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Lichen planus (LP) is a common, chronic relapsing inflammatory disorder of the skin and mucous membranes which often poses a major therapeutic challenge due to its refractory course. Novel pathogenesis-based therapies are urgently needed. As several studies have shown that IL-17 may contribute to LP pathogenesis, we investigated whether therapeutic targeting of IL-17 T cells leads to clinical improvement of mucosal and cutaneous LP lesions. A total of five patients with lichen planus were treated in a compassionate use trial with either secukinumab (anti-IL-17; 3 patients with acute and chronic recalcitrant muco-cutaneous LP), ustekinumab (anti-IL-12/IL-23; 1 patient with recalcitrant oral LP) or guselkumab (anti-IL-23; 1 patient with recalcitrant oral LP). The clinical course of the patients was assessed by the Autoimmune Bullous Skin Disorder Intensity Score (ABSIS) reflecting both extent and severity of disease and functional sequelae of oral involvement for at least 12 weeks. The inflammatory infiltrate in lesional and post-lesional skin was analyzed by immunohistochemistry before and after treatment. Furthermore, the cytokine profile of peripheral blood T cells from the treated patients was assessed by flow cytometry and/or ELISpot assay. Treatment with secukinumab induced rapid and prolonged clinical amelioration of muco-cutaneous LP. Clinical improvement was accompanied by a strong reduction of the Th1 and Th17/Tc17 cellular mucosal and cutaneous infiltrate. Moreover, long-term treatment of one patient with recalcitrant oral LP with ustekinumab led to healing of the ulcerative oral lesions and a reduction of peripheral blood and lesional IL-17 T cells. Finally, treatment with guselkumab led to a marked clinical improvement in a patient with recalcitrant erosive oral LP. These findings show for the first time that therapeutic targeting of Th17/Tc17 cells leads to a pronounced clinical amelioration of mucosal and cutaneous LP and strongly suggests that IL-17-producing T cells are central to disease pathogenesis. Thus, therapeutic targeting of Th17/Tc17 cells opens new therapeutic avenues in the treatment of recalcitrant LP.

Paraneoplastic autoimmune multi-organ syndrome (PAMS) is a rare clinical condition characterized by variable and heterogeneous clinical phenotypes in the presence of neoplasias which largely depend on the activation of humoral and cellular immune responses. Clinically, these patients present with a spectrum of antibody-driven pemphigus-like lesions to graft-vs.-host-disease-like exanthemas with a lichenoid inflammatory infiltrate in the skin. PAMS is occasionally associated with thymoma, in which altered immune surveillance eventually leads to multiorgan autoimmunity which often includes variable cutaneous symptoms. This disorder is associated with a profound disturbance of peripheral immune tolerance against human autoantigens. We here present a patient with relapsing thymoma who developed PAMS with several cutaneous and extracutaneous autoimmune disorders. Peripheral blood mononuclear cells (PBMC), sera, and lesional skin biopsies were obtained at different clinical disease stages. Peripheral T cell subsets were characterized phenotypically and the cytokine profile of the peripheral blood T cellular response against distinct epidermal and dermal autoantigens of the skin was analyzed by ELISpot assay. Serological screening was performed by ELISA and immunoblot analysis. Skin biopsies were subjected to immunohistochemical analysis of distinct T cell subsets. Thymoma tissue was analyzed for the presence of T regulatory cells and compared with adult thymus and indolent thymoma. In the present case, thymoma was the cause of the observed multi-organ autoimmune syndromes as its recurrence and surgical removal was associated with the relapse and regression of the cutaneous symptoms, respectively. Initially, the patient presented with two autoimmune disorders with Th2/Th1 imbalance, myasthenia gravis (MG) and pemphigus foliaceus (PF), which regressed upon immunosuppressive treatment. Months later, the patient developed a lichenoid exanthema with a Th1-dominated skin infiltrate. Further clinical evaluation revealed the recurrence of the thymoma and the lichenoid exanthema gradually regressed upon thymectomy. Our contention that T cell recognition against distinct cutaneous autoantigens, such as desmoglein 1 (Dsg1), shifted from a Th2 to a Th1-dominated immune response could not be fully substantiated as the patient was on a stringent immunosuppressive treatment regimen. We could only observe a decrease of the initially present serum IgG autoantibodies against Dsg1. Phenotypic analysis of the associated thymoma showed a lower number of T regulatory cells compared to adult thymus and indolent thymoma, suggesting that impaired thymus-derived immune surveillance had a direct impact on the outcome of the observed cutaneous autoimmune disorders.

