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Background Native allergen extracts or chemically modified allergoids are routinely used to induce allergen tolerance in allergen-specific immunotherapy (AIT), although mechanistic side-by-side studies are rare. It is paramount to balance optimal dose and allergenicity to achieve efficacy warranting safety. AIT safety and efficacy could be addressed by allergen dose reduction and/or use of allergoids and immunostimulatory adjuvants, respectively. In this study, immunological effects of experimental house dust mite (HDM) AIT were investigated applying high-dose HDM extract and low-dose HDM allergoids with and without the adjuvants microcrystalline tyrosine (MCT) and monophosphoryl lipid A (MPL) in a murine model of HDM allergy. Methods Cellular, humoral, and clinical effects of the different AIT strategies were assessed applying a new experimental AIT model of murine allergic asthma based on physiological, adjuvant-free intranasal sensitization followed by subcutaneous AIT. Results While low-dose allergoid and high-dose extract AIT demonstrated comparable potency to suppress allergic airway inflammation and Th2-type cytokine secretion of lung-resident lymphocytes and draining lymph node cells, low-dose allergoid AIT was less effective in inducing a potentially protective IgG1 response. Combining low-dose allergoid AIT with MCT or MCT and dose-adjusted MPL promoted Th1-inducing mechanisms and robust B-cell activation counterbalancing the allergic Th2 immune response. Conclusion Low allergen doses induce cellular and humoral mechanisms counteracting Th2-driven inflammation by using allergoids and dose-adjusted adjuvants. In light of safety and efficacy improvement, future therapeutic approaches may use low-dose allergoid strategies to drive cellular tolerance and adjuvants to modulate humoral responses.

Der technische Fortschritt in der Medizin hat dazu gefuhrt, dass Herzfrequenz und Herzrhythmus nicht nur mittels professioneller Gerate aufgezeichnet werden konnen, sondern dies inzwischen auch vom Laien durch von jedermann erwerbbare sog. Wearables moglich ist. Unter Wearables versteht man direkt am Korper oder der Kleidung getragene elektronische Gerate, die in der Lage sind, biophysikalische Daten zu erheben. Zu den bekanntesten Wearables zahlen Smartwatches, Armbander und Brustgurte. Wearables sind in der Lage, Herzfrequenz, Pulskurven und das EKG zu erfassen. So konnen Wearables als Eventrekorder mit Symptom-getriggerter Aufzeichnung von Arrhythmien oder zum aktiven oder passiven Screening auf Vorhofflimmern genutzt werden. Dazu stehen prinzipiell 2 Verfahren zur Verfugung: die Elektrokardiographie und die Photoplethysmographie. Mit beiden Verfahren ist es inzwischen moglich, Software-unterstutzt mit einer hohen Sensitivitat und Spezifitat Vorhofflimmern zu identifizieren. Ziel dieses Positionspapiers ist es, einen Uberblick zur aktuellen Datenlage und zum Einsatz der Wearables bei der Detektion von symptomatischen und asymptomatischen Arrhythmien zu geben. Zusatzlich werden gesundheitsokonomische und auch rechtliche Aspekte im Umgang mit Wearables beleuchtet.

BACKGROUND Studies show that proallergic TH 2 cells decrease after successful allergen-specific immunotherapy (AIT). It is likely that iatrogenic administration of allergens drives these cells to exhaustion due to chronic T-cell receptor stimulation. This study aimed to investigate the exhaustion of T cells in connection with allergen exposure during AIT in mice and two independent patient cohorts. METHODS OVA-sensitized C57BL/6J mice were challenged and treated with OVA, and the development of exhaustion in local and systemic TH 2 cells was analyzed. In patients, the expression of exhaustion-associated surface markers on TH 2 cells was evaluated using flow cytometry in a cross-sectional grass pollen allergy cohort with and without AIT. The treatment effect was further studied in PBMC collected from a prospective long-term AIT cohort. RESULTS The exhaustion-associated surface markers CTLA-4 and PD-1 were significantly upregulated on TH 2 cells upon OVA aerosol exposure in OVA-allergic compared to non-allergic mice. CTLA-4 and PD-1 decreased after AIT, in particular on the surface of local lung TH 2 cells. Similarly, CTLA-4 and PD-1 expression was enhanced on TH 2 cells from patients with allergic rhinitis with an even stronger effect in those with concomitant asthma. Using an unbiased Louvain clustering analysis, we discovered a late-differentiated TH 2 population expressing both markers that decreased during up-dosing but persisted long term during the maintenance phase. CONCLUSIONS This study shows that allergen exposure promotes CTLA-4 and PD-1 expression on TH 2 cells and that the dynamic change in frequencies of exhausted TH 2 cells exhibits a differential pattern during the up-dosing versus the maintenance phases of AIT.

Background Nonsteroidal anti-inflammatory drug–exacerbated respiratory disease (N-ERD) is a chronic inflammatory condition, which is driven by an aberrant arachidonic acid metabolism. Macrophages are major producers of arachidonic acid metabolites and subject to metabolic reprogramming, but they have been neglected in N-ERD. Objective This study sought to elucidate a potential metabolic and epigenetic macrophage reprogramming in N-ERD. Methods Transcriptional, metabolic, and lipid mediator profiles in macrophages from patients with N-ERD and healthy controls were assessed by RNA sequencing, Seahorse assays, and LC-MS/MS. Metabolites in nasal lining fluid, sputum, and plasma from patients with N-ERD (n = 15) and healthy individuals (n = 10) were quantified by targeted metabolomics analyses. Genome-wide methylomics were deployed to define epigenetic mechanisms of macrophage reprogramming in N-ERD. Results This study shows that N-ERD monocytes/macrophages exhibit an overall reduction in DNA methylation, aberrant metabolic profiles, and an increased expression of chemokines, indicative of a persistent proinflammatory activation. Differentially methylated regions in N-ERD macrophages included genes involved in chemokine signaling and acylcarnitine metabolism. Acylcarnitines were increased in macrophages, sputum, nasal lining fluid, and plasma of patients with N-ERD. On inflammatory challenge, N-ERD macrophages produced increased levels of acylcarnitines, proinflammatory arachidonic acid metabolites, cytokines, and chemokines as compared to healthy macrophages. Conclusions Together, these findings decipher a proinflammatory metabolic and epigenetic reprogramming of macrophages in N-ERD.

Background Children with asthma have impaired production of interleukin (IL) 37; in mice, IL-37 reduces hallmarks of experimental allergic asthma (EAA). However, it remains unclear how IL-37 exerts its inhibitory properties in asthma. This study aimed to identify the mechanism(s) by which IL-37 controls allergic inflammation. Methods IL-37 target cells were identified by single-cell RNA-seq of IL-1R5 and IL-1R8. Airway tissues were isolated by laser-capture microdissection and examined by microarray-based gene expression analysis. Mononuclear cells (MNC) and airway epithelial cells (AECs) were isolated and stimulated with allergen, IL-1β, or IL-33 together with recombinant human (rh) IL-37. Wild-type, IL-1R1- and IL-33-deficient mice with EAA were treated with rhIL-37. IL-1β, IL-33, and IL-37 levels were determined in sputum and nasal secretions from adult asthma patients without glucocorticoid therapy. Results IL-37 target cells included AECs, T cells, and dendritic cells. In mice with EAA, rhIL-37 led to differential expression of >90 genes induced by IL-1β and IL-33. rhIL-37 reduced production of Th2 cytokines in allergen-activated MNCs from wild-type but not from IL-1R1-deficient mice and inhibited IL-33-induced Th2 cytokine release. Furthermore, rhIL-37 attenuated IL-1β- and IL-33-induced pro-inflammatory mediator expression in murine AEC cultures. In contrast to wild-type mice, hIL-37 had no effect on EAA in IL-1R1- or IL-33-deficient mice. We also observed that expression/production ratios of both IL-1β and IL-33 to IL-37 were dramatically increased in asthma patients compared to healthy controls. Conclusion IL-37 downregulates allergic airway inflammation by counterbalancing the disease-amplifying effects of IL-1β and IL-33.

Summary The aim of this study was to evaluate the long-term outcomes of Gillies and McLaughlin's dynamic muscle support with regard to functional outcomes and assess possible effects of comorbidities on both functional outcomes and reoperation and complication rates. A retrospective single-centre study was conducted in all patients (n = 154) who underwent surgical correction of irreversible facial paralysis from 1994 to 2018. Patients with either Gillies procedure or McLaughlin's dynamic muscle support or a combination of these techniques were included in the analysis. Data on reoperations, comorbidities, complications, functional outcomes and patient satisfaction were analysed. Sixty-nine patients had Gillies and McLaughlin combination, 12 patients had Gillies and 33 patients had McLaughlin procedure alone. Patient satisfaction was generally high (>80%) and highest when McLaughlin procedure alone was performed and in patients without comorbidities. Reoperations were performed in 80 patients (70%; mean 2.2 ± 1.7) and complications affected 16 patients (14%). Smile ability and movement control of the corner of the mouth were achieved in >85% of patients operated, whereas complete eyelid closure and facial symmetry at rest were attained in only 46%‒68% of patients. Patients with no underlying medical conditions were able to smile more often, had motor control of the corner of the mouth, better facial symmetry at rest and fewer complications. Although newer surgical techniques are offered in many centres, this study shows that conventional facial reanimation of irreversible facial paralysis with Gillies or McLaughlin's dynamic muscle support or a combination of both produces yield good results and, therefore, continues to be a viable treatment option for many patients.

