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Mitogen-activated protein kinase kinase kinase kinase 1 (MAP4K1) is a serine/threonine kinase that acts as an immune checkpoint downstream of T-cell receptor stimulation. MAP4K1 activity is enhanced by prostaglandin E2 (PGE2) and transforming growth factor beta (TGFβ), immune modulators commonly present in the tumor microenvironment. Therefore, its pharmacological inhibition is an attractive immuno-oncology concept for inducing therapeutic T-cell responses in cancer patients. Here, we describe the systematic optimization of azaindole-based lead compound 1 , resulting in the discovery of potent and selective MAP4K1 inhibitor 38 (BAY-405) that displays nanomolar potency in biochemical and cellular assays as well as in vivo exposure after oral dosing. BAY-405 enhances T-cell immunity and overcomes the suppressive effect of PGE2 and TGFβ. Treatment of tumor-bearing mice shows T-cell-dependent antitumor efficacy. MAP4K1 inhibition in conjunction with PD-L1 blockade results in a superior antitumor impact, illustrating the complementarity of the single agent treatments.

Background: Earlier studies suggested a potential association between tobacco smoking and nickel sensitization, but little is known about other contact allergens., Objectives: To investigate the association of smoking status and contact sensitizations as well as subtypes of dermatitis, and to analyse the sensitization profiles of tobacco smokers., Patients and Methods: Within the Information Network of Departments of Dermatology (IVDK), we performed a cross-sectional multicentre pilot study comprising 1091 patch-tested patients from 9 departments, comparing 541 patients with a history of cigarette smoking (281 current and 260 former smokers) with 550 never-smokers., Results: We could not confirm the previously reported association between nickel sensitization and tobacco smoking. Moreover, sensitizations to other allergens, including colophony, fragrance mix I, Myroxylon pereirae and formaldehyde, were not increased in cigarette smokers compared with never smokers. Hand dermatitis (50.6% vs. 33.6%) and occupational cause (36.2% vs. 22.5%) were significantly more frequent among cigarette smokers compared with never-smokers as shown by non-overlapping 95% confidence intervals., Conclusions: Although our study does not allow a firm conclusion on whether smoking status contributes to certain contact sensitizations, it confirms an association of smoking with hand dermatitis and occupational cause., (© 2024 The Author(s). Contact Dermatitis published by John Wiley & Sons Ltd.)

Background: The metabolism of tryptophan to kynurenines (KYN) by indoleamine-2,3-dioxygenase or tryptophan-2,3-dioxygenase is a key pathway of constitutive and adaptive tumor immune resistance. The immunosuppressive effects of KYN in the tumor microenvironment are predominantly mediated by the aryl hydrocarbon receptor (AhR), a cytosolic transcription factor that broadly suppresses immune cell function. Inhibition of AhR thus offers an antitumor therapy opportunity via restoration of immune system functions., Methods: The expression of AhR was evaluated in tissue microarrays of head and neck squamous cell carcinoma (HNSCC), non-small cell lung cancer (NSCLC) and colorectal cancer (CRC). A structure class of inhibitors that block AhR activation by exogenous and endogenous ligands was identified, and further optimized, using a cellular screening cascade. The antagonistic properties of the selected AhR inhibitor candidate BAY 2416964 were determined using transactivation assays. Nuclear translocation, target engagement and the effect of BAY 2416964 on agonist-induced AhR activation were assessed in human and mouse cancer cells. The immunostimulatory properties on gene and cytokine expression were examined in human immune cell subsets. The in vivo efficacy of BAY 2416964 was tested in the syngeneic ovalbumin-expressing B16F10 melanoma model in mice. Coculture of human H1299 NSCLC cells, primary peripheral blood mononuclear cells and fibroblasts mimicking the human stromal-tumor microenvironment was used to assess the effects of AhR inhibition on human immune cells. Furthermore, tumor spheroids cocultured with tumor antigen-specific MART-1 T cells were used to study the antigen-specific cytotoxic T cell responses. The data were analyzed statistically using linear models., Results: AhR expression was observed in tumor cells and tumor-infiltrating immune cells in HNSCC, NSCLC and CRC. BAY 2416964 potently and selectively inhibited AhR activation induced by either exogenous or endogenous AhR ligands. In vitro, BAY 2416964 restored immune cell function in human and mouse cells, and furthermore enhanced antigen-specific cytotoxic T cell responses and killing of tumor spheroids. In vivo, oral application with BAY 2416964 was well tolerated, induced a proinflammatory tumor microenvironment, and demonstrated antitumor efficacy in a syngeneic cancer model in mice., Conclusions: These findings identify AhR inhibition as a novel therapeutic approach to overcome immune resistance in various types of cancers., Competing Interests: Competing interests: CK, NS, LR, UR, BB, DS, FP, MG, HGR, CO, GL, HI, RL, JL, MO-W, RC, HW, IVH, BK and IG are current or former employees of Bayer. NS, UR, BB, MG, GL, HI, RL, JL, FC, DB, CAO, HW, IVH and IG are stockholders of Bayer AG. CK, NS, LR, UR, BB, DS, HI, RC, MP and IG hold patents connected to this work.AS and CAO are founders and managing directors of cAHRmeleon Bioscience GmbH. Some of the authors have patents on AHR inhibitors in cancer (WO2013034685, MP; CAO); A method to multiplex tryptophan and its metabolites (WO2017072368, MP, CAO); A transcriptional signature to determine AHR activity (WO2020201825, AS, CAO); Interleukin-4-induced gene 1 (IL4I1) as a biomarker (WO2020208190, AS,CAO); Interleukin-4-induced gene 1 (IL4I1) and its metabolites as biomarkers for cancer (WO2021116357, AS, CAO).No disclosures were reported by the other authors., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Cerebral pulsation is a vital aspect of cerebral hemodynamics. Changes in arterial pressure in response to cardiac pulsation cause cerebral pulsation, which is related to cerebrovascular compliance and cerebral blood perfusion. Cerebrovascular compliance and blood perfusion influence the mechanical properties of the brain, causing pulsation-induced changes in cerebral stiffness. However, there is currently no imaging technique available that can directly quantify the pulsation of brain stiffness in real time. Methods: Therefore, we developed non-invasive ultrasound time-harmonic elastography (THE) technique for the real-time detection of brain stiffness pulsation. We used state-of-the-art plane-wave imaging for interleaved acquisitions of shear waves at a frequency of 60 Hz to measure stiffness and color flow imaging to measure cerebral blood flow within the middle cerebral artery. In the second experiment, we used cost-effective lineby-line B-mode imaging to measure the same mechanical parameters without flow imaging to facilitate future translation to the clinic. Results: In 10 healthy volunteers, stiffness increased during the passage of the arterial pulse wave from 4.8% ± 1.8% in the temporal parenchyma to 11% ± 5% in the basal cisterns and 13% ± 9% in the brain stem. Brain stiffness peaked in synchrony with cerebral blood flow at approximately 180 ± 30 ms after the cardiac R-wave. Line-by-line THE provided the same stiffness values with similar time resolution as high-end plane-wave THE, demonstrating the robustness of brain stiffness pulsation as an imaging marker. Discussion: Overall, this study sets the background and provides reference values for time-resolved THE in the human brain as a cost-efficient and easy-touse mechanical biomarker associated with cerebrovascular compliance., Competing Interests: The authors declare that this study received funding from Pfizer. The authors declare that the research was conducted in the absence of any other commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Meyer, Kreft, Bergs, Antes, Anders, Wellge, Braun, Doyley, Tzschätzsch and Sack.)