Background Differential diagnosis is a crucial skill for primary care physicians. General practice plays an increasing important role in undergraduate medical education. Via general practice, students may be presented with an overview of the whole spectrum of differential diagnosis in regard to common symptoms encountered in primary care. This project evaluated the impact of a blended learning program (using the inverted classroom approach) on student satisfaction and development of skills and knowledge. Methods An elective seminar in differential diagnosis in primary care, which utilized an inverted classroom design, was offered to students. Evaluation followed a mixed methods design: participants completed a pre- and post-test, a questionnaire, and a focus group discussion. Interviews were transcribed verbatim and answers were grouped according to different themes. Test results were analysed using the Wilcoxon matched-pairs signed-ranks test. Results Participants (n = 17) rated the course concept very positively. Especially the inverted classroom approach was appreciated by all students, as it allowed for more time during the seminar to concentrate on interactive and practice based learning. Students (n = 16) showed a post-test significant overall gain in skills and knowledge of 33%. Conclusions This study showed a positive effect of the inverted classroom approach on students’ satisfaction and skills and knowledge. Further research is necessary in order to explore the potentials of this approach, especially the impact on development of clinical skills.

Background: The COVID-19 pandemic has notably affected the epidemiology of various infectious diseases. The imposed public health measures and disruptions in vaccination programs have potentially altered the patterns of these diseases post pandemic. Objective: To investigate the change in epidemiology of otorhinolaryngological infectious diseases in adult and pediatric patients after the COVID-19 pandemic and the relaxation of public health measures. Methods: A retrospective cohort study was conducted at a large tertiary university otolaryngology department in the south of Germany, examining admissions with specific ICD-10 diagnoses from 2019 to 2023. Data were seasonally categorized and statistically analyzed. Results: A total of 1728 inpatient cases were analyzed. There was a significant increase in otorhinolaryngological infections in the post-pandemic winter of 2022, particularly of peritonsillar abscesses, acute tonsillitis and acute mastoiditis. No significant post-pandemic spike in mononucleosis was observed. The duration of hospitalization was shorter in 2022, and the median age of patients did not change significantly pre- versus post-pandemic. Conclusions: The study indicates a significant post-pandemic rise in otorhinolaryngological infections. Remarkably, the typical “dip” in infections during the summer months was not observed in the post pandemic years, possibly reflecting the impact of the termination of non-pharmaceutical interventions. Mononucleosis was the only infection not following this pattern.

High expression of the receptor tyrosine kinase (RTK) insulin-like growth factor-1 receptor (IGF1R) and RTK mutations are associated with high-risk/worse prognosis in multiple myeloma (MM). Combining the pIGF1R/pINSR inhibitor linsitinib with the proteasome inhibitor (PI) bortezomib seemed promising in a clinical trial, but IGF1R expression was not associated with therapy response. Because the oncogenic impact of IGF1R mutations is so far unknown, we investigated the functional impact of IGF1R mutations on survival signaling, viability/proliferation and survival response to therapy. We transfected four human myeloma cell lines (HMCLs) with IGF1RWT, IGF1RD1146N and IGF1RN1129S (Sleeping Beauty), generated CRISPR-Cas9 IGF1R knockouts in the HMCLs U-266 (IGF1RWT) and L-363 (IGF1RD1146N) and tested the anti-MM activity of linsitinib alone and in combination with the second-generation PI carfilzomib in seven HMCLs. IGF1R knockout entailed reduced proliferation. Upon IGF1R overexpression, survival signaling was moderately increased in all HCMLs and slightly affected by IGF1RN1129S in one HMCL, whereby the viability remained unaffected. Expression of IGF1RD1146N reduced pIGF1R-Y1135, especially under serum reduction, but did not impact downstream signaling. Linsitinib and carfilzomib showed enhanced anti-myeloma activity in six out of seven HMCL irrespective of the IGF1R mutation status. In conclusion, IGF1R mutations can impact IGF1R activation and/or downstream signaling, and a combination of linsitinib with carfilzomib might be a suitable therapeutic approach for MM patients potentially responsive to IGF1R blockade.