Zusammenfassung Hintergrund Anomalien des Gefäßsystems des Unterarmes können bei der mikrochirurgischen Hebung einer A. radialis-Lappenplastik von großer Bedeutung sein. Insbesondere bei der Verwendung der fasziokutanen Radialislappenplastik zur Bildung eines Penoids ist auf Grund der erforderlichen Größenausmaße der Lappenplastik eine suffiziente arterielle Versorgung von grundlegender Bedeutung. Beim Auftreten einer persistierenden A. mediana können dabei die Perfusionsverhältnisse im Versorgungsgebiet der A. radialis und der A. ulnaris verändert oder diese sogar vollständig rückgebildet worden sein. Patienten und Methoden Es erfolgte eine retrospektive Auswertung aller in unserer Klinik durchgeführten Phalloplastiken mit Radialispenoid von Januar 2016 bis Dezember 2018. Bei allen Patienten wurde die Technik nach Gottlieb und Levine oder nach Chang angewandt. Ergebnisse In der retrospektiv untersuchten Kohorte von 48 Patienten wurde bei zwei Patienten intraoperativ eine persistierende A. mediana gefunden, was einer Inzidenz von 4,2 % entspricht. Bei beiden Patienten gelang die hinsichtlich der Perfusion komplikationslose Bildung eines Radialispenoids ohne Einschränkungen der Lappenperfusion oder der Perfusion der Hand. Eine Literaturübersicht liefert einen Überblick über die Inzidenz auftretender Aberrationen der Vaskularisierung des Unterarmes und die daraus ableitbaren Konsequenzen für die Planung einer A. radialis-Lappenplastik. Schlussfolgerung Auch im Falle einer verlässlichen mikrochirurgischen Lappenplastik wie der A. radialis-Lappenplastik sollten dem mikrochirurgisch tätigen Chirurgen die Möglichkeiten der anatomischen Varianten der arteriellen Versorgung des Unterarmes, wie das Vorhandensein einer persistierenden A. mediana, bekannt sein. Der standardmäßig durchzuführende Allen-Test liefert in vielen Fällen keine eindeutige Rückschlussmöglichkeit und bedingt somit häufig erst intraoperative Zufallsbefunde. Eine sorgfältige präoperative Planung und Evaluation der Perfusion sowie die Erörterung von Alternativtechniken sind hierbei notwendig.

Zusammenfassung Hintergrund Ziele einer Phalloplastik sind ein möglichst natürliches Erscheinungsbild im Nacktzustand, die Fähigkeit zur Miktion im Stehen und die Kohabitationsfähigkeit. Die vorliegende Arbeit stellt zwei seltenere Indikationen und Techniken dar, die Phalloplastik mittels freier A. radialis-Lappenplastik vom nicht dominanten Unterarm bei Intersexualität sowie nach Penisamputation infolge eines Peniskarzinoms. Patienten und Methoden In unserer Klinik wurden im Verlauf der letzten Jahre zahlreiche Phalloplastiken bei transidenten Personen nach Gottlieb und Levine mittels freier A. radialis-Lappenplastik des nicht dominanten Unterarmes durchgeführt. Diese Technik hat jedoch ebenso ihre Bedeutung zur Penoidkonstruktion bei nicht transidenten Personen. Zwei Patienten werden detailliert hinsichtlich der Indikationsstellung und OP Technik betrachtet und wurden multimodal nachuntersucht. Bei Fall 1 handelt es sich um einen 35-jährigen genetisch männlichen Patienten mit Mikropenis bei Pseudohermaphroditismus masculinus und Androgenresistenz. Bei Fall 2 handelt es sich um einen 51-jährigen Patienten, bei dem aufgrund eines Peniskarzinoms eine Penisteilamputation auf Höhe der Peniswurzel notwendig war. Nach Rezidivfreiheit von 1,5 Jahren erfolgte die Penisrekonstruktion nach kompletter Resektion des noch vorhandenen Restpenis und der Restschwellkörper. Beide Patienten wurden 15 Monate postoperativ hinsichtlich der Sensorik der Phalloplastik und der Einschränkungen im Bereich der Lappenhebestelle multimodal nachuntersucht. Ergebnisse Bei beiden Patienten, mit unterschiedlichen Indikationen, konnten ästhetische und hinsichtlich der Miktion funktionell akzeptable Phalloplastiken mittels freier A. radialis-Lappenplastik erzielt werden. Die multimodale Nachuntersuchung 15 Monate postoperativ ergab relevante Unterschiede in den sensorischen Befunden beider Patienten, die in der unterschiedlichen Anatomie der Reinnervation begründet sind. Schlussfolgerung In mikrochirurgisch versierten Abteilungen kann auch bei den gezeigten selteneren Indikationen die Technik der A. radialis-Phalloplastik nach Gottlieb und Levine erfolgreich angewendet werden, d. h. ein zufriedenstellendes Ergebnis in Bezug auf Funktion und Ästhetik erreicht werden. Die gezeigten Komplikationen unterscheiden sich nicht von der Anwendung der Phalloplastik bei transidenten Patienten.

ObjectiveTGF-β2 (TGF-β, transforming growth factor beta), the less-investigated sibling of TGF-β1, is deregulated in rodent and human liver diseases. Former data from bile duct ligated and MDR2 knockout (KO) mouse models for human cholestatic liver disease suggested an involvement of TGF-β2 in biliary-derived liver diseases.DesignAs we also found upregulated TGFB2 in liver tissue of patients with primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC), we now fathomed the positive prospects of targeting TGF-β2 in early stage biliary liver disease using the MDR2-KO mice. Specifically, the influence of TgfB2 silencing on the fibrotic and inflammatory niche was analysed on molecular, cellular and tissue levels.ResultsTgfB2-induced expression of fibrotic genes in cholangiocytes and hepatic stellate cellswas detected. TgfB2 expression in MDR2-KO mice was blunted using TgfB2-directed antisense oligonucleotides (AON). Upon AON treatment, reduced collagen deposition, hydroxyproline content and αSMA expression as well as induced PparG expression reflected a significant reduction of fibrogenesis without adverse effects on healthy livers. Expression analyses of fibrotic and inflammatory genes revealed AON-specific regulatory effects on Ccl3, Ccl4, Ccl5, Mki67 and Notch3 expression. Further, AON treatment of MDR2-KO mice increased tissue infiltration by F4/80-positive cells including eosinophils, whereas the number of CD45-positive inflammatory cells decreased. In line, TGFB2 and CD45 expression correlated positively in PSC/PBC patients and localised in similar areas of the diseased liver tissue.ConclusionsTaken together, our data suggest a new mechanistic explanation for amelioration of fibrogenesis by TGF-β2 silencing and provide a direct rationale for TGF-β2-directed drug development.

Introduction: Data on treatment outcomes of surgical correction of irreversible facial paralysis is rare and long-term outcomes are scarce in the literature, making treatment choices difficult for operating surgeons. Objective: This study evaluated 25-year outcomes of treatment of irreversible facial paralysis with Gillies and McLaughlin techniques with a focus on general functional and age-related functional outcomes. Methods: Data of all patients who underwent surgical correction of facial paralysis using either Gillies or McLaughlin procedure between 1994 and 2018 were included in the analysis of this retrospective, single-centre study (n = 154). Results: Gillies surgery was performed on 12 and McLaughlin technique on 33 patients. Gillies and McLaughlin surgeries were associated with high patient satisfaction (75–86%), low complication rates (8–24%), and achievement of full or partial eyelid closure in 75% as well as smile reanimation in 97% of patients operated. Achievement of resting facial symmetry was low for both techniques and ranged from 27 to 46%. Age-related functional outcomes were generally superior in middle-aged patients (21–59 years) with fewer complications and reoperations compared to younger and older patients. Conclusions: Surgical correction with Gillies or McLaughlin dynamic muscle support techniques yielded good clinical results with high patient satisfaction and should, therefore, be included as a treatment option for facial reanimation of irreversible facial paralysis. Patient age may play a role in treatment outcomes and reoperation and complication rates and should be taken into careful consideration during treatment planning.