Not available., Competing Interests: The information on interests was collected using the AWMF form of 2018 and assessed by Prof. Dr. Monika Raulf for a thematic relation to the guideline. Guideline-relevant lecturing or consulting activities for manufacturers of devices for allergy diagnosis were categorized as a low conflict of interest, and direct financial secondary interests (e.g., share ownership, patent) as a moderate/high conflict of interest. Low conflicts of interest resulted in abstention from voting. Strong conflicts of interest were not present. Protective factors counteracting conflict of interest bias were the pluralistic composition of the guideline group, structured consensus building under neutral moderation, discussion on interests, and handling of conflicts of interest at the beginning of each consensus meeting, and a public consultation version. Abbreviations.Abbreviations. ADRAdverse drug reactionAGEPAcute generalized exanthematous pustulosisAWMFGerman Association of the Scientific Medical SocietiesCOPDChronic obstructive pulmonary diseaseDGAKIGerman Society for Allergology and Clinical ImmunologyDRESSDrug reaction with eosinophilia and systemic symptomsINNInternational non-proprietary nameMPEMaculopapular exanthemNSAIDNon-steroidal anti-inflammatory drugsSJSStevens-Johnson syndromeTENToxic epidermal necrolysis Table 1.Definitions.Adverse drug reaction (ADR): A noxious and unintended reaction that occurs in addition to the intended effect of a drug, for which a causal relationship between the use of the drug and the adverse effect is suspected. ADRs can be both type A (pharmacological/toxic) and type B (hypersensitivity).Type A (“augmented” = pharmacological/toxic (on-target) drug effects): Disease manifestations due to dose-dependent predictable pharmacological/toxic effects of a drug at the recommended dose (examples: sedative effect of older antihistamines, hair loss due to cytostatics) or increased dosage (intoxication).Type B (“bizarre” = hypersensitivity (off-target) reactions): Individual, unpredictable clinical reaction to a drug, i.e., symptoms occur only in specially predisposed patients. Two forms can be distinguished:   –Drug allergy: Hypersensitivity is based on an immunological reaction (types I – IV according to Coombs and Gell).   –Non-allergic drug hypersensitivity: An allergic mechanism is not detectable. Previously, this type of reaction was further divided into:      –Drug intolerance: Typical symptoms of pharmacological action (toxicity) develop even at low doses that are usually tolerated.      –Drug idiosyncrasy: The symptoms differ from the pharmacological substance effect. In cases where the symptomatology of this form of hypersensitivity looked similar to an allergic reaction, the term pseudoallergy has also been used. Table 2.Time interval, clinic, and pathomechanism – three levels for classifying a drug hypersensitivity reaction. 1) Time reaction intervalsa) For those already sensitized   –Immediate reaction (“immediate”) immediate up to 60 minutes (in rare exceptions up to 6 hours)   –Delayed reaction (“non-immediate”) > 6 hours to several weeksb) In case of new sensitization under therapy   –Typical sensitization latency 7 – 10 days2) Clinical manifestationsa) Immediate reaction: E.g., flush, urticaria, angioedema, bronchospasm, anaphylaxis.b) Late reaction: Maculopapular exanthem (MPE), acute generalized exanthematous pustulosis (AGEP). Severe cutaneous drug reactions: Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS).c) Others: E.g., hepatitis, cytopenia, autoimmune diseases (e.g., lupus erythematosus, drug-induced linear IgA dermatosis)3) Pathomechanisma) Allergic hypersensitivity: Immediate type (type I according to Coombs and Gell, IgE mediated): typical manifestation, immediate-type symptoms (reaction time: 0 – 6 hours)b) Non-allergic hypersensitivity: Typical manifestation immediate-type symptoms (reaction time: 0 – 6 hours, rarely up to 12 hours)c) Allergic hypersensitivity: Delayed-type (type IV according to Coombs and Gell, T-cell mediated): typical manifestation delayed-type (reaction time: 24 – 72 hours, begin rarely after 6 – 24 hours).d) Other forms of immunologically mediated hypersensitivity (type II, type III according to Coombs and Gell, IgG, IgA, or IgM mediated): Cytopenias, serum sickness, immune complex vasculitis (vasculitis allergica); (reaction time: 24 hours or more).e) In case of new sensitization under therapy: Typical immunologic sensitization latency 5 – 7 days for types I –IV, with reaction latency of 1 –3 days). Onset of MPE after 7 –10 days. However, the reaction in SJS/TEN, DRESS may occur after weeks, that in autoimmune diseases (e.g., lupus erythematosus) after months, probably due to sensitization only after prolonged exposure (e.g., sensitization or triggering favored by cofactors). Table 3.Typical time interval between start of drug intake and first occurrence of reactions. Reaction patternTime intervalUrticaria, asthma, anaphylaxis≤ 1 hour, rarely up to 6 hours after start of exposureFixed drug exanthem ≤ 48 hours, rarely later after start of exposureMaculopapular drug exanthem4 – 14 days after start of exposure*AGEP1 –12 days after start of exposure**SJS/TEN4 – 28 days after start of exposure***DRESS2 – 8 weeks after start of exposureAGEP = acute exanthematous generalized pustulosis; SJS = Stevens-Johnson Syndrome; TEN = toxic epidermal necrolysis; DRESS = drug reaction with eosinophilia and systemic symptoms. *In repeat reactions, time interval typically shortened compared to initial reaction. In maculopapular drug exanthem typically reaction after 1 – 4 days, in AGEP, SJS, TEN, DRESS typical time interval after repeat reactions not studied. **For antibiotics mostly 1 – 2 days, for other drugs often 7 – 12 days. ***Sometimes longer for allopurinol. Table 4.Important clinical and anamnestic information for the test plan. A) Clinical manifestation   – Documentation of clinical manifestations and/or organ systems involved: e.g., skin, airways, cardiovascular system, gastrointestinal tract, liver, kidney.   – Exact description of the clinical-morphological findings (especially in case of skin manifestations/mucosal reactions) additionally photo documentation   – General symptoms: Fever, reduced general condition   – Course of the reaction (onset of the reaction in temporal relation to the drug administration, duration of the reaction, morphological change of the reaction).   – Laboratory findings (e.g., blood count changes such as eosinophilia, thrombocytopenia; liver and kidney values; serum tryptase).   – If necessary, histological findings (especially in the case of blistering skin reactions)B) Other circumstances of the reaction   – Acute illness at the time of the reaction (e.g., concurrent infectious disease).   – Co-factors that may lower the threshold for an allergic or non-allergic reaction: stress, physical exertion, food intake, alcohol intake, UV exposure, menstruation.C) Documentation of drugs used in temporal relation to the reaction.   – Indication for drug use   – Trade name   – Mode of application   – Ingredients (active ingredients)   – Duration of application   – Dosage   – Tolerance after previous or during renewed applicationD) General history and findings   – Known hypersensitivity reactions (allergy passport)   – Similar reactions without drug application (e.g., natural latex allergy)   – Atopic diseases, food allergy   – Disposing diseases (e.g., asthma, nasal polyps, chronic urticaria, mastocytosis, infections, e.g., HIV, EBV)   – Other relevant past or current medical conditions (including somatoform or mental health conditions)   – Noxious agents: Nicotine, alcohol, drugs   – Current medication (long-term medication)E) Chronology of the hypersensitivity reaction   – Timing in relation to drug application   – First occurrence   – Course and resolution   – Therapeutic measures and responseF) Diagnosis and pathophysiological classification of the clinical reaction taking into account (see Table 1):   – Morphology and symptoms   – Time courseNote: In the case of multiple reactions, the information for each individual reaction is required. Table 5.Non-irritant skin test concentrations of commonly tested drugs [17]. Drug or classSkin prick testIntradermal test8Patch testBeta-lactam antibiotics   Benzylpenicilloyl-octa-L-lysine8.6 × 10-5 mol/L8.6 × 10-5 mol/LNA   Sodium benzylpenilloate1.5 × 10-3 mol/L1.5 × 10-3 mol/LNA   Benzylpenicillin10,000 UI/mL10,000 UI/mL5%   Amoxicillin20 mg/mL20 mg/mL5%   Ampicillin20 mg/mL20 mg/mL5%   Cephalosporins20 mg/mL1020 mg/mL105%Anticoagulants   Heparins1Undiluted81/10 dilutedUndiluted8   Heparinoids2Undiluted81/10 dilutedUndiluted8Platinum salts   Carboplatin10 mg/mL1 mg/mLNA   Oxaliplatin1 mg/mL0.1 mg/mLNA   Cisplatin1 mg/mL0.1 mg/mLNANSAID   Pyrazolone3Suspension90.1 – 1 mg/mL10%   Coxibe4Suspension910%   Other NSAIDs5Suspension90.1 – 1 mg/mL10%Biologics   Adalimumab50 mg/mL50 mg/mLUndiluted8   Etanercept25 mg/mL5 mg/mLNA   Infliximab10 mg/mL10 mg/mLNA   Omalizumab1.25 µg/mL1.25 µg/mLNAOther   Local anestheticsUndiluted81/10 dilutedUndiluted8   X-ray contrast agentUndiluted81/10 dilutedUndiluted8   Gadolinium chelatesUndiluted81/10 dilutedNA   Patent blueUndiluted1/10 dilutedNA   Methylene blueUndiluted1/100 dilutedNA   FluoresceinUndiluted81/10 dilutedUndiluted8   Proton pump inhibitors6Undiluted940 mg/mL10%   Anticonvulsants7NANA10%   Chlorhexidine digluconate5 mg/mL0.002 mg/mL1% 1Heparins: unfractionated heparin, nadroparin, dalteparin, enoxaparin; testing contraindicated in heparin-induced thrombocytopenia. 2Heparinoids: danaparoid, fondaparinux. 3Pyrazolones: metamizole, propyphenazone, aminopyrine, phenazone, phenylbutazone. 4Coxibs: celecoxib, etoricoxib, valdecoxib. 5Other nonsteroidal anti-inflammatory drugs: e.g., aspirin, ibuprofen, naproxen, indomethacin, diclofenac, fenoprofen, meloxicam, mefenamic acid, nimesulide. 6For lasoprazole and rabeprazole no intravenous solution for intradermal test (IDT), only skin prick test. 7For severe reactions, first test with 1%. 8Use of commercially available solution for intravenous infusion or subcutaneous injection. 9Crushing of the tablet and preparation of a suspension with physiological saline solution. 10Only for cefepime 2 mg/mL each. NA = not applicable or no concentration recommended. Table 6.Selection of commercial tests for the determination of specific IgE antibodies against drugs in serum*. – Ampicilloyl1– Amoxicylloyl1– Cefaclor2– Chlorhexidine2– Gelatin (bovine)1 Galactoseα−1,3-galactose (α-gal)1,3– Insulin (Human) 1– Morphine2– Penicilloyl G1– Penicilloyl V1– Pholcodin2– Suxamethonium (succinylcholine) 2*When determining sIgE for drugs, attention must be paid to the validation of the test methods. CE certification requires at least five, FDA registration at least 30 positive patient sera, as well as studies on stability and reproducibility. If these criteria are not met, test reagents may be offered for research purposes. Here, particular attention should be paid to the quality of the deposited literature. In routine diagnostics, no determinations of sIgE should be performed against substances for which no IgE-mediated allergic reactions have been described so far. 1CE-certified and FDA-registered; 2CE-certified,3 α-gal, this is an IgE-reactive sugar epitope which is held responsible for anaphylactic reactions to cetuximab and infusion solutions containing gelatine. Figure 1.Diagnostic algorithm for suspected drug hypersensitivity [2]., (© Dustri-Verlag Dr. K. Feistle.)

