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This document presents the findings of a study on the presence of eosinophils and basophils in patients with bullous pemphigoid (BP) and non-bullous pemphigoid (NBP) skin. The study found that the number of eosinophils and basophils was significantly higher in BP lesional skin compared to BP perilesional skin and NBP skin. The activation of eosinophils and basophils in BP lesional skin was also observed. These findings suggest that eosinophils and basophils play an important role in the pathophysiology of BP and may contribute to the itch experienced by pemphigoid patients. Further research is needed to validate these findings. [Extracted from the article]

Phase Resolved Optical Emission Spectroscopy (PROES) measurements combined with 1d3v Particle-in-Cell/Monte Carlo Collisions simulations are performed to investigate the excitation dynamics in low-pressure capacitively coupled plasmas (CCPs) in argon-oxygen mixtures. The system used for this study is a geometrically symmetric CCP reactor operated in a 70% Ar-30% O2 mixture at 120 Pa, applying a peak-to-peak voltage of 350 V, with a wide range of driving RF frequencies (2 MHz ⩽ f ⩽ 15 MHz). The measured and calculated spatio-temporal distributions of the electron impact excitation rates from the Ar ground state to the Ar 2 p 1 level show good qualitative agreement. The distributions show significant frequency dependence, which is generally considered to be predictive of transitions in the dominant discharge operating mode. Three frequency ranges can be distinguished, showing distinctly different excitation characteristics: (i) in the low frequency range ( f ⩽ 3 MHz), excitation is strong at the sheaths and weak in the bulk region; (ii) at intermediate frequencies (3.5 MHz ⩽ f ⩽ 5 MHz), the excitation rate in the bulk region is enhanced and shows striation formation; (iii) above 6 MHz, excitation in the bulk gradually decreases with increasing frequency. Boltzmann term analysis was performed to quantify the frequency-dependent contributions of the Ohmic and ambipolar terms to the electron power absorption. [ABSTRACT FROM AUTHOR]

Plasma simulations are powerful tools for understanding fundamental plasma science phenomena and for process optimisation in applications. To ensure their quantitative accuracy, they must be validated against experiments. In this work, such an experimental validation is performed for a one dimensional in space and three dimensional in velocity space particle-in-cell simulation complemented with the Monte Carlo treatment of collision processes of a capacitively coupled radio frequency plasma driven at 13.56 MHz and operated in neon gas. In a geometrically symmetric reactor the electron density in the discharge centre and the spatio-temporal distribution of the electron impact excitation rate from the ground into the Ne 2p1 level are measured by a microwave cutoff probe and phase resolved optical emission spectroscopy, respectively. The measurements are conducted for electrode gaps between 50 mm and 90 mm, neutral gas pressures between 20 mTorr and 50 mTorr, and peak-to-peak values of the driving voltage waveform between 250 V and 650 V. Simulations are performed under identical discharge conditions. In the simulations, various combinations of surface coefficients characterising the interactions of electrons and heavy particles with the anodised aluminium electrode surfaces are adopted. We find, that the simulations using a constant effective heavy particle induced secondary electron (SE) emission coefficient of 0.3 and a realistic electron–surface interaction model (which considers energy-dependent and material specific elastic and inelastic electron reflection, as well as the emission of true SEs from the surface) yield results which are in good quantitative agreement with the experimental data. [ABSTRACT FROM AUTHOR]

For the Hungarian People's Republic, the events of the world politics in the 1960s allowed for significant international activity. Respecting the framework of the regime, decades of active engagement on both sides of the Iron Curtain could be initiated. Considering the country's resources, one of the most important elements in its foreign relations efforts was the continuous expansion of cultural and educational relations, which allowed the country's higher education system--which experienced extensive growth during the same period--to play a prominent role. The Eötvös Loránd University (ELTE), one of the largest higher education institutions in Hungary, hosted students from nearly 90 countries with its diverse training portfolio. The internationalization process promoted by the government provided the university with a major opportunity to build a position in the wider international academic community, to establish partnerships, to diversify its training, and to improve its quality continuously. Relations with capitalist and developing countries were particularly valuable. At the same time, it was confronted with a number of problems in teaching and supporting incoming students, as well as systemic rigidities and inadequate funding, problems which remained unresolved before the transition. This paper seeks to showcase these processes through archival documents and contemporary press sources, examining the opportunities, constraints, and challenges from an institutional perspective, thus illustrating the frequent political ambitions of the state and its political institutions. [ABSTRACT FROM AUTHOR]

