Open Access

Background Protease‐activated receptor 2 (PAR2) signaling controls skin barrier function and inflammation, but the roles of immune cells and PAR2‐activating proteases in cutaneous diseases are poorly understood. Objective To dissect PAR2 signaling contributions to skin inflammation with new genetic and pharmacological tools. Methods/Results We found markedly increased numbers of PAR2+ infiltrating myeloid cells in skin lesions of allergic contact dermatitis (ACD) patients and in the skin of contact hypersensitivity (CHS) in mice, a murine ACD model for T cell–mediated allergic skin inflammation. Cell type–specific deletion of PAR2 in myeloid immune cells as well as mutation‐induced complete PAR2 cleavage insensitivity significantly reduced skin inflammation and hapten‐specific Tc1/Th1 cell response. Pharmacological approaches identified individual proteases involved in PAR2 cleavage and demonstrated a pivotal role of tissue factor (TF) and coagulation factor Xa (FXa) as upstream activators of PAR2 in both the induction and effector phase of CHS. PAR2 mutant mouse strains with differential cleavage sensitivity for FXa versus skin epithelial cell–expressed proteases furthermore uncovered a time‐dependent regulation of CHS development with an important function of FXa‐induced PAR2 activation during the late phase of skin inflammation. Conclusions Myeloid cells and the TF–FXa–PAR2 axis are key mediators and potential therapeutic targets in inflammatory skin diseases. Myeloid cells infiltrate the skin in contact hypersensitivity (CHS) and promote skin inflammation through protease activated receptor (PAR) 2 signaling. PAR2 mutants with resistance to selective proteases implicate coagulation FXa as a driver for the persistence of inflammation after allergen challenge. Pharmacological inhibitions indicate that the TF‐FXa‐PAR2 axis is a potential therapeutic target in CHS.

Introduction: Since the beginning of the pandemic in 2020, COVID-19 has changed the medical landscape. International recommendations for localized prostate cancer (PCa) include deferred treatment and adjusted therapeutic routines. Materials and methods: To longitudinally evaluate changes in PCa treatment strategies in urological and radiotherapy departments in Germany, a link to a survey was sent to 134 institutions covering two representative baseline weeks prior to the pandemic and 13 weeks from March 2020 to February 2021. The questionnaire captured the numbers of radical prostatectomies, prostate biopsies and case numbers for conventional and hypofractionation radiotherapy. The results were evaluated using descriptive analyses. Results: A total of 35% of the questionnaires were completed. PCa therapy increased by 6% in 2020 compared to 2019. At baseline, a total of 69 radiotherapy series and 164 radical prostatectomies (RPs) were documented. The decrease to 60% during the first wave of COVID-19 particularly affected low-risk PCa. The recovery throughout the summer months was followed by a renewed reduction to 58% at the end of 2020. After a gradual decline to 61% until July 2020, the number of prostate biopsies remained stable (89% to 98%) during the second wave. The use of RP fluctuated after an initial decrease without apparent prioritization of risk groups. Conventional fractionation was used in 66% of patients, followed by moderate hypofractionation (30%) and ultrahypofractionation (4%). One limitation was a potential selection bias of the selected weeks and the low response rate. Conclusion: While the diagnosis and therapy of PCa were affected in both waves of the pandemic, the interim increase between the peaks led to a higher total number of patients in 2020 than in 2019. Recommendations regarding prioritization and fractionation routines were implemented heterogeneously, leaving unexplored potential for future pandemic challenges.

Dendritic cells (DC) are uniquely capable of initiating and directing immune responses. The range of their activities grounds in the heterogeneity of DC subsets and their functional plasticity. Numerical and functional DC changes influence the development and progression of disease, and correction of such dysregulations has the potential to treat disease causally. In this review, we discuss the major advances in our understanding of the regulation of DC lineage formation, differentiation, and function in the skin. We describe the alteration of DC in disease as well as possibilities for therapeutic reprogramming with a focus on tolerogenic DC. Because regulatory T cells (Treg) are indispensable partners of DC in the induction and control of tolerance, we pay special attention to the interactions with these cells. Above all, we would like to arouse fascination for this cell type and its therapeutic potential in skin diseases.

Background Auditory verbal hallucinations are a major burden for patients with schizophrenia spectrum disorder and are often resistant to pharmacological and psychotherapeutic interventions. Repetitive transcranial magnetic stimulation (rTMS) of the temporo-parietal cortex has been proposed as a treatment for persistent auditory verbal hallucinations. We aimed to compare the efficacy and safety of bilateral continuous theta burst stimulation (cTBS), a brief and efficient form of rTMS, in adults with auditory verbal hallucinations versus sham cTBS. Methods This multicentre, randomised, sham-controlled, triple-blind phase 3 clinical trial was conducted at seven German psychiatric university hospitals and followed a planned two-stage adaptive design. Eligible patients were aged 18–65 years, had experienced persistent auditory verbal hallucinations at least once per week for a minimum of 3 months, and scored 3 points or higher on item P3 (hallucinatory behaviour) of the clinician-rated Positive Scale of the Positive and Negative Syndrome Scale (PANSS). 138 adults with treatment-persistent auditory verbal hallucinations and schizophrenia spectrum disorder were randomly assigned (1:1) to receive 15 sessions of active (n=70) or sham cTBS (n=68) administered sequentially as 600 pulses to the left and 600 pulses to the right temporo-parietal cortex over a 3-week period. The primary outcome was the change in the auditory hallucinations subscale of the Psychotic Symptom Rating Scales (PSYRATS-AH) from baseline to the end of treatment at 3 weeks, analysed in the intention-to-treat population, which included all randomly assigned patients who received at least one stimulation session. Safety was assessed in all patients who received at least one stimulation session. Follow-up assessments were performed at 1, 3, and 6 months after the end of treatment. People with lived experience were not involved in the study. This trial was registered at ClinicalTrials.gov, NCT02670291. Findings Between Oct 24, 2015, and May 1, 2023, 2583 patients were screened for eligibility, of whom 138 patients were randomly assigned to active cTBS (n=70; 32 [46%] females and 38 [54%] males) or sham treatment (n=68; 24 [35%] females and 44 [65%] males). Race and ethnicity data were not collected. The primary intention-to-treat analysis (66 patients in the active cTBS group; 64 patients in the sham cTBS group), combining stages 1 and 2, showed patients in the active cTBS group had a significantly greater decrease in the PSYRATS-AH score at end of treatment than did patients in the sham cTBS group (–6·36 [SD 7·97] vs –3·74 [SD 5·79]; adjusted difference –2·36 [95% CI –4·71 to –0·01]; p=0·042). Overall, 85 adverse events (43 in the active cTBS group; 42 in the sham cTBS group) were reported in 22 (33%) of 66 patients in the active cTBS group and 21 (33%) of 64 patients in the sham cTBS group. Headache was the most common adverse event in both groups (n=13 active cTBS group vs n=17 sham cTBS group). One serious adverse event occurred in the active group. Interpretation Sequential bilateral temporo-parietal cTBS over 3 weeks was safe and effective for reducing auditory verbal hallucinations in adults with schizophrenia spectrum disorder. This trial establishes cTBS as a treatment option for the care of these patients. Further research is needed to evaluate maintenance strategies, identify treatment predictors, and assess long-term efficacy.