Purpose: Magnetic resonance elastography (MRE) generates quantitative maps of the mechanical properties of biological soft tissues. However, published values obtained by brain MRE vary largely and lack detail resolution, due to either true biological effects or technical challenges. We here introduce cerebral tomoelastography in two and three dimensions for improved data consistency and detail resolution while considering aging, brain parenchymal fraction (BPF), systolic blood pressure, and body mass index (BMI). Methods: Multifrequency MRE with 2D- and 3D-tomoelastography postprocessing was applied to the brains of 31 volunteers (age range: 22-61 years) for analyzing the coefficient of variation (CV) and effects of biological factors. Eleven volunteers were rescanned after 1 day and 1 year to determine intraclass correlation coefficient (ICC) and identify possible long-term changes. Results: White matter shear wave speed (SWS) was slightly higher in 2D-MRE (1.28 ± 0.02 m/s) than 3D-MRE (1.22 ± 0.05 m/s, p < 0.0001), with less variation after 1 day in 2D (0.33 ± 0.32%) than in 3D (0.96 ± 0.66%, p = 0.004), which was also reflected in a slightly lower CV and higher ICC in 2D (1.84%, 0.97 [0.88-0.99]) than in 3D (3.89%, 0.95 [0.76-0.99]). Remarkably, 3D-MRE was sensitive to a decrease in white matter SWS within only 1 year, whereas no change in white matter volume was observed during this follow-up period. Across volunteers, stiffness correlated with age and BPF, but not with blood pressure and BMI. Conclusion: Cerebral tomoelastography provides high-resolution viscoelasticity maps with excellent consistency. Brain MRE in 2D shows less variation across volunteers in shorter scan times than 3D-MRE, while 3D-MRE appears to be more sensitive to subtle biological effects such as aging., Competing Interests: The authors declare no potential conflicts of interest with respect to the research, authorship, and publication of this article., (Copyright © 2022 Herthum, Hetzer, Kreft, Tzschätzsch, Shahryari, Meyer, Görner, Neubauer, Guo, Braun and Sack.)

