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Background: Observational studies have indicated a link between autoimmune liver diseases (AILD) and chronic hepatitis B (CHB) through observational studies. The association between AILD and CHB remains indeterminate., Methods: A two-sample Mendelian randomization (MR) analysis was conducted to scrutinize the causal nexus between AILD and CHB utilizing summary statistics derived from extensive genome-wide association studies (GWASs) in European populations. The primary statistical methodology employed was the inverse variance-weighted (IVW) method to deduce the causal connection of AILD on CHB. This study incorporated primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), and autoimmune hepatitis (AIH) as subtypes of AILD. Additionally, we conducted a multivariable MR (MVMR) analysis to account for the potential confounding effects of smoking, alcohol consumption, body mass index (BMI), and some autoimmune diseases., Results: Our MR investigation encompassed a cohort of 725,816 individuals. The MR analysis revealed that genetically predicted PSC significantly correlated with a reduced risk of CHB (IVW OR = 0.857; 95%CI: 0.770-0.953, P = 0.005). Conversely, the reverse MR analysis suggested that genetic susceptibility to PSC might not modify the risk of CHB (IVW OR = 1.004; 95% CI: 0.958-1.053, P = 0.866). Genetically proxied PBC and AIH exhibited no discernible causal association with CHB in the MR analysis using the IVW method (P = 0.583; P = 0.425). The MVMR analysis still indicated a decreased risk of CHB associated with PSC (OR = 0.853, P = 0.003)., Conclusion: Our study elucidates a causal relationship between PSC and a diminished risk of CHB., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2023. Published by Elsevier Inc.)

Background: Checkpoint inhibitors revolutionized the treatment of metastatic melanoma patients. Although tumor burden and lactate dehydrogenase (LDH) are associated with overall survival (OS), the impact of tumor growth kinetics remains elusive and in part contradictory. The aims of this study were to develop a novel simple and rapid method that estimates pretreatment metastatic growth rate (MGR) and to investigate its prognostic impact in melanoma patients treated with antiprogrammed death receptor-1 (PD-1) antibodies., Methods: MGR was assessed in three independent cohorts of a total of 337 unselected consecutive metastasized stage IIIB-IV melanoma patients (discovery cohort: n=53, confirmation cohort: n=126, independent multicenter validation cohort: n=158). MGR was computed during the pretreatment period before initiation of therapy with anti-PD-1 antibodies nivolumab or pembrolizumab by measuring the increase of the longest diameter of the largest target lesion. Tumor doubling time served as quality control. Kaplan-Meier analysis and univariable as well as multivariable Cox regression were used to examine the prognostic impact of MGR., Results: Pretreatment MGR >3.9 mm/month was associated with impaired OS in the discovery cohort (HR 6.19, 95% CI 2.92 to 13.10, p<0.0001), in the confirmation cohort (HR 3.62, 95% CI 2.19 to 5.98, p<0.0001) and in the independent validation cohort (HR 2.57, 95% CI 1.56 to 4.25, p=0.00023). Prior lines of systemic treatment did not influence the significance of MGR. Importantly, the prognostic impact of MGR was independent of total tumor burden, diameter of the largest metastasis, number of prior lines of systemic treatment, LDH, as well as liver and brain metastasis (discovery and confirmation cohorts: both p<0.0001). Superiority of MGR compared with these variables was confirmed in the independent multicenter validation cohort (HR 2.92, 95% CI 1.62 to 5.26, p=0.00036)., Conclusions: High pretreatment MGR is an independent strong prognostic biomarker associated with unfavorable survival of melanoma patients receiving anti-PD-1 antibodies. Further investigations are warranted to assess the predictive impact of MGR in distinct systemic therapeutic regimens., Competing Interests: Competing interests: NBW reports a consulting/advisory role for Sanofi and has received travel support from AbbVie and Amgen outside the submitted work. RL has received research funding from Bristol-Myers Squibb, Pierre Fabre and Roche, honoraria and travel support from Merck Sharp & Dohme and travel support from Amgen. AO is a consultant/advisory board member for MSD and Bristol-Myers Squibb. AF has received speaker’s honoraria from Bristol-Myers Squibb, MSD, Roche, and Novartis, is advisory board