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Objectives: To determine the surgical and oncologic outcomes of salvage radical prostatectomy (sRP) after FT failure., Materials and Methods: Patients who consecutively underwent primary RP or sRP after FT failure between 2008 and 2022 were retrospectively selected. Primary or sRP were performed with either a robot-assisted or open approach. All surgeries were performed by surgeons with experience of ≥ 500 cases. Biochemical recurrence-free survival (BFS), intra- and postoperative surgical and functional outcomes were assessed. To evaluate the impact of surgical setting, propensity score (PS) matching was performed., Results: 80 patients received sRP. Outcomes were analyzed using PS-matched cohorts (203 RPs vs. 68 sRPs). After a median follow-up of 25.4 months, sRP and RP had equal BFS (24mo-BFS: 72.4% vs. 76.0% (p = 0.8)). No statistically significant differences were found between sRP and RP in terms of median operative time (OT) (171 min vs. 168 min), estimated blood loss (EBL) (500 ml vs. 500 ml), length of hospital stay (LOS) (7 days vs. 7 days) and time to catheter removal (11 days vs. 11 days) and 1-year continence rates (all standardized mean differences ≤ 0.1). The main limitation is the retrospective study design., Conclusion: In the hands of experienced surgeons, sRP after FT offered comparable surgical and oncologic outcomes as RP in a primary setting., Competing Interests: Declaration. Conflict of interest: The authors declare that they have no conflict of interest., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The classic approach of nonsteroidal anti-inflammatory drug (NSAID)-exacerbated respiratory disease (NSAID-ERD) includes pharmaceutical and surgical treatments, as well as avoidance of cyclooxygenase 1-inhibitor NSAIDs. The introduction of biologics in the treatment of severe asthma and chronic rhinosinusitis with nasal polyps represents an alternative therapeutic approach to the classical aspirin therapy after desensitization (ATAD) in some regions, and with convincing results. However, their use is limited due to approval and/or high-cost restrictions. NSAID-ERD is a mainly type 2 and highly eosinophilic disease, and mAbs targeting IgE or IL-5, IL-4, and IL-13 have been shown to be effective for both severe asthma and severe chronic rhinosinusitis with nasal polyps. So far, dupilumab demonstrated greater efficacy in patients with NSAID-ERD than in aspirin-tolerant patients with regard to several clinical outcomes. Patients with NSAID-ERD respond very rapidly to omalizumab also, with reduction in the release of prostaglandin D 2 and cysteinyl leukotrienes. Patients favored biologic treatment over ATAD in multiple retrospective analyses, which must be acknowledged when choosing one or the other option. Although this review will summarize ATAD in general, it will more prominently focus on when ATAD should be considered, even when type 2 biologics are available. In addition, there are conflicting studies as to whether patients on a type 2 biologic become desensitized to NSAIDs, because omalizumab proved to restore tolerance to aspirin in only two-third of patients. This goal of NSAID tolerance should be considered as part of disease control future approaches, representing one of many aspects in a patient-centered care approach., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a prevalent chronic inflammatory condition affecting the nose and paranasal sinuses, posing a significant socio-economic impact with substantial challenges in management. Biologics targeting type 2 inflammation such as dupilumab, have emerged as promising options. This study addresses a critical knowledge gap by comprehensively evaluating the 3-year impact of sustained dupilumab therapy in CRSwNP., Methods: A multicentric, retrospective collection of real-world data from five tertiary referral centers in Germany was conducted, enrolling 150 adult patients. The study investigated patient-reported outcomes, disease-specific indices and clinical measures, focusing on therapeutic response persistence, adverse events, and factors influencing treatment continuity., Results: Results indicate significant improvements in clinical parameters from baseline (n = 150) with sustained effectiveness after 36 months (n = 138) as indicated in mean score ± standard deviation. Dupilumab treatment significantly improved overall disease-related impairment (VAS score: 7.5 ± 2.5 to 1.6 ± 1.3) and rhinosinusitis symptoms (SNOT-22: 59.4 ± 19.4 to 18.0 ± 15.0). Nasal Polyp Scores (NPS) decreased (5.3 ± 1.8 to 0.7 ± 1.1), and olfactory function improved (3.2 ± 2.5 to 8.4 ± 2.8), with three out of four patients achieving normosmia or hyposmia after 36 months. An "Excellent" treatment response according to EUFOREA23 criteria was observed in 76.5% of patients after 36 months. Sixteen patients discontinued Dupilumab, 12 permanently. Adverse events totaled 69 in 48 patients, commonly self-limiting., Conclusion: The study highlights the enduring effectiveness and lack of habituation to dupilumab after a sustained therapy of 3 years, providing valuable insights into its long-term therapeutic implications for CRSwNP patients., (© 2024 The Author(s). Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Equation of state measurements at Jovian or stellar conditions are currently conducted by dynamic shock compression driven by multi-kilojoule multi-beam nanosecond-duration lasers. These experiments require precise design of the target and specific tailoring of the spatial and temporal laser profiles to reach the highest pressures. At the same time, the studies are limited by the low repetition rate of the lasers. Here, we show that by the irradiation of a thin wire with single-beam Joule-class short-pulse laser, a converging cylindrical shock is generated compressing the wire material to conditions relevant to the above applications. The shockwave was observed using Phase Contrast Imaging employing a hard X-ray Free Electron Laser with unprecedented temporal and spatial sensitivity. The data collected for Cu wires is in agreement with hydrodynamic simulations of an ablative shock launched by highly impulsive and transient resistive heating of the wire surface. The subsequent cylindrical shockwave travels toward the wire axis and is predicted to reach a compression factor of 9 and pressures above 800 Mbar. Simulations for astrophysical relevant materials underline the potential of this compression technique as a new tool for high energy density studies at high repetition rates., (© 2024. The Author(s).)

Working during pregnancy and breastfeeding is a special situation for both the employee and the employer/supervisor. The amended version of the Maternity Protection Act (MuSchG), which came into force on January 1st, 2018, protects the health of women and their children while working, training or studying during pregnancy, after giving birth and while breastfeeding. Women should be able to continue their employment or related activities during this time without jeopardising their health or that of their child. This law was furthermore reformed to prevent discrimination against the working mother during this time. In order to create the best and safest possible framework conditions for employment during pregnancy and breastfeeding, the DGHNO-KHC and the BVHNO would like to present a "general positive list" and a "positive list for surgical activities" as part of this statement, which should serve as a guideline for all relevant parties. This agreed positive list is intended to enable pregnant and breastfeeding doctors to carry out patient-related activities as well as head and neck surgeries in accordance with the MuSchG of 2018. Hereby, affected colleagues should have the opportunity to continue working self-determined., Competing Interests: Frau Dr. Sharma gibt an: Advisory Board Merck Die Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht., (Thieme. All rights reserved.)

High-resolution X-ray imaging of noncrystalline objects is often achieved through the approach of scanning coherent diffractive imaging known as ptychography. The imaging resolution is usually limited by the scattering properties of the sample, where weak diffraction signals at the highest scattering angles compete with parasitic scattering. Here, we demonstrate that X-ray multilayer Laue lenses with a high numerical aperture (NA) can be used to create a strong reference beam that holographically boosts weak scattering from the sample over a large range of scattering angles, enabling high-resolution imaging that is tolerant of such background. An imaging resolution of sub-10 nm was achieved at a photon energy of 17.4 keV with lenses of 0.014 NA from a Siemens star test object and a sample of hierarchical nanoporous gold, recording projection holograms at an effective magnification of more than 30,000 directly on a pixel-array detector. A numerical study compared this approach to low-NA far-field ptychography, indicating significant advantages for using high-NA lenses in the presence of background noise. This imaging modality is particularly fast and efficient at recording high-resolution transmission phase-contrast images over large fields of view in a facile manner.

The growth pattern of oropharyngeal squamous cell carcinomas (OPSCC) varies from compact tumor cell aggregates to diffusely infiltrating tumor cell-clusters. The influence of the growth pattern on local tumor control and survival has been studied mainly for surgically treated oral cavity carcinomas on a visual basis. In this study, we used multiplex immunofluorescence staining (mIF) to examine the antigens pan-cytokeratin, p16INK4a, Ki67, CD271, PD-L1, and CD8 in pretherapeutic biopsies from 86 OPSCC. We introduce Tumor-stroma contact ratio (TSC), a novel parameter, to quantify the relationship between tumor cells in contact with the stromal surface and the total number of epithelial tumor cells. mIF tumor cores were analyzed at the single-cell level, and tumor-stromal contact area was quantified using the R package "Spatstat". TSC was correlated with the visually assessed invasion pattern by two independent investigators. Furthermore, TSC was analyzed in relation to clinical parameters and patient survival data to evaluate its potential prognostic significance. Higher TSC correlated with poor response to (chemo-)radiotherapy (r = 0.3, p < 0.01), and shorter overall (OS) and progression-free (PFS) survival (median OS: 13 vs 136 months, p < 0.0001; median PFS: 5 vs 85 months, p < 0.0001). Visual categorization of growth pattern according to established criteria of tumor aggressiveness showed interobserver variability increasing with more nuanced categories (2 categories: k = 0.7, 95 %-CI: 0.55 - 0.85; 4 categories k = 0.48, 95 %-CI: 0.35 - 0.61). In conclusion, TSC is an objective and reproducible computer-based parameter to quantify tumor-stroma contact area. We demonstrate its relevance for the response of oropharyngeal carcinomas to primary (chemo-)radiotherapy., Competing Interests: Declaration of competing interest J. Kaufmann, M. Haist, I. Kur, S.Zimmer, J. Hagemann, C. Matthias, S. Grabbe, H. Schmidberger, A. Weigert and A. Mayer declare that they have no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

The prevalence of analgesic intolerance syndrome (AIS), internationally known as NSAID-exacerbated respiratory disease (NERD), is reported to be 0.5-5.7% in the general population. The disease often begins with nasal symptoms, which are later joined by chronic rhinosinusitis with nasal polyposis (CRSwNP), asthma, and respiratory hypersensitivity reactions following use of nonsteroidal anti-inflammatory drugs (NSAIDs). In the setting of chronic respiratory disease, the type 2 inflammatory endotype is predominant in approximately 80% of patients with CRSwNP, rendering biologics directed against interleukin (IL)-4, IL‑5, IL-13, and IgE of high clinical interest, particularly in patients with severe CRSwNP and NERD. NERD is often associated with CRSwNP and asthma. Patients with CRSwNP and NERD have been treated, among other therapies, with aspirin therapy after desensitization (ATAD). With the approval of monoclonal antibodies for CRSwNP and asthma, the question arises as to what extent ATAD, which is associated with undesirable side effects, is still useful in the treatment of CRSwNP. In this manuscript, the use of ATAD in CRSwNP patients is discussed from different medical and socioeconomic points of view, both alternatively to or in combination with monoclonal antibodies. Accordingly, both ATAD and biologics continue to play a supporting role in modern treatment of CRSwNP in NERD patients, and should be used judiciously to complement each other., (© 2024. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Nanotomography with hard X-rays is a widely used technique for high-resolution imaging, providing insights into the structure and composition of various materials. In recent years, tomographic approaches based on simultaneous illuminations of the same sample region from different angles by multiple beams have been developed at micrometre image resolution. Transferring these techniques to the nanoscale is challenging due to the loss in photon flux by focusing the X-ray beam. We present an approach for multi-beam nanotomography using a dual-beam Fresnel zone plate (dFZP) in a near-field holography setup. The dFZP generates two nano-focused beams that overlap in the sample plane, enabling the simultaneous acquisition of two projections from slightly different angles. This first proof-of-principle implementation of the dual-beam setup allows for the efficient removal of ring artifacts and noise using machine-learning approaches. The results open new possibilities for full-field multi-beam nanotomography and pave the way for future advancements in fast holotomography and artifact-reduction techniques., (open access.)

Background: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a type‑2 inflammatory disease of the upper airways, with severe impairment of quality of life. Persons affected by NSAID-exacerbated respiratory disease (NERD) usually present with highly dynamic recurrence of polyps and disease despite prior treatment with sinus surgeries, oral corticosteroids, and aspirin desensitization (ATAD). Biologic therapy has fundamentally changed the choice of therapeutic concept; however, limited data exist on subgroups such as NERD patients. The aim of the current article is to report on a multicenter retrospective study on add-on therapy with dupilumab, omalizumab, and mepolizumab in patients with NERD., Methods: This is a retrospective cohort study of patients (NERD+, status after ATAD) in three reference centers in Germany (Munich, Mainz, Berlin). Subjective and objective parameters were collected at 4, 8, and 12 months after biologic therapy initiation in accordance with current EPOS/EUFOREA (European Position Paper on Rhinosinusitis and Nasal Polyps/European Forum for Research and Education in Allergy and Airway Diseases) guidelines. Biologic agents were chosen depending on availability and patient characteristics., Results: Treatment was commenced in 122 patients meeting the criteria for CRSwNP and NERD. The endoscopic polyp score, SNOT-22 questionnaire score, visual analogue scoring of total symptoms/severity of disease, and sense of smell (psychophysical testing with Sniffin'Sticks/Brief Smell Identification Test, B‑SIT; Sensonics, Inc., Haddon Heights, NJ, USA) improved significantly after 4 and 12 months of add-on therapy (p < 0.0001). All three biologic agents significantly improved one or more disease parameter. Adverse events were not life threatening but led to change of biologic agent in 4 cases. Patients rated biologic therapy significantly better than ATAD, with improved long-term disease control., Conclusion: Add-on biologic therapy is effective, safe, and widely accepted among CRSwNP + NERD patients. Future studies might allow for personalized algorithms with sequential surgery, ATAD, and/or biologic therapy., (© 2024. The Author(s).)