(1) Background: Protruding ears are the most common auricular malformation affecting approximately 5% of the population. One common factor leading to auricular protrusion is a deficiency or total absence of the antihelix. A technique first described by Gottfried Lemperle in 2003 attempts cartilage thinning, folding, and fixation by non-absorbable mattress sutures after ventral skin incision along the ventral helical rim. (2) Methods: Retrospective analysis of patient records was performed for otoplasties according to this technique, performed between 1985 and 2014 at Agaplesion Markus Hospital in Frankfurt, Germany. All recorded complications were examined. (3) Results: A total of 912 single otoplasties were performed according to this technique from 1985 to 2014. Overall complications included 26% minor complications not requiring further surgery and 11% major complications leading to revision surgery. Within those requiring revision surgery, the most common reason was recurrence of auricular protrusion (5%), followed by suture granulomas (5%) and hematomas (2%). (4) Conclusions: Lemperle’s otoplasty technique addresses the open thinning and shaping of the antihelix through a ventral incision along the helix to prevent irregularities and possible ridges. Results show a low complication rate comparable to data found in published studies. This technique is easy to perform, safe, and avoids often seen contour irregularities of the antihelix compared to techniques with a posterior approach.

TGF-β1 is known to have a pro-inflammatory impact by inducing Th9 cells, while it also induces anti-inflammatory Treg cells (Tregs). In the context of allergic airway inflammation (AAI) its dual role can be of critical importance in influencing the outcome of the disease. Here we demonstrate that TGF-β acts in AAI by driving effector T cells into Th9 cells, while Tregs differentiate independently. Induction of experimental AAI and airway hyperreactivity in a mouse model with inducible genetic ablation of the TGFβ-receptor 2 (TGFBR2) on CD4+T cells significantly reduced the disease phenotype. Further, it blocked the induction of Th9 cell frequencies, but increased Treg cells. To translate these findings into a human clinically relevant context, Th9 and Treg cells were quantified both locally in induced sputum and systemically in blood of allergic rhinitis and asthma patients with or without allergen-specific immunotherapy (AIT). Natural allergen exposure induced local and systemic Th2, Th9 cell and reduced Tregs, while therapeutic allergen exposure by AIT suppressed Th2 and Th9 cell frequencies along with TGF-β and IL-9 secretion. Altogether, these findings support that neutralization of TGF-β represents a viable therapeutic option in allergy and asthma, not posing the risk of immune dysregulation by impacting Tregs.

Scientific reports 11(1), 16800 (2021). doi:10.1038/s41598-021-96397-2, Published by Macmillan Publishers Limited, part of Springer Nature, [London]

Abstract SARS-CoV-2 has evolved to enter the host via the ACE2 receptor which is part of the kinin-kallikrein pathway. This complex pathway is only poorly understood in context of immune regulation but critical to control infection. This study examines SARS-CoV-2-infection and epithelial mechanisms of the kinin-kallikrein-system at the kinin B2 receptor level in SARS-CoV-2-infection that is of direct translational relevance. From acute SARS-CoV-2-positive study participants and -negative controls, transcriptomes of nasal curettages were analyzed. Primary airway epithelial cells (NHBEs) were infected with SARS-CoV-2 and treated with the approved B2R-antagonist icatibant. SARS-CoV-2 RNA RT-qPCR, cytotoxicity assays, plaque assays, and transcriptome analyses were performed. The treatment effect was further studied in a murine airway inflammation model in vivo. Here, we report a broad and strong upregulation of kallikreins and the kinin B2 receptor (B2R) in the nasal mucosa of acutely symptomatic SARS-CoV-2-positive study participants. A B2R-antagonist impeded SARS-CoV-2 replication and spread in NHBEs, as determined in plaque assays on Vero-E6 cells. B2R-antagonism reduced the expression of SARS-CoV-2 entry receptor ACE2, G protein–coupled receptor signaling, and ion transport in vitro and in a murine airway inflammation in vivo model. In summary, this study provides evidence that treatment with B2R-antagonists protects airway epithelial cells from SARS-CoV-2 by inhibiting its replication and spread, through the reduction of ACE2 levels and the interference with several cellular signaling processes. Future clinical studies need to shed light on the airway protection potential of approved B2R-antagonists, like icatibant, in the treatment of early-stage COVID-19. Graphical Abstract Key messages Induction of kinin B2 receptor in the nose of SARS-CoV-2-positive patients. Treatment with B2R-antagonist protects airway epithelial cells from SARS-CoV-2. B2R-antagonist reduces ACE2 levels in vivo and ex vivo. Protection by B2R-antagonist is mediated by inhibiting viral replication and spread.

IntroductionGPR30 is an intracellular transmembrane G protein-coupled receptor that mediates non-genomic estrogen signaling. The GPR30 agonist G-1 modulates glucose homeostasis and vascular function. However, its impact on vascular inflammation and atherogenesis has not yet been investigated in the atherosclerotic apolipoprotein E-deficient(ApoE-/-) mouse model.Material and methodsApoE-/- mice were fed a high-cholesterol diet for 7 weeks while being treated with the selective GPR30 agonist G-1 (n=6-7). After the treatment period, vascular relaxation capacity, vascular oxidative stress, and atherosclerotic plaque burden were assessed. In vitro, reactive oxygen species, expression levels of the angiotensin II type1(AT1) receptor, and proliferation rate were quantified in human coronary artery smooth muscle cells(HCASMC).ResultsG-1 significantly improved glucose tolerance in vivo (142.2±8.1mg/dl vs. 204.6±13.3mg/dl), G-1 reduced vascular oxidative stress (221±88RLU/s/mg vs.1,983±885RLU/s/mg) and improved endothelium-dependent vasodilation (relaxation to 35.1±4.5% vs.63.0±4.6%). Furthermore, treatment with G-1 significantly reduced the atherosclerotic plaque burden of female ApoE-/- mice (56.5±3.7% vs.75.5±2.9%). In vitro, G-1 provoked a significant downregulation of the AT1 receptor in HCASMC (0.67±0.09-fold). Furthermore, G-1 blunted angiotensin II-induced ROS production by HCASMC (817±7RLU/s/mg vs.1,625±105 RLU/s/mg) and diminished HCASMC proliferation (-26.8±2.7% vs.+50.4±1.7%).ConclusionsSelective GPR30 activation improves glucose tolerance in vivo and decreases vascular ROS production in vitro and in vivo. In vitro, the antioxidant effect might be mediated by downregulation of the AT1 receptor. In vivo, the antioxidant effect of G-1 is associated with an improved endothelial function and a reduced atherosclerotic plaque burden in ApoE-deficient mice, indicating beneficial vascular effects of GPR30 activation. GPR30 agonism might thus be a compelling treatment strategy against atherosclerosis.

This study examined the disease‐specific quality of life (QoL) in lipoedema patients undergoing treatment for the condition with liposuction. We conducted a retrospective analysis of all patients (n = 69) who underwent liposuction for treatment of lipoedema between 2004 and 2019, and gathered data on patient age, body mass index, the number of liposuction sessions, and the amount of fat removed per side. The study also prospectively evaluated the QoL in 20 lipoedema patients before and after liposuction using the Freiburg Life Quality Assessment for lymphatic diseases questionnaire. The mean age was 50.6 ± 12.8 years, and the average number of liposuction sessions performed was 2.9 ± 1.9, with a mean volume of 1868 ± 885.5 mL of fat removed per side. Before treatment with liposuction, disease‐specific QoL in patients with lipoedema was low on every single subscale as well as on the global score and showed a significant improvement in all aspects after liposuction. There was a significant correlation between a higher number of liposuction treatment sessions and general health status in lipoedema patients (P = .007). Liposuction greatly improves the QoL in lipoedema patients. A higher number of liposuction treatment sessions seem to have a positive effect on general health status in these patients.

Background Mastectomy in male transgender patients is an important (and often the first) step toward physical manhood. At our department, mastectomies in transgender patients have been performed for several decades. Methods Recorded data were collected and analyzed for all male transgender patients undergoing mastectomy over a period of 24 years at our department. Results In total, 268 gender-reassigning mastectomies were performed. Several different mastectomy techniques (areolar incision, n=172; sub-mammary incision, n=96) were used according to patients’ habitus and breast features. Corresponding to algorithms presented in the current literature, certain breast qualities were matched with a particular mastectomy technique. Overall, small breasts with marginal ptosis and good skin elasticity allowed small areolar incisions as a method of access for glandular removal. In contrast, large breasts and those with heavy ptosis or poor skin elasticity often required larger incisions for breast amputation. The secondary correction rate (38%) was high for gender reassignment mastectomy, as is also reflected by data in the current literature. Secondary correction frequently involved revision of chest wall recontouring, suggesting inadequate removal of the mammary tissue, as well as scar revision, which may reflect intense traction during wound healing (36%). Secondary corrections were performed more often after using small areolar incision techniques (48%) than after using large sub-mammary incisions (21%). Conclusions Choosing the suitable mastectomy technique for each patient requires careful individual evaluation of breast features such as size, degree of ptosis, and skin elasticity in order to maximize patient satisfaction and minimize secondary revisions.