Complete remission off therapy was achieved by two patients (29%) with BP and five patients (31%) with MMP (Table 1). Overall, eight patients (35%) relapsed after a median time of 56 weeks [two patients with BP (29%) and six patients with MMP (38%)] (Table 1). In particular, the number of patients receiving prednisone decreased from 18 patients (78%) at M0 to 13 patients (57%) at M6. [Extracted from the article]

When stratifying patients by disease severity, patients with self-reported moderate-to-severe disease were more likely to report worsening of symptoms during pregnancy than those with mild disease (32% vs. 17%). This study is limited by small sample size, recall bias, the small number of patients with mild disease and patient-reported disease severity and complications. Dear Editor, Hidradenitis suppurativa (HS) affects predominantly women of reproductive age and frequently flares during the perimenstrual period, indicating a hormonal influence.1-3 Studies on the effect of pregnancy on HS disease severity have reported improvement, no change and worsening during pregnancy.4-8 We aimed to assess changes in HS disease course during pregnancy and postpartum and identify potential predictors of HS pregnancy outcomes. [Extracted from the article]

We hypothesized that PD-1 inhibitors would have a limited place in clinical practice, as a large proportion of patients with advanced disease are immunocompromised (e.g. organ transplant patients) and would have a contraindication for PD-1 inhibitors. Dear Editor, Systemic treatment with programmed death receptor 1 (PD-1) inhibitors has been approved for patients with advanced cutaneous squamous cell carcinoma (cSCC) ineligible for curative surgery or radiation. Thirty-six patients (52%) were excluded due to relative contraindications, including one patient with both an absolute and a relative contraindication, leading to 30 (43%) patients fulfilling the study eligibility criteria. [Extracted from the article]

Background: Despite impaired humoral response in patients treated with immunosuppressants (ISPs), recent studies found similar severity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) breakthrough infection compared to controls. One potential explanation is the rapid generation of humoral response on infection, but evidence is lacking., Objectives: We investigated the longitudinal dynamics of the SARS-CoV-2 antibody repertoire after SARS-CoV-2 delta and omicron breakthrough infection in patients with immune-mediated inflammatory diseases (IMIDs) receiving ISP therapy and controls., Methods: As a prospective substudy of the national Target-to-B! (T2B!) consortium, we included IMID patients receiving ISPs therapy and controls who reported SARS-CoV-2 breakthrough infection between July 1, 2021, and April 1, 2022. To get an impression of the dynamics of the antibody repertoire, 3 antibody titers of wild-type RBD, wild-type S, and omicron RBD were measured at 4 time points after SARS-CoV-2 breakthrough infection., Results: We included 302 IMID patients receiving ISPs and 178 controls. Antibody titers increased up to 28 days after breakthrough infection in both groups. However, in IMID patients receiving therapy with anti-CD20 and sphingosine-1 phosphate receptor modulators, antibody titers were considerably lower compared to controls. In the anti-TNF group, we observed slightly lower antibody titers in the early stages and a faster decline of antibodies after infection compared to controls. Breakthrough infections were mostly mild, and hospitalization was required in less than 1% of cases., Conclusions: Most ISPs do not influence the dynamics of the SARS-CoV-2 antibody repertoire and exhibit a rapid recall response with cross-reactive antibody clones toward new virus variants. However, in patients treated with anti-CD20 therapy or sphingosine-1 phosphate receptor modulators, the dynamics were greatly impaired, and to a lesser extent in those who received anti-TNF. Nevertheless, only a few severe breakthrough cases were reported., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Several novel copper (II) complexes of reduced Schiff bases containing fluoride substituents were prepared and structurally characterized by single-crystal X-ray diffraction. The complexes exhibited diverse structures, with the central atom in distorted tetrahedral geometry. The biological effects of the products were evaluated, specifically their cytotoxicity, antimicrobial, and antiurease activities, as well as affinity for albumin (BSA) and DNA (ct-DNA). The complexes showed marked cytotoxic activities in the HepG2 hepatocellular carcinoma cell line, considerably higher than the standard cisplatin. The cytotoxicity depended significantly on the substitution pattern. The best activity was observed in the complex with a trifluoromethyl group in position 4 of the benzene ring-the dichloro[(±)-trans- N , N '-bis-(4-trifluoromethylbenzyl)-cyclohexane-1,2-diamine]copper (II) complex, whose activity (IC 50 28.7 μM) was higher than that of the free ligand and markedly better than the activity of the standard cisplatin (IC 50 336.8 μM). The same complex also showed the highest antimicrobial effect in vitro. The affinity of the complexes towards bovine serum albumin (BSA) and calf thymus DNA (ct-DNA) was established as well, indicating only marginal differences between the complexes. In addition, all complexes were shown to be excellent inhibitors of the enzyme urease, with the IC 50 values in the lower micromolar region.

