Voltage imaging holds great potential for biomedical research by enabling noninvasive recording of the electrical activity of excitable cells such as neurons or cardiomyocytes. Camera-based detection can record from hundreds of cells in parallel, but imaging entire volumes is limited by the need to focus through the sample at high speeds. Remote focusing techniques can remedy this drawback, but have so far been either too slow or light-inefficient. Here, we introduce flipped image remote focusing, a remote focusing method that doubles the light efficiency compared to conventional beamsplitter-based techniques and enables high-speed volumetric voltage imaging at 500 volumes/s. We show the potential of our approach by combining it with light sheet imaging in the zebrafish spinal cord to record from >100 spontaneously active neurons in parallel.

Introduction. The World Stroke Organization (WSO) Brain & Heart Task Force developed The Brain & hEart globAl iniTiative (BEAT), a pilot feasibility implementation program aimed at establishing clinical collaborations between cardiologists and stroke physicians who work at large healthcare facilities. Methods. The WSO BEAT pilot project focused on atrial fibrillation (AF) and patent foramen ovale (PFO) detection and management, and post-stroke cardiovascular complications known as the stroke-heart syndrome. The program included 10 sites from 8 countries: Brazil, China, Egypt, Germany, Japan, Mexico, Romania, and the USA. The primary composite feasibility outcome was the achievement of the following 3 implementation metrics (1) developing site-specific clinical pathways for the diagnosis and management of AF, PFO, and the stroke heart syndrome; (2) establishing regular Neurocardiology rounds (e.g., monthly); and (3) incorporating a cardiologist to the stroke team. The secondary objectives were (1) to identify implementation challenges to guide a larger program and (2) to describe qualitative improvements.Results. The WSO BEAT pilot feasibility program achieved the pre-specified primary composite outcome in 9 of 10 (90%) sites. The most common challenges were the limited access to specific medications (e.g., direct oral anticoagulants) and diagnostic (e.g., prolonged cardiac monitoring) or therapeutic (e.g., PFO closure devices) technologies. The most relevant qualitative improvement was the achievement of a more homogeneous diagnostic and therapeutic approach.Discussion/Conclusion. The WSO BEAT pilot program showed that developing Neurocardiology collaborations is feasible. The long-term sustainability of the WSO BEAT program and its impact on quality of stroke care and clinical outcomes needs to be tested in a larger and longer-duration program.

Die Charité – Universitätsmedizin Berlin unterstützt ihre angehörigen Autor*innen beim Publizieren im Open Access seit 2018 finanziell und ist daran interessiert, auch in nachhaltige Infrastruktur für eine offene Wissenschaft zu investieren. Im Rahmen des Programms „Open-Access-Publikationskosten“ werden Mittel zur Deckung von Mehrkosten beantragt, die der Charité als publikationsstarker Einrichtung in der Transformation zu einem artikelbasierten Abrechnungs- und Finanzierungssystem entstehen. Strukturen und Prozesse für das Monitoring von Publikations- und Kostendaten sollen weiterentwickelt und technisch optimiert werden. Angestrebt werden größtmögliche Transparenz der Kosten und Finanzierungsströme sowie Standardisierung der Publikationsdaten zur einfachen Weiterverarbeitung in verschiedenen internen und externen Kontexten. Eine umfassende Unterstützung von Wissenschaftler*innen beim Open Access Publizieren und eine unkomplizierte Förderung sollen dauerhaft sichergestellt werden.

Swelling-associated changes in extracellular matrix (ECM) occur in many pathological conditions involving inflammation or oedema. Here we show that alterations in the proportion of loosely bound water in ECM correlate with changes in ECM elasticity and stress relaxation, owing to the strength of water binding to ECM being primarily governed by osmolality and the electrostatic properties of proteoglycans. By using mechanical testing and small-angle X-ray scattering, as well as magnetic resonance imaging (MRI) to detect changes in loosely bound water, we observed that enhanced water binding manifests as greater resistance to compression (mechanical or osmotic), resulting from increased electrostatic repulsion between negatively charged proteoglycans rather than axial contraction in collagen fibrils. This indicates that electrostatic contributions of proteoglycans regulate elasticity and stress relaxation independently of hydration. Our ex vivo experiments in osmotically modulated tendon elucidate physical causes of MRI signal alterations, in agreement with pilot in vivo MRI of inflammatory Achilles tendinopathy. We suggest that the strength of water binding to ECM regulates cellular niches and can be exploited to enhance MRI-informed diagnostics of swelling-associated tissue pathology.