Frauke Pedersen,1,2 Ulrich M Zissler,3 Henrik Watz,2 Klaus F Rabe,1 Jens M Hohlfeld,4,5 Olaf Holz41LungenClinic Grosshansdorf, Airway Research Center North (ARCN), German Center for Lung Research (DZL), Grosshansdorf, Germany; 2Pulmonary Research Institute at LungenClinic Grosshansdorf, Airway Research Center North (ARCN), German Center for Lung Research (DZL), Grosshansdorf, Germany; 3Center of Allergy & Environment (ZAUM), Technical University of Munich and Helmholtz Center Munich, German Research Center for Environmental Health, Germany, Member of the German Center for Lung Research (DZL), Munich, Germany; 4Fraunhofer ITEM, Clinical Airway Research – Biomedical Research in End-stage and Obstructive Lung Disease Hannover (BREATH), German Center for Lung Research (DZL), Hannover, Germany; 5Department of Respiratory Medicine, Hannover Medical School (MHH), Biomedical Research in End-stage and Obstructive Lung Disease Hannover (BREATH), Hannover, GermanyBackgroundInduced sputum is a method to assess airway inflammation in clinical trials for asthma and COPD.1–3 Sputum is a heterogeneous, viscous material containing inflammatory cell plugs, cellular debris, mucus, and saliva with squamous cells.The quality of sputum cell preparations for differential cell count analysis depends on multiple factors and can be highly variable.4,5 Percentage of squamous cell contamination (SQ%) is often used to assess the quality of sputum cell preparations.6Here, we evaluated a comprehensive quality score,7 which also includes an assessment of the inflammatory cell morphology and amount of cellular debris.&nbsp

BACKGROUND Therapy of peritoneal metastases (PM) in solid organ transplant recipients is challenging. Pressurized intraperitoneal aerosol chemotherapy (PIPAC) might constitute a new therapeutic opportunity for these patients. MATERIAL AND METHODS This was a single-center, retrospective analysis of prospective registry data (NCT03210298) in a tertiary care center between 1.7.2016 and 31.12.2017. Intraperitoneal administration of oxaliplatin 92 mg/m² body surface or a combination of cisplatin 7.5 mg/m² and doxorubicin 1.5 mg/m², repeated every 6 weeks. Objective tumor response was documented via histology (Peritoneal Regression Grading Score, PRGS), adverse events according to Common Terminology Criteria for Adverse Events (CTCAE) 4.0. RESULTS Out of 71 consecutive patients treated with PIPAC, 2 patients (2.8%) were solid organ transplant recipients. The first patient had metachronous PM of colonic cancer origin after liver transplantation. The second patient had synchronous PM of pancreatic cancer origin after combined kidney-pancreas transplantation. After repeated combined systemic and PIPAC chemotherapy, objective histological response was documented in both patients. No adverse events >CTCAE 2 were recorded. There was no measurable liver or renal toxicity. PIPAC procedures could be repeated (2, resp. 3 cycles) without any interruption of immunosuppressive medication or impairment of respective plasmatic drug levels. The first patient passed away 7 months after the first PIPAC, the second patient was still alive after 8 months. CONCLUSIONS PIPAC can induce objective regression of PM in solid organ transplant recipients without inducing organ toxicity or interfering with immunosuppressive therapy.

Background: Because of the importance of adrenoreceptors in regulating the cardiovascular (CV) system and the role of the CV system in thermoregulation, understanding the response to these two stressors is of interest. The purpose of this study was to assess changes of arterial geometry and function in vivo during thermal and β-adrenergic stress induced in mice and quantified by MRI. Methods: Male mice were anesthetized and imaged at 7 T. Anatomical and functional data were acquired from the neck (carotid artery), torso (suprarenal and infrarenal aorta and iliac artery) and periphery (femoral artery). Intravenous dobutamine (tail vein catheter, 40 µg/kg/min, 0.12 mL/h) was used as β-adrenergic stressor. Baseline and dobutamine data were acquired at minimally hypothermic (35 °C) and minimally hyperthermic (38 °C) core temperatures. Cross-sectional vessel area and maximum cyclic strain were measured across the cardiac cycle. Results: Vascular response varied by location and by core temperature. For minimally hypothermic conditions (35 °C), average, maximum and minimum areas decreased with dobutamine only at the suprarenal aorta (avg: −17.9%, max: −13.5%, min: −21.4%). For minimally hyperthermic conditions (38 °C), vessel areas decreased between baseline and dobutamine at the carotid (avg: −19.6%, max: −15.5%, min: −19.3%) and suprarenal aorta (avg: −24.2%, max: −17.4%, min: −17.3%); whereas, only the minimum vessel area decreased for the iliac artery (min: −14.4%). Maximum cyclic strain increased between baseline and dobutamine at the iliac artery for both conditions and at the suprarenal aorta at hyperthermic conditions. Conclusions: At hypothermic conditions, the vessel area response to dobutamine is diminished compared to hyperthermic conditions where the vessel area response mimics normothermic dobutamine conditions. The varied response emphasizes the need to monitor and control body temperature during medical conditions or treatments that may be accompanied by hypothermia, especially when vasoactive agents are used.

BACKGROUND One of the primary biomechanical factors influencing arterial health is their deformation across the cardiac cycle, or cyclic strain, which is often associated with arterial stiffness. Deleterious changes in the cardiovascular system, e.g., increased arterial stiffness, can remain undetected until the system is challenged, such as under a cardiac stressor like dobutamine. PURPOSE To quantify cyclic strain in mice at different locations along the arterial tree prior to and during dobutamine infusion, while evaluating the effects of sex and age. STUDY TYPE Control/cohort study. ANIMAL MODEL Twenty C57BL/6 mice; male, female; ∼12 and 24 weeks of age; n = 5 per group. FIELD STRENGTH/SEQUENCE 7T; CINE MRI with 12 frames, velocity compensation, and prospective cardiac gating. ASSESSMENT Prior to and during the infusion of dobutamine, Green-Lagrange circumferential cyclic strain was calculated from perimeter measurements derived from CINE data acquired at the carotid artery, suprarenal and infrarenal abdominal aorta, and iliac artery. STATISTICAL TESTS Analysis of variance (ANOVA) followed by post-hoc tests was used to evaluate the influence of dobutamine, anatomical location, sex, and age. RESULTS Heart rates did not differ between groups prior to or during dobutamine infusion (P = 0.87 and P = 0.08, respectively). Dobutamine increased cyclic strain in each group. Within a group, increases in strain were similar across arteries. At the suprarenal aorta, strain was reduced in older mice at baseline (young 27.6 > mature 19.3%, P = 0.01) and during dobutamine infusion (young 53.0 > mature 36.2%, P = 0.005). In the infrarenal aorta, the response (dobutamine - baseline) was reduced in older mice (young 21.9 > mature 13.5%, P = 0.04). DATA CONCLUSION Dobutamine infusion increases circumferential cyclic strain throughout the arterial tree of mice. This effect is quantifiable using CINE MRI. The results demonstrate that strain prior to and during dobutamine is influenced by anatomical location, sex, and age. LEVEL OF EVIDENCE 3 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2019;49:69-80.

As a leading cause of death worldwide, heart failure is a serious medical condition in which many critically ill patients require temporary mechanical circulatory support (MCS) as a bridge-to-recovery or bridge-to-decision. In many cases, the TandemHeart system is used to unload the left heart by draining blood from the left atrium (LA) to the femoral artery via a transseptal multistage cannula. However, even though the correct positioning of the cannula is crucial for a safe treatment, the long cannula tip currently used in transseptal cannulas complicates positioning, making the cannula vulnerable to displacement during MCS. To overcome these limitations, we propose the development of a new tipless transseptal cannula with improved hemodynamic properties. We discuss the tipless cannula concept by comparing it to the common multistage cannula concept using computational fluid dynamics simulations and assess the flow field in the LA, the wall shear stresses (WSS), and the pressure loss. Across the two distinct time points of end-systole and end-diastole and two drainage flow rates of 3.5 and 5.0 L/min, we find a more homogeneous inlet flow pattern for the tipless cannula concept, accompanied by a remarkably reduced area of platelet-activating WSS (up to 10-times smaller area compared to the multistage cannula). Moreover, pressure loss is up to 14.5% lower in the tipless cannula concept, confirming overall improved hemodynamic properties of the tipless cannula concept. Finally, a diameter-dependent study reveals that lower WSS and pressure losses can be further reduced by large-lumen designs for any simulation setting. Overall, our results suggest that a tipless cannula concept remedies the crucial disadvantages of a long-tip multistage cannula by reducing the risk of misplacement, and it furthermore promotes optimized hemodynamics. With this successful proof-of-concept, we underscore the potential for and encourage the realization of further experimental investigations regarding the development of a tipless transseptal cannula for MCS.