Severe, blistering, adverse drug reactions involving the skin include Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). Allopurinol, anticonvulsants, sulphonamide antibiotics and non-steroidal anti-inflammatory drugs in the oxicam class have been repeatedly described as triggers. Increasingly, immunotherapies are also coming into focus as triggers of severe skin reactions. Two patients with bullous skin symptoms after administration of the checkpoint inhibitor pembrolizumab are presented. As the clinical picture does not always allow an unequivocal classification, a histological assessment is often indispensable., (© 2022. The Author(s).)

Background: Patch test (PT) readings are recommended after 48 h and 72 h (D3). An additional day 7 (D7) reading has been suggested by some, although data on efficient patient selection are scarce. We investigated positive D7 reactions regarding (i) allergens in the baseline series and additional PT series of the German Contact Dermatitis Research Group (DKG) and (ii) characteristics of the patients tested., Methods: Retrospective, multicentre analysis of 190 allergens derived from 17 DKG test series in 4687 patients with an additional D7 reading. Patients were patch tested with the baseline series and additional series, if required. Occurrence of novel D7 reactions as well as increasing skin reactions from D3 to D7 was analysed separately., Results: Depending on the allergen tested, waiving D7 readings would have missed 4.4-26.8% of positive PT results. Patch test series with the highest number of novel D7 reactions were baseline series, metal series, and leather/shoe series. New positive reactions on D7 were associated with age over 50 years and with a negative irritant control containing sodium lauryl sulphate. Of note, application of the PT allergens for 48 h instead of 24 h was positively associated with late PT reactions., Conclusion: Within the most frequently tested allergens, without late readings, on average 11.7% of sensitizations would have been missed. Novel late reacting allergens were identified. This study comprehensively dissects patient-, allergen- and test-dependent parameters in support for D7 readings. We propose to always consider late readings individually based on effort-benefit considerations., (© 2021 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Objective: A method for measuring intracranial pressure (ICP) noninvasively has long been sought after in neurology and neurosurgery. Treatment failure in individuals presenting with unspecific symptoms such as headache, gait disturbance, or visual impairment occurring in response to increased ICP can lead to irreversible brain injury, progressive disability, and death. Guidelines for diagnostic ICP measurement recommend intracranial placement of pressure tip catheters or lumbar puncture (LP) despite their invasiveness and possible complications. As ICP fluctuations are closely associated with changes in brain stiffness, ultrasound elastography could be a valid method to detect ICP noninvasively and with short examination times., Materials and Methods: In this pilot study, we have investigated the use of time-harmonic shear waves, introduced into the brain by an external shaker, and measured in real-time by transtemporal ultrasound, for deducing a noninvasive imaging marker sensitive to elevated ICP. To this end, we developed cerebral ultrasound time-harmonic elastography for the noninvasive quantification of shear wave speed (SWS) as a surrogate marker of cerebral stiffness in a short examination time of a few minutes., Results: We found that SWS in patients enrolled for LP with confirmed intracranial hypertension was 1.81 ± 0.10 m/s, distinguishing them from healthy volunteers with excellent diagnostic accuracy (1.55 ± 0.08 m/s; P < 0.001; area under the curve, 0.99). Interestingly, values in symptomatic patients decreased to normal stiffness immediately after LP (1.56 ± 0.06 m/s, P < 0.001). Moreover, invasively measured opening pressure correlated with SWS measured before LP and liquid volume drained through the spinal tap with the SWS difference between the 2 measurements., Conclusions: Collectively, our results suggest a tight link between cerebral stiffness and ICP and demonstrate that intracranial hypertension can be detected noninvasively within short examination times, opening avenues for diagnostic applications of cerebral ultrasound time-harmonic elastography in neurology and emergency medicine., Competing Interests: Conflicts of interest and sources of funding: none declared., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Despite limited evidence on clinical efficacy and increasing resistance problems, topical antibiotics are still used in everyday clinical practice. However, topical antiseptic agents such, as octenidine and polyhexanide, often have a broader efficacy spectrum. They also have a broader target tropism because of their non-specific cellular mechanisms of action. Repeated use of topical antibiotics also carries the risk of contact sensitization, which could limit potential subsequent use as systemic antibiotics. Contact allergy is a clinically relevant problem, particularly in patients with barrier-damaged skin, pre-existing dermatosis, or occupational exposure. It can be concluded that with the use of modern antiseptics, topical antibiotic therapy is rarely indicated and should be avoided, not only because of the risk of contact sensitization but also because of the unfavorable and potentially consequential resistance problem., (© Dustri-Verlag Dr. K. Feistle.)

This paper summarises evidence from a rapid review of international findings on the effects of cash transfers. The learnings were used to inform the design of urgent response social protection during the COVID-19 pandemic. The summary demonstrates that in response to widespread disruption, cash transfers have broad benefits for children, adults, and the wider economy. First, cash grants for child support have been shown to reduce hunger, increase dietary diversity, and reduce secondary school dropout. Transfers may also reduce child malnutrition. Second, there is some evidence that cash grants could encourage job search and economic activity. By contrast, there is little evidence that grants discourage adults from working, or increase spending on temptation goods (alcohol, tobacco). Third, for the wider economy, there is little evidence that grants will increase inflation, while some studies find that transfers create a fiscal multiplier and stimulate the local economy. Finally, we review evidence on design considerations and find that unconditional cash transfers (UCTs) are particularly well suited to rapid response when compared to conditional cash transfers (CCTs). Outside crisis settings, there is some evidence that getting recipients to enrol children in school or attend health check-ups improves these outcomes more than unconditional grants. However, the differences are small and the additional costs of implementing conditions outweigh these benefits in circumstances where response is required urgently. Comparing evidence on cash grants and food vouchers suggests both achieve similar improvements in nutrition; however, cash transfers are likely to be more cost-effective for governments, especially where a system to distribute grants is already set up.

Carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6), a cell surface receptor, is expressed on normal epithelial tissue and highly expressed in cancers of high unmet medical need, such as non-small cell lung, pancreatic, and colorectal cancer. CEACAM receptors undergo homo- and heterophilic interactions thereby regulating normal tissue homeostasis and angiogenesis, and in cancer, tumor invasion and metastasis. CEACAM6 expression on malignant plasma cells inhibits antitumor activity of T cells, and we hypothesize a similar function on epithelial cancer cells. The interactions between CEACAM6 and its suggested partner CEACAM1 on T cells were studied. A humanized CEACAM6-blocking antibody, BAY 1834942, was developed and characterized for its immunomodulating effects in co-culture experiments with T cells and solid cancer cells and in comparison to antibodies targeting the immune checkpoints programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), and T cell immunoglobulin mucin-3 (TIM-3). The immunosuppressive activity of CEACAM6 was mediated by binding to CEACAM1 expressed by activated tumor-specific T cells. BAY 1834942 increased cytokine secretion by T cells and T cell-mediated killing of cancer cells. The in vitro efficacy of BAY 1834942 correlated with the degree of CEACAM6 expression on cancer cells, suggesting potential in guiding patient selection. BAY 1834942 was equally or more efficacious compared to blockade of PD-L1, and at least an additive efficacy was observed in combination with anti-PD-1 or anti-TIM-3 antibodies, suggesting an efficacy independent of the PD-1/PD-L1 axis. In summary, CEACAM6 blockade by BAY 1834942 reactivates the antitumor response of T cells. This warrants clinical evaluation., Competing Interests: Competing interests: JP, MT, WDD, RC, GB, JMG, DS, and JWi are employees of Bayer AG. JP, MT, WDD, OvA, and JWi are stockholders of Bayer AG. JP, HHB, MT, EMG, RC, CF, JMG, DS, and JWi are authors of CEACAM6 patents. CF, MLE, OvA, and JWe are former employees of Bayer AG., (© 2021 The Author(s). Published with license by Taylor & Francis Group, LLC.)