Das MM ist eine maligne Erkrankung, die von biologischer und klinischer Heterogenität geprägt ist. Sie ist durch die monoklonale Vermehrung von Plasmazellen charakterisiert. In vorangegangenen Studien wurde eine Häufung von Mutationen in RTK nachgewiesen. Diese gingen mit einem negativen Einfluss auf das Überleben von MM Patientinnen und Patienten einher.Im Rahmen dieser Arbeit wurde der Einfluss des IGF1R an HMZL mittels siRNAvermitteltem IGF1R-Knockdown untersucht und dessen Effekt auf das Signalnetzwerk mittels Western Blot Analysen ermittelt. Um die Heterogenität des MM besser abzubilden, wurden sechs verschiedenen HMZL ausgewählt.Der IGF1R-Knockdown war in allen HMZL sowohl anhand der Reduktion der IGF1R-Expression als auch der IGF1R-Aktivierung deutlich nachweisbar. Stellvertretend für den PI3K/AKT Signalweg wurde die AKT-Aktivierung untersucht, welche nach IGF1R-Knockdown in allen Linien abnahm. Im Ras/Raf/MEK/ERK Signalweg fiel eine deutliche Reduktion der ERK1/2- und MEK-Aktivierung in den von PCL stammenden HMZL L-363 und MM.1S, sowie in JJN-3 mit der Hochrisikotranslokation t(14;16) auf. Entsprechend der Beobachtungen für die AKT-Aktivierung, nahm die PYK2-Aktivierung in allen HMZL nach IGF1R-Knockdown ab, was auf ein Zusammenspiel von IGF1R, PYK2 und AKT in allen HMZL hindeutet.Zukünftige Untersuchungen werden zeigen, ob IGF1R Inhibitoren alleine oder in Kombination mit z.B. AKT, PYK2 oder Proteasomen-Inhibitoren in bestimmten molekularen MM Subgruppen ein effektives therapeutisches Ziel sind.

Background Data regarding the importance of multidimensional frailty to guide clinical decision making for remdesivir use in older patients with coronavirus disease 2019 (COVID-19) are largely unexplored. Objective The aim of this research was to evaluate if the Multidimensional Prognostic Index (MPI), a multidimensional frailty tool based on the Comprehensive Geriatric Assessment (CGA), may help physicians in identifying older hospitalized patients affected by COVID-19 who might benefit from the use of remdesivir. Methods This was a multicenter, prospective study of older adults hospitalized for COVID-19 in 10 European hospitals, followed-up for 90 days after hospital discharge. A standardized CGA was performed at hospital admission and the MPI was calculated, with a final score ranging between 0 (lowest mortality risk) and 1 (highest mortality risk). We assessed survival with Cox regression, and the impact of remdesivir on mortality (overall and in hospital) with propensity score analysis, stratified by MPI = 0.50. Results Among 496 older adults hospitalized for COVID-19 (mean age 80 years, female 59.9%), 140 (28.2% of patients) were treated with remdesivir. During the 90 days of follow-up, 175 deaths were reported, 115 in hospital. Remdesivir treatment significantly reduced the risk of overall mortality (hazard ratio [HR] 0.54, 95% confidence interval CI 0.35–0.83 in the propensity score analysis) in the sample as whole. Stratifying the population, based on MPI score, the effect was observed only in less frail participants (HR 0.47, 95% CI 0.22–0.96 in propensity score analysis), but not in frailer subjects. In-hospital mortality was not influenced by remdesivir use. Conclusions MPI could help to identify less frail older adults hospitalized for COVID-19 who could benefit more from remdesivir treatment in terms of long-term survival.