Introduction: COL4A3 degradation is significantly increased in severe, exacerbating type 2 asthmatics and correlates with increased chymase positive mast cells (mouse model of asthma). However, whether chymase is sufficient/necessary for COL4A3 degradation and if this mode of action is responsive to therapeutic intervention, is unknown. We hypothesized, that mast cell chymase is necessary for COL4A3 degradation and that treatment with anti-IgE reduces COL4A3 degradation. Methods: The COL4A3 fibrolysis marker C4Ma3 (Nordic Bioscience, Denmark) was measured in female 6-8 week old Balb/C mice, which were sensitized (OVA i.p., day 1, 14, 21) and challenged with aerosol (OVA i.n., day 26, 27, 28) to induce acute allergic airway inflammation. Acute exacerbations were provoked by instillation of poly(cytidylic-inosinic, i.n. day 28) and Chymase was inhibited with Fulacimstat (i.t.). Allergic, uncontrolled asthmatics (n=19, Omalizumab treatment), were monitored over six months. Treatment response was set as Asthma Control Test (ACT) improvement of g3 points. Serum levels of C4Ma3 were determined at baseline, 3 and 6 months. Results: Chymase inhibition prevented OVA-challenge induced C4Ma3 increase. Recombinant chymase alone did not induce elevated C4Ma3 level. Ten out of 19 patients had ACT score increases of g3 points after treatment. Responders mean level of circulating C4Ma3 was 8.87 ng/mL (confidence interval (CI): 7.02-10.72ng/mL), which decreased to 6.57 ng/mL (CI: 4.95-8.1ng/mL, pl0.01) after six months treatment. Non-responders did not show any change in serum levels of after treatment. Conclusion: COL4A3 degradation depends on mast cell chymase in vivo and monitoring serum C4Ma3, may afford a novel avenue to stratify and monitor anti-IgE therapy in severe, allergic asthma.

Introduction: Remodeling of the airway wall is a hallmark feature of asthma. Under physiological conditions, a finely tuned balance maintains a functional state of the extracellular matrix. This balance is disrupted in asthma. COL4A3 is reduced 18-fold in lung tissue from asthmatics, however, the mechanism leading to the diminished levels of COL4A3 has remained elusive. Methods: The COL4A3 fibrolysis marker C4Ma3 (Nordic Bioscience, Denmark) was measured in the ALLIANCE cohort study participants (Fuchs et al. 2018). Pediatric controls/cases: 34/134; Adult control/cases 31/149. C4Ma3 data was correlated with clinical data, serum cytokine profiles (27-Bioplex, Biorad). Female 6-8 week old Balb/C mice were sensitized (OVA i.p., day 1, 14, 21) and challenged with aerosol (OVA i.n., day 26, 27, 28) to induce acute allergic airway inflammation. Acute exacerbations were provoked by instillation of poly(cytidylic-inosinic, i.n. day 28). Murine precision cut lung slices (PCLS) were used to elucidate the role of sensitisation for COL4A3 degradation. Results: Increased C4Ma3 correlated with asthma exacerbation (pl0.01) and elevated levels of Th2/Th9 cytokines in the ALLIANCE cohort. Serum levels of C4Ma3 were elevated in OVA challenged mice (pl0.0001) and correlated with lung tissue levels of mast cell chymase (pl0.01), but not with neutrophils or matrix-metallo-proteinase 9. C4MA3 was elevated in PCLS of allergic, HDM challenged mice (pl0.05) with no further increase after PolyIC. Conclusion: COL4A3 degradation (circulating C4Ma3), is elevated in severe, exacerbating type 2 asthmatics. C4Ma3 levels correlate with chymase positive mast cells in a mouse model of asthma exacerbation. These data highlight that the degradation of COL4A3 is a central part of the pathology of asthma.

BackgroundAsthma is a heterogeneous syndrome substantiating the urgent requirement for endotype-specific biomarkers. Dysbalance of fibrosis and fibrolysis in asthmatic lung tissue leads to reduced levels of the inflammation-protective collagen 4 (COL4A3).ObjectiveTo delineate the degradation of COL4A3 in allergic airway inflammation and evaluate the resultant product as a biomarker for anti-IgE therapy response.MethodsThe serological COL4A3 degradation marker C4Ma3 (Nordic Bioscience, Denmark) and serum cytokines were measured in the ALLIANCE cohort (paediatric cases/controls: n=134/n=35; adult cases/controls: n=149/n=31). Exacerbation of allergic airway disease in mice was induced by sensitising to ovalbumin (OVA), challenge with OVA aerosol and instillation of poly(cytidylic-inosinic). Fulacimstat (chymase inhibitor; Bayer) was used to determine the role of mast cell chymase in COL4A3 degradation. Patients with cystic fibrosis (n=14) and cystic fibrosis with allergic bronchopulmonary aspergillosis (ABPA; n=9) as well as patients with severe allergic uncontrolled asthma (n=19) were tested for COL4A3 degradation. Omalizumab (anti-IgE) treatment was assessed using the Asthma Control Test.ResultsSerum levels of C4Ma3 were increased in asthma in adults and children alike and linked to a more severe, exacerbating allergic asthma phenotype. In an experimental asthma mouse model, C4Ma3 was dependent on mast cell chymase. Serum C4Ma3 was significantly elevated in cystic fibrosis plus ABPA and at baseline predicted the success of the anti-IgE therapy in allergic, uncontrolled asthmatics (diagnostic OR 31.5).ConclusionC4Ma3 levels depend on lung mast cell chymase and are increased in a severe, exacerbating allergic asthma phenotype. C4Ma3 may serve as a novel biomarker to predict anti-IgE therapy response.

In past 10 years, microRNAs (miRNAs) have gained scientific attention due to their importance in the pathophysiology of allergic diseases and their potential as biomarkers in liquid biopsies. They act as master post‐transcriptional regulators that control most cellular processes. As one miRNA can target several mRNAs, often within the same pathway, dysregulated expression of miRNAs may alter particular cellular responses and contribute, or lead, to the development of various diseases. In this review, we give an overview of the current research on miRNAs in allergic diseases, including atopic dermatitis, allergic rhinitis, and asthma. Specifically, we discuss how individual miRNAs function in the regulation of immune responses in epithelial cells and specialized immune cells in response to different environmental factors and respiratory viruses. In addition, we review insights obtained from experiments with murine models of allergic airway and skin inflammation and offer an overview of studies focusing on miRNA discovery using profiling techniques and bioinformatic modeling of the network effect of multiple miRNAs. In conclusion, we highlight the importance of research into miRNA function in allergy and asthma to improve our knowledge of the molecular mechanisms involved in the pathogenesis of this heterogeneous group of diseases.

Allergy 76(4), 1010-1023 (2021). doi:10.1111/all.14645, Published by Wiley, Oxford

Background While several systemic immunomodulatory effects of allergen-specific immunotherapy (AIT) have been discovered, local anti-inflammatory mechanisms in the respiratory tract are largely unknown. We sought to elucidate local and epithelial mechanisms underlying allergen-specific immunotherapy in a genome-wide approach. Methods We induced sputum in hay fever patients and healthy controls during the pollen peak season and stratified patients by effective allergen immunotherapy or as untreated. Sputum was directly processed after induction and subjected to whole transcriptome RNA microarray analysis. Nasal secretions were analyzed for Secretoglobin1A1 (SCGB1A1) and IL-24 protein levels in an additional validation cohort at three defined time points during the 3-year course of AIT. Subsequently, RNA was extracted and subjected to an array-based whole transcriptome analysis. Results Allergen-specific immunotherapy inhibited pro-inflammatory CXCL8, IL24, and CCL26mRNA expression, while SCGB1A1, IL7, CCL5, CCL23, and WNT5BmRNAs were induced independently of the asthma status and allergen season. In our validation cohort, local increase of SCGB1A1 occurred concomitantly with the reduction of local IL-24 in upper airways during the course of AIT. Additionally, SCGB1A1 was identified as a suppressor of epithelial gene expression. Conclusions Allergen-specific immunotherapy induces a yet unknown local gene expression footprint in the lower airways that on one hand appears to be a result of multiple regulatory pathways and on the other hand reveals SCGB1A1 as novel anti-inflammatory mediator of long-term allergen-specific therapeutic intervention in the local environment.