Allergic rhinitis (AR) is the most common allergic disease worldwide and one of the most common chronic diseases in general. Allergic rhinitis is caused by inhalant allergens from outdoor and indoor environments with varying significance of different allergens in global regions. We provide options for the current management for AR including pharmacological treatments and nonpharmacological options and allergen immunotherapy (AIT). A literature review has been conducted in Medline, Pubmed, as well as the national and international study (ClinicalTrials.gov) and guideline registers and the Cochrane Library. Human studies published on the topic in the period up to and including November 2023 were taken into account. Allergen avoidance measures, pharmacotherapy, and AIT are the cornerstones of AR treatment. Nonpharmacological measures and behavioral recommendations should be adequately added. Tools of precision medicine are already playing a significant role and will be part of the diagnostic and therapeutic standard in the future. Patients benefit most in a network of different pharmacological and nonpharmacological treatment measures including AIT. Application of precision medicine tools for diagnosis and treatment will improve standards of care., (Copyright © 2024 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: With targeted inhibition of type 2 inflammation, biologics represent the standard add-on therapy for inadequately controlled severe forms of chronic rhinosinusitis with nasal polyps (CRSwNP). Despite standardization with paper-based checklists, the documentation of medical history and current findings pertinent to indication criteria are a significant challenge for physicians. Through development of an application based on structured reporting, the current study aimed to improve documentation quality and simplify the decision-making process. Previously available paper checklists served as a comparison., Methods: For this study, a digital incremental tool was programmed to record current findings and check for fulfilment of indication criteria. The tool was compared with other checklists in terms of completeness, time required, and readability., Results: A total of 20 findings were collected for each of the three documentation options and included in the analysis. Documentation with the two paper-based checklists had comparable information content: 17.5 ± 5.1/21.7 ± 7.6 points out of a maximum of 43 points; p > 0.05. Documentation using the digital application led to a significant increase in information content compared to all paper-based documentation. The average score was 38.25 ± 3.7 (88.9% of maximum; p < 0.001). On average, user satisfaction was high (9.6/10). Use of the digital application was initially more time consuming, but as more cases were documented, the time taken improved significantly., Conclusion: In the future, structured reporting using apps could replace paper-based reporting for the indication of biologic therapy in CRSwNP patients and offer additional benefits in terms of data quality and traceability of results. The increasing volume of documentation in the future, the progress of digitalization, and the possibility of networking between individual centers make introduction of the app in the near future both likely and economical., (© 2024. The Author(s).)

The phase problem is a well known ill-posed reconstruction problem of coherent lens-less microscopic imaging, where only the squared magnitude of a complex wavefront is measured by a detector while the phase information of the wave field is lost. To retrieve the lost information, common algorithms rely either on multiple data acquisitions under varying measurement conditions or on the application of strong constraints such as a spatial support. In X-ray near-field holography, however, these methods are rendered impractical in the setting of time sensitive in situ and operando measurements. In this paper, we will forego the spatial support constraint and propose a projected gradient descent (PGD) based reconstruction scheme in combination with proper preprocessing and regularization that significantly reduces artifacts for refractive reconstructions from only a single acquired hologram without a spatial support constraint. We demonstrate the feasibility and robustness of our approach on different data sets obtained at the nano imaging endstation of P05 at PETRA III (DESY, Hamburg) operated by Helmholtz-Zentrum Hereon.

Background: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a multifactorial inflammatory disease of the mucous membranes of the nose and sinuses. Eosinophilic inflammation is described as a common endotype. The anti-IL-5 antibody mepolizumab was approved in November 2021 as an add-on therapy to intranasal glucocorticosteroids for the treatment of adults with severe chronic rhinosinusitis with nasal polyps when systemic glucocorticosteroids or surgery do not provide adequate disease control. While national and international recommendations exist for the use of mepolizumab in CRSwNP, it has not yet been adequately specified how this therapy should be monitored, what follow-up documentation is necessary, and when it should be discontinued if necessary., Materials and Methods: A literature search was performed to analyze previous data on the treatment of CRSwNP with mepolizumab and to determine the available evidence by searching Medline, Pubmed, the national and international trial and guideline registries, and the Cochrane Library. Human studies published in the period up to and including 10/2022 were considered., Results: Based on the international literature and previous experience by an expert panel, recommendations for follow-up, adherence to therapy intervals, and possible therapy breaks as well as discontinuation of therapy when using mepolizumab for the indication CRSwNP in the German healthcare system are given on the basis of a documentation sheet., Conclusion: Understanding the immunological basis of CRSwNP opens up new non-surgical therapeutic approaches with biologics for patients with severe, uncontrolled courses. Here, we provide recommendations for follow-up, adherence to therapy intervals, possible therapy pauses, or discontinuation of therapy when mepolizumab is used as add-on therapy with intranasal glucocorticosteroids to treat adult patients with severe CRSwNP that cannot be adequately controlled with systemic glucocorticosteroids and/or surgical intervention., Competing Interests: B. Wollenberg has received honoraria and/or research funding from MSD, Sanofi, AstraZeneca, Novartis, BMS Adboard outside the present work. J. Hagemann states that he has received payments for lectures and fees for advisory boards from the companies Sanofi Aventis, Novartis Pharma GmbH, and GlaxoSmithKline. A.M. Chaker provides consulting services (e.g., Advisory Boards, DSMBs), lectures, or other activities via the Technical University of Munich (TUM) or has conducted clinical studies or received research funding via TUM from: Allergopharma, ALK-Abello, AstraZenecaa, Bencard/Allergen Therapeutics, GSK, HAL Allergy, Immunotek, Novartis, SanofiGenzyme and Regeneron, Zeller AG, EIT Health, BMBF. AMC is also an officer of EUFOREA, EAACI, AeDA, and DGAKI. H. Olze has received honoraria and/or research funding from F. Hoffmann-La Roche Ltd., Sanofi-Aventis Deutschland GmbH, AstraZeneca GmbH, GlaxoSmithKline GmbH & Co KG, and Novartis Pharma GmbH. L. Klimek reports grants and/or honoraria from Allergopharma, MEDA/Mylan, HAL Allergie, ALK Abelló, LETI Pharma, Stallergenes, Quintiles, Sanofi, ASIT Biotech, Lofarma, Allergy Therapeut., AstraZeneca, GSK, Inmunotk, outside the submitted work; and membership in the following organizations: AeDA, DGHNO, German Academy for Allergology and Clinical Immunology, HNO-BV GPA, EAACI. U. Förster-Ruhrmann received honoraria for lectures from Novartis, AstraZeneca, Sanofi. and GSK outside the present work. S. Strieth reports grants from the German Research Foundation (DFG), Bonn, grants from the Head and Neck Tumor Research Foundation, Wiesbaden, grants and non-financial support from MED-EL AG, Innsbruck, personal fees from Auris Medical, Basel, personal fees from Merck Serono, Darmstadt, personal fees from Otonomy, Inc, San Diego (USA), personal fee Nordmark Arzneimittel, Uetersen, grant Andreas Fahl Medizintechnik-Vertrieb, Cologne, grant Atos Medical, Troisdorf, grant Tracoe Medical, Nieder-Olm, grants from Heimomed Heinze, Kerpen, grants from Bromepithetik, Heidelberg, grants from Fresenius Kabi, Bad Hersfeld, personnel fee from Sonofi Genzyme, Berlin, personal fee from ALK-Abelló Arzneimittel, Hamburg, outside the submitted work. M. Cuevas has received honoraria and/or non-financial support from Novartis, Sanovi-Aventis, Allergopharma, HAL Allergy, Leti Pharma, AstraZeneca, GlaxoSmithKline, ALK Abelló, Bencard Allergy, Stallergenes, and Roxall outside the submitted work and reports memberships with the following organizations: AeDA, DGHNO. A.G. Beule has received honoraria for lectures, consulting, or research activities from Allakos, AstraZenecaa, BMS, GSK, Medtronic, MSD, Novartis, Olympus, Pharmalog, Pohl Boskamp, and Sanofi Aventis outside the present work. O. Guntinas-Lichius has received honoraria from MED-EL, Merck, Novartis, MEDICE, and Merz outside the present work; and he is a member of the following organizations: DGHNO, BVHNO. T.K. Hoffmann participates in honorary advisory boards of the companies Merck, MSD, and BMS, but outside the scope of this work. C. Bachert received honoraria/research funding from the companies Sanofi, GSK, Novartis, Astra Zeneca, and ALK outside the present work. H. Wrede reports lecture fees from Allergopharma, MEDA/Mylan, HAL Allergie, LETI Pharma, Stallergenes, Sanofi, Lofarma, Allergy Therapeut., GSK outside the submitted work; and membership of the following organizations: AeDA, HNO-BV. T. Stöver has received research and study funding as well as fees for lectures and/or consultancy work from MED-EL Elektromedizinische Geräte Deutschland GmbH and Cochlear Deutschland GmbH & Co. KG outside the submitted work. He is a member of the DGHNO-KHC, the expert committee on medical devices and in-vitro diagnostics on behalf of the EU, the advisory board of the Hörzentrum Oldenburg GmbH, the task force ‘Living Practice Guidelines’, the advisory board of the Lower Saxony Center for Biomathematics, as chairman of the advisory board of the Friedberg Foundation for Hearing and Speech Promotion and as co-editor of the journal Laryngo-Rhino-Otology. C. Beutner on fees from GSK, Sanofi and Novartis, ALK Abello outside the present work. M. Laudien supported and received support, lecture, and consulting fees in the last 5 years from: Olympus Deutschland GmbH, Olympus Europa SE & CO. KG, Novartis Pharma GmbH, Sanofi-Aventis Deutschland GmbH, Brainlab Sales GmbH, GlaxoSmithKline GmbH & Co KG and the John Grube Foundation outside the present work. M. Gröger reports grants and lecture fees from Sanofi, Novartis, AstraZeneca, and GSK outside the submitted work. C. Bergmann reports on grants and fees from GlaxoSmithKline (GSK), Sanofi Aventis, Bencard Allergy GmbH/Allergy Therapeutics, HAL Allergie GmbH/HAL Allergy Holding BV outside the present work. O. Pfaar receives honoraria and/or study funding from ALK-Abelló, Altamira, Allergopharma, Stallergenes Greer, HAL Allergy Holding B.V./HAL Allergie, AAAAI, Bencard Allergy/Allergy Therapeutics, Lofarma, Biomay, Circassia, ASIT Biotech Tools S.A., Danish Consultation, Laboratorios LETI/LETI Pharma, MEDA Pharma/MYLAN, Anergis S.A., Mobile Chamber Experts, Indoor Biotechnologies, GlaxoSmithKline, Astellas Pharma Global, EUFOREA, ROXALL, Novartis, Sanofi-Aventis and Sanofi-Genzyme, Med Update Europe, streamedup!, Pohl-Boskamp, Inmunotek S.L., Wiley and Sons, Paul Martini Foundation, Regeneron Pharmaceuticals Inc, RG Aerztefortbildung, Firma Meinhardt, PneumoLIVE, Institut für Disease Management, Deutsche Forschungsgesellschaft, Springer, Thieme, AstraZeneca, Deutsche Allergie-Liga, AeDA, IQVIA Commercial, Ingress Health, Wort&Bild Verlag, Verlag ME, Procter&Gamble, Alfried-Krupp Krankenhaus, all outside the present work; and he is a member of the board/excom of the EAACI and a member of the extended board of the DGAKI. He is also the main author or co-author of various guidelines and position papers in allergology and rhinology. A.S. Hoffmann has received honoraria from GSK, Sanofi, and Novartis for lectures and advisory boards outside this work. T. Hildenbrand reports on lecture fees from AstraZeneca and Novartis outside the present work. R. Weber has received fees for lecturing and consulting activities from GSK, Infectopharm, KARL STORZ SE & Co KG, NMP, Sanofi, Sidroga-Pharma, and Stryker. W. Schlenter, S. Becker, F. Bärhold, T. Deitmer, H.J. Welkoborsky, S. Dazert, T. Huppertz, C.A. Hintschich, J. Zuberbier, C. Rudack, J. Gosepath, P. Werminghaus, F. Klimek and I. Casper have no conflicts of interest in connection with the present work. Figure 1Documentation form for the German healthcare system. Table 1.Objectifiable parameters for a response to mepolizumab therapy after 6 months (at least 1 parameter should be fulfilled) (modified from [6]). Nasal obstruction: improvement of the nasal congestion score (0 – 3) by > 0.5 or improvement of objective tests (e.g., increase in nasal inspiratory peak flow or nasal volume flow in active anterior rhinomanometry by > 20 L/min, reduction in resistance)Nasal polyp score (NPS): Reduction of the endoscopically determined NPS (0 – 8) by > 1 score point compared to the initial valueSNOT-22/quality of life: reduction in SNOT-22 score (0 – 110) by > 8.9 (validated minimum clinically relevant difference)Symptomatology in visual analog scale (VAS): reduction in total VAS symptoms (0 – 10 score points) by > 2Smelling ability: improvement in the 16-point Sniffin‘ Sticks identification test by > 3 points (validated minimum clinically relevant difference) Table 2.Objectifiable parameters for an evaluation of long-term mepolizumab therapy (> 12 months) (modified from [6]). All symptoms are only moderately pronounced or at least improved compared to the status before the start of therapyTotal nasal polyp score < 4 (added on both sides)Nasal congestion score < 2 (the nasal passage allows almost normal breathing at rest)Visual analog scale total symptoms < 5SNOT-22 value < 30Chronic rhinosinusitis with nasal polys (CRSwNP) should not currently require the administration of systemic glucocorticosteroids or surgery for CRSwNP (except surgery to remove mechanical obstructions such as synechiae, mucoceles, etc.)., (© Dustri-Verlag Dr. K. Feistle.)

