OBJECTIVE: To identify the most impactful histological criteria for a predictive diagnostic model to discriminate MF from atopic dermatitis (AD). METHODS: In this multicentre study, two cohorts of patients with either unequivocal AD or MF were evaluated by two independent dermatopathologists. Based on 32 histological attributes, a hypothesis-free prediction model was developed and validated on an independent patient's cohort. RESULTS: A reduced set of two histological features (presence of atypical lymphocytes in either epidermis or dermis) was trained. In an independent validation cohort, this model showed high predictive power (95% sensitivity and 100% specificity) to differentiate MF from AD and robustness against inter-individual investigator differences. LIMITATIONS: The study investigated a limited number of cases and the classifier is based on subjectively evaluated histological criteria. CONCLUSION: Aiming at distinguishing early MF from AD, the proposed binary classifier performed well in an independent cohort and across observers. Combining this histological classifier with immunohistochemical and/or molecular techniques (such as clonality analysis or molecular classifiers) could further promote differentiation of early MF and AD.