Atopic dermatitis is a chronic inflammatory disease that arises from polygenic disposition, a dysfunction of the physicochemical epithelial barrier, a cutaneous dysbiosis, and a faulty neurosensory activity and shows a highly individual acuity due to epigenetic factors. An essential component of therapeutic management is the application of anti-inflammatory topical medication. Currently, topical glucocorticoids and topical calcineurin inhibitors are routinely used in reactive and proactive therapy. In recent years, the development of molecular medicine has identified several new therapeutic targets that have enabled the development of innovative therapeutic approaches. In addition to phosphodiesterase-4 inhibitors and aryl hydrocarbon receptor modulators, it is mainly Janus kinase inhibitors with different selectivity that are emerging as new effective and safe options for topical therapy. The current data suggests that in the coming months and years representatives of the above-mentioned substance classes will be approved for topical use., (© Dustri-Verlag Dr. K. Feistle.)

Ocular manifestations of syphilis with visual impairment symptoms may occur already at the stage of secondary syphilis. They may also be the only manifestation of syphilis and mimic other diseases of the eye. Therefore, in all patients with uveitis, optic neuritis, optic atrophy, acute ocular muscle paresis, or loss of visual acuity, syphilis infection should be ruled out, even if the medical history does not initially raise suspicion. Ocular involvement should be treated as neurosyphilis. Delayed diagnosis and inadequate therapy are often associated with irreversible consequences for the affected patient. As with any syphilis infection, HIV infection should be considered and excluded, especially in the case of ocular manifestations., (© 2021 The Authors. Journal der Deutschen Dermatologischen Gesellschaft published by John Wiley & Sons Ltd on behalf of Deutsche Dermatologische Gesellschaft.)

Background: Wheat is one of the most commonly consumed foods and a known elicitor of anaphylaxis in children and adults. Reactions in adults are often cofactor dependent and characterized by a prolonged time between food intake and the onset of symptoms making the diagnosis of wheat anaphylaxis challenging., Objective: To characterize a cohort of patients with the history of wheat anaphylaxis to better understand this atypical phenotype of anaphylaxis., Methods: Data from the European Anaphylaxis Registry from 2007 to 2019 (n = 10,636) including 250 patients (213 adults and 37 children) with a history of anaphylaxis caused by wheat were analyzed., Results: Wheat was the most common food elicitor of anaphylaxis in adults in the registry in Central Europe. Reactions to wheat in adults were frequently associated with exercise as a cofactor (82.8%) and partially delayed (57.5%). Only 36.9% of patients had atopic comorbidities, which was uncommonly low for adult patients allergic to other kinds of foods (63.2%). Anaphylaxis to wheat presented frequently with cardiovascular symptoms (86.7%) including severe symptoms such as loss of consciousness (41%) and less often with respiratory symptoms (53.6%). The reactions to wheat were more severe than reactions to other foods (odds ratio [OR] = 4.33), venom (OR = 1.58), or drugs (OR = 2.11)., Conclusions: Wheat is a relevant elicitor of anaphylaxis in adults in Central Europe. Wheat anaphylaxis is highly dependent on the presence of cofactors and less frequently associated with atopic diseases compared with other food allergies. More data on mechanisms of wheat-induced anaphylaxis are required to develop preventive measures for this potentially life-threatening disease., (Copyright © 2021 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Not available., (© Dustri-Verlag Dr. K. Feistle.)

Hydration influences blood volume, blood viscosity, and water content in soft tissues - variables that determine the biophysical properties of biological tissues including their stiffness. In the brain, the relationship between hydration and stiffness is largely unknown despite the increasing importance of stiffness as a quantitative imaging marker. In this study, we investigated cerebral stiffness (CS) in 12 healthy volunteers using ultrasound time-harmonic elastography (THE) in different hydration states: (i) during normal hydration, (ii) after overnight fasting, and (iii) within 1 h of drinking 12 ml of water per kg body weight. In addition, we correlated shear wave speed (SWS) with urine osmolality and hematocrit. SWS at normal hydration was 1.64 ± 0.02 m/s and decreased to 1.57 ± 0.04 m/s ( p < 0.001) after overnight fasting. SWS increased again to 1.63 ± 0.01 m/s within 30 min of water drinking, returning to values measured during normal hydration ( p = 0.85). Urine osmolality at normal hydration (324 ± 148 mOsm/kg) increased to 784 ± 107 mOsm/kg ( p < 0.001) after fasting and returned to normal (288 ± 128 mOsm/kg, p = 0.83) after water drinking. SWS and urine osmolality correlated linearly ( r = -0.68, p < 0.001), while SWS and hematocrit did not correlate ( p = 0.31). Our results suggest that mild dehydration in the range of diurnal fluctuations is associated with significant softening of brain tissue, possibly due to reduced cerebral perfusion. To ensure consistency of results, it is important that cerebral elastography with a standardized protocol is performed during normal hydration., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Kreft, Bergs, Shahryari, Danyel, Hetzer, Braun, Sack and Tzschätzsch.)

Inhibition of monopolar spindle 1 (MPS1) kinase represents a novel approach to cancer treatment: instead of arresting the cell cycle in tumor cells, cells are driven into mitosis irrespective of DNA damage and unattached/misattached chromosomes, resulting in aneuploidy and cell death. Starting points for our optimization efforts with the goal to identify MPS1 inhibitors were two HTS hits from the distinct chemical series "triazolopyridines" and "imidazopyrazines". The major initial issue of the triazolopyridine series was the moderate potency of the HTS hits. The imidazopyrazine series displayed more than 10-fold higher potencies; however, in the early project phase, this series suffered from poor metabolic stability. Here, we outline the evolution of the two hit series to clinical candidates BAY 1161909 and BAY 1217389 and reveal how both clinical candidates bind to the ATP site of MPS1 kinase, while addressing different pockets utilizing different binding interactions, along with their synthesis and preclinical characterization in selected in vivo efficacy models.