Hyalomma marginatum, a vector for the high-consequence pathogen, the Crimean-Congo hemorrhagic fever virus (CCHFV), needs particular attention due to its impact on public health. Although it is a known vector for CCHFV, its general virome is largely unexplored. Here, we report findings from a citizen science monitoring program aimed to understand the prevalence and diversity of tick-borne pathogens, particularly focusing on Hyalomma ticks in Hungary. In 2021, we identified one adult specimen of Hyalomma marginatum and subjected it to Illumina-based viral metagenomic sequencing. Our analysis revealed sequences of the uncharacterized Volzhskoe tick virus, an unclassified member of the class Bunyaviricetes. The in silico analysis uncovered key genetic regions, including the glycoprotein and the RNA-dependent RNA polymerase (RdRp) coding regions. Phylogenetic analysis indicated a close relationship between our Volzhskoe tick virus sequences and other unclassified Bunyaviricetes species. These related species of unclassified Bunyaviricetes were detected in vastly different geolocations. These findings highlight the remarkable diversity of tick specific viruses and emphasize the need for further research to understand the transmissibility, seroreactivity or the potential pathogenicity of Volzhskoe tick virus and related species., (© 2024. The Author(s).)

Legumes have evolved a nitrogen-fixing symbiotic interaction with rhizobia, and this association helps them to cope with the limited nitrogen conditions in soil. The compatible interaction between the host plant and rhizobia leads to the formation of root nodules, wherein internalization and transition of rhizobia into their symbiotic form, termed bacteroids, occur. Rhizobia in the nodules of the Inverted Repeat-Lacking Clade legumes, including Medicago truncatula, undergo terminal differentiation, resulting in elongated and endoreduplicated bacteroids. This transition of endocytosed rhizobia is mediated by a large gene family of host-produced nodule-specific cysteine-rich (NCR) peptides in M. truncatula. Few NCRs have been recently found to be essential for complete differentiation and persistence of bacteroids. Here, we show that a M. truncatula symbiotic mutant FN9285, defective in the complete transition of rhizobia, is deficient in a cluster of NCR genes. More specifically, we show that the loss of the duplicated genes NCR086 and NCR314 in the A17 genotype, found in a single copy in Medicago littoralis R108, is responsible for the ineffective symbiotic phenotype of FN9285. The NCR086 and NCR314 gene pair encodes the same mature peptide but their transcriptional activity varies considerably. Nevertheless, both genes can restore the effective symbiosis in FN9285 indicating that their complementation ability does not depend on the strength of their expression activity. The identification of the NCR086/NCR314 peptide, essential for complete bacteroid differentiation, has extended the list of peptides, from a gene family of several hundred members, that are essential for effective nitrogen-fixing symbiosis in M. truncatula., (© 2024 The Author(s). The Plant Journal published by Society for Experimental Biology and John Wiley & Sons Ltd.)

Competing Interests: Conflicts of interest Dr Zee reports fees (Advisory Boards, Consultations) from AbbVie, Novartis Pharma UCB Pharma, InflaRX, Insmed. Dr Horváth reports fees from Janssen-Cilag (Advisory Boards, Educational grants, Consultations, Investigator Initiative Studies), AbbVie (Advisory Boards, Educational grants, Consultations, Investigator Initiative Studies), Novartis Pharma (Advisory Boards, Consultations, Investigator Initiative Studies), UCB Pharma (Advisory Boards, Consultations), Leo Pharma (Consultations), Solenne B.V. (Investigator Initiative Studies), Celgene (Consultations, Investigator Initiative Studies), Akari therapeutics (Consultations, Investigator Initiative Studies), Philips (Consultation), Roche (Consultation), Regeneron (Consultation), and Sanofi (Consultation), which were paid to the institution. Drs Koerts and Huijstee and Mr Weijden and Mr Spence have no conflicts of interest to declare.