Introduction: Eosinophilic granulomatosis with polyangiitis (EGPA) was formerly known as Churg-Strauss syndrome. The condition is characterized by disseminated necrotizing vasculitis with extravascular granulomas associated with hypereosinophilia. The vasculitides affect small vessels and are associated with antineutrophil cytoplasmic antibodies (ANCAs) detectable in the blood. Distinguishing between type 2-mediated chronic airway inflammation such as chronic rhinosinusitis with nasal polyps (CRSwNP) without vasculitis can be clinically challenging and should be considered., Materials and Methods: Immunological background, diagnosis, and therapy of EGPA were identified through literature searches in Medline, PubMed, as well as national and international studies (ClinicalTrials.gov) and the Cochrane Library. Human studies published up to and including 10/2023 on the topic were considered., Results: In cases of deteriorating general health with previously known eosinophilic inflammation of the upper and lower airways, EGPA and its interdisciplinary investigation should be considered. Various types of eosinophilic inflammation and syndromes must be considered differentially., Conclusion: Characterization of mucosal airway inflammation through biomarker determination is meaningful and occasionally makes the difference for targeted therapy., Competing Interests: J. Hagemann received grants from GSK, Sanofi, HAL Allergy, Novartis Pharma GmbH for lectures and consultations, outside the submitted work. M. Laudien received funds and/or fees from Olympus Deutschland GmbH, Olympus Europa SE & CO. KG, Novartis Pharma GmbH, Sanofi-Aventis Deutschland GmbH, Brainlab Sales GmbH, CSL Vifor, GlaxoSmithKline GmbH & Co. KG, Medtronic, Fiagon AG Medical Technologies, AEDA. He is board member of John Grube Foundation and chair of AG Rhinologie/Rhinochirurgie DGHNO. M. Cuevas has received honoraria from AstraZeneca, GSK, Sanofi, and Novartis, outside the submitted work. L. Klimek has received research grants and/or lecture fees from Allergy Therapeutics/ Bencard, UK/Germany; ALK-Abelló, Denmark; Allergopharma, Germany; ASIT Biotech, Belgium; AstraZeneca, Sweden, Bionorica, Germany; Biomay, Austria, Boehringer Ingelheim, Germany, Circassia, USA; Stallergene, France; Cytos, Switzerland; Curalogic, Denmark; HAL, Netherlands; Hartington, Spain; Lofarma, Italy; MEDA/Mylan, Sweden/USA; Novartis, Switzerland, Leti, Spain; ROXALL, Germany; GlaxoSmithKline (GSK), UK; Sanofi, France outside the submitted work and/or acted in an advisory capacity for the above-mentioned pharmaceutical companies. L. Klimek is editor of Allergo Journal and Allergo Journal International and he is the current President of AeDA (Ärzteverband Deutscher Allergologen) and Vice President of EAACI. R. Kianfar and F. Klimek report no conflicts of interest in connection with the present work. Table 1.Diseases involving the respiratory tract and hypereosinophilia [1]. Adult-onset eCRSwNPEGPAN-ERDAdult-onset asthmaABPAPrevalence (asthma/CRS patients)3 – 10%0.6%5 – 10%21 – 48%2.5%M : W2 : 11 : 21 : 22 : 31 : 1Appearance at the age of...30 – 505635 – 3630 – 4625 – 55   under 12RareRareRaren.a.Rare   over 60RarePossibleRarePossiblePossibleClinical peculiarityNasal polyps, loss of smellSystemic vasculitis, granulomatosisSalicylate intoleranceRapid decrease in LuFuMucus plugs (bronchial tubes)Biomarkers   Blood-Eo↑↑↑↑↑↑↑↑↑↑   Serum IgE (IU/mL)Variable100 – 300VariableVariable1,000 – 10,000   FeNO↑↑↑↑↑   Serum periostin↑↑→↑↑↑↑   U LTE4↑↑↑↑↑↑   EETs/EETosis++Lumen/tissuePossible++Lumen/tissue++Lumen   Charcot-Leyden crystals++Lumen/tissuePossible++Lumen/tissue++Lumen   OtherCST-1, eotaxin-3, IgG4ANCA, eotaxin-3, lösIL-2RMast cell/ tile markerReversibility in LuFu for diagnosisResponse to biologicsanti-IgE+++++anti-IL-5(R)+++++++++anti-IL-4R++++++anti-TSLP(+)++eCRSwNP = eosinophilic chronic rhinosinusitis with nasal polyps; EGPA = eosinophilic polyangiitis with granulomatosis; N-ERD = non-steroidal-exacerbated respiratory disease; ABPA = allergic bronchopulmonary aspergillosis; LuFu = lung function test; FeNO = fractional expiratory NO; leukotriene E4 = LTE4; EETs/EETosis = extracellular eosinophil traps; ANCA = antineutrophil cytoplasmic antibody. Table 2.The following criteria are only to be applied in the case of histological evidence of small vessel vasculitis. Clinical criteriaObstructive airway disease+3Nasal polyps / CRSwNP+3Mononeuritis multiplex+1Laboratory and biopsy criteriaBlood eosinophilia of >1,000 cells/µL or 1 × 109/L (blood)+5Extravascular, predominantly eosinophilic inflammation (biopsy)+2cANCA + / anti-PR3 + (blood)–3Hematuria–1A score of > 6 makes EGPA likely. CRSwNP = chronic rhinosinusitis with nasal polyps; cANCA = antineutrophil cytoplasmic antibody.., (© Dustri-Verlag Dr. K. Feistle.)

Introduction: Eosinophils play an important regulatory and immunomodulatory role in airway mucosa and have antiparasitic and antiviral properties as well as pro-inflammatory effects that may also cause persistence of inflammation with tissue remodeling. The number of eosinophils and the detection of specific mediators in biological samples from, e.g., blood, nasal secretions, and bronchial fluid can serve as biomarkers that reflect the underlying pathophysiology of certain diseases, predict treatment success, and detect therapy effects., Materials and Methods: A literature search was conducted to determine the immunologic basis, mode of action, clinical significance, and available evidence for therapeutic approaches using eosinophil-targeted monoclonal antibodies by searching Medline, Pubmed, and the national and international trial database (ClinicalTrials.gov) and guideline registries as well as the Cochrane Library. Human studies published on the topic in the period up to and including 10/2023 were considered., Results: Based on the international literature and previous experience, the results are summarized, and recommendations are given., Conclusion: The important role of eosinophils in immunological processes in the airway mucosa is comprehensively analyzed and can serve as a basis for current and future treatment approaches., Competing Interests: J. Hagemann received grants from Novartis Pharma GmbH, GlaxoSmithKline Deutschland GmbH, Sanofi, HAL Allergy for advisory boards and lectures outside the submitted work. M. Cuevas has received honoraria from ALK-Abelló, Allergopharma, AstraZeneca, Bencard Allergie/ Allergy Therapeutics, GalaxoSmithKline, HAL Allergy, Leti Pharma, Novartis, Roxall, Sanofi-Aventis, Stallergenes outside the submitted work and memberships in the following organizations: AeDA, DGHNO. L. Klimek has received research grants and/or lecture honoraria from Allergy Therapeutics/Bencard, UK/Germany; ALK-Abelló, Denmark; Allergopharma, Germany; ASIT Biotech, Belgium; AstraZeneca, Sweden, Bionorica, Germany; Biomay, Austria, Boehringer Ingelheim, Germany, Circassia, USA; Stallergene, France; Cytos, Switzerland; Curalogic, Denmark; HAL, Netherlands; Hartington, Spain; Lofarma, Italy; MEDA/Mylan, Sweden/USA; Novartis, Switzerland, Leti, Spain; ROXALL, Germany; GlaxoSmithKline (GSK), UK; Sanofi, France and/or acted as a consultant for the above-mentioned pharmaceutical companies. Dr. Klimek is editor of Allergo Journal and Allergo Journal International and is the current President of AeDA (Medical Association of German Allergists) and Vice President of EAACI. O. Pfaar reports grants and/or personal fees from ALK-Abelló, Allergopharma, Stallergenes Greer, HAL Allergy Holding B.V./HAL Allergie GmbH, Bencard Allergie GmbH/Allergy Therapeutics, Lofarma, ASIT Biotech Tools S.A., Laboratorios LETI/LETI Pharma, GlaxoSmithKline, ROXALL Medizin, Novartis, Sanofi-Aventis and Sanofi-Genzyme, Med Update Europe GmbH, streamedup! GmbH, Pohl-Boskamp, Inmunotek S.L., John Wiley and Sons, AS, Paul-Martini-Stiftung (PMS), Regeneron Pharmaceuticals Inc., RG Aerztefortbildung, Institut für Disease Management, Springer GmbH, AstraZeneca, IQVIA Commercial, Ingress Health, Wort&Bild Verlag, Verlag ME, Procter&Gamble, ALTAMIRA, Meinhardt Congress GmbH, Deutsche Forschungsgemeinschaft, Thieme, Deutsche AllergieLiga e.V., AeDA, Alfried-Krupp Krankenhaus, Red Maple Trials Inc., Königlich Dänisches Generalkonsulat, Medizinische Hochschule Hannover, ECM Expro&Conference Management, Technische Universität Dresden, Lilly, Paul Ehrlich Institut (PEI), Japanese Society of Allergy, Forum für Medizinische Fortbildung, Dustri Verlag, all outside the submitted work and within the last 36 months; and he is member of EAACI Excom, member of ext. board of directors DGAKI; coordinator, main- or co-author of different position papers and guidelines in rhinology, allergology, and allergen-immunotherapy and Associate Editor of the journal(s) Allergy and Clinical Translational Allergy (CTA). S. Becker has received honoraria for lectures, consulting and research from ALK Abéllo, Allergopharme, HAL Allergie, Bencard Allergie, Allergy Therapeutics, Therma Fisher Scientific, Novartis, AstraZeneca, Sanofi Genzyme, GSK, MSD, Mylan, Viatris, Karl Storz GmbH, Altamira, Auris Medical, Smart Reporting, Stryker, Helix Biopharm, BMBF. C. Bergmann, I. Casper, and F. Klimek have no conflict of interest in connection with this work., (© Dustri-Verlag Dr. K. Feistle.)

Small voids in the absorber layer of thin-film solar cells are generally suspected to impair photovoltaic performance. They have been studied on Cu(In,Ga)Se 2 cells with conventional laboratory techniques, albeit limited to surface characterization and often affected by sample-preparation artifacts. Here, synchrotron imaging is performed on a fully operational as-deposited solar cell containing a few tens of voids. By measuring operando current and X-ray excited optical luminescence, the local electrical and optical performance in the proximity of the voids are estimated, and via ptychographic tomography, the depth in the absorber of the voids is quantified. Besides, the complex network of material-deficit structures between the absorber and the top electrode is highlighted. Despite certain local impairments, the massive presence of voids in the absorber suggests they only have a limited detrimental impact on performance., (© 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.)

In this work, we study the jetting dynamics of individual cavitation bubbles using x-ray holographic imaging and high-speed optical shadowgraphy. The bubbles are induced by a focused infrared laser pulse in water near the surface of a flat, circular glass plate, and later probed with ultrashort x-ray pulses produced by an x-ray free-electron laser (XFEL). The holographic imaging can reveal essential information of the bubble interior that would otherwise not be accessible in the optical regime due to obscuration or diffraction. The influence of asymmetric boundary conditions on the jet's characteristics is analysed for cases where the axial symmetry is perturbed and curved liquid filaments can form inside the cavity. The x-ray images demonstrate that when oblique jets impact the rigid boundary, they produce a non-axisymmetric splash which grows from a moving stagnation point. Additionally, the images reveal the formation of complex gas/liquid structures inside the jetting bubbles that are invisible to standard optical microscopy. The experimental results are analysed with the assistance of full three-dimensional numerical simulations of the Navier-Stokes equations in their compressible formulation, which allow a deeper understanding of the distinctive features observed in the x-ray holographic images. In particular, the effects of varying the dimensionless stand-off distances measured from the initial bubble location to the surface of the solid plate and also to its nearest edge are addressed using both experiments and simulations. A relation between the jet tilting angle and the dimensionless bubble position asymmetry is derived. The present study provides new insights into bubble jetting and demonstrates the potential of x-ray holography for future investigations in this field., Supplementary Information: The online version contains supplementary material available at 10.1007/s00348-023-03759-9., Competing Interests: Conflict of interestThe authors have no conflicts of interest to declare that are relevant to the content of this article., (© The Author(s) 2024.)

Background and Purpose: Squamous cell carcinoma of unknown primary (SCC-CUP) of the head and neck region remains a clinical challenge, with uncertainty surrounding the necessity of contralateral irradiation of cervical lymphatic drainage in cases of unilateral involvement., Materials and Methods: A retrospective study was conducted at the Department of Radiation Oncology, University Medical Center Mainz, on a cohort of 50 patients with unilateral SCC-CUP of the head and neck region treated between 2005 and 2019. 30 patients received bilateral and 20 received unilateral cervical radiotherapy. The majority (n = 38, 76 %) were treated with modern IMRT/ VMAT (Intensity-modulated Radiation Therapy/ Volumetric Modulated Arc Therapy) techniques., Results: After a median follow-up of 64.5 months, locoregional recurrences occurred in 26 % of cases (n = 13/50), all of which were ipsilateral and predominantly within the volume of the previous irradiated CTV (clinical target volume) (85 %, n = 11/13). No patient treated unilaterally developed a contralateral recurrence in the neck. After 3 years, we observed 7 locoregional recurrences in the bilateral irradiated group (n = 7/30, 23 %), and 5 locoregional recurrences in the unilateral irradiated group (n = 5/20, 25 %). After 3 years, 12 patients had died in the bilateral irradiated group (n = 12/30, 40 %), and 7 in the unilateral irradiated group (n = 7/20, 35 %). 7 Patients showed distant metastases after 3 years in the bilateral irradiated group (n = 7/30, 23 %), and 2 in the unilateral irradiated group (n = 2/20, 10 %). Locoregional control (LRC) at 5 years was 66.2 % in the bilaterally irradiated group, and 70.0 % in the unilaterally irradiated group. Overall survival (OS) was 52.6 % (bilateral) and 64.0 % (unilateral). Distant metastasis-free survival (DMFS) was 74.7 % (bilateral) and 84.4 % (unilateral). No significant differences were observed in OS (p = 0.37), LRC (p = 0.91), and DMFS (p = 0.91) between the groups.Acute toxicity ≥ °2 accordingly CTCAE (Common Terminology Criteria of Adverse Events) was high with 97% while late toxicity ≥ °2 was moderate with 31%. There was no statistically significant difference between the group of unilateral and bilateral irradiated patients., Conclusion: These data suggest that contralateral cervical irradiation may be of limited benefit in patients with SCC-CUP, as recurrences occured ipsilaterally, and predominantly within the area of prior irradiation. Unilateral irradiation seems to be adequate for carefully selected patients., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Author(s).)