member for Roche and Novartis and received travel support from Roche, Novartis, and Bristol-Myers Squibb. UL is a consultant/advisory board member for and has received honoraria from MSD, Novartis, and Roche. MG is an advisory board member of Novartis and has received grants from Novartis outside the submitted work. CB has received speaker's honoraria and consultancy fees from Amgen, Bristol-Myers Squibb, Merck, MSD, Novartis, Pierre Fabre, Regeneron, Roche, and Sanofi-Aventis outside the submitted work, and has received travel support from Bristol-Myers Squibb. ER has received honoraria from and has a consultancy or advisory role for Amgen, Bayer, Bristol-Myers Squibb, MSD, Merck, Novartis, Pierre Fabre, Roche and Sanofi, reports speakers' bureau for Amgen, Bristol-Myers Squibb, MSD, Merck, Novartis, Pierre Fabre and Sanofi, received research funding (at the institution) from Amgen, Bristol-Myers Squibb, MSD, Novartis, Pierre Fabre and Roche, is a member of the research funding steering committee of Novartis, and received travel accommodations and/or expenses from Amgen, Bristol-Myers Squibb, MSD, Merck, Novartis, Pierre Fabre, Roche and Sanofi. JM has intermittent project focused consultant or advisory relationships with Merck/Pfizer, Merck Sharp & Dohme, Amgen, Novartis, Bristol-Myers Squibb and Pierre Fabre, and has received travel support from Ultrasun, L’Oreal, Merck Sharp & Dohme, Bristol-Myers Squibb and Pierre Fabre outside of the submitted work. PT has received honoraria and/or consultancy fees from Bristol-Myers Squibb, Curevac, Merck, MSD, Novartis, Pierre Fabre, Roche, and Sanofi outside the submitted work, and has received travel support from Bristol-Myers Squibb and Pierre-Fabre. CL is a consultant/advisory board member for and has received advisory board fees, speaker's fees and/or travel reimbursements from Roche, Pierre Fabre, Novartis, Bristol-Myers Squibb, Merck, MSD, Biontech, Almiral Hermal, Kyowa Kirin, Sun Pharma and Sanofi. VAN has received speaker’s honoraria and consultancy fees from Amgen, Bristol-Myers Squibb, GlaxoSmithKline, Merck Sharp & Dohme, Novartis, Roche, and Takeda outside of the submitted work. CGe has received personal speaker/advisory board fees from Amgen, Beiersdorf, BMS, MSD, Novartis, Pierre Fabre, Roche, Sun Pharma and Sanofi Genzyme. FM has received travel support or/and speaker’s fees or/and advisor’s honoraria by Novartis, Roche, BMS, MSD and Pierre Fabre, and research funding from Novartis and Roche. SD has received travel support from MSD. AC has received consultancy fees from AbbVie, BMS, Almirall, Amgen, Eli Lilly, Galderma, Janssen, Kyowa Kirin, Leo, Novartis, and Sanofi. LF reports grants from the Swiss National Science Foundation, Swiss Cancer League, Hookipa Pharma and Novartis Foundation as well as an advisory role for Novartis and Bristol-Myers Squibb. CGa has received grants and personal fees from Bristol-Myers Squibb, Roche, Novartis and personal fees from Amgen, MSD and Philogen outside the submitted work. TE is a consultant/advisory board member for Philogen, Bristol-Myers Squibb, Novartis, Roche and Sanofi. No other disclosures were reported., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Patients with a history of anaphylaxis are at risk of future anaphylactic reactions. Thus, secondary prevention measures are recommended for these patients to prevent or attenuate the next reaction., Methods: Data from the Anaphylaxis Registry were analyzed to identify secondary prevention measures offered to patients who experienced anaphylaxis. Our analysis included 7788 cases from 10 European countries and Brazil., Results: The secondary prevention measures offered varied across the elicitors. A remarkable discrepancy was observed between prevention measures offered in specialized allergy centers (84% of patients were prescribed adrenaline autoinjectors following EAACI guidelines) and outside the centers: Here, EAACI guideline adherence was only 37%. In the multivariate analysis, the elicitor of the reaction, age of the patient, mastocytosis as comorbidity, severity of the reaction, and reimbursement/availability of the autoinjector influence physician's decision to prescribe one., Conclusions: Based on the low implementation of guidelines concerning secondary prevention measures outside of specialized allergy centers, our findings highlight the importance of these specialized centers and the requirement of better education for primary healthcare and emergency physicians., (© 2019 The Authors. Allergy published by John Wiley & Sons Ltd.)