Nicotinamide adenine dinucleotide (NAD(+)), a coenzyme for more than 500 enzymes, plays a central role in energy production, metabolism, cellular signaling, and DNA repair. Until recently, NAD(+) was primarily considered to be an intracellular molecule (iNAD(+)), however, its extracellular species (eNAD(+)) has recently been discovered and has since been associated with a multitude of pathological conditions. Therefore, accurate quantification of eNAD(+) in bodily fluids such as plasma is paramount to answer important research questions. In order to create a clinically meaningful and reliable quantitation method, we analyzed the relationship of cell lysis, routine clinical laboratory parameters, blood collection techniques, and pre-analytical processing steps with measured plasma eNAD(+) concentrations. Initially, NAD(+) levels were assessed both intracellularly and extracellularly. Intriguingly, the concentration of eNAD(+) in plasma was found to be approximately 500 times lower than iNAD(+) in peripheral blood mononuclear cells (0.253 +/- 0.02 mu M vs. 131.8 +/- 27.4 mu M, p = 0.007, respectively). This stark contrast suggests that cellular damage or cell lysis could potentially affect the levels of eNAD(+) in plasma. However, systemic lactate dehydrogenase in patient plasma, a marker of cell damage, did not significantly correlate with eNAD(+) (n = 33; r = -0.397; p = 0.102). Furthermore, eNAD(+) was negatively correlated with increasing c-reactive protein (CRP, n = 33; r = -0.451; p = 0.020), while eNAD(+) was positively correlated with increasing hemoglobin (n = 33; r = 0.482; p = 0.005). Next, variations in blood drawing, sample handling and pre-analytical processes were examined. Sample storage durations at 4 degrees C (0-120 min), temperature (0 degrees to 25 degrees C), cannula sizes for blood collection and tourniquet times (0 - 120 s) had no statistically significant effect on eNAD(+) (p > 0.05). On the other hand, prolonged centrifugation (> 5 min) and a faster braking mode of the centrifuge rotor (< 4 min) resulted in a significant decrease in eNAD(+) levels (p < 0.05). Taken together, CRP and hemoglobin appeared to be mildly correlated with eNAD(+) levels whereas cell damage was not correlated significantly to eNAD(+) levels. The blood drawing trial did not show any influence on eNAD(+), in contrast, the preanalytical steps need to be standardized for accurate eNAD(+) measurement. This work paves the way towards robust eNAD(+) measurements, for use in future clinical and translational research, and provides an optimized hands-on protocol for reliable eNAD(+) quantification in plasma.

Crohn's disease (CD) is associated with changes in the microbiome. The role of these changes and their precise association with disease course and activity remain ambiguous. In this prospective single-center study, the mucosal microbiome of surgical CD and non-CD patients was compared at the time of surgery. Microbial analyses were individually performed for ileal and colonic tissue samples obtained during surgery using 16S-rRNA-gene amplicon sequencing. Three groups out of the 46 included patients were formed: 1) a study group of CD of patients who received ileocecal resection due to CD involvement (CD study, n=10); 2) a control group of non-CD of patients who received intestinal resection due to indications other than CD (non-CD control, n=27); and 3) a second control group of CD who underwent resection of the intestine not affected by CD (CD non-affected control, n=9). Species richness and Shannon diversity were not different between all formed groups and regions analyzed (p>0.05). Several significant taxonomic differences were seen at the phylum-, order-, and genus-levels between the formed groups, such as a decrease of Firmicutes (phylum-level) and an increase of Bacteroides and Escherichia/Shigella/Pseudescherichia (genus-level) in CD study - colon vs. the non-CD control - colon (p <= 0.05). The CD non-affected control presented the largest amount of differentially abundant taxa in comparison to the other groups. These results underline that CD is accompanied by changes in affected and non-affected intestinal regions compared to non-CD controls. This study contributes the mucosal microbiome of a well-defined subset of surgical CD patients without confounding aspects of the fecal microbiome or regional microbial differences to the existing literature.

Women with endometriosis (EM), particularly the manifestations of adenomyosis (AM) and deep infiltrating endometriosis (DIE), suffer from pain and sterility. DIE also appears with several specific obstetric complications. To determine the risk profile, we designed a retrospective case-control study. Primary outcomes were defined as the risk of preterm birth and caesarean delivery (CD). Primiparous singleton pregnancies in women with DIE were compared with controls without EM. We matched for mode of conception and maternal age. A total of 41 women diagnosed with DIE and 164 controls were recruited. A total of 92.7% of the cases were also diagnosed with AM. Preterm birth occurred in 12.2% of cases and in 6.7% of controls. The difference was not statistically significant (OR: 1.932; 95% CI: 0.632-5.907). The rate of CD was similar in both groups. Remarkably, placental implantation disorders in the form of placenta praevia were eight times more frequent in women with DIE (9.8%) than in controls (1.2%, OR: 8.757; 95% CI: 1.545-49.614). Neonatal outcome was similar in both groups. Four out of fourteen cases reported abdominal wall endometriosis after CD. Women with DIE/AM and with placenta praevia are at risk of bleeding complications. After CD, they can develop abdominal wall EM. We therefore suggest evaluating the birth mode in each woman with DIE/AM.

