Dominant immune tolerance in the intestinal tract imposed by RelB-dependent migratory dendritic cells regulates protective type 2 immunity.

Dendritic cells (DCs) are crucial for initiating protective immune responses and have also been implicated in the generation and regulation of Foxp3+ regulatory T cells (Treg cells). Here, we show that in the lamina propria of the small intestine, the alternative NF-κB family member RelB is necessary for the differentiation of cryptopatch and isolated lymphoid follicle-associated DCs (CIA-DCs). Moreover, single-cell RNA sequencing reveals a RelB-dependent signature in migratory DCs in mesenteric lymph nodes favoring DC-Treg cell interaction including elevated expression and release of the chemokine CCL22 from RelB-deficient conventional DCs (cDCs). In line with the key role of CCL22 to facilitate DC-Treg cell interaction, RelB-deficient DCs have a selective advantage to interact with Treg cells in an antigen-specific manner. In addition, DC-specific RelB knockout animals show increased total Foxp3+ Treg cell numbers irrespective of inflammatory status. Consequently, DC-specific RelB knockout animals fail to mount protective Th2-dominated immune responses in the intestine after infection with Heligmosomoides polygyrus bakeri. Thus, RelB expression in cDCs acts as a rheostat to establish a tolerogenic set point that is maintained even during strong type 2 immune conditions and thereby is a key regulator of intestinal homeostasis.

Bridging the gap through telemedicine: Pilot study on the acceptance and use of teledermatology for urticaria.

BACKGROUND: Chronic spontaneous urticaria (CSU) significantly impairs patients' quality of life. Despite advances in diagnosis and therapy, treatment is still unsatisfactory. Telemedicine offers a promising solution to improve treatment. This pilot study assesses the acceptability and utilization of a digital health model for CSU, examines its impact on disease management, and identifies technical challenges. PATIENTS AND METHODS: In this prospective pilot study, CSU patients at a university hospital in Germany were included. Over 12 months, participants interacted with physicians via a telemedicine platform, which was the study-specific intervention. After each three-month digital visit, symptoms and quality of life were assessed using electronic patient reported outcomes (ePROs) and online questionnaires. In the end, patients and doctors rated the overall satisfaction, the user-friendliness of the platform and the technical challenges. RESULTS: 24 patients completed the study. The majority (92%) reported that the digital concept could be a promising alternative to traditional consultations. Analysis from baseline to end of study revealed that disease control remained stable while quality of life improved. All physicians found the digital application reliable and time-saving. CONCLUSIONS: This pilot study demonstrates the feasibility and high acceptance of a digital health model for the management of CSU. Further research with larger cohorts is needed and planned to determine broader applicability.

Bifidobacterium breve DSM 32583 and Limosilactobacillus fermentum CECT5716 postbiotics attenuate S. aureus and IL-33-induced Th2 responses.

Over the past decades, the prevalence of allergic diseases noticeably increased in industrialized countries. The Th2 immune response plays a central role in these pathologies and its modulation using pro-/postbiotics constitutes a promising approach to prevent or alleviate disease symptoms. The aim of this in vitro study, was to investigate the ability of human milk-derived Bifidobacterium breve DSM 32583 (Bb) and Limosilactobacillus fermentum CECT5716 (Lf), to modulate the Th2 induced responses. To this end, Th2 cells were generated by co-culturing of human naïve Th cells with monocyte-derived dendritic cells (moDCs) either stimulated with Staphylococcus aureus or IL-33. The immunomodulatory effects of pro-/postbiotic preparations of Bb and Lf on moDCs and Th2 cells were evaluated in terms of maturation markers expression and cytokines production. Remarkably, the tested strains induced the anti-inflammatory cytokine IL-10 in moDCs, in a strain-, dose- and viability-dependent manner with no significant upregulation of IL-12p70 nor CD83, CD86 or HLA-DR. Interestingly, Bb and Lf postbiotics were able to dampen the Th2/Th1 response induced upon S. aureus- or IL-33 stimulation. They were also able to synergistically induce IL-10 in moDCs and T cells, upon co-stimulation with LPS. Finally, we observed that live probiotics triggered a mild Th1 response that was attenuated in the presence of galacto-oligosaccharides. Altogether, Bb and Lf pro-/postbiotics exhibited remarkable immune regulatory effects on both moDCs and Th2 cells. Therefore, further in vivo studies should be considered to validate these findings and assess their ability to prevent allergy or alleviate its symptoms in affected patients.