Fast-spiking interneurons (FSINs) provide fast inhibition that synchronizes neuronal activity and is critical for cognitive function. Fast synchronization frequencies are evolutionary conserved in the expanded human neocortex despite larger neuron-to-neuron distances that challenge fast input-output transfer functions of FSINs. Here, we test in human neurons from neurosurgery tissue, which mechanistic specializations of human FSINs explain their fast-signaling properties in human cortex. With morphological reconstructions, multipatch recordings, and biophysical modeling, we find that despite threefold longer dendritic path, human FSINs maintain fast inhibition between connected pyramidal neurons through several mechanisms: stronger synapse strength of excitatory inputs, larger dendrite diameter with reduced complexity, faster AP initiation, and faster and larger inhibitory output, while Na + current activation/inactivation properties are similar. These adaptations underlie short input-output delays in fast inhibition of human pyramidal neurons through FSINs, explaining how cortical synchronization frequencies are conserved despite expanded and sparse network topology of human cortex.

Background: Kenya is endemic for soil-transmitted helminths (STH) with over 6 million children in 27 counties currently at-risk. A national school-based deworming programme (NSBDP) was launched in 2012 with a goal to eliminate parasitic worms as a public health problem. This study used model-based geostatistical (MBG) approach to design and analyse the impact of the NSBDP and inform treatment strategy changes., Methods: A cross-sectional study was used to survey 200 schools across 27 counties in Kenya. The study design, school selection and analysis followed the MBG approach which incorporated historical data on treatment, morbidity and environmental covariates to efficiently predict the helminths prevalence in Kenya., Results: Overall, the NSBDP geographic area prevalence for any STH was estimated to sit between 2 % and <10 % with a high predictive probability of >0.999. Species-specific thresholds were between 2 % and <10 % for Ascaris lumbricoides, 0 % to <2 % for hookworm, and 0 % to <2 % for Trichuris trichiura , all with high predictive probability of >0.999., Conclusions: Based on the World Health Organization guidelines, STH treatment requirements can now be confidently refined. Ten counties may consider suspending treatment and implement appropriate surveillance system, while another 10 will require treatment once every two years, and the remaining seven will require treatment once every year., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 Published by Elsevier Ltd.)

Functional materials feature hierarchical microstructures that define their unique set of properties. The prediction and tailoring of these require a multiscale knowledge of the mechanistic interaction of microstructure and property. An important material in this respect is biodegradable magnesium alloys used for implant applications. To correlate the relationship between the microstructure and the nonlinear degradation process, high-resolution in situ three-dimensional (3D) imaging experiments must be performed. For this purpose, a novel experimental flow cell is presented which allows for the in situ 3D-nano imaging of the biodegradation process of materials with nominal resolutions below 100 nm using nanofocused hard X-ray radiation from a synchrotron source. The flow cell setup can operate under adjustable physiological and hydrodynamic conditions. As a model material, the biodegradation of thin Mg-4Ag wires in simulated body fluid under physiological conditions and a flow rate of 1 mL/min is studied. The use of two full-field nanotomographic imaging techniques, namely transmission X-ray microscopy and near-field holotomography, is compared, revealing holotomography as the superior imaging technique for this purpose. Additionally, the importance of maintaining physiological conditions is highlighted by the preliminary results. Supporting measurements using electron microscopy to investigate the chemical composition of the samples after degradation are performed.

Introduction: Approximately 5%-12% of the population worldwide suffer from chronic rhinosinusitis (CRS). CRS is defined as a chronic respiratory disease and is considered to be a risk factor for COVID-19 patients., Areas Covered: A non-systematic literature research was conducted on COVID-19 and treatment options for CRSwNP. The latest international publications in medical databases, international guidelines, and the internet were reviewed. Since there were no publications on all aspects of this topic during the pandemic, we included our own experience in this report. Based on the conducted literature research in addition to our previously reported experience, we discuss the treatment of CRSwNP during the COVID-19 pandemic and what can be taken for future pandemics., Expert Opinion: Intranasal corticosteroids remain the standard treatment for CRS in patients with SARS-CoV-2 infection. Indications for surgical treatment of CRS should be critically evaluated and reserved for patients with complications and those with no other treatment options. For this purpose, COVID-19 status should be known if possible and, in case of unclear status (emergency), using appropriate personal protective equipment. Systemic corticosteroids should be avoided were possible. Biological treatment should be continued under careful monitoring in uninfected patients and should be temporarily interrupted during COVID-19 infection.

Introduction: Type 2 targeting biologics have reached the market first for asthma and since 2019 also for CRSwNP. As clear guidelines and predictors for optimal biological choice are missing, patients are sometimes required to switch biologic therapy in order to find the optimal treatment result. In this paper, we evaluate reasons for switching biologics and the treatment effects after each sequential switch., Materials and Methods: Ninety-four patients who switched from one biologic to another for their treatment of CRSwNP and asthma were evaluated., Results: Twenty patients experienced satisfactory control of CRSwNP, but insufficient control of severe asthma. Fifty-one patients experienced satisfactory control of severe asthma, but insufficient control of CRSwNP/EOM. Twenty-eight patients experienced insufficient control of both upper and lower airways. Thirteen patients had to switch because of side effects. Furthermore, two cases are described to clarify clinical decision-making., Discussion: For abovementioned patients, a multidisciplinary approach is mandatory to find the best suitable biologic. It seems ineffective to switch to a second anti-IL5 treatment if the first one is not successful. Most patients that failed omalizumab and/or an anti-IL-5 treatment are well controlled on dupilumab. Therefore, we suggest to use dupilumab as first choice when switching biologic agents.

Allergic rhinitis is an IgE-mediated, type‑2 inflammatory disease. neuropeptides are released by neurons and interact with immune cells. Via colocalization, neuroimmune cell units such as nerve-mast cell units, nerve-type 2 innate lymphoid cell (ILC2) units, nerve-eosinophil units, and nerve-basophil units are formed. Markedly elevated tryptase levels were found in nasal lavage fluid and were strongly associated with neuropeptide levels. A close anatomical connection allows bidirectional communication between immune and neuronal cells. Transient receptor potential vanilloid 1 (TRPV1) and transient receptor potential ankyrin repeat 1 (TRPA1) are critically involved in immunological reactions in the setting of allergic rhinitis. Neuroimmunological communication plays an important role in the inflammatory process, so that allergic rhinitis can no longer be considered a purely immunological disease, but rather a combined neuroimmunological disease., (© 2023. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Sengis (order Macroscelidea) are small mammals endemic to Africa. The taxonomy and phylogeny of sengis has been difficult to resolve due to a lack of clear morphological apomorphies. Molecular phylogenies have already significantly revised sengi systematics, but until now no molecular phylogeny has included all 20 extant species. In addition, the age of origin of the sengi crown clade and the divergence age of its two extant families remain unclear. Two recently published studies based on different datasets and age-calibration parameters (DNA type, outgroup selection, fossil calibration points) proposed highly different divergent age estimates and evolutionary scenarios. We obtained nuclear and mitochondrial DNA from mainly museum specimens using target enrichment of single-stranded DNA libraries to generate the first phylogeny of all extant macroscelidean species. We then explored the effects of different parameters (type of DNA, ratio of ingroup to outgroup sampling, number and type of fossil calibration points) and their resulting impacts on age estimates for the origin and initial diversification of Macroscelidea. We show that, even after correcting for substitution saturation, both using mitochondrial DNA in conjunction with nuclear DNA or alone results in much older ages and different branch lengths than when using nuclear DNA alone. We further show that the former effect can be attributed to insufficient amounts of nuclear data. If multiple calibration points are included, the age of the sengi crown group fossil prior has minimal impact on the estimated time frame of sengi evolution. In contrast, the inclusion or exclusion of outgroup fossil priors has a major effect on the resulting node ages. We also find that a reduced sampling of ingroup species does not significantly affect overall age estimates and that terminal specific substitution rates can serve as a means to evaluate the biological likeliness of the produced temporal estimates. Our study demonstrates how commonly varied parameters in temporal calibration of phylogenies affect age estimates. Dated phylogenies should therefore always be seen in the context of the dataset which was used to produce them., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Competing Interests: B. Wollenberg hat Honorare und/oder Forschungsgelder von MSD, Sanofi, Astra Zeneca, Novartis, BMS Adboard außerhalb der vorliegenden Arbeit erhalten.J. Hagemann gibt an, Zuwendungen für Vorträge und Honorare für Advisory Boards von den Firmen Sanofi Aventis, Fa. Novartis Pharma GmbH und GlaxoSmithKline erhalten zu haben.A. M. Chaker führt über die Technische Universität München (TUM) Beratungsleistungen (z. B. Advisory Boards, DSMBs), Vorträge oder weitere Aktivitäten durch oder hat über die TUM klinische Studien durchgeführt oder Forschungsgelder erhalten von: Allergopharma, ALK-Abello, AstraZeneca, Bencard/Allergen Therapeutics, GSK, HAL Allergy, Immunotek, Novartis, SanofiGenzyme und Regeneron, Zeller AG, EIT Health, BMBF. AMC ist ferner Funktionsträger der EUFOREA, EAACI, AeDA und DGAKI.H. Olze erhielt Honorare und/oder Forschungsgelder von F. Hoffmann-La Roche Ltd, Sanofi-Aventis Deutschland GmbH, AstraZeneca GmbH, GlaxoSmithKline GmbH & Co. KG und Novartis Pharma GmbH.L. Klimek berichtet über Zuschüsse und/oder Honorare von Allergopharma, MEDA/Mylan, HAL Allergie, ALK Abelló, LETI Pharma, Stallergenes, Quintiles, Sanofi, ASIT Biotech, Lofarma, Allergy Therapeut., AstraZeneca, GSK, Inmunotk außerhalb der eingereichten Arbeit und Mitgliedschaft bei folgenden Organisationen: AeDA, DGHNO, Deutsche Akademie für Allergologie und klinische Immunologie, HNO-BV GPA, EAACI.U. Förster-Ruhrmann erhielt Honorare für Vorträge von Novartis, AstraZeneca, Sanofi und GSK außerhalb der vorliegenden Arbeit.S. Strieth berichtet über Stipendien der Deutschen Forschungsgemeinschaft (DFG), Bonn, Stipendien der Stiftung Tumorforschung Kopf-Hals, Wiesbaden, Stipendien und nichtfinanzielle Förderungen der MED-EL AG, Innsbruck, Personalhonorar von Auris Medical, Basel, Personalhonorar von Merck Serono, Darmstadt, Personalhonorar Otonomy, Inc., San Diego (USA), Personalhonorar Nordmark Arzneimittel, Uetersen, Zuschuss Andreas Fahl Medizintechnik-Vertrieb, Köln, Zuschuss Atos Medical, Troisdorf, Zuschuss Tracoe Medical, Nieder-Olm, Stipendien von Heimomed Heinze, Kerpen, Stipendien von Bromepithetik, Heidelberg, Stipendien von Fresenius Kabi, Bad Hersfeld, Personalhonorar von Sonofi Genzyme, Berlin, Personalhonorar von ALK-Abelló Arzneimittel, Hamburg, außerhalb der eingereichten Arbeit.M. Cuevas erhielt Honorare und/oder nichtfinanzielle Unterstützung von Novartis, Sanovi-Aventis, Allergopharma, HAL Allergie, Leti Pharma, AstraZeneca, GlaxoSmithKline, ALK Abelló, Bencard Allergie,Stallergenes und Roxall außerhalb der eingereichten Arbeit und berichtet über Mitgliedschaften bei folgenden Organisationen: AeDA, DGHNO.O. Guntinas-Lichius erhielt Honorare von MED-EL, Merck, Novartis, MEDICE und Merz außerhalb dieser Arbeit, und er ist Mitglied bei den folgenden Organisationen: DGHNO, BVHNO.T. K. Hoffmann nimmt an honorierten Advisory Boards der Firmen Merck, MSD und BMS teil, thematisch jedoch außerhalb der vorliegenden Arbeit.H. Wrede berichtet über Vortragshonorare von Allergopharma, MEDA/Mylan, HAL Allergie, LETI Pharma, Stallergenes, Sanofi, Lofarma, Allergy Therapeut. und GSK außerhalb der eingereichten Arbeit; und Mitgliedschaft bei folgenden Organisationen: AeDA, HNO-BV.T. Stöver erhielt Forschungs- und Studiengelder sowie Honorare für Vortrags- und/oder Beratertätigkeiten von MED-EL Elektromedizinische Geräte Deutschland GmbH und Cochlear Deutschland GmbH & Co. KG außerhalb der eingereichten Arbeit. Es bestehen Mitgliedschaften bei der DGHNO-KHC, im Expertengremium über Medizinprodukte und In-vitro-Diagnostika im Auftrag der EU, im Beirat des Hörzentrums Oldenburg GmbH, in der Task Force ‚Living Practice Guidelines‘, im Beirat des Niedersächsischen Zentrums für Biomathematik, als Vorsitzender des Stiftungsbeirats der Stiftung zur Hör- und Sprachförderung Friedberg sowie als Mitherausgeber der Zeitschrift Laryngo-Rhino-Otologie.C. Beutner berichtet über Honorare von GSK, Sanofi und Novartis, ALK Abello außerhalb dieser Arbeit.M. Laudien unterstützte und erhielt in den letzten 5 Jahren Unterstützungs-, Vortrags- und Beraterhonorare von Olympus Deutschland GmbH, Olympus Europa SE & CO. KG, Novartis Pharma GmbH, Sanofi-Aventis Deutschland GmbH, Brainlab Sales GmbH, GlaxoSmithKline GmbH & Co. KG und der John Grube Foundation außerhalb der vorliegenden Arbeit.M. Gröger berichtet über Zuschüsse und Vortragshonorare von Sanofi, Novartis, AstraZeneca und GSK außerhalb der eingereichten Arbeit.C. Bergmann berichtet über Zuschüsse und Honorare von GlaxoSmithKline (GSK), Sanofi Aventis, Bencard Allergy GmbH/Allergy Therapeutics, HAL Allergie GmbH/HAL Allergy Holding BV außerhalb dieser Arbeit.A. S. Hoffmann erhielt Honorare von GSK, Sanofi und Novartis für Vorträge und Advisory Boards außerhalb dieser Arbeit.T. Hildenbrand berichtet über Vortragshonorare von AstraZeneca und Novartis außerhalb dieser Arbeit.R. Weber hat Honorare für Vortrags- und Beratungstätigkeiten der Firmen GSK, Infectopharm, KARL STORZ SE & Co KG, NMP, Sanofi, Sidroga-Pharma und Stryker erhalten.S. Becker berichtet über Honorae für AdBoards und Vortragshonorare von Sanofi, Novartis, AstraZeneca und GSK außerhalb der eingereichten Arbeit.W. Schlenter, S. Becker, F. Bärhold, T. Deitmer, H. J. Welkoborsky, S. Dazert, T. Huppertz, C. A. Hintschich, J. Zuberbier, C. Rudack, P. Werminghaus, F. Klimek und I. Casper haben keine Interessenkonflikte im Zusammenhang mit der vorliegenden Arbeit.