The immunoglobulin-like domain containing receptor 2 (ILDR2), a type I transmembrane protein belonging to the B7 family of immunomodulatory receptors, has been described to induce an immunosuppressive effect on T-cell responses. Besides its expression in several nonlymphoid tissue types, we found that ILDR2 was also expressed in fibroblastic reticular cells (FRC) in the stromal part of the lymph node. These immunoregulatory cells were located in the T-cell zone and were essential for the recruitment of naïve T cells and activated dendritic cells to the lymph nodes. Previously, it has been shown that an ILDR2-Fc fusion protein exhibits immunomodulatory effects in several models of autoimmune diseases, such as multiple sclerosis, rheumatoid arthritis, and type I diabetes. Herein, we report the generation and characterization of a human/mouse/monkey cross-reactive anti-ILDR2 hIgG2 antibody, BAY 1905254, developed to block the immunosuppressive activity of ILDR2 for cancer immunotherapy. BAY 1905254 was shown to promote T-cell activation in vitro and enhance antigen-specific T-cell proliferation and cytotoxicity in vivo in mice. BAY 1905254 also showed potent efficacy in various syngeneic mouse cancer models, and the efficacy was found to correlate with increasing mutational load in the cancer models used. Additive or even synergistic antitumor effects were observed when BAY 1905254 was administered in combination with anti-PD-L1, an immunogenic cell death-inducing chemotherapeutic, or with tumor antigen immunization. Taken together, our data showed that BAY 1905254 is a potential drug candidate for cancer immunotherapy, supporting its further evaluation., (©2020 American Association for Cancer Research.)

This guideline on diagnostic procedures for suspected beta-lactam antibiotic (BLA) hypersensitivity was written by the German and Austrian professional associations for allergology, and the Paul-Ehrlich Society for Chemotherapy in a consensus procedure according to the criteria of the German Association of Scientific Medical Societies. BLA such as penicillins and cephalosporins represent the drug group that most frequently triggers drug allergies. However, the frequency of reports of suspected allergy in patient histories clearly exceeds the number of confirmed cases. The large number of suspected BLA allergies has a significant impact on, e.g., the quality of treatment received by the individual patient and the costs to society as a whole. Allergies to BLA are based on different immunological mechanisms and often manifest as maculopapular exanthema, as well as anaphylaxis; and there are also a number of less frequent special clinical manifestations of drug allergic reactions. All BLA have a beta-lactam ring. BLA are categorized into different classes: penicillins, cephalosporins, carbapenems, monobactams, and beta-lactamase inhibitors with different chemical structures. Knowledge of possible cross-reactivity is of considerable clinical significance. Whereas allergy to the common beta-lactam ring occurs in only a small percentage of all BLA allergic patients, cross-reactivity due to side chain similarities, such as aminopenicillins and aminocephalosporins, and even methoxyimino cephalosporins, are more common. However, the overall picture is complex and its elucidation may require further research. Diagnostic procedures used in BLA allergy are usually made up of four components: patient history, laboratory diagnostics, skin testing (which is particularly important), and drug provocation testing. The diagnostic approach - even in cases where the need to administer a BLA is acute - is guided by patient history and risk - benefit ratio in the individual case. Here again, further studies are required to extend the present state of knowledge. Performing allergy testing for suspected BLA hypersensitivity is urgently recommended not only in the interests of providing the patient with good medical care, but also due to the immense impact of putative BLA allergies on society as a whole., (© Dustri-Verlag Dr. K. Feistle.)

In-vivo brain viscoelasticity measured by magnetic resonance elastography (MRE) is a sensitive imaging marker for long-term biophysical changes in brain tissue due to aging and disease; however, it is still unknown whether MRE can reveal short-term periodic alterations of brain viscoelasticity related to cerebral arterial pulsation (CAP). We developed cardiac-gated steady-state MRE (ssMRE) with spiral readout and stroboscopic sampling of continuously induced mechanical vibrations in the brain at 20, 31.25, and 40 Hz frequencies. Maps of magnitude |G*| and phase ϕ of the complex shear modulus were generated by multifrequency dual visco-elasto inversion with a temporal resolution of 40 ms over 4 s. The method was tested in 12 healthy volunteers. During cerebral systole, |G*| decreased by 6.6 ± 1.9% (56 ± 22 Pa, p  < 0.001, mean ± SD), whereas ϕ increased by 0.5 ± 0.5% (0.006 ± 0.005 rad, p  = 0.002). The effect size of CAP-induced softening slightly decreased with age by 0.10 ± 0.05% per year ( p  = 0.04), indicating lower cerebral vascular compliance in older individuals. Our data show for the first time that the brain softens and becomes more viscous during systole, possibly due to an effect of CAP-induced arterial expansion and increased blood volume on effective-medium tissue properties. This sensitivity to vascular-solid tissue interactions makes ssMRE potentially useful for detection of cerebral vascular disease.

Cerebral blood flow, cerebral stiffness (CS) and intracranial pressure are tightly linked variables of cerebrovascular reactivity and cerebral autoregulation. Transtemporal ultrasound time-harmonic elastography was used for rapid measurement of CS changes in 10 volunteers before, during and after administration of a gas mixture of 95% O 2 and 5% CO 2 (carbogen). Within the first 2.2 ± 2.0 min of carbogen breathing, shear wave speed determined as a surrogate parameter of CS increased from 1.57 ± 0.04 to 1.66 ± 0.05 m/s (p < 0.01) in synchrony with end-tidal CO 2 while post-hypercapnic CS recovery was delayed by 2.7 ± 1.4 min in relation to end-tidal CO 2 . Our results indicate that CS is highly sensitive to changes in CO 2 levels of inhaled air. Possible mechanisms underlying the observed CS changes might be associated with cerebrovascular reactivity, cerebral blood flow adaptation and intracranial regulation, all of which are potentially relevant for future diagnostic applications of transtemporal time-harmonic elastography in a wide spectrum of neurologic diseases., Competing Interests: Conflict of interest disclosure The authors have no conflicts of interest to disclose, (Copyright © 2019 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.)

Background: Preservatives in cosmetics are often suspected as contact sensitizers and hence frequently patch tested in dermatitis patients. Exposure in this field has changed over the course of years., Objective: To describe the frequency of contact sensitization to various preservatives., Materials and Methods: Retrospective data analysis from the Information Network of Departments of Dermatology (IVDK) for the years 2009-2018., Results: Frequency of sensitization to methylisothiazolinone (MI) has increased from 2.0% in 2009 to 7.2% in 2013. Since 2014, the rate has been falling again. Increasing the patch test concentration of methyldibromo glutaronitrile (MDBGN) in 2016 has caused a sudden rise in positive patch test reactions from 2.0% to more than 4.5%. Allergic reactions to other preservatives occurred in less than 1% of the patients tested., Discussion: Since 2014, the worldwide "epidemic" of sensitization to MI has been subsiding in Central Europe, thanks to corresponding restrictions on use. Since 2008, there is no longer any widespread exposure to MDBGN; the new, higher test concentration elicits many false-positive test reactions and explains the sudden rise in positive patch test reactions since 2016. Despite widespread use, phenoxyethanol, benzoates, benzyl alcohol, parabens and sorbates rarely cause allergic reactions. Therefore, they can be recommended for cosmetics from the epidemiological-allergological point of view.