BACKGROUND Several microRNAs (miRs) have been described as potential biomarkers in liquid biopsies and in the context of allergic asthma, while therapeutic effects on the airway expression of miRs remain elusive. In this study, we investigated epigenetic miR-associated mechanisms in the sputum of grass pollen-allergic patients with and without allergen-specific immunotherapy (AIT). METHODS Induced sputum samples of healthy controls (HC), AIT-treated and -untreated grass pollen-allergic rhinitis patients with (AA) and without asthma (AR) were profiled using miR microarray and whole-transcriptome microarray analysis of the same samples. miR targets were predicted in silico and used to identify inverse regulation. Local PGE2 levels were measured using ELISA. RESULTS Two hundred and fifty nine miRs were upregulated in the sputum of AA patients compared with HC, while only one was downregulated. The inverse picture was observed in induced sputum of AIT-treated patients: while 21 miRs were downregulated, only 4 miRs were upregulated in asthmatics upon AIT. Of these 4 miRs, miR-3935 stood out, as its predicted target PTGER3, the prostaglandin EP3 receptor, was downregulated in treated AA patients compared with untreated. The levels of its ligand PGE2 in the sputum supernatants of these samples were increased in allergic patients, especially asthmatics, and downregulated after AIT. Finally, local PGE2 levels correlated with ILC2 frequencies, secreted sputum IL-13 levels, inflammatory cell load, sputum eosinophils and symptom burden. CONCLUSIONS While profiling the sputum of allergic patients for novel miR expression patterns, we uncovered an association between miR-3935 and its predicted target gene, the prostaglandin E3 receptor, which might mediate AIT effects through suppression of the PGE2 -PTGER3 axis.

BackgroundThere are no studies identified that address professionals' knowledge of sexual behaviour problems in children aged 0-12 years. However, it seems essential for child professionals to be able to identify the healthy or pathological nature of sexual behaviour.Case presentationWe proposed a cross-sectional, descriptive and comparative observational study using anonymous questionnaires distributed to medico-social professionals in France. They were questioned on their knowledge of normal sexual development, risk factors for developing sexual behaviour problems, and the future of minors presenting these behaviours.Conclusions Among the 93 respondents whose questionnaires were usable, there were 12 men and 81 women. The majority of respondents didn’t know the age at which psychosexual and emotional child development begins (73.1%) or didn’t know the age limits for sexual behaviour problems (95.7%). Very often, these professionals represented children with sexual behaviour problems as "children who have been abused" (81.72% of respondents) and/or who "will become child perpetrators of sexual violence" (70.87% of respondents). All these answers highlight the lack of training of these professionals, at the risk of proposing a reply that is not adapted to children with these disorders. So, it seems essential to offer more systematic and adapted courses to professionals who take care of minors in institutions.

Summary Background In phalloplasty, there is a lack of standardized follow-up examinations of motor function and strength after harvesting oversized radial forearm free flaps (RFFF). Methods We evaluated the donor site of 20 transmen after phalloplasty, using a multimodal, standardized approach, assessing the following parameters: opposition of the thumb, composite range of motion of the finger joints, grip strength, mobility of the wrist, lesion of the superficial branch of the radial nerve, the dorsal branch of the ulnar nerve, the sensation of pain, and cold intolerance. The contralateral, nonoperated forearm was used as a control. Results No impairment of the mobility of the thumb (Kapandji score median 10, range 5–10) or fingers (all fingers at both sides pulp-to-palm 0 cm, nail-to-table 0 cm) were detected. Grip strength (median 36,3kg, p=0.629) and wrist extension (62.5°vs.70°, p=0.357), flexion (70°vs.70°, p=0.535), pronation (90°vs.90°), supination (90°vs.90°), radial (30°vs.30°, p=0.195), and ulnar deviation (40°vs.50°, p=0.125) did not statistically differ between donor and control hand. Injury of the dorsal branch of the ulnar nerve was uncommon (0% hypoesthesia, 10% positive Tinel's sign). We did not observe any persistent pain of the donor forearm (NRS median 0, range 0–9). We did observe irritation of the superficial branch of the radial nerve (hypoesthesia 40%, neuroma 45%). Conclusion The harvest of an oversized RFFF for phalloplasty does not cause any significant difference in motor function or strength between the donor and nonoperated hand. A potential risk of injuring the radial nerve branch is to be avoided. An aesthetic impairment could be addressed in future studies.

Introduction: Capsular contracture most often leads to implant revision surgery for aesthetic or reconstructive purposes. However, little is known about which operation is chosen when revision surgery has to be performed. We performed analysis of revision indications and performed revision surgery considering implant removal or replacement and additional surgical procedures. To our knowledge, this study presents the largest German single-center analysis regarding implant revision surgery after the onset of complications. Methods: Retrospective 10-year data analysis of a single-center population undergoing breast implant revision surgery. Results: Capsular contracture was the most frequent finding before reoperation, both removal and replacement (p < 0.05). It was linked to longer duration of in situ implant placement (p < 0.05) and more frequently in reconstructive patients (p < 0.05). Implant replacement was performed more often before definite implant removal for reconstructive patients (p < 0.05). Mean duration of in situ implant placement before definite removal was lower for reconstructive patients (p = 0.005). Overall reconstructive patients were older than aesthetic patients (p < 0.05). After implant removal, 61.7% of aesthetic patients chose to undergo mastopexy, 54.7% of reconstructive patients opted for autologous breast reconstruction, and 25.4% did not choose an additional surgical procedure after implant removal. Conclusion: Significant differences are observed for reconstructive and aesthetic patients regarding indication leading to revision surgery, time of revision surgery, and the type of performed revision surgery itself. After implant removal, more than 60% of aesthetic patients undergo mastopexy, more than half of reconstructive patients choose autologous breast reconstruction, and over a quarter of patients choose no additional surgical procedures.

Background The safe execution of local flaps tends to be challenging for surgical residents. Thus, the purpose of the study was to evaluate a training model of local flaps based on fresh human skin excised from body contouring procedures. Materials and methods A questionnaire and surgical skills evaluation—analyzing the theoretical and procedural knowledge about local flaps—were held both before and after the surgical skills training. All surgical procedures were executed on a simulation model based on fresh human skin. Skills evaluation was done according to a modified version of the Objective Structured Assessment of Technical Skills Score. Results before and after the training were compared using SPSS, version 21. Results In pretraining evaluation, residents showed great difficulty regarding the accuracy of flap design and sufficiency of wound coverage indicating the need for surgical training outside the operating theater. After training, the procedural skills significantly improved as depicted by the modified Objective Structured Assessment of Technical Skills score with a mean cumulative pretraining score of 26.81 ± 5.41 and posttraining score of 43.59 ± 5.72 (P = 0.008). Also, theoretical knowledge significantly improved in the posttraining evaluation with exception to the indication of a Z-plasty (P = 0.257). The training model itself was generally regarded as highly useful and thus recommendable to others. Conclusions Surgical handling and the understanding of tissue rotation clearly improved by the presented model which mimics very realistic conditions. The simulation model based on fresh human skin shows cost-effectiveness and allows a broad range for flap procedures wherefore its use should be further promoted.

An inexpensive, accurate focused ultrasound stereotactic targeting method guided by pretreatment magnetic resonance imaging (MRI) images for murine brain models is presented. An uncertainty of each sub-component of the stereotactic system was analyzed. The entire system was calibrated using clot phantoms. The targeting accuracy of the system was demonstrated with an in vivo mouse glioblastoma (GBM) model. The accuracy was quantified by the absolute distance difference between the prescribed and ablated points visible on the pre treatment and posttreatment MR images, respectively. A precalibration phantom study ( ${N} = {6}$ ) resulted in an error of 0.32 ± 0.31, 0.72 ± 0.16, and 1.06 ± 0.38 mm in axial, lateral, and elevational axes, respectively. A postcalibration phantom study ( ${N} = {8}$ ) demonstrated a residual error of 0.09 ± 0.01, 0.15 ± 0.09, and 0.47 ± 0.18 mm in axial, lateral, and elevational axes, respectively. The calibrated system showed significantly reduced ( ${p} ) error of 0.20 ± 0.21, 0.34 ± 0.24, and 0.28 ± 0.21 mm in axial, lateral, and elevational axes, respectively, in the in vivo GBM tumor-bearing mice ( ${N} = {10}$ ).

Objective To evaluate the outcome of a single-center series of penile reconstruction using the radial free forearm flap in rare indications. Materials and Methods From April 1993 until September 2016, 23 nontranssexual patients underwent phallic reconstruction by the use of a neuromicrovascular free radial forearm flap in our clinic. Patient-specific characteristics, surgical techniques, complications, and outcomes were retrospectively evaluated and interpreted. Results The indications for surgery were: disorders of sex development (34.8%), reconstruction after oncologic surgery (34.8%), automutilation (8.7%), iatrogenic (8.7%), microphallus (8.7%), and 1 case of priapism (4.3%). Two patients (8.7%) had a total flap necrosis and 2 patients (8.7%) had a partial flap necrosis; 3 out of these 4 patients were heavy smokers. Urinary fistulae and strictures were frequent but were successfully managed by urologists in all cases. There was no statistically significant correlation between smoking, comorbidities, number of venous anastomoses, and complications. Conclusion In departments experienced in microsurgery, the goals of penile reconstruction could also be achieved in patients with rare indications by the use of the neuromicrovascular free radial forearm flap. Despite the high rate of postoperative complications, penile reconstruction with the free radial forearm flap yields satisfying results. An intensive cooperation between the plastic-reconstructive team and the urological team is a prerequisite to achieve the best surgical result.