Pinewood VOC emissions protect from oxazolone-induced inflammation and dysbiosis in a mouse model of atopic dermatitis.

Pinewood, increasingly used in construction and interior fittings, emits high amounts of volatile organic compounds (VOCs), which tend to accumulate in indoor air. Whether indoor VOCs affect the development of atopic dermatitis (AD) is a matter of debate. We aimed to evaluate the effects of pinewood VOCs on the development of AD-like inflammatory phenotype and linked microbiome alterations, both hallmarks of AD. An oxazolone-induced mouse model of AD was exposed to three different VOC concentrations emitted by pinewood plates throughout the experiment. The disease course and associated immunological and microbiological changes were evaluated. To validate and translate our results to humans, human keratinocytes were exposed to a synthetic pinewood VOCs mixture in an AD environment. Pinewood emitted mainly terpenes, which at a total concentration of 5 mg/m3 significantly improved oxazolone-induced key AD parameters, such as serum total IgE, transepidermal water loss, barrier gene alteration, inflammation, and dysbiosis. Notably, exposure to pinewood VOCs restored the loss of microbial richness and inhibit Staphylococci expansion characteristic of the oxazolone-induced mouse AD model. Most beneficial effects of pinewood VOCs were dose-dependent. In fact, lower (<3 mg/m3) or higher (>10 mg/m3) pinewood VOC levels maintained only limited beneficial effects, such as preserving the microbiome richness or impeding Staphylococci expansion, respectively. In the human in-vitro model, exposure of keratinocytes grown in an AD environment to a pinewood VOCs mixture reduced the release of inflammatory markers. In conclusion, our results indicate that airborne phytochemicals emitted from pinewood have beneficial effects on an AD-like phenotype and associated dysbiosis. These investigations highlight the effects of terpenes as environmental compounds in the prevention and/or control of atopic skin disease.

Basophil activation test in Hymenoptera venom allergy.

Before starting venom-specific immunotherapy (VIT), systemic sting reactions to Hymenoptera venoms require allergological workup in order to prove an IgE-mediated reaction and to identify the culprit insect venom. In addition to skin tests and the determination of specific IgE antibodies, the basophil activation test (BAT) using flow cytometry has emerged as a powerful tool and sensitive marker for this purpose in recent years. BAT seems to have a better informative value in terms of clinical relevance compared to the other tests. In Hymenoptera venom allergies, BAT is particularly useful for the diagnosis of cases with unclear or contradictory history and sensitization profile. Its results are associated with adverse reactions during VIT and efficacy of VIT and therefore have a certain predictive value for side effects and treatment failure of VIT. In research, it is mainly used to characterize the allergenic components of Hymenoptera venoms. This review article focuses on these topics.

Digital Media Usage Behavior and Its Impact on the Physician-Patient Relationship: Cross-Sectional Study Among Individuals Affected by Psoriasis in Germany.