Asthma, rhinitis, and atopic dermatitis (AD) are interrelated clinical phenotypes that partly overlap in the human interactome. The concept of "one-airway-one-disease," coined over 20 years ago, is a simplistic approach of the links between upper- and lower-airway allergic diseases. With new data, it is time to reassess the concept. This article reviews (i) the clinical observations that led to Allergic Rhinitis and its Impact on Asthma (ARIA), (ii) new insights into polysensitization and multimorbidity, (iii) advances in mHealth for novel phenotype definitions, (iv) confirmation in canonical epidemiologic studies, (v) genomic findings, (vi) treatment approaches, and (vii) novel concepts on the onset of rhinitis and multimorbidity. One recent concept, bringing together upper- and lower-airway allergic diseases with skin, gut, and neuropsychiatric multimorbidities, is the "Epithelial Barrier Hypothesis." This review determined that the "one-airway-one-disease" concept does not always hold true and that several phenotypes of disease can be defined. These phenotypes include an extreme "allergic" (asthma) phenotype combining asthma, rhinitis, and conjunctivitis. Rhinitis alone and rhinitis and asthma multimorbidity represent two distinct diseases with the following differences: (i) genomic and transcriptomic background (Toll-Like Receptors and IL-17 for rhinitis alone as a local disease; IL-33 and IL-5 for allergic and non-allergic multimorbidity as a systemic disease), (ii) allergen sensitization patterns (mono- or pauci-sensitization versus polysensitization), (iii) severity of symptoms, and (iv) treatment response. In conclusion, rhinitis alone (local disease) and rhinitis with asthma multimorbidity (systemic disease) should be considered as two distinct diseases, possibly modulated by the microbiome, and may be a model for understanding the epidemics of chronic and autoimmune diseases., (© 2023 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Allergic rhinitis (AR) is a very common disease with a high prevalence worldwide. It is an IgE-mediated type 2 inflammatory disease following exposure to inhalant allergens. A multitude of different neuropeptides including substance P, vasoactive intestinal peptide (VIP), calcitonin gene-related peptide (CGRP), nerve growth factor (NGF), and neuromedin U (NMU) can be released via peripheral axon or central reflexes, interact with immune cells, and thus contribute to neurogenic inflammation which causes the nasal hyperreactivity (NHR) characteristic of AR. Independent production of neuroendocrine hormones and neuropeptides by immune cells has also been demonstrated. Neuro-immune cell units arise when immune and neuronal cells colocalize, for which typical anatomic regions are, e.g., the mast cell-nerve functional unit. The focus of this review is the elucidation of neuroimmune communication mechanisms in AR., (© 2023. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Competing Interests: B. Wollenberg hat Honorare und/oder Forschungsgelder von MSD, Sanofi, Astra Zeneca, Novartis, BMS Adboard außerhalb der vorliegenden Arbeit erhalten.J. Hagemann gibt an, Zuwendungen für Vorträge und Honorare für Advisory Boards von den Firmen Sanofi Aventis, Fa. Novartis Pharma GmbH und GlaxoSmithKline erhalten zu haben.A. M. Chaker führt über die Technische Universität München (TUM) Beratungsleistungen (z. B. Advisory Boards, DSMBs), Vorträge oder weitere Aktivitäten durch oder hat über die TUM klinische Studien durchgeführt oder Forschungsgelder erhalten von: Allergopharma, ALK-Abello, AstraZeneca, Bencard/Allergen Therapeutics, GSK, HAL Allergy, Immunotek, Novartis, SanofiGenzyme und Regeneron, Zeller AG, EIT Health, BMBF. AMC ist ferner Funktionsträger der EUFOREA, EAACI, AeDA und DGAKI.H. Olze erhielt Honorare und/oder Forschungsgelder von F. Hoffmann-La Roche Ltd, Sanofi-Aventis Deutschland GmbH, AstraZeneca GmbH, GlaxoSmithKline GmbH & Co. KG und Novartis Pharma GmbH.L. Klimek berichtet über Zuschüsse und/oder Honorare von Allergopharma, MEDA/Mylan, HAL Allergie, ALK Abelló, LETI Pharma, Stallergenes, Quintiles, Sanofi, ASIT Biotech, Lofarma, Allergy Therapeut., AstraZeneca, GSK, Inmunotk außerhalb der eingereichten Arbeit und Mitgliedschaft bei folgenden Organisationen: AeDA, DGHNO, Deutsche Akademie für Allergologie und klinische Immunologie, HNO-BV GPA, EAACI.U. Förster-Ruhrmann erhielt Honorare für Vorträge von Novartis, AstraZeneca, Sanofi und GSK außerhalb der vorliegenden Arbeit.S. Strieth berichtet über Stipendien der Deutschen Forschungsgemeinschaft (DFG), Bonn, Stipendien der Stiftung Tumorforschung Kopf-Hals, Wiesbaden, Stipendien und nichtfinanzielle Förderungen der MED-EL AG, Innsbruck, Personalhonorar von Auris Medical, Basel, Personalhonorar von Merck Serono, Darmstadt, Personalhonorar Otonomy, Inc., San Diego (USA), Personalhonorar Nordmark Arzneimittel, Uetersen, Zuschuss Andreas Fahl Medizintechnik-Vertrieb, Köln, Zuschuss Atos Medical, Troisdorf, Zuschuss Tracoe Medical, Nieder-Olm, Stipendien von Heimomed Heinze, Kerpen, Stipendien von Bromepithetik, Heidelberg, Stipendien von Fresenius Kabi, Bad Hersfeld, Personalhonorar von Sonofi Genzyme, Berlin, Personalhonorar von ALK-Abelló Arzneimittel, Hamburg, außerhalb der eingereichten Arbeit.M. Cuevas erhielt Honorare und/oder nichtfinanzielle Unterstützung von Novartis, Sanovi-Aventis, Allergopharma, HAL Allergie, Leti Pharma, AstraZeneca, GlaxoSmithKline, ALK Abelló, Bencard Allergie,Stallergenes und Roxall außerhalb der eingereichten Arbeit und berichtet über Mitgliedschaften bei folgenden Organisationen: AeDA, DGHNO.O. Guntinas-Lichius erhielt Honorare von MED-EL, Merck, Novartis, MEDICE und Merz außerhalb dieser Arbeit, und er ist Mitglied bei den folgenden Organisationen: DGHNO, BVHNO.T. K. Hoffmann nimmt an honorierten Advisory Boards der Firmen Merck, MSD und BMS teil, thematisch jedoch außerhalb der vorliegenden Arbeit.H. Wrede berichtet über Vortragshonorare von Allergopharma, MEDA/Mylan, HAL Allergie, LETI Pharma, Stallergenes, Sanofi, Lofarma, Allergy Therapeut. und GSK außerhalb der eingereichten Arbeit; und Mitgliedschaft bei folgenden Organisationen: AeDA, HNO-BV.T. Stöver erhielt Forschungs- und Studiengelder sowie Honorare für Vortrags- und/oder Beratertätigkeiten von MED-EL Elektromedizinische Geräte Deutschland GmbH und Cochlear Deutschland GmbH & Co. KG außerhalb der eingereichten Arbeit. Es bestehen Mitgliedschaften bei der DGHNO-KHC, im Expertengremium über Medizinprodukte und In-vitro-Diagnostika im Auftrag der EU, im Beirat des Hörzentrums Oldenburg GmbH, in der Task Force ‚Living Practice Guidelines‘, im Beirat des Niedersächsischen Zentrums für Biomathematik, als Vorsitzender des Stiftungsbeirats der Stiftung zur Hör- und Sprachförderung Friedberg sowie als Mitherausgeber der Zeitschrift Laryngo-Rhino-Otologie.C. Beutner berichtet über Honorare von GSK, Sanofi und Novartis, ALK Abello außerhalb dieser Arbeit.M. Laudien unterstützte und erhielt in den letzten 5 Jahren Unterstützungs-, Vortrags- und Beraterhonorare von Olympus Deutschland GmbH, Olympus Europa SE & CO. KG, Novartis Pharma GmbH, Sanofi-Aventis Deutschland GmbH, Brainlab Sales GmbH, GlaxoSmithKline GmbH & Co. KG und der John Grube Foundation außerhalb der vorliegenden Arbeit.M. Gröger berichtet über Zuschüsse und Vortragshonorare von Sanofi, Novartis, AstraZeneca und GSK außerhalb der eingereichten Arbeit.C. Bergmann berichtet über Zuschüsse und Honorare von GlaxoSmithKline (GSK), Sanofi Aventis, Bencard Allergy GmbH/Allergy Therapeutics, HAL Allergie GmbH/HAL Allergy Holding BV außerhalb dieser Arbeit.A. S. Hoffmann erhielt Honorare von GSK, Sanofi und Novartis für Vorträge und Advisory Boards außerhalb dieser Arbeit.T. Hildenbrand berichtet über Vortragshonorare von AstraZeneca und Novartis außerhalb dieser Arbeit.R. Weber hat Honorare für Vortrags- und Beratungstätigkeiten der Firmen GSK, Infectopharm, KARL STORZ SE & Co KG, NMP, Sanofi, Sidroga-Pharma und Stryker erhalten.S. Becker berichtet über Honorae für AdBoards und Vortragshonorare von Sanofi, Novartis, AstraZeneca und GSK außerhalb der eingereichten Arbeit.W. Schlenter, S. Becker, F. Bärhold, T. Deitmer, H. J. Welkoborsky, S. Dazert, T. Huppertz, C. A. Hintschich, J. Zuberbier, C. Rudack, P. Werminghaus, F. Klimek und I. Casper haben keine Interessenkonflikte im Zusammenhang mit der vorliegenden Arbeit.

Full-field X-ray nanoimaging is a widely used tool in a broad range of scientific areas. In particular, for low-absorbing biological or medical samples, phase contrast methods have to be considered. Three well established phase contrast methods at the nanoscale are transmission X-ray microscopy with Zernike phase contrast, near-field holography and near-field ptychography. The high spatial resolution, however, often comes with the drawback of a lower signal-to-noise ratio and significantly longer scan times, compared with microimaging. In order to tackle these challenges a single-photon-counting detector has been implemented at the nanoimaging endstation of the beamline P05 at PETRA III (DESY, Hamburg) operated by Helmholtz-Zentrum Hereon. Thanks to the long sample-to-detector distance available, spatial resolutions of below 100 nm were reached in all three presented nanoimaging techniques. This work shows that a single-photon-counting detector in combination with a long sample-to-detector distance allows one to increase the time resolution for in situ nanoimaging, while keeping a high signal-to-noise level., (open access.)

Vitamin D (VitD) and its receptor (VDR) have been intensively investigated in many cancers. As knowledge for head and neck cancer (HNC) is limited, we investigated the (pre)clinical and therapeutic relevance of the VDR/VitD-axis. We found that VDR was differentially expressed in HNC tumors, correlating to the patients' clinical parameters. Poorly differentiated tumors showed high VDR and Ki67 expression, whereas the VDR and Ki67 levels decreased from moderate to well-differentiated tumors. The VitD serum levels were lowest in patients with poorly differentiated cancers (4.1 ± 0.5 ng/mL), increasing from moderate (7.3 ± 4.3 ng/mL) to well-differentiated (13.2 ± 3.4 ng/mL) tumors. Notably, females showed higher VitD insufficiency compared to males, correlating with poor differentiation of the tumor. To mechanistically uncover VDR/VitD's pathophysiological relevance, we demonstrated that VitD induced VDR nuclear-translocation (VitD < 100 nM) in HNC cells. RNA sequencing and heat map analysis showed that various nuclear receptors were differentially expressed in cisplatin-resistant versus sensitive HNC cells including VDR and the VDR interaction partner retinoic acid receptor (RXR). However, RXR expression was not significantly correlated with the clinical parameters, and cotreatment with its ligand, retinoic acid, did not enhance the killing by cisplatin. Moreover, the Chou-Talalay algorithm uncovered that VitD/cisplatin combinations synergistically killed tumor cells (VitD < 100 nM) and also inhibited the PI3K/Akt/mTOR pathway. Importantly, these findings were confirmed in 3D-tumor-spheroid models mimicking the patients' tumor microarchitecture. Here, VitD already affected the 3D-tumor-spheroid formation, which was not seen in the 2D-cultures. We conclude that novel VDR/VitD-targeted drug combinations and nuclear receptors should also be intensely explored for HNC. Gender-specific VDR/VitD-effects may be correlated to socioeconomic differences and need to be considered during VitD (supplementation)-therapies.