Pemphigus vulgaris (PV) is a rare autoimmune bullous disease characterized by blistering of the skin and mucosa owing to the presence of autoantibodies against the desmosome proteins desmoglein 3 and occasionally in conjunction with desmoglein 1. Fundamental research into the pathogenesis of PV has revolutionized its treatment and outcome with rituximab, a B-cell-depleting therapy. The critical contribution of B cells to the pathogenesis of pemphigus is well accepted. However, the exact pathomechanism, mechanisms of onset, disease course and relapse remain unclear. In this narrative review, we provide an overview of the fundamental research progress that has unfolded over the past few centuries to give rise to current and emerging therapies. Furthermore, we summarize the multifaceted roles of B cells in PV, including their development, maturation and antibody activity. Finally, we explored how these various aspects of B-cell function contribute to disease pathogenesis and pave the way for innovative therapeutic interventions., Competing Interests: Conflicts of interest A.G. reports fees from AbbVie, Sanofi and UCB (advisory boards, shares, speaker); Eli Lilly, Janssen and Pfizer (advisory boards, shares); Leo Pharma and Regeneron (advisory boards); and GSK (shares). B.H. reports fees from AbbVie and Janssen-Cilag (advisory boards, consultations, educational grants, investigator initiative studies); Novartis Pharma (advisory boards, consultations, investigator initiative studies); Argenx, Boehringer-Ingelheim and UCB Pharma (advisory boards, consultations); Akari Therapeutics and Celgene (consultations, investigator initiative studies); Leo Pharma, Philips, Regeneron, Roche and Sanofi (consultations); and Solenne B.V. (investigator initiative studies); which fees were paid to the institution. A.-L.S., J.B., G.F.H.D., E.A., H.H.P., M.W.-B., G.A.H., P.H., and J.D.L. declare that they have no conflicts of interest regarding the scope of this work., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Association of Dermatologists.)

Background: The noninflammatory immunoglobulin G4 (IgG4) is linked to tolerance and is unique to humans. Although poorly understood, prolonged antigenic stimulation and IL-4-signaling along the T helper 2-axis may be instrumental in IgG4 class switching. Recently, repeated SARS-CoV-2 mRNA vaccination has been linked to IgG4 skewing. Although widely used immunosuppressive drugs have been shown to only moderately affect humoral responses to SARS-CoV-2 mRNA vaccination, the effect on IgG4 switching has not been investigated., Methods: Here we study the impact of such immunosuppressive drugs, including the IL-4 receptor-blocking antibody dupilumab, on IgG4 skewing upon repeated SARS-CoV-2 mRNA vaccination. Receptor-binding domain (RBD) specific antibody responses were longitudinally measured in 600 individuals, including patients with immune-mediated inflammatory diseases treated with a TNF inhibitor (TNFi) and/or methotrexate (MTX), dupilumab, and healthy/untreated controls, after repeated mRNA vaccination., Results: We observed a substantial increase in the proportion of RBD-specific IgG4 antibodies (median 21%) in healthy/untreated controls after third vaccination. This IgG4 skewing was profoundly reduced in dupilumab-treated patients (<1%). Unexpectedly, an equally strong suppression of IgG4 skewing was observed in TNFi-treated patients (<1%), whereas MTX caused a modest reduction (7%). RBD-specific total IgG levels were hardly affected by these immunosuppressive drugs. Minimal skewing was observed, when primary vaccination was adenoviral vector-based., Conclusions: Our results imply a critical role for IL-4/IL-13 as well as TNF in vivo IgG4 class switching. These novel findings advance our understanding of IgG4 class switch dynamics, and may benefit humoral tolerance induction strategies, treatment of IgG4 pathologies and mRNA vaccine optimization., (© 2024 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Current density, the membrane current value divided by membrane capacitance (C m ), is widely used in cellular electrophysiology. Comparing current densities obtained in different cell populations assume that C m and ion current magnitudes are linearly related, however data is scarce about this in cardiomyocytes. Therefore, we statistically analyzed the distributions, and the relationship between parameters of canine cardiac ion currents and C m , and tested if dividing original parameters with C m had any effect. Under conventional voltage clamp conditions, correlations were high for I K1 , moderate for I Kr and I Ca,L , while negligible for I Ks . Correlation between I to1 peak amplitude and C m was negligible when analyzing all cells together, however, the analysis showed high correlations when cells of subepicardial, subendocardial or midmyocardial origin were analyzed separately. In action potential voltage clamp experiments I K1, I Kr and I Ca,L parameters showed high correlations with C m . For I NCX , I Na,late and I Ks there were low-to-moderate correlations between C m and these current parameters. Dividing the original current parameters with C m reduced both the coefficient of variation, and the deviation from normal distribution. The level of correlation between ion currents and C m varies depending on the ion current studied. This must be considered when evaluating ion current densities in cardiac cells., (© 2024. The Author(s).)