BACKGROUND: Psoriasis is a chronic skin disorder with a high burden of disease. People affected with psoriasis increasingly use the internet for health-related reasons, especially those with younger age, higher education, and higher disease severity. Despite advantages such as enhancing the individuals' knowledge with the use of digital media for health-related issues, disadvantages were also present such as quality control, and variability in the individuals' health information literacy. While patients with psoriasis within medical settings generally trust physicians over digital media, they commonly withhold their web-based research findings from health care providers. OBJECTIVE: The study aims to (1) identify further factors associated with regular psoriasis-related internet use, (2) rank specific digital media platforms used, and (3) examine digital media within the physician-patient relationship among individuals with and without dermatological treatment. METHODS: A cross-sectional, questionnaire-based study was conducted among individuals with self-reported psoriasis in Germany between September 2021 and February 2022. Participants were recruited via digital media platforms and in person at a University Hospital Department of Dermatology in southern Germany. The questionnaire asked about demographic and medical information, individual psoriasis-related digital media use, and the impact of digital media on the physician-patient relationship. Data were analyzed descriptively, and logistic regression models were performed to assess the factors associated with regular psoriasis-related internet use. RESULTS: Among 321 individuals with a median age of 53 (IQR 41-61) years (nonnormally distributed; females: 195/321), female sex, shorter disease duration, moderate mental burden of disease, and good self-assessed psoriasis-related knowledge were associated with regular psoriasis-related internet use. Of the 188 participants with a mean age of 51.2 (SD 13.9) years (normally distributed) who used digital media 106 (56.4%) usually searched for information on psoriasis-based websites and 98 (52.1%) on search engines, primarily for obtaining information about the disease and therapy options, while social media were less frequently used (49/188, 26.1%). Nearly two-thirds of internet users (125/188) claimed that their physicians did not recommend digital media platforms. About 44% (82/188) of the individuals reported to seek for additional information due to the insufficient information provided by their physician. CONCLUSIONS: This study revealed the importance of digital media in the context of psoriasis, especially among women, individuals with shorter disease duration, and moderate mental disease severity. The lack of physicians' digital media recommendations despite their patients' desire to receive such and being more involved in health-related decisions seems to be a shortcoming within the physician-patient relationships. Physicians should guide their patients on digital media by recommending platforms with evidence-based information, thereby potentially creating an adequate framework for shared decision-making. Future research should focus on strategies to prevent the spread of false information on digital media and address the needs of patients and physicians to enhance health-related digital media offerings.

A qualitative exploration of the patient journey in axial spondyloarthritis towards a people-centered understanding.

This exploratory qualitative study aims to gain a people-centered understanding of the patient journey in axial spondyloarthritis (axSpA). Semi-structured interviews were conducted with 15 individuals diagnosed with axSpA, aged 18 years and older, who were purposively recruited from a rheumatologic practice in southern Germany. The interviews were carried out as web-based video calls between September and October 2021, audio-recorded, transcribed verbatim, and analyzed according to Kuckartz's qualitative content analysis. Patient journey narratives encompassed both healthcare journeys and personal journeys. Healthcare journeys were characterized as fragmented and difficult to navigate, with diagnosis often marking a turning point toward more coordinated care. Post-diagnosis, new challenges emerged (e.g., time management for treatment). Personal journeys comprised perceptions of axSpA in social contexts (e.g., stigmatization) and the continuous interplay of comorbidities and biographical events with healthcare related to axSpA. This study proposes a people-centered perspective on the patient journey in axSpA, emphasizing the interplay of biographies, comorbidities, and social context with healthcare events. Recognizing these personal factors in clinical practice is encouraged to address complex health needs and tailor treatment to each individual. Further efforts should promote collaboration between medical disciplines and integrate healthcare and social support at all stages of the axSpA patient journey.

Brief Communication: Treatment Outcomes for Advanced Melanoma of Unknown Primary Compared With Melanoma With Known Primary.

SUMMARY: Most patients with advanced melanomas have a known primary site [melanoma of known primary (MKP)]. However, 2%-9% of patients are diagnosed with melanoma metastasis of unknown primary (MUP). As MUP and MKP have similar UV-induced mutations and molecular signatures, it is proposed that the primary tumor has regressed completely in patients with MUP. As regression of the primary tumor could be indicative of enhanced recognition of melanoma antigens, we hypothesize that patients with advanced MUP have a better outcome compared with MKP.Patients with advanced MUP from 10 German university hospitals were retrospectively analyzed and matched with MKP based on the type of systemic treatment (BRAF and MEK inhibitors, PD-1 inhibitor monotherapy, combined CTLA-4 and PD-1 inhibitor therapy) therapy line (first or second line) and AJCC stage (IIIC, IV M1a-M1d). Three hundred thirty-seven patients with MUP were identified, and 152 treatments with PD-1 and CTLA-4 inhibitors, 142 treatments with PD-1 inhibitors, and 101 treatments with BRAF and MEK inhibitors were evaluated. Median time to treatment failure was significantly prolonged in patients with MUP treated with PD-1 monotherapy (17 mo, 95% CI: 9-25, P = 0.002) compared with MKP (5 mo, 95% CI: 3.4-6.6), as well as in MUP treated with combined PD-1 and CTLA-4 therapy (11 mo, 95% CI: 4.5-17.5, P < 0.0001) compared with MKP (4 mo, 95% CI: 2.9-5.1) Occurrence of immune-related adverse events and time to treatment failure for patients with BRAF and MEK inhibitors was similar in MKP and MUP. In our multicentre collective, patients with MUP have better outcomes under immunotherapy compared with MKP.