Refractory anaphylaxis (unresponsive to treatment with at least two doses of minimum 300 μg adrenaline) is a rare and often fatal hypersensitivity reaction. Comprehensive data on its definition, prevalence, and risk factors are missing. Using the data from the European Anaphylaxis Registry (11,596 cases in total) we identified refractory anaphylaxis cases ( n = 42) and analyzed these in comparison to a control group of severe anaphylaxis cases ( n = 4,820). The data show that drugs more frequently elicited refractory anaphylaxis (50% of cases, p < 0.0001) compared to other severe anaphylaxis cases (19.7%). Cases elicited by insects ( n = 8) were more often due to bees than wasps in refractory cases (62.5 vs. 19.4%, p = 0.009). The refractory cases occurred mostly in a perioperative setting (45.2 vs. 9.05, p < 0.0001). Intramuscular adrenaline (as a first line therapy) was administered in 16.7% of refractory cases, whereas in 83.3% of cases it was applied intravenously (significantly more often than in severe anaphylaxis cases: 12.3%, p < 0.0001). Second line treatment options (e.g., vasopression with dopamine, methylene blue, glucagon) were not used at all for the treatment of refractory cases. The mortality rate in refractory anaphylaxis was significantly higher (26.2%) than in severe cases (0.353%, p < 0.0001). Refractory anaphylaxis is associated with drug-induced anaphylaxis in particular if allergens are given intravenously. Although physicians frequently use adrenaline in cases of perioperative anaphylaxis, not all patients are responding to treatment. Whether a delay in recognition of anaphylaxis is responsible for the refractory case or whether these cases are due to an overflow with mast cell activating substances-requires further studies. Reasons for the low use of second-line medication (i.e., methylene blue or dopamine) in refractory cases are unknown, but their use might improve the outcome of severe refractory anaphylaxis cases., (Copyright © 2019 Francuzik, Dölle-Bierke, Knop, Scherer Hofmeier, Cichocka-Jarosz, García, Lang, Maris, Renaudin and Worm.)

Introduced for mass immunization in the 1920s, vaccines against diphtheria are among the oldest and safest vaccines known. The basic principle of their production is the inactivation of purified diphtheria toxin by formaldehyde cross-linking, which converts the potentially fatal toxin in a completely harmless protein aggregate, which is still immunogenic. Since in addition to diphtheria toxin also other proteins may be secreted by Corynebacterium diphtheriae during cultivation, we assumed that diphtheria toxoid might not be the only component present in the vaccine. To address this question, we established a protocol to reverse formaldehyde cross-linking and carried out mass spectrometric analyses. Different secreted, membrane-associated and cytoplasmic proteins of C. diphtheriae were detected in several vaccine preparations from across the world. Based on these results, bioinformatics and Western blot analyses were applied to characterize if these proteins are immunogenic and may therefore support protection against C. diphtheriae. In frame of this study, we could show that the C. diphtheriae toxoid vaccines induce antibodies against different C. diphtheriae proteins and against diphtheria toxin secreted by Corynebacterium ulcerans, an emerging pathogen which is outnumbering C. diphtheriae as cause of diphtheria-like illness in Western Europe., (Copyright © 2019. Published by Elsevier Ltd.)

Background: Current guidelines recommend intramuscular administration of epinephrine as the first-line drug for the emergency treatment of severe allergic reactions (anaphylaxis), but no randomized trial evidence supports this consensus., Objective: We aimed to assess anaphylaxis treatment practices over 10 years, covering several European regions, all allergen sources, and all age groups., Methods: The European Anaphylaxis Register tracks elicitors, symptoms, emergency treatment, diagnostic workups, and long-term counseling for anaphylaxis incidents through web-based data entry from tertiary allergy specialists, covering information from the emergency respondent, patient, tertiary referral, and laboratory/clinical test results., Results: We analyzed 10,184 anaphylaxis incidents. In total, 27.1% of patients treated by a health professional received epinephrine and, in total, 10.5% received a second dose. Successful administration was less frequent in German-speaking countries (minimum 19.6%) than in Greece, France, and Spain (maximum 66.7%). Over the last decade, epinephrine administration from a health professional almost doubled to reach 30.6% in 2015-2017, half of which was applied intramuscularly. A total of 14.7% of lay- or self-treated cases were treated with an autoinjector. Of those without treatment, 22.4% carried a device for administration. No change in successful administration by lay emergency respondents was found over the last 10 years. Of the reaction and patient characteristics analyzed, only clinical severity considerably influenced the likelihood of receiving epinephrine, with 66.9% of successful administrations in near-fatal (grade IV) reactions., Conclusions: Despite clear recommendations, only a small proportion of anaphylaxis incidents are treated with epinephrine. We demonstrated a slight increase in treated patients when handled by professionals, but stagnation in lay- or self-treated anaphylaxis. The reaction circumstances, the respondent's professional background, and patient characteristics did not explain which reactions were treated., (Copyright © 2018 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Anaphylaxis in children and adolescents is a potentially life-threatening condition. Its heterogeneous clinical presentation and sudden occurrence in virtually any setting without warning have impeded a comprehensive description., Objective: We sought to characterize severe allergic reactions in terms of elicitors, symptoms, emergency treatment, and long-term management in European children and adolescents., Methods: The European Anaphylaxis Registry recorded details of anaphylaxis after referral for in-depth diagnosis and