Background: Hidradenitis suppurativa (HS) is a multifactorial inflammatory skin disease that is considered to be an immune-mediated inflammatory disease (IMID). Up till now, the impact of lifestyle on (the development of) HS has not been thoroughly investigated., Objectives: To investigate the effect of dietary intake and physical activity (PA) on (the development of) HS., Materials and Methods: A nested case-control study was performed within the longitudinal Lifelines Cohort Study, that took place in the Northern Netherlands, and identified 1004 adult eligible HS patients and 5000 age-matched controls. Dietary data were collected using a validated food frequency questionnaire, subsequently translated to the Lifelines Diet Score (LLDS), alternate Mediterranean Diet Score (aMED) and Dutch Dietary Guidelines score (DDG), with higher scores reflecting healthier dietary habits. PA was measured by the Short Questionnaire to Assess Health-enhancing PA score. Logistic regression analyses were performed between dietary/PA scores, and the prevalence/development and severity of HS., Results: Compared to controls, HS patients scored lower on the LLDS [OR = 0.98; 95% CI 0.96-0.99], aMED [0.93; 0.89-0.97] and DDG [0.93; 0.88-0.97] with multivariable regression analysis. Overall, this indicates less adherence to dietary recommendations and consumption of a low-quality diet in the HS population. Lower adherence to the LLDS and DDG was also significantly associated with a higher likelihood to HS development in univariable regression analysis [0.96; 0.94-0.99 and 0.91; 0.84-0.99, respectively], and a trend of decreased adherence to the aMED [0.93; 0.85-1.02] was noted. Besides, PA levels were found significantly lower in HS patients (p ≤ 0.001)., Conclusions and Relevance: Poor diet quality and lower quantities of PA were associated with HS in the general population. Identifying dietary and PA habits of HS patients can contribute to the development of prevention strategies for HS specifically, and for IMIDs in general., (© 2023 The Authors. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and Venereology.)

Background: Up to 45% of febrile returning travellers remain undiagnosed after a thorough diagnostic work-up, even at referral centres. Although metagenomic next-generation sequencing (mNGS) has emerged as a promising tool, evidence of its usefulness in imported fever is very limited., Methods: Travellers returning with fever were prospectively recruited in three referral clinics from November 2017 to November 2019. Unbiased mNGS optimised for virus detection was performed on serum samples of participants with acute undifferentiated febrile illness (AUFI), and results were compared to those obtained by reference diagnostic methods (RDM)., Results: Among 507 returned febrile travellers, 433(85.4%) presented with AUFI. Dengue virus (n = 86) and Plasmodium spp. (n = 83) were the most common causes of fever. 103/433(23.8%) AUFI remained undiagnosed at the end of the follow-up.Metagenomic next-generation sequencing unveiled potentially pathogenic microorganisms in 196/433(38.7%) AUFI. mNGS identifications were more common in patients with a shorter duration of fever (42.3% in ≤5 days vs 28.7% in >5 days, P = 0.005). Potential causes of fever were revealed in 25/103(24.2%) undiagnosed AUFI and 5/23(21.7%) travellers with severe undiagnosed AUFI. Missed severe aetiologies included eight bacterial identifications and one co-infection of B19 parvovirus and Aspergillus spp.Additional identifications indicating possible co-infections occurred in 29/316(9.2%) travellers with AUFI, and in 11/128(8.6%) travellers with severe AUFI, who had received a diagnosis through RDM. The most common co-infections detected in severe AUFI were caused by Gram-negative bacteria. Serum mNGS was unable to detect >50% of infectious diagnoses achieved by RDM and also yielded 607 non-pathogenic identifications., Discussion: mNGS of serum can be a valuable diagnostic tool for selected travellers with undiagnosed AUFI or severe disease in addition to reference diagnostic techniques, especially during the first days of symptoms. Nevertheless, mNGS results interpretation presents a great challenge. Further studies evaluating the performance of mNGS using different sample types and protocols tailored to non-viral agents are needed., (© International Society of Travel Medicine 2024. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