Next generation mycological diagnosis: Artificial intelligence-based classifier of the presence of Malassezia yeasts in tape strip samples.

BACKGROUND: Malassezia yeasts are almost universally present on human skin worldwide. While they can cause diseases such as pityriasis versicolor, their implication in skin homeostasis and pathophysiology of other dermatoses is still unclear. Their analysis using native microscopy of skin tape strips is operator dependent and requires skill, training and significant amounts of hands-on time. OBJECTIVES AND METHODS: To standardise and improve the speed and quality of diagnosis of Malassezia in skin tape strip samples, we sought to create an artificial intelligence-based algorithm for this image classification task. Three algorithms, each using different internal architectures, were trained and validated on a manually annotated dataset of 1113 images from 22 samples. RESULTS: The Vision Transformer-based algorithm performed the best with a validation accuracy of 94%, sensitivity of 94.0% and specificity of 93.5%. Visualisations providing insight into the reasoning of the algorithm were presented and discussed. CONCLUSION: Our image classifier achieved very good performance in the diagnosis of the presence of Malassezia yeasts in tape strip samples of human skin and can therefore improve the speed and quality of, and access to this diagnostic test. By expanding data sources and explainability, the algorithm could also provide teaching points for more novice operators in future.

Continuously monitoring the human machine? - A cross-sectional study to assess the acceptance of wearables in Germany.

Background: Wearables have the potential to transform healthcare by enabling early detection and monitoring of chronic diseases. This study aimed to assess wearables' acceptance, usage, and reasons for non-use. Methods: Anonymous questionnaires were used to collect data in Germany on wearable ownership, usage behaviour, acceptance of health monitoring, and willingness to share data. Results: Out of 643 respondents, 550 participants provided wearable acceptance data. The average age was 36.6 years, with 51.3% female and 39.6% residing in rural areas. Overall, 33.8% reported wearing a wearable, primarily smartwatches or fitness wristbands. Men (63.3%) and women (57.8%) expressed willingness to wear a sensor for health monitoring, and 61.5% were open to sharing data with healthcare providers. Concerns included data security, privacy, and perceived lack of need. Conclusion: The study highlights the acceptance and potential of wearables, particularly for health monitoring and data sharing with healthcare providers. Addressing data security and privacy concerns could enhance the adoption of innovative wearables, such as implants, for early detection and monitoring of chronic diseases.

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.

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.

Disease-Related Internet Use and its Relevance to the Patient-Physician Relationship in Atopic Dermatitis: A Cross-Sectional Study in Germany.

Background: Health-related internet use presents both opportunities and challenges for patients and physicians and requires a comprehensive understanding to improve individual health care in atopic dermatitis (AD). Objective: To explore differences between regular and irregular disease-related internet users, reasons for disease-related internet use, and its relevance to the patient-physician relationship in AD. Methods: This cross-sectional study recruited 221 adults with AD online and from a German university clinic between August 2021 and February 2022. The questionnaire queried sociodemographic and disease-related information, reasons for and against using the internet, types of channels used, and the impact on the patient-physician relationship. Participants were categorized as regular (≥once per month) and irregular (

Test Panel of Hidden Allergens for "Idiopathic Anaphylaxis" Reveals Wheat Allergy Dependent on Augmentation Factors as Common Final Diagnosis.