Background: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a multifactorial inflammatory disease of the mucous membranes of the nose and sinuses. Eosinophilic inflammation is described as a common endotype. The anti-IL5 antibody mepolizumab was approved in November 2021 as an add-on therapy to intranasal glucocorticosteroids for the treatment of adults with severe chronic rhinosinusitis with nasal polyps when systemic glucocorticosteroids or surgery do not provide adequate disease control. While national and international recommendations exist for the use of mepolizumab in CRSwNP, it has not yet been adequately specified how this therapy is to be monitored, what follow-up documentation is necessary, and when it should be terminated if necessary., Methods: A literature search was performed to analyze previous data on the treatment of CRSwNP with mepolizumab and to determine the available evidence by searching Medline, Pubmed, the national and international trial and guideline registries and the Cochrane Library. Human studies published in the period up to and including 10/2022 were considered., Results: Based on the international literature and previous experience by an expert panel, recommendations for follow-up, adherence to therapy intervals and possible therapy breaks, as well as termination of therapy when using mepolizumab for the indication CRSwNP in the German health care system are given on the basis of a documentation sheet., Conclusions: Understanding the immunological basis of CRSwNP opens up new non-surgical therapeutic approaches with biologics for patients with severe, uncontrolled courses. Here, we provide recommendations for follow-up, adherence to therapy intervals, possible therapy pauses, or discontinuation of therapy when mepolizumab is used as add-on therapy with intranasal glucocorticosteroids to treat adult patients with severe CRSwNP that cannot be adequately controlled with systemic glucocorticosteroids and/or surgical intervention., Competing Interests: B. Wollenberg hat Honorare und/oder Forschungsgelder von MSD, Sanofi, Astra Zeneca, Novartis, BMS Adboard außerhalb der vorliegenden Arbeit erhalten.J. Hagemann gibt an, Zuwendungen für Vorträge und Honorare für Advisory Boards von den Firmen Sanofi Aventis, Fa. Novartis Pharma GmbH und GlaxoSmithKline erhalten zu haben.A.M. Chaker führt über die Technische Universität München (TUM) Beratungsleistungen (z. B. Advisory Boards, DSMBs), Vorträge oder weitere Aktivitäten durch oder hat über die TUM klinische Studien durchgeführt oder Forschungsgelder erhalten von: Allergopharma, ALK-Abello, Astra Zeneca, Bencard/Allergen Therapeutics, GSK, HAL Allergy, Immunotek, Novartis, SanofiGenzyme und Regeneron, Zeller AG; EIT Health; BMBF. AMC ist ferner Funktionsträger der EUFOREA, EAACI, AeDA und DGAKI.H. Olze erhielt Honorare und/oder Forschungsgelder von F. Hoffmann- La Roche Ltd, Sanofi-Aventis Deutschland GmbH, AstraZeneca GmbH, GlaxoSmithKline GmbH & Co. KG und Novartis Pharma GmbH.L. Klimek berichtet über Zuschüsse und/oder Honorare von Allergopharma, MEDA/Mylan, HAL Allergie, ALK Abelló, LETI Pharma, Stallergenes, Quintiles, Sanofi, ASIT Biotech, Lofarma, Allergy Therapeut., AstraZeneca, GSK, Inmunotk außerhalb der eingereichten Arbeit, und Mitgliedschaft bei folgenden Organisationen: AeDA, DGHNO, Deutsche Akademie für Allergologie und klinische Immunologie, HNO-BV GPA, EAACI.U. Förster-Ruhrmann erhielt Honorare für Vorträge von Novartis, AstraZeneca, Sanofi und GSK außerhalb der vorliegenden Arbeit.S. Strieth berichtet über Stipendien der Deutschen Forschungsgemeinschaft (DFG), Bonn, Stipendien der Stiftung Tumorforschung Kopf-Hals, Wiesbaden, Stipendien und nichtfinanzielle Förderungen der MED-EL AG, Innsbruck, Personalhonorar von Auris Medical, Basel, Personalhonorar von Merck Serono, Darmstadt, Personalhonorar Otonomy, Inc., San Diego (USA), Personalhonorar Nordmark Arzneimittel, Uetersen, Zuschuss Andreas Fahl Medizintechnik-Vertrieb, Köln, Zuschuss Atos Medical, Troisdorf, Zuschuss Tracoe Medical, Nieder-Olm, Stipendien von Heimomed Heinze, Kerpen, Stipendien von Bromepithetik, Heidelberg, Stipendien von Fresenius Kabi, Bad Hersfeld, Personalhonorar von Sonofi Genzyme, Berlin, Personalhonorar von ALK-Abelló Arzneimittel, Hamburg, außerhalb der eingereichten Arbeit.M. Cuevas erhielt Honorare und/oder nichtfinanzielle Unterstützung von Novartis, Sanovi-Aventis, Allergopharma, HAL Allergie, Leti Pharma, AstraZeneca, GlaxoSmithKline, ALK Abelló, Bencard Allergie, Stallergenes und Roxall außerhalb der eingereichten Arbeit und berichtet über Mitgliedschaften bei folgenden Organisationen: AeDA, DGHNO.A. G. Beule hat Honorare für Vorträge, Berater- oder Forschungstätigkeiten von Allakos, Astra Zeneca, BMS, GSK, Medtronic, MSD, Novartis, Olympus, Pharmalog, Pohl Boskamp und Sanofi Aventis außerhalb der vorliegenden Arbeit erhalten.O. Guntinas-Lichius erhielt Honorare von MED-EL, Merck, Novartis, MEDICE und Merz außerhalb dieser Arbeit, und er ist Mitglied bei den folgenden Organisationen: DGHNO, BVHNO.T. K. Hoffmann nimmt an honorierten Advisory Boards der Firmen Merck, MSD und BMS teil, thematisch jedoch außerhalb der vorliegenden Arbeit.C. Bachert erhielt Honorare/Forschungsgelder von den Firmen Sanofi, GSK, Novartis, AstraZeneca und ALK außerhalb der vorliegenden Arbeit.H. Wrede berichtet über Vortragshonorare von Allergopharma, MEDA/Mylan, HAL Allergie, LETI Pharma, Stallergenes, Sanofi, Lofarma, Allergy Therapeut. und GSK außerhalb der eingereichten Arbeit und Mitgliedschaft bei folgenden Organisationen: AeDA, HNO-BV.T. Stöver erhielt Forschungs- und Studiengelder sowie Honorare für Vortrags- und/oder Beratertätigkeiten von MED-EL Elektromedizinische Geräte Deutschland GmbH und Cochlear Deutschland GmbH & Co. KG außerhalb der eingereichten Arbeit. Es bestehen Mitgliedschaften bei der DGHNO-KHC, im Expertengremium über Medizinprodukte und In-vitro-Diagnostika im Auftrag der EU, im Beirat des Hörzentrums Oldenburg GmbH, in der Task Force „Living Practice Guidelines“, im Beirat des Niedersächsischen Zentrums für Biomathematik, als Vorsitzender des Stiftungsbeirats der Stiftung zur Hör- und Sprachförderung Friedberg sowie als Mitherausgeber der Zeitschrift Laryngo-Rhino-Otologie.C. Beutner berichtet über Honorare von GSK, Sanofi und Novartis, ALK Abello außerhalb dieser Arbeit.M. Laudien unterstützte und erhielt in den letzten 5 Jahren Unterstützung, Vortrags- und Beraterhonorare von Olympus Deutschland GmbH, Olympus Europa SE & CO. KG, Novartis Pharma GmbH, Sanofi-Aventis Deutschland GmbH, Brainlab Sales GmbH, GlaxoSmithKline GmbH & Co. KG und der John Grube Foundation außerhalb der vorliegenden Arbeit.M. Gröger berichtet über Zuschüsse und Vortragshonorare von Sanofi, Novartis, AstraZeneca und GSK außerhalb der eingereichten Arbeit.C. Bergmann berichtet über Zuschüsse und Honorare von GlaxoSmithKline (GSK), Sanofi Aventis, Bencard Allergy GmbH/Allergy Therapeutics, HAL Allergie GmbH/HAL Allergy Holding BV außerhalb dieser Arbeit.O. Pfaar gibt Honorare und/oder Studiengelder von ALK-Abelló, Altamira, Allergopharma, Stallergenes Greer, HAL Allergy Holding B.V./HAL Allergie, AAAAI, Bencard Allergie /Allergy Therapeutics, Lofarma, Biomay, Circassia, ASIT Biotech Tools S.A., Dänisches Konsultat, Laboratorios LETI/LETI Pharma, MEDA Pharma/MYLAN, Anergis S.A., Mobile Chamber Experts, Indoor Biotechnologies, GlaxoSmithKline, Astellas Pharma Global, EUFOREA, ROXALL, Novartis, Sanofi-Aventis and Sanofi-Genzyme, Med Update Europe, streamedup!, Pohl-Boskamp, Inmunotek S.L., Wiley and Sons, Paul-Martini-Stiftung, Regeneron Pharmaceuticals Inc., RG Aerztefortbildung, Firma Meinhardt, PneumoLIVE, Institut für Disease Management, Deutsche Forschungsgesellschaft, Springer, Thieme, AstraZeneca, Deutsche Allergie-Liga, AeDA, IQVIA Commercial, Ingress Health, Wort&Bild Verlag, Verlag ME, Procter&Gamble, Alfried-Krupp Krankenhaus an, alle außerhalb des vorliegenden Positionspapiers, und er ist Mitglied des Vorstandes/Excom der EAACI und Mitglied des erweiterten Vorstandes der DGAKI. Ferner ist er Hauptautor oder Co-Autor diverser Leitlinien und Positionspapiere in der Allergologie und Rhinologie.A. S. Hoffmann erhielt Honorare von GSK, Sanofi und Novartis für Vorträge und Advisory Boards außerhalb dieser Arbeit.T. Hildenbrand berichtet über Vortragshonorare von AstraZeneca und Novartis außerhalb dieser Arbeit.R. Weber hat Honorare für Vortrags- und Beratungstätigkeit der Firmen GSK, Infectopharm, KARL STORZ SE & Co KG, NMP, Sanofi, Sidroga-Pharma und Stryker erhalten.W. Schlenter, S. Becker, F. Bärhold, T. Deitmer, H.J. Welkoborsky, S. Dazert, T. Huppertz, C.A. Hintschich, J. Zuberbier, C. Rudack, J. Gosepath, P. Werminghaus, F. Klimek und I. Casper haben keine Interessenkonflikte im Zusammenhang mit der vorliegenden Arbeit., (Thieme. All rights reserved.)

Dynamic deacetylation of non-histone proteins by histone deacetylases (HDACs) is a key regulator of protein functions, interactions, and turnover. Among class I HDACs, human HDAC1 and HDAC2 share more than 80% global homology at the amino acid level. However, despite the high redundancy, there are examples for differential substrate specificities of HDAC1 and HDAC2. Until now it remains quite unclear how specific and overlapping functions of HDAC1/HDAC2 are regulated in different contexts. Here, we describe molecular cloning techniques for the generation of HDAC1/HDAC2 hybrid proteins, HDAC1/HDAC2 mutants lacking known interaction domains, and HDAC1/HDAC2 hybrid proteins with interchanged N-terminal domains. These proteins are tools for the analysis of specific protein interactions and functions in mammalian cells., (© 2023. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

MASK-air ® , a validated mHealth app (Medical Device regulation Class IIa) has enabled large observational implementation studies in over 58,000 people with allergic rhinitis and/or asthma. It can help to address unmet patient needs in rhinitis and asthma care. MASK-air ® is a Good Practice of DG Santé on digitally-enabled, patient-centred care. It is also a candidate Good Practice of OECD (Organisation for Economic Co-operation and Development). MASK-air ® data has enabled novel phenotype discovery and characterisation, as well as novel insights into the management of allergic rhinitis. MASK-air ® data show that most rhinitis patients (i) are not adherent and do not follow guidelines, (ii) use as-needed treatment, (iii) do not take medication when they are well, (iv) increase their treatment based on symptoms and (v) do not use the recommended treatment. The data also show that control (symptoms, work productivity, educational performance) is not always improved by medications. A combined symptom-medication score (ARIA-EAACI-CSMS) has been validated for clinical practice and trials. The implications of the novel MASK-air ® results should lead to change management in rhinitis and asthma., (© 2023 The Authors. Clinical and Translational Allergy published by John Wiley & Sons Ltd on behalf of European Academy of Allergy and Clinical Immunology.)