The reduction of crude protein (CP) content of broiler diets with balanced amino acid supply can increase the nitrogen (N) utilization efficiency and reduce ammonia emission, the risk of many health problems in birds. Feeding low protein (LP) diets without the impairment of performance traits needs the optimized dietary levels of threonine (Thr) and the non-essential amino acid (AA) glycine (Gly) and serine (Ser). However, the required concentrations and interactions of Thr and Gly + Ser, expressed as Gly equivalent (Gly equi ), in LP diets are not fully understood. Therefore, the aim of this study was to investigate the effects of three LP (LP1-3) grower (11-24 days) and finisher (25-35 days) diets with 2% CP reduction compared to the control (C), differing in standardized ileal digestible (SID) Thr to lysine (Lys) ratio (C, LP1, LP3: 63%, LP2: 72%) and Gly equi levels (C: 15.65 g/kg, LP1: 13.74 g/kg, LP2: 13.70 g/kg, LP3: 15.77). The LP treatments did not impair the performance traits of broilers. The LP2 treatment with increased SID Thr-to-Lys ratio (+9.0%) resulted in significantly higher body weight gain and a more advantageous feed conversion ratio in the whole fattening compared to the control treatment with normal CP level ( p  < 0.05). The LP3 treatment containing swine meat meal with similar Gly equi levels compared to the normal CP treatment led to the most advantageous feed conversion ratio in the finisher phase and the highest nitrogen retention efficiency ( p  < 0.05). However, the LP3 treatment with a high starch-to-CP ratio negatively influenced the relative carcass weight and the ratio of abdominal fat of broilers ( p  < 0.05)., 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 © 2024 Strifler, Horváth, Such, Dublecz and Pál.)

The use of locally available protein sources in poultry nutrition is challenging for feed manufacturers and farmers. Sunflower meal (SFM) is available in high quantities in several European countries and could be used as a poultry feedstuff at higher inclusion rates. However, its maximum inclusion rate in the diets of different poultry species and age categories is unknown. Pullets and laying hens can probably tolerate higher amounts of SFM, but only limited information is available on these poultry groups. Therefore, a digestibility trial was carried out with 8-week-old layer type pullets and 50-week-old laying hens. Beside a basal diet, SFM was fed at 10, 20 and 30% inclusion rates. Feeding SFM significantly improved the digestibility of essential amino acids (AA) of threonine, valine, lysine, tyrosine, glycine, aspartic acid, and arginine in the pullet diets. No such improvement was found in laying hens. Only the absorption of the two branch-chain AAs, leucin (pullets) and isoleucine (hens), declined due to SFM. The AA digestibility of the SFM itself was also calculated by linear regression. The coefficients were, in all cases, higher in hens than in pullets. Comparing the measured digestibility coefficients of SFM with table values, it can be concluded that high variance exists because of the differences in the methodology and the test animals in the digestibility trials. From the present trial, it can be concluded that SFM can entirely replace extracted soybean meal in pullet and layer diets, without negative effects on the protein digestion of birds., Competing Interests: ÁM was employed by the Agrofeed Ltd. The remaining 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 © 2024 Such, Mezőlaki, Tewelde, Pál, Horváth, Poór and Dublecz.)

Importance: Drug reaction with eosinophilia and systemic symptoms (DRESS) is a rare but potentially fatal drug hypersensitivity reaction. To our knowledge, there is no international consensus on its severity assessment and treatment., Objective: To reach an international, Delphi-based multinational expert consensus on the diagnostic workup, severity assessment, and treatment of patients with DRESS., Design, Setting, and Participants: The Delphi method was used to assess 100 statements related to baseline workup, evaluation of severity, acute phase, and postacute management of DRESS. Fifty-seven international experts in DRESS were invited, and 54 participated in the survey, which took place from July to September 2022., Main Outcomes/measures: The degree of agreement was calculated with the RAND-UCLA Appropriateness Method. Consensus was defined as a statement with a median appropriateness value of 7 or higher (appropriate) and a disagreement index of lower than 1., Results: In the first Delphi round, consensus was reached on 82 statements. Thirteen statements were revised and assessed in a second round. A consensus was reached for 93 statements overall. The experts agreed on a set of basic diagnostic workup procedures as well as severity- and organ-specific further investigations. They reached a consensus on severity assessment (mild, moderate, and severe) based on the extent of liver, kidney, and blood involvement and the damage of other organs. The panel agreed on the main lines of DRESS management according to these severity grades. General recommendations were generated on the postacute phase follow-up of patients with DRESS and the allergological workup., Conclusions and Relevance: This Delphi exercise represents, to our knowledge, the first international expert consensus on diagnostic workup, severity assessment, and management of DRESS. This should support clinicians in the diagnosis and management of DRESS and constitute the basis for development of future guidelines.