Key summary points Aim Testing the role of the Multidimensional Prognostic Index (MPI), based on the Comprehensive Geriatric Assessment (CGA), in predicting the risk of incident delirium in hospitalized older patients with COVID-19. Findings The MPI showed a good accuracy in predicting incident delirium (AUC = 0.71). Its accuracy is higher than the ones of two validated predictive models (AWOL delirium risk-stratification score’s AUC = 0.63; Martinez Model’s AUC = 0.61; p < 0.0001 for both comparisons). Message The MPI is a sensitive tool for risk-stratification of the incident delirium in hospitalized older COVID-19 patients. Purpose Incident delirium is a frequent complication among hospitalized older people with COVID-19, associated with increased length of hospital stay, higher morbidity and mortality rates. Although delirium is preventable with early detection, systematic assessment methods and predictive models are not universally defined, thus delirium is often underrated. In this study, we tested the role of the Multidimensional Prognostic Index (MPI), a prognostic tool based on Comprehensive Geriatric Assessment, to predict the risk of incident delirium. Methods Hospitalized older patients (≥ 65 years) with COVID-19 infection were enrolled (n = 502) from ten centers across Europe. At hospital admission, the MPI was administered to all the patients and two already validated delirium prediction models were computed (AWOL delirium risk-stratification score and Martinez model). Delirium occurrence during hospitalization was ascertained using the 4A’s Test (4AT). Accuracy of the MPI and the other delirium predictive models was assessed through logistic regression models and the area under the curve (AUC). Results We analyzed 293 patients without delirium at hospital admission. Of them 33 (11.3%) developed delirium during hospitalization. Higher MPI score at admission (higher multidimensional frailty) was associated with higher risk of incident delirium also adjusting for the other delirium predictive models and COVID-19 severity (OR = 12.72, 95% CI = 2.11–76.86 for MPI-2 vs MPI-1, and OR = 33.44, 95% CI = 4.55–146.61 for MPI-3 vs MPI-1). The MPI showed good accuracy in predicting incident delirium (AUC = 0.71) also superior to AWOL tool, (AUC = 0.63) and Martinez model (AUC = 0.61) ( p  < 0.0001 for both comparisons). Conclusions The MPI is a sensitive tool for early identification of older patients with incident delirium.

Effective conservation management and habitat restoration rely on understanding how biodiversity responds to environmental change. Centuries of silviculture have homogenized forests and their species communities globally, reducing biodiversity. To test whether restoring forest structural complexity can promote biodiversity, we conducted a large-scale, spatially explicit landscape experiment. At 11 sites across Germany, we compared bat and bird diversity in forests with experimentally enhanced heterogeneity by increasing deadwood and canopy complexity to homogeneous production forests. Both taxa were investigated by autonomous acoustic recorders and automatic species identification. We quantified within-patch (α-), between-patch (β-), and landscape-level (γ-) diversity, emphasizing infrequent to highly frequent species for taxonomic, functional, and phylogenetic diversity. The pairwise comparisons of the sites were synthesized using a newly developed meta-analysis of rarefaction-extrapolation curves. γ-diversity increased significantly in structurally heterogeneous forests for both taxa, albeit through distinct taxon-specific mechanisms. Bat γ-diversity gains were primarily driven by higher β-diversity, indicating greater dissimilarity in species assemblages among patches, while bird γ-diversity increased via higher α-diversity within patches. Bat diversity increases were mainly taxonomic, suggesting functional similarity in the communities, whereas birds showed the highest gains in functional diversity, indicating that experimental treatments resulted in greater trait dissimilarity. Our results provide experimental evidence under real-world conditions that γ-diversity can be shaped by different diversity mechanisms. These patterns likely originate from differences in activity ranges, such as the large-scale movements of foraging bats in contrast to the more spatially restricted, territorial behavior of birds. This highlights the need for taxon-specific restoration strategies in homogenized landscapes.