counseling to 1 of 90 tertiary allergy centers in 10 European countries, aiming to oversample the most severe reactions. Data were retrieved from medical records by using a multilanguage online form., Results: Between July 2007 and March 2015, anaphylaxis was identified in 1970 patients younger than 18 years. Most incidents occurred in private homes (46%) and outdoors (19%). One third of the patients had experienced anaphylaxis previously. Food items were the most frequent trigger (66%), followed by insect venom (19%). Cow's milk and hen's egg were prevalent elicitors in the first 2 years, hazelnut and cashew in preschool-aged children, and peanut at all ages. There was a continuous shift from food- to insect venom- and drug-induced anaphylaxis up to age 10 years, and there were few changes thereafter. Vomiting and cough were prevalent symptoms in the first decade of life, and subjective symptoms (nausea, throat tightness, and dizziness) were prevalent later in life. Thirty percent of cases were lay treated, of which 10% were treated with an epinephrine autoinjector. The fraction of intramuscular epinephrine in professional emergency treatment increased from 12% in 2011 to 25% in 2014. Twenty-six (1.3%) patients were either admitted to the intensive care unit or had grade IV/fatal reactions., Conclusions: The European Anaphylaxis Registry confirmed food as the major elicitor of anaphylaxis in children, specifically hen's egg, cow's milk, and nuts. Reactions to insect venom were seen more in young adulthood. Intensive care unit admissions and grade IV/fatal reactions were rare. The registry will serve as a systematic foundation for a continuous description of this multiform condition., (Copyright © 2015 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Occurrence, elicitors and treatment of severe allergic reactions are recognized and reported differently between countries. We aimed to collect standardized data throughout Europe on anaphylaxis referred for diagnosis and counselling., Methods: Tertiary allergy, dermatology and paediatric units in 10 European countries took part in this pilot phase of the first European Anaphylaxis Registry, from June 2011 to March 2014. An online questionnaire was used to collect data on severe allergic reactions based on the medical history and diagnostics., Results: Fifty-nine centres reported 3333 cases of anaphylaxis, with 26.7% below 18 years of age. Allergic reactions were mainly caused by food (children and adults 64.9% and 20.2%, respectively) and insect venom (20.2% and 48.2%) and less often by drugs (4.8% and 22.4%). Most reactions occurred within 30 min of exposure (80.5%); a delay of 4+ hours was mainly seen in drug anaphylaxis (6.7%). Symptom patterns differed by elicitor, with the skin being affected most often (84.1%). A previous, usually milder reaction to the same allergen was reported by 34.2%. The mainstay of first-line treatment by professionals included corticoids (60.4%) and antihistamines (52.8%). Only 13.7% of lay- or self-treated reactions to food and 27.6% of insect anaphylaxis received on-site adrenaline., Conclusion: This pilot phase of a pan-European registry for severe allergic reactions provides for the first time data on anaphylaxis throughout Europe, demonstrates its potential functionality and allows a comparison of symptom patterns, elicitors and treatment habits between referral centres and countries., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Although recognized as a valuable diagnostic tool for more than 60 years, many laryngologists do not routinely use laryngeal electromyography (LEMG). This may be due to a persisting lack of agreement on methodology, interpretation, validity, and clinical application of LEMG. To achieve consensus in these fields, a laryngeal electromyography working group of European neurolaryngologic experts was formed in order to (1) evaluate guidelines for LEMG performance and (2) identify issues requiring further clarification. To obtain an overview of existing knowledge and research, English-language literature about LEMG was identified using Medline. Additionally, cited works not detected in the initial search were screened. Evidence-based recommendations for the performance and interpretation of LEMG and also for electrostimulation for functional evaluation were considered, as well as published reports based on expert opinion and single-institution retrospective case series. To assess the data obtained by this literature evaluation, the working group met five times and performed LEMG together on more than 20 patients. Subsequently, the results were presented and discussed at the 8th Congress of the European Laryngological Society in Vienna, Austria, September 1-4, 2010, and consensus was achieved in the following areas: (1) minimum requirements for the technical equipment required to perform and record LEMG; (2) best practical implementation of LEMG; (3) criteria for interpreting LEMG. Based on this consensus, prospective trials are planned to improve the quality of evidence guiding the proceedings of practitioners.

In order to understand the repeated occurrences of auditory impairments caused by toy pistols, an analysis of the circumstances involved was performed at Justus-Liebig University of Giessen. The acoustic impact of toy pistols on the ear was determined with a special measuring system for impulse noise. Results were compared with the acoustic impacts of the G3 common rifle of the German military on the ear of the soldier. It was apparent that all of the five randomly selected types of toy pistols were much louder than the military rifle, if fired close to the ear. The current standard of the European Union related to the safety of toys (EN 71-1) tolerates peaks of impulse noise from toy pistols that are actually illegal for workplaces without auditory protection. Measurements showed that the toy pistols tested were even louder than that tolerated by the EU standard. Problems related to acute acoustic trauma caused by these toys are discussed using recent examples. In order to prevent such injuries, we suggest limiting the loudness of the "worst case" instead of using unrealistic measurements.