Background: Hidradenitis suppurativa (HS) is a chronic, devastating, multifactorial skin disease. Patients generally develop HS after puberty and the prevalence of the disease is assumed to decrease with higher age. Data outside the usual age range are limited, especially for elderly patients., Objectives: To investigate the prevalence, clinical characteristics and associated comorbidities among the elderly HS population., Methods: Data were collected through a population-wide survey-based study within the Lifelines Cohort Study in the Netherlands. The clinical characteristics of elderly patients with HS (≥ 60 years) were compared with an adult population (< 60 years) with HS. The comorbidities in elderly patients with HS were compared with those of a non-HS sex- and age-matched elderly population in a 1 : 4 ratio. HS in the elderly was defined as active HS in patients aged 60 years and older. Within the HS elderly group, two subgroups were defined, late-onset HS (HS developed after 60 years of age) and persistent HS (HS developed from a younger age but continuing after 60 years of age)., Results: Within the Lifelines cohort 209 elderly patients with HS were identified as well as an adult (< 60 years) group with HS (n = 793) and a non-HS sex- and age-matched control elderly group (n = 810). The prevalence of HS among the elderly bootstrap analysis population was 0.8% [95% confidence interval (CI) 0.4-1.2]. A significantly higher age of HS symptom onset was found compared with the adult HS group: respectively, 40 vs. 23 years (odds ratio 1.056, 95% CI 1.05-1.07). Among the elderly HS cohort (in the Discussion, the HS tarda cohort) a female : male ratio of 1.7 : 1.0 and a higher family history for HS were found. Moreover, elderly patients with HS had a significantly higher risk of having HS-associated comorbidities compared with the sex- and age-matched controls., Conclusions: The prevalence of HS in the elderly is not rare. Among the elderly a shift from female predominance towards a lower female : male ratio in HS is observed. In addition, HS in the elderly showed significant variation in age of onset and involved body areas. Moreover, elderly patients with HS were more susceptible to multimorbidity. Finally, we propose defining HS in the elderly as 'HS tarda' and subdividing it as late-onset and persistent HS tarda., Competing Interests: Conflicts of interest D.v.d.W., N.D.K.K. and B.C.v.M. report no conflicts of interest. H.H.v.d.Z. reports fees (advisory boards, consultations) from AbbVie, InflaRX, Insmed, Novartis Pharma and UCB Pharma. B.H. reports fees (paid to the institution) for the following: advisory boards, consultations, educational grants and investigator initiative studies from AbbVie and Janssen-Cilag; advisory boards, consultations and investigator initiative studies from Novartis Pharma; advisory boards and consultations from UCB Pharma; consultations and investigator initiative studies from Akari Therapeutics and Celgene; consultations from LEO Pharma, Philips, Regeneron, Roche and Sanofi; and investigator initiative studies from Solenne B.V., (© The Author(s) 2023. Published by Oxford University Press on behalf of British Association of Dermatologists.)

Recent advances in molecular diagnostics are transforming the classification of malignant tumours, it has long played a major role in the field of CNS tumours. Examination of 1p/19q codeletion is indispensable in case of diffuse gliomas. Glioblastoma may be diagnosed even in the absence of characteristic morphological features, when EGFR amplification, TERT promoter mutation or +7/-10 copy number abnormalities are present. The number of entities defined by a genetic abnormality is growing. Comprehensive analysis of DNA methylation may be of considerable help in addition to histology and basic molecular studies, especially in case of small samples. Keeping up with the ever-expanding diagnostic repertoire is difficult, however, advantages and disadvantages of these methods and the context in which they may be useful should be understood by those who are involved in the diagnosis of CNS tumours. This summary provides a general overview of the main methods used in molecular diagnostics.

The host-produced nodule specific cysteine-rich (NCR) peptides control the terminal differentiation of endosymbiotic rhizobia in the nodules of IRLC legumes. Although the Medicago truncatula genome encodes about 700 NCR peptides, only few of them have been proven to be crucial for nitrogen-fixing symbiosis. In this study, we applied the CRISPR/Cas9 gene editing technology to generate knockout mutants of NCR genes for which no genetic or functional data were previously available. We have developed a workflow to analyse the mutation and the symbiotic phenotype of individual nodules formed on Agrobacterium rhizogenes-mediated transgenic hairy roots. The selected NCR genes were successfully edited by the CRISPR/Cas9 system and nodules formed on knockout hairy roots showed wild type phenotype indicating that peptides NCR068, NCR089, NCR128 and NCR161 are not essential for symbiosis between M. truncatula Jemalong and Sinorhizobium medicae WSM419. We regenerated stable mutants edited for the NCR068 from hairy roots obtained by A. rhizogenes-mediated transformation. The analysis of the symbiotic phenotype of stable ncr068 mutants showed that peptide NCR068 is not required for symbiosis with S. meliloti strains 2011 and FSM-MA either. Our study reports that gene editing can help to elicit the role of certain NCRs in symbiotic nitrogen fixation., (© 2023. The Author(s).)