Respiratory arrest is a major life-threatening condition leading to cessation of vital functions and hypoxic-anoxic injury of the brain. The progressive structural tissue changes characterizing the dying brain biophysically are unknown. Here we use noninvasive magnetic resonance elastography to show that biomechanical tissue properties are highly sensitive to alterations in the brain in the critical period before death. Our findings demonstrate that brain stiffness increases after respiratory arrest even when cardiac function is still preserved. Within 5 min of cardiac arrest, cerebral stiffness further increases by up to 30%. This early mechanical signature of the dying brain can be explained by water accumulation and redistribution from extracellular spaces into cells. These processes, together, increase interstitial and intracellular pressure as revealed by magnetic resonance spectroscopy and diffusion-weighted imaging. Our data suggest that the fast response of cerebral stiffness to respiratory arrest enables the monitoring of life-threatening brain pathology using noninvasive in vivo imaging. STATEMENT OF SIGNIFICANCE: Hypoxia-anoxia is a life-threatening condition eventually leading to brain death. Therefore, monitoring vital brain functions in patients at risk is urgently required during emergency care or treatment of acute brain damage due to insufficient oxygen supply. In mouse model of hypoxia-anoxia, we have shown for the first time that biophysical tissue parameters such as brain stiffness changed markedly during the process of death., (Copyright © 2019. Published by Elsevier Ltd.)

Epicutaneous patch testing is the diagnostic standard for the detection of allergic contact dermatitis. The present guidelines are aimed at residents and board-certified physicians in the fields of dermatology and allergology as well as other medical specialties involved in establishing the indication for patch testing and its execution in patients with contact dermatitis and other forms of delayed-type hypersensitivity. The target audience also includes other health care providers and insurance funds. Based on a systematic literature search and a formal consensus process (S3), the guidelines were developed by dermatologists in collaboration with pediatricians, occupational medicine physicians, nursing staff as well as patient representatives. The systematic methodological approach and appraisal of evidence upon which the recommendations are based are outlined in a separate method report that also contains evidence tables. The guidelines address general aspects of patch testing as well as medicolegal issues. The recommendations given relate to topics such as the indication for patch testing, informed patient consent, as well as the choice of test substances, test chambers and test site, duration of exposure, reading times and interpretation of test reactions. Furthermore, recommendations are provided with respect to endogenous and exogenous factors, specific patient groups (children, pregnant women, immunosuppressed individuals) as well as possible risks and adverse events associated with patch testing using contact allergens., (© 2019 The Authors | Journal compilation © Blackwell Verlag GmbH, Berlin.)

Background: Contact urticaria (CU) is an infrequent, mostly occupational disease that may be life-threatening (CU syndrome stage 4)., Objectives: To identify the current frequency, elicitors and cofactors of CU., Patients: Three cohorts were retrospectively analysed for CU: (a) patients from the Information Network of Departments of Dermatology (IVDK) database (2000-2014; n = 159 947); (b) patients from an allergy unit (Department of Dermatology, University Hospital Erlangen, 2000-2015; n = 4741); and (c) patients from the Anaphylaxis Registry (2007-2015: 6365 reported cases, including 2473 patients with Ring and Messmer grade III-IV reactions) for severe cases with skin/mucosal manifestations occurring at the workplace vs cases not occurring at the workplace (n = 68 vs n = 1821)., Results: Four hundred and forty-eight CU patients (0.28%) were diagnosed in the IVDK cohort, and 16 (0.34%) (10 of immunological aetiology, and 6 of non-immunological aetiology) in the Erlangen cohort. The most frequent elicitors in the IVDK cohort were cosmetics, creams, sun protection agents (although these were less frequent in CU patients than in controls without CU; 26.8% vs 35.6%, P < .0001), and gloves (significantly more frequent in CU patients than in controls; 18.1% vs 6.5%, P < .0001). The most frequent elicitors in the Erlangen cohort were natural rubber latex and sorbic acid. Among the MOAHLFA index characteristics, in both cohorts occupational disease was more common in CU patients than in patients without CU. CU was significantly associated with allergic rhinitis and allergic asthma. Wet work was a relevant cofactor. In the Anaphylaxis Registry, 19 cases (0.3%) were identified with severe reactions including skin symptoms at the workplace linked to common occupational elicitors., Conclusions: CU is a rare occupational skin manifestation with a frequency of <0.4% in the examined patients; it may, however, progress to anaphylaxis. Preventive measures are important, and should take into account the identified elicitors and cofactors., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Epicutaneous patch testing is the diagnostic standard for the detection of allergic contact dermatitis. The present guidelines are aimed at residents and board-certified physicians in the fields of dermatology and allergology as well as other medical specialties involved in establishing the indication for patch testing and its execution in patients with contact dermatitis and other forms of delayed-type hypersensitivity. The target audience also includes other health care providers and insurance funds. Based on a systematic literature search and a formal consensus process (S3), the guidelines were developed by dermatologists in collaboration with pediatricians, occupational medicine physicians, nursing staff as well as patient representatives. The systematic methodological approach and appraisal of evidence upon which the recommendations are based are outlined in a separate method report that also contains evidence tables. The guidelines address general aspects of patch testing as well as medicolegal issues. The recommendations given relate to topics such as the indication for patch testing, informed patient consent, as well as the choice of test substances, test chambers and test site, duration of exposure, reading times and interpretation of test reactions. Furthermore, recommendations are provided with respect to endogenous and exogenous factors, specific patient groups (children, pregnant women, immunosuppressed individuals) as well as possible risks and adverse events associated with patch testing using contact allergens. Note: This publication is part 1 of the short version of the S3 guidelines for "Epicutaneous patch testing using contact allergens and drugs" (registry no. 013 - 018; date: March 20, 2019; valid until December 31, 2021). Part 2 of the short version will be published in the next issue. The long version of these guidelines can be accessed at www.awmf.org. The method report is available as online publication (https://www.awmf.org/leitlinien/detail/ll/013-018.html) and contains the evidence tables in its appendix., (© 2019 The Authors | Journal compilation © Blackwell Verlag GmbH, Berlin.)

Cerebral stiffness (CS) reflects the biophysical environment in which neurons grow and function. While long-term CS changes can occur in the course of chronic neurological disorders and aging, little is known about acute variations of CS induced by intracranial pressure variations. Current gold standard methods for CS and intracranial pressure such as magnetic resonance elastography and direct pressure recordings are either expensive and slow or invasive. The study objective was to develop a real-time method for in vivo CS measurement and to demonstrate its sensitivity to physiological aging and intracranial pressure variations induced by the Valsalva maneuver in healthy volunteers. We used trans-temporal ultrasound time-harmonic elastography (THE) with external shear-wave stimulation by continuous and superimposed vibrations in the frequency range from 27 to 56 Hz. Multifrequency wave inversion generated maps of shear wave speed (SWS) as a surrogate maker of CS. On average, cerebral SWS was 1.56 ± 0.08 m/s with a tendency to reduce with age (R = -0.76, p < 0.0001) while Valsalva maneuver induced an immediate stiffening of the brain as reflected by a 10.8 ± 2.5% increase (p < 0.0001) in SWS. Our results suggest that CS is tightly linked to intracranial pressure and might be used in the future as non-invasive surrogate marker for intracranial pressure, which otherwise requires invasive measurements.