Wound-healing disorders are common complications in bilateral reduction mammaplasty. Traditional electrosurgical devices generate large amounts of thermal energy, often causing extensive thermal-related collateral tissue damage. This study aimed to retrospectively analyse the operative performance of a novel low-thermal plasma dissection device (pulsed electron avalanche knife-PEAK PlasmaBlade™) compared with traditional electrosurgery. Twenty patients with breast hypertrophy were randomly treated with PEAK PlasmaBlade™ on one breast and conventional electrosurgery on the other. Primary outcome measures were resection weight, drain duration, total drainage volume, and drain output on the first postoperative day. Breasts treated with PEAK PlasmaBlade™ had significantly higher resection weights (728.0 ± 460.1 g vs 661.6 ± 463.4 g; P = .038), significantly lower drain output on the first postoperative day (15.9 ± 15.2 mL vs 27.6 ± 23.5 mL; P = .023), and significantly lower drain durations (2.8 ± 1.0 days vs 3.3 ± 1.0 days; P = .030). Mean total drainage volume was lower where breast reduction was performed with PEAK PlasmaBlade™, but this difference was not significant. No major complications occurred, but wound-healing disorders were documented in almost one-third of the patients (35.0%, n = 7). The PEAK PlasmaBlade™ seems to be superior to conventional electrosurgery for bilateral reduction mammaplasty in terms of tissue damage and wound healing.

Background Post-bariatric patients present a surgical challenge within abdominoplasty because of residual obesity and major comorbidities. In this study, we analyzed complications following abdominoplasty in post-bariatric patients and evaluated potential risk factors associated with these complications. Objectives The authors sought to determine the complications and risk factors following abdominoplasty in post-bariatric patients. Methods A retrospective study of patients who underwent abdominoplasty was performed from January 2009 to December 2018 at our institution. Variables analyzed were sex, age, body mass index (BMI), smoking, surgical technique, operative time, resection weight, drain output, and complications. Results A total of 406 patients were included in this study (320 female and 86 male) with a mean age of 44.4 years and a BMI of 30.6 kg/m2. Abdominoplasty techniques consisted of traditional (64.3%), fleur-de-lis technique (27.3%), and panniculectomy without umbilical displacement (8.4%). Overall complications recorded were 41.9%, the majority of these being wound-healing problems (32%). Minor and major complications were found in 29.1% and 12.8% of patients, respectively. A BMI value of ≥30 kg/m2 was associated with an increased risk for wound-healing problems (P = 0.001). The frequency of total complications was significantly related to age (P = 0.007), BMI (P = 0.004), and resection weight (P = 0.001). Abdominoplasty technique tended to influence total complications. Conclusions This study demonstrates in a fairly large sample of post-bariatric patients (n = 406) that abdominoplasty alone can be performed safely, with an acceptable complication rate. Age, BMI, and resection weight are shown to be significant risk factors for total complications. The role of surgical technique needs to be evaluated further. Level of Evidence: 4

Subcutaneous mastectomy, the first step in sexual reassignment surgery of female-to-male transsexuals, is associated with high rates of complication and revision surgery. Also, conventional electrosurgery and the associated thermal tissue damage may compromise outcome. This retrospective randomised clinical study evaluated the effect of low-thermal plasma dissection device (PEAK PlasmaBlade, Medtronic, Minneapolis, Minnesota) in comparison with conventional electrosurgery. A total of 17 female-to-male transsexuals undergoing mastectomy were randomised to PEAK PlasmaBlade on one breast side and to monopolar electrosurgery on the other side of the same patient. Wounds of 17 patients were examined histologically for acute thermal injury. Significantly less total volume of drain output (58.8 ± 37.4 mL vs 98.5 ± 76.4 mL; P = .012) was found on the PEAK PlasmaBlade side compared with the electrosurgery side. Duration of drain was significantly shorter on the PEAK PlasmaBlade side (2.5 ± 0.7 days vs 3.2 ± 0.6 days; P = .010). Furthermore, the PEAK PlasmaBlade side showed fewer thermal damages (41.2% vs 82.4%; P = .039) and thermal injury depth from PEAK PlasmaBlade side was less (3170 vs 4060 μm). PEAK PlasmaBlade appears to be superior to monopolar electrosurgery for mastectomy in female-to-male transsexuals, because it demonstrated less thermal tissue damage, less total volume of drain output, and shorter duration of drain, resulting in faster wound healing.

The immune response to antigens is a key aspect of immunology, as it provides opportunities for therapeutic intervention. However, the induction of immunological tolerance is an evolving area that is still not sufficiently understood. Allergen immunotherapy (AIT) is a disease-modulating therapy available for immunoglobulin E (IgE)-mediated airway diseases such as allergic rhinitis or allergic asthma. This disease-modifying effect is not only antigen driven but also antigen specific. The specificity and also the long-lasting, often life-long symptom reduction make the therapy attractive for patients. Additionally, the chance to prevent the onset of asthma by treating allergic rhinitis with AIT is important. The mechanism and, in consequence, therapy guiding biomarker are still in its infancy. Recent studies demonstrated that the interaction of T, B, dendritic, and epithelial cells and macrophages are individually contributing to clinical tolerance and therefore underline the need for a system to monitor the progress and success of AIT. As clinical improvement is often accompanied by decreases in numbers of effector cells in the tissue, analyses of cellular responses and cytokine pattern provide a good insight into the mechanisms of AIT. The suppression of type-2 immunity is accompanied by decreased levels of type-2 mediators such as epithelial CCL-26 and interleukin (IL)-4, IL-13 produced by T cells that are constituting the immune memory and are increasingly controlled by regulatory T and B cells following AIT. Immune tolerance is also associated with increased production of type-1 mediators like interferon-gamma, tissue-homeostating factors like indoleamine 2,3-dioxygenase (IDO) expressed by macrophages and dendritic cells. Although these individual genes were convincingly demonstrated to play a role immune tolerance, they do not predict therapy outcomes of AIT on an individual level. Therefore, combinations or ratios of gene expression levels are a promising way to achieve predictive value and definition of helpful biomarker.

Cardiotoxicity is a frequent side effect of chemotherapy leading to impaired outcomes in cancer survivors. Because of that cardiooncology has recently gained more importance in clinical practice. We aim to echocardiographically evaluate the development of cardiotoxicity and to detect early signs for preventing severe cardiomyopathies by repeated strain analysis. We included 80 patients (46.7 ± 14.7 years, 75% female) under diverse cardiotoxic chemotherapies (43.7% breast cancer, 43.7% haematological malignancy, 12.5% others). All patients underwent echocardiography before and during treatment. Follow-up echocardiography was performed approximately 5.5 ± 1.2 months after the first application of the chemotherapy. The apical four-chamber view was used to perform strain analysis employing dedicated and automated offline software as shown previously. Eight patients deceased due to oncological complications during follow up. Twelve patients showed significant reduced left ventricle ejection fraction (LVEFbaseline 63.2 ± 4.5%, LVEFFollow-up 48.6 ± 7.8%, p = 0.02) correlated with decrease in left ventricular global longitudinal strain (LV-GLSbaseline 17.1 ± 5.2%, LV-GLSFollow-up 9.7 ± 3.2%, p = 001). All of these patients presented heart failure symptoms, mostly with dyspnoea (85% functional NYHA class > II) and oedema (65%). In 15 patients we found a reduction of left ventricular global longitudinal strain from Delta LV-GLS (LV-GLSbaseline – LV-GLSFollow-up) was found to be strongest independent predictor of mortality. Baseline LV-GLS Solely LVEF is insufficient to detect cardiotoxicity and to estimate prognosis of patients under cardiotoxic chemotherapy. In our small patient collective we found baseline LV-GLS 5% a strongest independent predictor for mortality in patients with preserved LVEF under cardiotoxic chemotherapy.