Background: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a multifactorial inflammatory disease of the nasal and paranasal mucosa. A Type-2 inflammation is described as the most common endotype. Since October 2019 the anti-IL-4/-IL-13 antibody dupilumab has been approved in Germany as an add-on therapy to intranasal corticosteroids for the treatment of adults with severe chronic rhinosinusitis with nasal polyps, when systemic corticosteroids alone or surgery do not provide adequate disease control. While recommendations for the use of dupilumab in CRSwNP exist at both national and international levels, until now it has not been adequately established, how therapy should be monitored and when it should be discontinued in the German Health Care System., Methods: A literature search was performed analyzing previous data on the treatment of CRSwNP with dupilumab and to determine the available evidence by searching Medline, Pubmed, the national and international trial and guideline registries and the Cochrane Library. Human studies published in the period up to 05/2022 were included., Results: Based on international literature and previous experience, recommendations are given by an expert panel for follow-up and possible therapy breaks, therapy intervals or termination of therapy when using dupilumab for the indication CRSwNP in the German health care system based on a documentation form., Conclusions: Understanding the immunological basis of CRSwNP opens new non-surgical therapy approaches with biologics for patients with severe courses. The authors give recommendations for follow-up, possible therapy breaks, therapy intervals and a termination for dupilumab treatment as add-on therapy with intranasal corticosteroids for the treatment of adult patients with severe CRSwNP that cannot be adequately controlled with systemic corticosteroids and/or surgical intervention., Competing Interests: B. Wollenberg hat Honorare und/oder Forschungsgelder von MSD, Sanofi, Astra Zeneca, Novartis, BMS Adboard außerhalb der vorliegenden Arbeit erhalten.A. Sperl hat für Berater- und Vortragstätigkeit Honorare von Sanofi erhalten.J. Hagemann gibt an, Zuwendungen der Fa. Novartis Pharma GmbH für Vorträge und Honorare für advisory-borads von den Firmen Sanofi Aventis, Novartis und GlaxoSmithKline erhalten zu haben.A. Chaker führt über die Technische Universität München Beratungsleistungen (z. B. Advisory Boards, DSMBs), Vorträge oder weitere Aktivitäten für Allergopharma, ALK-Abello, Astra Zeneca, GSK, HAL Allergy, Mundipharma, Nexter, Immunotek, Lofarma, SanofiGenzyme und Regeneron durch; hat klinische Studien oder Forschungsgelder über die Technische Universität München erhalten von ALK, Allergopharma, Astra Zeneca, Bencard/Allergen Therapeutics, ASIT Biotech, GSK, Novartis, Roche, und Zeller AG, ferner Forschungsmittel erhalten vom Umweltbundesamt der Bundesrepublik Deutschland, EIT Health und DZL (BMBF). AMC hat ferner Honorare und Reisekostenerstattungen erhalten vom Bayerischen Ärzteblatt, der Deutschen Gesellschaft für Allergologie und klinische Immunologie (DGAKI) und der European Academy of Allergy and Clinical Immunology.H. Olze erhielt Honorare und/oder Forschungsgelder von F. Hoffmann- La Roche Ltd, Sanofi-Aventis Deutschland GmbH, AstraZeneca GmbH, GlaxoSmithKline GmbH & Co. KG und Novartis Pharma GmbH.L. Klimek berichtet über Zuschüsse und/oder Honorare von Allergopharma, MEDA/Mylan, HAL Allergie, ALK Abelló, LETI Pharma, Stallergenes, Quintiles, Sanofi, ASIT Biotech, Lofarma, Allergy Therapeut., AstraZeneca, GSK, Inmunotk, außerhalb der eingereichten Arbeit; und Mitgliedschaft bei folgenden Organisationen: AeDA, DGHNO, Deutsche Akademie für Allergologie und klinische Immunologie, HNO-BV GPA, EAACIU. Förster-Ruhrmann erhielt Honorare für Vorträge von Novartis, AstraZeneca, Sanofi und GSK außerhalb der vorliegenden Arbeit.S. Strieth berichtet über Stipendien der Deutschen Forschungsgemeinschaft (DFG), Bonn, Stipendien der Stiftung Tumorforschung Kopf-Hals, Wiesbaden, Stipendien und nichtfinanzielle Förderungen der MED-EL AG, Innsbruck, Personalhonorar von Auris Medical, Basel, Personalhonorar von Merck Serono, Darmstadt, Personalhonorar Otonomy, Inc., San Diego (USA), Personalhonorar Nordmark Arzneimittel, Uetersen, Zuschuss Andreas Fahl Medizintechnik-Vertrieb, Köln, Zuschuss Atos Medical, Troisdorf, Zuschuss Tracoe Medical, Nieder-Olm, Stipendien von Heimomed Heinze, Kerpen, Stipendien von Bromepithetik, Heidelberg, Stipendien von Fresenius Kabi, Bad Hersfeld, Personalhonorar von Sonofi Genzyme, Berlin, Personalhonorar von ALK-Abelló Arzneimittel, Hamburg, außerhalb der eingereichten Arbeit;M. Cuevas erhielt Honorare von AstraZeneca, GSK, Sanofi und Novartis, außerhalb dieser Arbeit;A. G. Beule hat Honorare für Vorträge, Berater- oder Forschungstätigkeiten von Allakos, Astra Zeneca, BMS, GSK, Medtronic, MSD, Novartis, Olympus, Pharmalog, Pohl Boskamp und Sanofi Aventis außerhalb der vorliegenden Arbeit erhalten.O. Guntinas-Lichius erhielt Honorare von MED-EL, Merck, Novartis, MEDICE und Merz, außerhalb dieser Arbeit; und er ist Mitglied bei den folgenden Organisationen: DGHNO, BVHNO.T. K. Hoffmann nimmt an honorierten Advisory-boards der Firmen Merck, MSD und BMS teil, thematisch jedoch außerhalb der vorliegenden Arbeit.C. Bachert erhielt Honorare/Forschungsgelder von den Firmen Sanofi, GSK, Novartis, Astra- Zeneca und ALK außerhalb der vorliegenden Arbeit.H. Wrede berichtet über Vortragshonorare von Allergopharma, MEDA/Mylan, HAL Allergie, LETI Pharma, Stallergenes, Sanofi, Lofarma, Allergy Therapeut., GSK, außerhalb der eingereichten Arbeit; und Mitgliedschaft bei folgenden Organisationen: AeDA, HNO-BV.T. Stöver erhielt Forschungs- und Studiengelder sowie Honorare für Vortrags- und/ oder Beratertätigkeiten von MED-EL Elektromedizinische Geräte Deutschland GmbH und Cochlear Deutschland GmbH & Co. KG, außerhalb der eingereichten Arbeit. Es bestehen Mitgliedschaften bei der DGHNO-KHC, im Expertengremium über Medizinprodukte und in-vitro-Diagnostika im Auftrag der EU, im Beirat des Hörzentrum Oldenburg GmbH, in der Task Force ‚Living Practice Guidelines‘, im Beirat des Niedersächsischen Zentrums für Biomathematik, als Vorsitzender des Stiftungsbeirats der Stiftung zur Hör- und Sprachförderung Friedberg sowie als Mit-Herausgeber der Zeitschrift Laryngo-Rhino-Otologie.C. Beutner berichtet über Honorare von GSK, Sanofi und Novartis, ALK Abello außerhalb dieser Arbeit;M. Laudien unterstützte und erhielt in den letzten 5 Jahren Unterstützung, Vortrags- und Beraterhonorare von: Olympus Deutschland GmbH, Olympus Europa SE & CO. KG, Novartis Pharma GmbH, Sanofi-Aventis Deutschland GmbH, Brainlab Sales GmbH, GlaxoSmithKline GmbH & Co. KG und der John Grube Foundation außerhalb der vorliegenden Arbeit.M. Gröger berichtet über Zuschüsse und Vortragshonorare von Sanofi, Novartis, AstraZeneca und GSK, außerhalb der eingereichten Arbeit.O. Pfaar berichtet über Zuschüsse und/oder Honorare von ALK-Abelló, Allergopharma, Stallergenes Greer, GlaxoSmithKline (GSK), HAL Allergy Holding BV/HAL Allergie GmbH, Bencard Allergie GmbH/Allergy Therapeutics, Lofarma, ASIT Biotech Tools SA, Laboratorios LETI/LETI Pharma, Anergis SA, SANOFI-AVENTIS, AstraZeneca, Zuschüsse von Biomay, Nuvo, Circassia, Inmunotek, und Honorare von MEDA Pharma/MYLAN, Mobile Chamber Experts (a GA2LEN Partner), Indoor Biotechnologies, Astellas Pharma Global, EUFOREA, Novartis, ROXALL, Procter&Gamble, IQVIA Commercial, Wort&Bild-Verlag, Verlag ME, WILEY&Sons, streamed-up! GmbH, RG Aerztefortbildung, Deutsche Fortbildungsgesellschaft für Hals-Nasen- und Ohrenärzte. Er ist Vorstandsmitglied/ExCom der Europäischen Akadamie für Allergologie und Klinische Immunologie (EAACI) und Mitglied des erweiterten Vorstandes der Deutschen Gesellschaft für Allergologie und Klinische Immunologie (DGAKI) und er ist/war eingebunden als Koordinator und/oder Mitglied/Autor verschiedener Leitlinien und Positionspapiere.A. S. Hoffmann erhielt Honorare von GSK, Sanofi und Novartis für Vorträge und Advisory Boards außerhalb dieser Arbeit.T. Hildenbrand berichtet über Vortragshonorare von AstraZeneca und Novartis außerhalb dieser Arbeit.R. Weber hat Honorare für Vortrags- und Beratungstätigkeit der Firmen GSK, Infectopharm, KARL STORZ SE & Co KG, NMP, Sanofi, Sidroga-Pharma und Stryker erhalten.W. Schlenter, S. Becker, T. Deitmer, H. J. Welkoborsky, S. Dazert, T. Huppertz, C. Bergmann, C.A. Hintschich, J. Zuberbier, C. Rudack, J. Gosepath, F. Klimek und I. Casper haben keine Interessenkonflikte im Zusammenhang mit der vorliegenden Arbeit., (Thieme. All rights reserved.)

Background: Olfactory dysfunction is one of the leading symptoms of COVID-19. Previous data suggest a different prevalence between the wild type virus and its subsequent variants. Here, we report on a prospective study to psychophysically compare olfactory function in acute SARS-CoV-2 infection between wild type, VOC alpha and VOC delta., Methods: SARS-CoV-2 was confirmed by reverse-transcription quantitative real-time PCR and virus variants were differentiated by high-sensitive next-generation sequencing. Home-quarantined were sent a validated and blinded smell identification test. A detailed instruction ensured correct self-administration., Results: A total of 125 patients were included in study. Patients with the wild type of SARS-CoV-2 self-evaluated their olfactory function significant lower on the visual analog score compared patients with the VOCs alpha or delta (4.1 ± 1.5 vs. 6.8 ± 2.9 and 7.3 ± 0.9; p < 0.001). Likewise, a significant difference of the prevalence of psychophysically confirmed hyposmia (wild type: 73%; alpha: 41%; delta 48%; p < 0.01) and smell test score (48 ± 25% vs. 70 ± 23% and 67 ± 18%; p < 0.01) could be seen between wild type on one side and VOCs alpha and delta on the other side., Conclusion: In this study, both self-reports and psychophysical testing revealed a significant higher prevalence of olfactory impairment in the wild type of SARS-CoV-2 compared to the VOCs alpha and delta., (© 2022. The Author(s).)

Treatment success of head and neck squamous cell carcinoma (HNSCC) is often hindered by cisplatin resistance. As inherent and acquired therapy resistance counteracts improvement in long-term survival, novel multi-targeting strategies triggering cancer cell apoptosis are urgently required. Here, we identify the vitamin D receptor (VDR) as being significantly overexpressed in tumors of HNSCC patients (n = 604; p = 0.0059), correlating with tumor differentiation ( p = 0.0002), HPV status ( p = 0.00026), and perineural invasion ( p = 0.0087). The VDR, a member of the nuclear receptor superfamily, is activated by its ligand vitamin D (VitD) and analogs, triggering multiple cellular responses. As we found that the VDR was also upregulated in our cisplatin-resistant HNSCC models, we investigated its effect on overcoming cisplatin resistance. We discovered that VitD/cisplatin combinations synergistically killed even cisplatin-resistant cells at clinically achievable levels. Similar results were obtained for the clinically used VitD analog Maxacalcitol. Moreover, VitD/cisplatin combinations inhibited tumor cell migration by E-cadherin upregulation. Signaling pathway analyses revealed that VitD co-treatments triggered cancer cell death by increasing the expression of the pro-apoptotic BCL-2 family protein BIM. BIM's pro-apoptotic activity in HNSCC cells was confirmed by ectopic overexpression studies. Importantly, BIM expression is positively associated with HNSCC patients' (n = 539) prognosis, as high expression correlated with improved survival ( p = 0.0111), improved therapy response ( p = 0.0026), and remission ( p = 0.004). Collectively, by identifying, for the first time, the VDR/BIM axis, we here provide a molecular rationale for the reported anti-cancer activity of VitD/analogs in combination therapies. Our data also suggest its exploitation as a potential strategy to overcome cisplatin resistance in HNSCC and other malignancies by inducing additional pro-apoptotic pathways.

Urban wildlife ecology is gaining relevance as metropolitan areas grow throughout the world, reducing natural habitats and creating new ecological niches. However, knowledge is still scarce about the colonisation processes of such urban niches, the establishment of new communities, populations and/or species, and the related changes in behaviour and life histories of urban wildlife. Wild boar (Sus scrofa) has successfully colonised urban niches throughout Europe. The aim of this study is to unveil the processes driving the establishment and maintenance of an urban wild boar population by analysing its genetic structure. A set of 19 microsatellite loci was used to test whether urban wild boars in Barcelona, Spain, are an isolated population or if gene flow prevents genetic differentiation between rural and urban wild boars. This knowledge will contribute to the understanding of the effects of synurbisation and the associated management measures on the genetic change of large mammals in urban ecosystems. Despite the unidirectional gene flow from rural to urban areas, the urban wild boars in Barcelona form an island population genotypically differentiated from the surrounding rural ones. The comparison with previous genetic studies of urban wild boar populations suggests that forest patches act as suitable islands for wild boar genetic differentiation. Previous results and the genetic structure of the urban wild boar population in Barcelona classify wild boar as an urban exploiter species. These wild boar peri-urban island populations are responsible for conflict with humans and thus should be managed by reducing the attractiveness of urban areas. The management of peri-urban wild boar populations should aim at reducing migration into urban areas and preventing phenotypic changes (either genetic or plastic) causing habituation of wild boars to humans and urban environments., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Olfactory dysfunction is common in COVID-19, and sudden-onset dysosmia is an early marker for wild-type SARS-CoV-2 infection. Over 10 000 mutations of SARS-CoV-2 have been registered, with variants of concern (VOC) under particular scrutiny. We report a telemedicine-based, multicentre, prospective cohort study with quantitative olfaction testing comparing 79 patients with a confirmed VOC-Delta (n = 21) or wild-type (WT) SARS-CoV-2 infection. Acute SARS-CoV-2 infection led to significant decrease of olfactory function in both cohorts. A majority of patients suffered from hyposmia or anosmia at inclusion with only 26 individuals performing normosmic. Sniffin'Sticks total scores were significantly higher for VOC-Delta patients at onset of illness, compared to WT patients (p < 0.001). At 4 weeks follow-up, olfaction scores recovered only partially for WT patients, thus odds of recovery were stronger in VOC-Delta patients. Also, subjective self-rating of chemosensory function was lower in WT, compared to VOC-Delta patients. The need for ongoing olfaction studies and their prognosis in SARS-CoV-2 background remains urgent, also in the light of increasing numbers of olfaction-related patient presentations., (© 2022 Published by Elsevier Inc. on behalf of World Allergy Organization.)