Although primary hyperhidrosis is a common disease, secondary symptomatic hyperhidrosis is rather rare. Primary hyperhidrosis is a complex neuropathic dysregulation with a genetic predisposition and is diagnosed when patients show pathologic sweating patterns and excessive sweating for at least 6 months and fulfill at least four of the following criteria: affected areas are axillae and/or palms and/or soles and/or forehead; symmetry; no night sweating; at least once a week; onset before the age of 25; positive family history; negative impact on daily activities. Frequently used therapies are topical aluminum salts and anticholinergics, iontophoresis in water, and intracutaneous botulinum toxin. Anticholinergics are also used as systemic treatment. Surgical procedures are used as a last result. Furthermore procedures using thermolysis have been developed.

Background: Glycoproteins and glycolipids of some mammalian species contain the disaccharide galactosyl-α-(1,3)-galactose (α-Gal). It is known that α-Gal is immunogenic in humans and causes glycan-specific IgG and also IgE responses with clinical relevance. α-Gal is part of the IgE-reactive monoclonal therapeutic antibody cetuximab (CTX) and is associated with delayed anaphylaxis to red meat. In this study, different α-Gal-containing analytes are examined in singleplex and multiplex assays to resolve individual sensitization patterns with IgE against α-Gal., Methods: Three serum groups, α-Gal-associated meat allergy (MA) patients, idiopathic anaphylaxis (IA) patients with suspected MA, and non-meat-allergic healthy control individuals (HC), were analyzed via singleplex allergy diagnostics and a newly established immunoblot diagnostic system. The new dot blot detection system resolved individual IgE sensitization profiles for α-Gal-containing analytes CTX, bovine thyroglobulin (Bos d TG), and human serum albumin (HSA)-conjugated α-Gal., Results: Singleplex allergy diagnostics using the α-Gal analytes CTX and Bos d TG confirms the history of MA patients in 91% and 88% of the cases, respectively. A novel dot blot-based assay system for the detection of IgE against α-Gal reveals individual IgE sensitization profiles for α-Gal-containing analytes. An α-Gal-associated IgE cross-reactivity profile (IgE against CTX, Bos d TG, and HSA-α-Gal) was identified, which is associated with MA., Conclusions: Detection of individual sensitization patterns with different α-Gal-containing analytes provides the basis for an individual allergy diagnosis for α-Gal-sensitized patients. Higher amounts of α-Gal in pork and beef innards compared to muscle meat as indicated by a higher staining intensity are a plausible explanation for the difference in allergic symptom severity., (© 2017 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)

Food allergens are frequent causes of anaphylaxis. In particular in children and adolescents they are the most frequent elicitors of severe allergic reactions, and in adults food allergens rank third behind insect venom and drugs. Since July 2006 severe allergic reactions from Germany, Austria, and Switzerland are collected in the anaphylaxis registry. Currently 78 hospitals and private practises are connected. From July 2006 until February 2009 1,156 severe allergic reactions were registered. Among children and adolescents (n = 187, age range from 3 months to 17 years) food allergens were the most frequent triggers, comprising 58% of cases. In the adult group (n = 968, 18 - 85 years) food allergens were in the third position (16.3%) behind insect venom and drugs. In children legumes (31%) and in particular peanuts were frequently responsible food allergens, followed by tree nuts (25%) with hazelnut being the most frequent elicitor. In adults fruits (13.4%) most often induced severe food-dependent anaphylaxis, but also animal products (12.2%); among these most frequently crustaceans and molluscs. Cofactors were often suspected in food-dependent anaphylaxis, namely in 39% of the adult group and in 14% of the pediatric group. In adults drugs (22%) and physical activity (10%) were reported to be the most frequent cofactors, in children physical activity was suspected in 8.7% and drugs in 2.6%. Concomitant diseases like atopic dermatitis, allergic asthma, or allergic rhinoconjunctivitis were reported in 78% of children and adolescents and in 67% of the adults. In conclusion, food-induced anaphylaxis, its cofactors and concomitant diseases are age-dependent. The data offers to identify risk factors of anaphylaxis.

Background: The standardized protocol for performing the strip patch test has proven to be valid, but evidence on its reliability is still missing., Objective: To estimate the parallel-test reliability of the strip patch test as compared with the conventional patch test., Methods: In this multicentre, prospective, randomized, investigator-blinded reliability study, 132 subjects were enrolled. Simultaneous duplicate strip and conventional patch tests were performed with the Finn Chambers ® on Scanpor ® tape test system and the patch test preparations nickel sulfate 5% pet., potassium dichromate 0.5% pet., and lanolin alcohol 30% pet. Reliability was estimated by the use of Cohen's kappa coefficient., Results: Parallel-test reliability values of the three standard patch test preparations turned out to be acceptable, with slight advantages for the strip patch test. The differences in reliability were 9% (95%CI: -8% to 26%) for nickel sulfate and 23% (95%CI: -16% to 63%) for potassium dichromate, both favouring the strip patch test., Conclusions: The standardized strip patch test method for the detection of allergic contact sensitization in patients with suspected allergic contact dermatitis is reliable. Its application in routine clinical practice can be recommended, especially if the conventional patch test result is presumably false negative., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

C4.4A (LYPD3) has been identified as a cancer- and metastasis-associated internalizing cell surface protein that is expressed in non-small cell lung cancer (NSCLC), with particularly high prevalence in the squamous cell carcinoma (SCC) subtype. With the exception of skin keratinocytes and esophageal endothelial cells, C4.4A expression is scarce in normal tissues, presenting an opportunity to selectively treat cancers with a C4.4A-directed antibody-drug conjugate (ADC). We have generated BAY 1129980 (C4.4A-ADC), an ADC consisting of a fully human C4.4A-targeting mAb conjugated to a novel, highly potent derivative of the microtubule-disrupting cytotoxic drug auristatin via a noncleavable alkyl hydrazide linker. In vitro , C4.4A-ADC demonstrated potent antiproliferative efficacy in cell lines endogenously expressing C4.4A and inhibited proliferation of C4.4A-transfected A549 lung cancer cells showing selectivity compared with a nontargeted control ADC. In vivo , C4.4A-ADC was efficacious in human NSCLC cell line (NCI-H292 and NCI-H322) and patient-derived xenograft (PDX) models (Lu7064, Lu7126, Lu7433, and Lu7466). C4.4A expression level correlated with in vivo efficacy, the most responsive being the models with C4.4A expression in over 50% of the cells. In the NCI-H292 NSCLC model, C4.4A-ADC demonstrated equal or superior efficacy compared to cisplatin, paclitaxel, and vinorelbine. Furthermore, an additive antitumor efficacy in combination with cisplatin was observed. Finally, a repeated dosing with C4.4A-ADC was well tolerated without changing the sensitivity to the treatment. Taken together, C4.4A-ADC is a promising therapeutic candidate for the treatment of NSCLC and other cancers expressing C4.4A. A phase I study (NCT02134197) with the C4.4A-ADC BAY 1129980 is currently ongoing. Mol Cancer Ther; 16(5); 893-904. ©2017 AACR ., (©2017 American Association for Cancer Research.)