Acetylcholine plays an essential role in the regulation of detrusor muscle contractions, and antimuscarinics are widely used in the management of overactive bladder syndrome. However, several adverse effects limit their application and patients' compliance. Thus, this study aimed to further analyze the signal transduction of M 2 and M 3 receptors in the murine urinary bladder to eventually find more specific therapeutic targets. Experiments were performed on adult male wild-type, M 2 , M 3 , M 2 /M 3 , or Gα q/11 knockout (KO), and pertussis toxin (PTX)-treated mice. Contraction force and RhoA activity were measured in the urinary bladder smooth muscle (UBSM). Our results indicate that carbamoylcholine (CCh)-induced contractions were associated with increased activity of RhoA and were reduced in the presence of the Rho-associated kinase (ROCK) inhibitor Y-27632 in UBSM. CCh-evoked contractile responses and RhoA activation were markedly reduced in detrusor strips lacking either M 2 or M 3 receptors and abolished in M 2 /M 3 KO mice. Inhibition of Gα i -coupled signaling by PTX treatment shifted the concentration-response curve of CCh to the right and diminished RhoA activation. CCh-induced contractile responses were markedly decreased in Gα q/11 KO mice; however, RhoA activation was unaffected. In conclusion, cholinergic detrusor contraction and RhoA activation are mediated by both M 2 and M 3 receptors. Furthermore, whereas both Gα i and Gα q/11 proteins mediate UBSM contraction, the activation at the RhoA-ROCK pathway appears to be linked specifically to Gα i . These findings may aid the identification of more specific therapeutic targets for bladder dysfunctions. NEW & NOTEWORTHY Muscarinic acetylcholine receptors are of utmost importance in physiological regulation of micturition and also in the development of voiding disorders. We demonstrate that the RhoA-Rho-associated kinase (ROCK) pathway plays a crucial role in contractions induced by cholinergic stimulation in detrusor muscle. Activation of RhoA is mediated by both M 2 and M 3 receptors as well as by G i but not G q/11 proteins. The G i -RhoA-ROCK pathway may provide a novel therapeutic target for overactive voiding disorders.

Importance: Although several clinician- and patient-reported outcome measures have been developed for trials in hidradenitis suppurativa (HS), there is currently no consensus on which measures are best suited for use in clinical practice. Identifying validated and feasible measures applicable to the practice setting has the potential to optimize treatment strategies and generate generalizable evidence that may inform treatment guidelines., Objective: To establish consensus on a core set of clinician- and patient-reported outcome measures recommended for use in clinical practice and to establish the appropriate interval within which these measures should be applied., Evidence Review: Clinician- and patient-reported HS measures and studies describing their psychometric properties were identified through literature reviews. Identified measures comprised an item reduction survey and subsequent electronic Delphi (e-Delphi) consensus rounds. In each consensus round, a summary of outcome measure components and scoring methods was provided to participants. Experts were provided with feasibility characteristics of clinician measures to aid selection. Consensus was achieved if at least 67% of respondents agreed with use of a measure in clinical practice., Findings: Among HS experts, response rates for item reduction, e-Delphi round 1, and e-Delphi round 2 surveys were 76.4% (42 of 55), 90.5% (38 of 42), and 92.9% (39 of 42), respectively; among patient research partners (PRPs), response rates were 70.8% (17 of 24), 100% (17 of 17), and 82.4% (14 of 17), respectively. The majority of experts across rounds were practicing dermatologists with 18 to 19 years of clinical experience. In the final e-Delphi round, most PRPs were female (12 [85.7%] vs 2 males [11.8%]) and aged 30 to 49 years. In the final e-Delphi round, HS experts and PRPs agreed with the use of the HS Investigator Global Assessment (28 [71.8%]) and HS Quality of Life score (13 [92.9%]), respectively. The most expert-preferred assessment interval in which to apply these measures was 3 months (27 [69.2%])., Conclusions and Relevance: An international group of HS experts and PRPs achieved consensus on a core set of HS measures suitable for use in clinical practice. Consistent use of these measures may lead to more accurate assessments of HS disease activity and life outcomes, facilitating shared treatment decision-making in the practice setting.