BACKGROUND: Idiopathic anaphylaxis (IA) is an unresolved concern. Hidden allergens may be relevant in IA and in nonsteroidal anti-inflammatory drug hypersensitivity (NSAID-HS). OBJECTIVE: To identify hidden elicitors for IA and NSAID-HS by a skin prick test (SPT) (13 allergens) and allergen-specific IgE (sIgE) panel (12 allergens) and to determine the value of each tested allergen. METHODS: We retrospectively included all patients from 2018 to 2021 referred with a suspicion of IA or NSAID-HS by history in whom SPT and/or sIgE to allergens of the IA panel were performed. Patient characteristics from patients' records included comorbidities, history and symptoms of anaphylaxis, serum baseline tryptase level, total IgE level, SPT, sIgE, challenge results, and final diagnoses. RESULTS: A total of 134 patients (77 female, mean age 39.7 ± 14.6 years) were included. Median serum baseline tryptase and total IgE levels were 4.23 µg/L and 133.5 kU/L, respectively. Allergologic workup with the IA panel resulted in positive SPT and sIgE in 61 (47%) and 66 (60%) patients, respectively. In those, confirmation or exclusion of allergy, mostly by challenge, led to a definitive diagnosis in 61 of 134 patients (46%). Skin prick test was most frequently positive to gluten (22.4%) and sIgE to ω5-gliadin (21.6%), which correlated with the history (r = 0.310, P < .001; and r = 0.407, P < .001, respectively). In 28 of 134 patients (21%) with initially suspected IA or NSAID-HS, challenges confirmed occult food allergy in which wheat allergy dependent on augmentation factors was the most frequent cause of anaphylaxis (19%). CONCLUSIONS: Wheat allergy dependent on augmentation factors should be considered in all patients with anaphylaxis of unknown cause or after NSAID intake.

Leveraging web search data in Germany to identify unmet needs of contraceptives on a population-based level: A longitudinal retrospective study.

BACKGROUND: There are a variety of possible contraceptives available. While medical advice is an important resource for selecting the individual contraceptive, previous research has shown that the Internet has become an increasingly important source of health care information. OBJECTIVES: This study aims to identify key trends in contraception-related web searches in Germany and thus allows conclusions about preferences and unmet needs with regard to pregnancy prevention. DESIGN: Longitudinal retrospective study. METHODS: Google Ads Keyword Planner was used to identify contraception-related keywords and their search volume in Germany and all federal states between 2018 and 2021. The keywords were categorized based on gender, hormonal/non-hormonal, and different contraceptive methods. Search volume and categories were analyzed for temporal trends, regional differences, and underlying socioeconomic variables. RESULTS: The 1481 contraception-related keywords corresponded to 15,081,760 searches. In total, a 56% increase in searches/100,000 inhabitants was observed. Highest mean search volume was observed in categories "woman," "woman/non-hormonal" and "woman/non-hormonal/barrier," respectively, and in the federal state Hamburg, while the lowest was seen in North Rhine-Westphalia. CONCLUSION: The increase in search volume reflects a high interest in contraception, particularly in non-hormonal female methods. This stands in contrast to the limited number of effective non-hormonal contraceptives available and points to an unmet need. In addition, the low search volume for male contraceptives demonstrates gender-specific responsibilities regarding family planning in German society.

Analyzing Google search volume to identify preferences and unmet needs in contraception in German societyContraception is a topic that occupies many people in their daily lives. There is a wide range of different contraceptives available. The decision for a particular contraceptive can be made with the help of a consultation with a gynecologist or through other sources, such as the Internet. Research has shown that the Internet has become an important source for obtaining health information. This study aims to identify key trends in contraception-related web searches in Germany and thus allows conclusions about preferences and unmet needs with regard to pregnancy prevention. Google Ads Keyword Planner was used to identify contraception-related keywords and their search volume in Germany and all federal states between 2018 and 2021. The keywords were assigned to different categories based on whether the woman or the man uses the contraceptive, whether the contraceptive methods contain hormones or no hormones, and which exact contraceptive methods are associated with the search term. The search volume was analyzed in terms of trends over time, regional differences in Germany and socioeconomic variables. A 56% increase in searches per 100,000 inhabitants was observed. The highest mean search volume was observed in the category woman, followed by female non-hormonal contraceptives and within that category, the contraceptive method "barrier." The study shows that there is a high interest in contraception, especially in non-hormonal female contraceptives. These results contrast with the limited number of non-hormonal and effective contraceptive methods available. In addition, the low search volume in the category man shows that women are the main responsible party in terms of contraception in German society.