Treatment success of head and neck cancer (HNC) is still hampered by tumor relapse due to metastases. Our study aimed to identify biomarkers by exploiting transcriptomics profiles of patient-matched metastases, primary tumors, and normal tissue mucosa as well as the TCGA HNC cohort data sets. Analyses identified osteoblast-specific factor 2 (OSF-2) as significantly overexpressed in lymph node metastases and primary tumors compared to normal tissue. High OSF-2 levels correlate with metastatic disease and reduced overall survival of predominantly HPV-negative HNC patients. No significant correlation was observed with tumor localization or therapy response. These findings were supported by the fact that OSF-2 expression was not elevated in cisplatin-resistant HNC cell lines. OSF-2 was strongly expressed in tumor-associated fibroblasts, suggesting a tumor microenvironment-promoting function. Molecular cloning and expression studies of OSF-2 variants from patients identified an evolutionary conserved bona fide protein secretion signal ( 1 MIPFLPMFSLLLLLIVNPINA 21 ). OSF-2 enhanced cell migration and cellular survival under stress conditions, which could be mimicked by the extracellular administration of recombinant protein. Here, OSF-2 executes its functions via ß1 integrin, resulting in the phosphorylation of PI3K and activation of the Akt/PKB signaling pathway. Collectively, we suggest OSF-2 as a potential prognostic biomarker and drug target, promoting metastases by supporting the tumor microenvironment and lymph node metastases survival rather than by enhancing primary tumor proliferation or therapy resistance.

The advent of hard X-ray free-electron lasers enables nanoscopic X-ray imaging with sub-picosecond temporal resolution. X-ray grating interferometry offers a phase-sensitive full-field imaging technique where the phase retrieval can be carried out from a single exposure alone. Thus, the method is attractive for imaging applications at X-ray free-electron lasers where intrinsic pulse-to-pulse fluctuations pose a major challenge. In this work, the single-exposure phase imaging capabilities of grating interferometry are characterized by an implementation at the I13-1 beamline of Diamond Light Source (Oxfordshire, UK). For comparison purposes, propagation-based phase contrast imaging was also performed at the same instrument. The characterization is carried out in terms of the quantitativeness and the contrast-to-noise ratio of the phase reconstructions as well as via the achievable spatial resolution. By using a statistical image reconstruction scheme, previous limitations of grating interferometry regarding the spatial resolution can be mitigated as well as the experimental applicability of the technique., (open access.)

The ability to visualize a sample undergoing a pressure-induced phase transition allows for the determination of kinetic parameters, such as the nucleation and growth rates of the high-pressure phase. For samples that are opaque to visible light (such as metallic systems), it is necessary to rely on x-ray imaging methods for sample visualization. Here, we present an experimental platform developed at beamline P02.2 at the PETRA III synchrotron radiation source, which is capable of performing simultaneous x-ray imaging and diffraction of samples that are dynamically compressed in piezo-driven diamond anvil cells. This setup utilizes a partially coherent monochromatic x-ray beam to perform lensless phase contrast imaging, which can be carried out using either a parallel- or focused-beam configuration. The capabilities of this platform are illustrated by experiments on dynamically compressed Ga and Ar. Melting and solidification were identified based on the observation of solid/liquid phase boundaries in the x-ray images and corresponding changes in the x-ray diffraction patterns collected during the transition, with significant edge enhancement observed in the x-ray images collected using the focused-beam. These results highlight the suitability of this technique for a variety of purposes, including melt curve determination.

Background: The epithelial immune regulation is an essential and protective feature of the barrier function of the mucous membranes of the airways. Damage to the epithelial barrier can result in chronic inflammatory diseases, such as chronic rhinosinusitis (CRS) or bronchial asthma. Thymic stromal lymphopoietin (TSLP) is a central regulator in the epithelial barrier function and is associated with type 2 (T2) and non-T2 inflammation., Materials and Methods: The immunology of chronic rhinosinusitis with polyposis nasi (CRSwNP) was analyzed in a literature search, and the existing evidence was determined through searches in Medline, Pubmed as well as the national and international study and guideline registers and the Cochrane Library. Human studies or studies on human cells that were published between 2010 and 2020 and in which the immune mechanisms of TSLP in T2 and non-T2 inflammation were examined were considered., Results: TSLP is an epithelial cytokine (alarmin) and a central regulator of the immune reaction, especially in the case of chronic airway inflammation. Induction of TSLP is implicated in the pathogenesis of many diseases like CRS and triggers a cascade of subsequent inflammatory reactions., Conclusion: Treatment with TSLP-blocking monoclonal antibodies could therefore open up interesting therapeutic options. The long-term safety and effectiveness of TSLP blockade has yet to be investigated., (© Dustri-Verlag Dr. K. Feistle.)

Detailed examination of tumor components is leading-edge to establish personalized cancer therapy. Accompanying research on cell-free DNA, the cell count of circulating tumor cells (CTCs) in patient blood is seen as a crucial prognostic factor. The potential of CTC analysis is further not limited to the determination of the overall survival rate but sheds light on understanding inter- and intratumoral heterogeneity. In this regard, commercial CTC isolation devices combining an efficient enrichment of rare cells with a droplet deposition of single cells for downstream analysis are highly appreciated. The Liquid biopsy platform CTCelect was developed to realize a fully-automated enrichment and single cell dispensing of CTCs from whole blood without pre-processing. We characterized each process step with two different carcinoma cell lines demonstrating up to 87 % enrichment (n = 10) with EpCAM coupled immunomagnetic beads, 73 % optical detection and dispensing efficiency (n = 5). 40 to 56.7 % of cells were recovered after complete isolation from 7.5 ml untreated whole blood (n = 6). In this study, CTCelect enabled automated dispensing of single circulating tumor cells from HNSCC patient samples, qPCR-based confirmation of tumor-related biomarkers and immunostaining. Finally, the platform was compared to commercial CTC isolation technologies to highlight advantages and limitations of CTCelect . This system offers new possibilities for single cell screening in cancer diagnostics, individual therapy approaches and real-time monitoring., Competing Interests: The authors have declared no conflicts of interest. All authors have read and agreed to the published version of the manuscript., (© 2022 The Authors. Engineering in Life Sciences published by Wiley‐VCH GmbH.)

Background:  Chronic rhinosinusitis with nasal polyps (CRSwNP) is a multifactorial inflammatory disease of the paranasal sinus mucosa with eosinophilic inflammation as the most common endotype. The anti-IL5 antibody mepolizumab was approved for the treatment of severe CRSwNP in the EU in November 2021., Methods:  A literature search was performed to analyze the immunology of CRSwNP and determine the available evidence by searching Medline, Pubmed, and the German national and international trial and guideline registries and the Cochrane Library. Human studies published in the period up to and including 12/2021 that investigated the effect of mepolizumab in CRSwNP were considered., Results:  Based on the international literature and previous experience, recommendations for the use of mepolizumab in CRSwNP in the German health care system are given by an expert panel on the basis of a documentation form., Conclusions:  Understanding about the immunological basis of CRSwNP opens new non-surgical therapeutic approaches with biologics for patients with severe courses. Mepolizumab is approved since November 2021 for add-on therapy with intranasal corticosteroids for the treatment of adult patients with severe CRSwNP who cannot be adequately controlled with systemic corticosteroids and/or surgical intervention., Competing Interests: U. Förster-Ruhrmann erhielt Honorare für Vorträge von Novartis, AstraZeneca, Sanofi und GSK außerhalb der vorliegenden Arbeit.S. Strieth berichtet über Stipendien der Deutschen Forschungsgemeinschaft (DFG), Bonn, Stipendien der Stiftung Tumorforschung Kopf-Hals, Wiesbaden, Stipendien und nicht-finanzielle Forderungen der MED-EL AG, Innsbruck, Personalhonorar von Auris Medical, Basel, Personalhonorar von Merck Serono, Darmstadt, Personalhonorar Otonomy, Inc., San Diego (USA), Personalhonorar Nordmark Arzneimittel, Uetersen, Zuschüsse Andreas Fahl Medizintechnik-Vertrieb, Koln, Zuschüsse Atos Medical, Troisdorf, Zuschüsse Tracoe Medical, Nieder-Olm, Stipendien von Heimomed Heinze, Kerpen, Stipendien von Bromepithetik, Heidelberg, Stipendien von Fresenius Kabi, Bad Hersfeld, Personalhonorar von Sonofi Genzyme, Berlin, Personalhonorar von ALK-Abello Arzneimittel, Hamburg, außerhalb der eingereichten Arbeit;H. Olze erhielt Honorare und/oder Forschungsgelder von F. Hoffmann-La Roche Ltd, Sanofi-Aventis Deutschland GmbH, AstraZeneca GmbH, GlaxoSmithKline GmbH & Co. KG.A. M. Chaker führt über die Technische Universitat München Beratungsleistungen (z. B. Advisory Boards, DSMBs), Vorträge oder weitere Aktivitäten für Allergopharma, ALK-Abello, Astra Zeneca, GSK, HAL Allergy, Mundipharma, Nexter, Immunotek, Lofarma, SanofiGenzyme und Regeneron durch; hat klinische Studien oder Forschungsgelder über die Technische Universität München erhalten von ALK, Allergopharma, Astra Zeneca, Bencard/Allergen Therapeutics, ASIT Biotech, GSK, Novartis, Roche, und Zeller AG, ferner Forschungsmittel erhalten vom Umweltbundesamt der Bundesrepublik Deutschland, EIT Health und DZL (BMBF).Ferner Honorare und Reisekostenerstattungen erhalten vom Bayerischen Arzteblatt, der Deutschen Gesellschaft fur Allergologie und klinische Immunologie (DGAKI) und der European Academy of Allergy and Clinical Immunology.B. Wollenberg hat Honorare und/oder Forschungsgelder von MSD, Sanofi, AstraZeneca, Novartis, BMS Adboard auserhalb der vorliegenden Arbeit erhalten.C. Bachert erhielt Honorare und/oder Forschungsgelder von Sanofi, Novartis, GSL, Astra-Zeneca außerhalb der vorliegenden Arbeit.L. Klimek berichtet über Zuschüsse und/oder Honorare von Allergopharma, MEDA/Mylan, HAL Allergie, ALK Abelló, LETI Pharma, Stallergenes, Quintiles, Sanofi, ASIT Biotech, Lofarma, Allergy Therapeut., AstraZeneca, GSK, Inmunotk außerhalb der eingereichten Arbeit und Mitgliedschaften bei folgenden Organisationen: AeDA, DGHNO, Deutsche Akademie für Allergologie und klinische Immunologie, HNO-BV GPA, EAACI.J. Hagemann gibt an, Zuwendungen der Fa. Novartis Pharma GmbH für Vorträge erhalten zu haben.M. Cuevas erhält Forschungshonorare im Rahmen einer Studie von AstraZeneca. M. Cuevas erhielt Honorare von AstraZeneca, GSK, Sanofi und Novartis (außerhalb dieser Arbeit).Ch. Bergmann, P.V. Tomazic, C. A. Hintschich, T. Huppertz, H.J. Welkoborsky, F. Klimek und T. Stöver, A. G. Beule, T. K. Hoffmann, S. Dazert, T. Deitmer, H. Wrede, W. Schlenter, J. Zuberbier, C. Rudack, O. Guntinas-Lichius, S. Becker haben keine Interessenkonflikte im Zusammenhang mit dieser Arbeit., (Thieme. All rights reserved.)

Competing Interests: L. Klimek berichtet über Zuschüsse und/oder Honorare von Allergopharma, MEDA/Mylan, HAL Allergie, ALK Abelló, LETI Pharma, Stallergenes, Quintiles, Sanofi, ASIT biotech, Lofarma, Allergy Therapeut., AstraZeneca, GSK, Inmunotk, Cassella med, außerhalb der eingereichten Arbeit; und folgende Mitgliedschaften: AeDA, DGHNO, Deutsche Akademie für Allergologie und klinische Immunolgie, HNO-BV, GPA, EAACI;Ch. Bergmann berichtet über Referentenhonorare von Sanofi Genzyme;S. Becker gibt folgende potenziellen Interessenkonflikte an: Wissenschaftliche Beratung: Novartis, Sanofi-Genzyme, Bencard Allergie; Vortragshonorare: Novartis, Sanofi-Genzyme, Bencard Allergie, HAL-Allergie, MSD, AstraZeneca; Studien: Otonomy, Regeneron, Sensorien, AstraZeneca, Auris medical;M. Cuevas berichtet über Honorare von AstraZeneca, GSK, Sanofi und Novartis;P. V. Tomazic, C. A. Hintschich, F. Klimek, U. Förster-Rurmann, I. Casper, H. J. Welkoborsky, J. Hagemann, K.-Ch. Bergmann, T. Huppertz hat keine Interessenkonflikte im Zusammenhang mit dieser Publikation.