Allergic bronchial asthma is a chronic disease of the airways that is characterized by symptoms like respiratory distress, chest tightness, wheezing, productive cough, and acute episodes of broncho-obstruction. This symptom-complex arises on the basis of chronic allergic inflammation of the airway wall. Consequently, the airway epithelium is central to the pathogenesis of this disease, because its multiple abilities directly have an impact on the inflammatory response and thus the formation of the disease. In turn, its structure and functions are markedly impaired by the inflammation. Hence, the airway epithelium represents a sealed, self-cleaning barrier, that prohibits penetration of inhaled allergens, pathogens, and other noxious agents into the body. This barrier is covered with mucus that further contains antimicrobial peptides and antibodies that are either produced or specifically transported by the airway epithelium in order to trap these particles and to remove them from the body by a process called mucociliary clearance. Once this first line of defense of the lung is overcome, airway epithelial cells are the first cells to get in contact with pathogens, to be damaged or infected. Therefore, these cells release a plethora of chemokines and cytokines that not only induce an acute inflammatory reaction but also have an impact on the alignment of the following immune reaction. In case of asthma, all these functions are impaired by the already existing allergic immune response that per se weakens the barrier integrity and self-cleaning abilities of the airway epithelium making it more vulnerable to penetration of allergens as well as of infection by bacteria and viruses. Recent studies indicate that the history of allergy- and pathogen-derived insults can leave some kind of memory in these cells that can be described as imprinting or trained immunity. Thus, the airway epithelium is in the center of processes that lead to formation, progression and acute exacerbation of asthma.

Rationale: The clinical relevance of sensitization to Aspergillus (A) fumigatus in cystic fibrosis (CF) is unclear. Some researchers propose that specific A fumigatus IgE is an innocent bystander, whereas others describe it as the major cause of TH-2-driven asthma-like disease.Objectives: Lung function parameters in mild CF patients may be different in patients with and without A fumigatus sensitization. We aimed to ascertain whether allergen exposure to A fumigatus by bronchial allergen provocation (BAP) induces TH-2 inflammation comparable to an asthma-like disease.Methods: A total of 35 patients, aged 14.8 +/- 8.5 years, and 20 healthy controls were investigated prospectively. The patients were divided into two groups: group 1 (n = 18): specific (s)IgE negative, and group 2 (n = 17): sIgE positive (>= 0.7 KU/L) for A fumigatus. Lung function, exhaled NO, and induced sputum were analysed. All sensitized patients with an FEV1 > 75% (n = 13) underwent BAP with A fumigatus, and cell counts, and the expression of IL-5, IL-13, INF-gamma, and IL-8 as well as transcription factors T-bet, GATA-3, and FoxP3, were measured.Results: Lung function parameters decreased significantly compared to controls, but not within the CF patient group. After BAP, 8 of 13 patients (61%) had a significant asthmatic response and increased eNO 24 hours later. In addition, marked TH-2-mediated inflammation involving eosinophils, IL-5, IL-13, and FoxP3 became apparent in induced sputum cells.Conclusion: Our study demonstrated the clinical relevance of A fumigatus for the majority of sensitized CF patients. A distinct IgE/TH-2-dominated inflammation was found in induced sputum after A fumigatus exposure.

The purpose of this study was to analyse the long-term outcomes of Gillies and McLaughlin's dynamic muscle support in patients with irreversible facial paralysis with regard to age-dependent outcomes of three different age groups. A retrospective single-centre study of 154 patients with surgical correction of irreversible facial paralysis that underwent either Gillies procedure or McLaughlin or a combination of both techniques between 1994-2018 was conducted. Gillies and McLaughlin's combination was performed in 69 cases and was the most commonly used procedure in middle-aged and older patients. Operating duration and reoperation rates were highest in older patients. Comparison of middle-aged patients regarding the aspects patient satisfaction (p=1), complication rates (p=0.759) and reoperation rates (p=0.669) were all non-significant. Comparison of resting facial symmetry showed a trend towards significance at p=0.064 for patients aged 60 and above. Patient satisfaction was high at >77% for all three age groups and overall complication rates ranged from 0-14%. Facial reanimation of irreversible facial paralysis with Gillies or McLaughlin's dynamic muscle support or a combination of the two techniques should be considered for patients of all ages. A standardized outcome measurement is needed for comparability between reanimation techniques.

Peritoneal carcinomatosis, a heterogeneous malignancy mostly not originating from the peritoneum itself, still has to be regarded as a tumor entity which is hard to combat despite a large variety of conventional treatment modalities being currently at hand. In this context, novel biological therapies which can be directly applied to the peritoneal cavity open up urgently needed new perspectives. Such biotherapies do not display any cross-resistances to standard therapies in contrast to locally or systemically applied chemotherapies, thereby making them ideal combination partners which potentially enhance antitumoral efficiency. New on the block are recent combinations of virotherapeutics with immune checkpoint inhibitors (ICIs). In this scheme, virotherapeutics work for an optimized induction of a systemic antitumoral immune response by concomitantly releasing viral antigens and tumor cell-associated antigens in a virus-induced, highly inflammatory tumor micromilieu, whereas ICIs optimize the execution of a systemic antitumoral immune response by releasing the “brakes” of the immune system, thus enabling T cells to kill cancer cells more efficiently. This and similar biotherapeutic approaches are of great promise regarding a further improvement of both curative and palliative approaches in the treatment of peritoneal carcinomatosis.

ZusammenfassungDie Brustrekonstruktion mit freiem Gewebetransfer vom Unterbauch als (muskelsparende) TRAM oder DIEP Lappenplastik stellt das Standardverfahren der autologen Brustrekonstruktion dar. Durch operative Fortschritte ist es gelungen die Hebedefektmorbidität durch muskelsparende bzw. perforatorbasierte Techniken zu minimieren. Hier stellt sich die Frage, in wie weit dies als ein notwendiger Standard angesehen werden kann oder ob auch Lappenplastiken mit Muskelanteilen (MS-TRAM) noch als zeitgemäß anzusehen sind. In einem Konsensusworkshop der 3 Jahrestagung der Deutschsprachigen Arbeitsgemeinschaft für Mikrochirurgie der peripheren Nerven und Gefäße (DAM) wurde die Datenlage kritisch geprüft und durch eine Expertengruppe ein Konsensus erarbeitet. Dieser beinhaltet neben den aktuellen Daten zu Lappensicherheit und Hebedefektmorbidität aus der Literatur auch ein aktuelles Meinungsbild der Expertengruppe bzgl. verschiedener technischer Details des operativen Vorgehens.

Background 17β-estradiol (E2) mediates vasculoprotection in various preclinical and clinical models of atherosclerosis and neointimal hyperplasia. However, the molecular mechanisms underlying these effects are still not fully elucidated. Previous studies have demonstrated the essential role of the peroxisome-proliferator-activated-receptor-γ (PPARγ) in mediating vasculoprotective effects of E2 in vivo. The aim of the current study was to investigate whether PPARγ is implicated in mediating vasculoprotective mechanisms of E2 in human coronary artery smooth muscle cells (HCASMC). Methods Primary HCASMC were purchased and stimulated with E2 [10 nM], the selective estrogen receptor α (ERα) agonist propylpyrazole triol (PPT) [50 nM] and the selective ERα antagonist methyl-piperidino-pyrazole (MPP) [1 μM], respectively. Changes in PPARγ mRNA and protein expression upon stimulation of ERα were assessed by qPCR and Western blot analyses. Nuclear PPARγ protein expression and DNA binding affinity was assessed after the isolation of the nuclear protein fraction. Hereafter, HCASMC were incubated with E2, PPARγ-antagonist GW9662 [1 μM – 30 μM], or both. HCASMC proliferation was assessed by nuclear BrdU staining and reactive oxygen species (ROS) formation was assessed by L-012- and DCF-DA assays. Results E2 significantly increased PPARγ expression in HCASMC (1.95±0.41 –fold; n=5; p=0.0335). This effect was mimicked by ERα agonist PPT (1.63±0.27 –fold; n=7; p=0.0489) and was abrogated by co-incubation with ERα antagonist MPP (1.17±0.18 –fold; n=3; pvs. control >0.05). Nuclear PPARγ expression was enhanced by E2 (1.53±0.16 –fold; n=4; pvs. control = 0.0074; Fig. 2A) whereas PPARγ's DNA binding activity to PPRE remained unchanged upon stimulation with E2 (0.94±0.11 –fold; n=4; pvs. control >0.05). Pharmacological inhibition of PI3K/Akt by LY294002 abrogated E2-induced expression of PPARγ (0.24±0.09 –fold; n=3; pvs. E2 = 0.0017), arguing for a PI3K/Akt-dependent activation by E2. The role of PPARγ in mediating vasculoprotective effects of E2 was assessed in functional assays using PPARγ-antagonist GW9662. E2 diminished HCASMC proliferation which was restored by GW9662. While E2 only slightly decreased ROS production by HCASMC, GW9662 significantly increased ROS levels (1,036±169 RLU x s–1 x cell–1 versus 561±99 RLU x s–1 x cell–1; n=5–6; p=0.0287). Conclusion In summary, the present study identifies PPARγ as a downstream mediator of E2-related atheroprotective effects in HCASMC. 17β-estradiol regulates vascular PPARγ-expression in HCASMC via the ERα receptor and the PI3K/Akt pathway. PPARγ agonism might be a promising therapeutic strategy to prevent cardiovascular events in postmenopausal women with depleted E2 plasma levels. Acknowledgement/Funding This work was supported by the Bonfor program of the University of Bonn [grant number O-109.0057 to JJ].