Background: Pretherapeutic chromogranin A, alkaline phosphatase (ALP), or De Ritis ratio (aspartate aminotransferase/alanine aminotransferase) are prognostic factors in patients with metastatic neuroendocrine tumors (NET) undergoing peptide receptor radionuclide therapy (PRRT). However, their value for intratherapeutic monitoring remains unclear. We evaluated if changes in plasma markers during PRRT can help identify patients with unfavorable outcomes. Methods: A monocentric retrospective analysis of 141 patients with NET undergoing PRRT with [177Lu]Lu-DOTATOC was conducted. Changes in laboratory parameters were calculated by dividing the values determined immediately before each cycle of PRRT by the pretherapeutic value. Patients with low vs. high PFS were compared with the Wilcoxon rank-sum test. Results: Progression, relapse, or death after PRRT was observed in 103/141 patients. Patients with low PFS showed a significant relative ALP increase before the third (p = 0.014) and fourth (p = 0.039) cycles of PRRT. Kaplan–Meier analysis revealed a median PFS of 24.3 months (95% CI, 20.7–27.8 months) in patients with decreasing ALP values (Δ > 10%) during treatment, 12.5 months (95% CI, 9.2–15.8 months) in patients with increasing ALP values (Δ > 10%), and 17.7 months (95% CI, 13.6–21.8 months) with stable ALP values (Δ ± 10%). Conclusions: Based on these exploratory data, a rise in plasma ALP might indicate disease progression and should be interpreted cautiously during therapy.

Arachidonic acid 15-lipoxygenases (ALOX15) play a role in mammalian erythropoiesis but they have also been implicated in inflammatory processes. Seven intact Alox genes have been detected in the mouse reference genome and the mouse Alox15 gene is structurally similar to the orthologous genes of other mammals. However, mouse and human ALOX15 orthologs have different functional characteristics. Human ALOX15 converts C20 polyenoic fatty acids like arachidonic acid mainly to the n-6 hydroperoxide. In contrast, the n-9 hydroperoxide is the major oxygenation product formed by mouse Alox15. Previous experiments indicated that Leu353Phe exchange in recombinant mouse Alox15 humanized the catalytic properties of the enzyme. To investigate whether this functional humanization might also work in vivo and to characterize the functional consequences of mouse Alox15 humanization we generated Alox15 knock-in mice (Alox15-KI), in which the Alox15 gene was modified in such a way that the animals express the arachidonic acid 15-lipoxygenating Leu353Phe mutant instead of the arachidonic acid 12-lipoxygenating wildtype enzyme. These mice develop normally, they are fully fertile but display modified plasma oxylipidomes. In young individuals, the basic hematological parameters were not different when Alox15-KI mice and outbred wildtype controls were compared. However, when growing older male Alox15-KI mice develop signs of dysfunctional erythropoiesis such as reduced hematocrit, lower erythrocyte counts and attenuated hemoglobin concentration. These differences were paralleled by an improved ex vivo osmotic resistance of the peripheral red blood cells. Interestingly, such differences were not observed in female individuals suggesting gender specific effects. In summary, these data indicated that functional humanization of mouse Alox15 induces defective erythropoiesis in aged male individuals.

Background: Maharishi Amrit Kalash (MAK) 4 and 5 are Ayurvedic herbal nutritional supplements that are believed to have beneficial effects on overall health and wellbeing. This study aimed to systematically review all available randomized controlled trials (RCTs) investigating the clinical effects and safety of MAK.

Methods: We included RCTs on therapy, health promotion, and prevention for patients and healthy volunteers of all ages. We systematically searched MEDLINE (via PubMed), EMBASE (via Ovid), the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library), DHARA, Clinicaltrials.gov, the World Health Organization (WHO) International Clinical Trials Registry Platform, and Google Scholar from inception through 7 May 2023, with no time or language restrictions. The risk of bias was assessed using the Cochrane Risk of Bias Tool version 1. The protocol was registered with PROSPERO before conducting the review (CRD42023421655).

Results: Three RCTs with 418 study participants were included. Two studies were on breast cancer patients and one on healthy adults. The two studies on cancer evaluated the efficacy of MAK in reducing the side effects of chemotherapy in women with breast cancer. The study on healthy adults evaluated whether MAK has an effect on an age-related alertness task as an indicator of cognitive aging. Both studies on breast cancer patients found beneficial effects on performance status, anorexia, vomiting, and body weight. One study reported positive effects regarding stomatitis. Regarding visual alertness, results showed that individuals who received MAK improved in performance. None of the three included studies reported adverse events. The risk of bias was mixed. Due to the small number and heterogeneity of the RCTs, no meta-analysis could be performed.

Conclusion: There is evidence that MAK may have supportive effects in chemotherapeutic treatments for breast cancer patients and for healthy individuals regarding visual discrimination. However, it is difficult to verify treatment effects due to the small number of RCTs and the mixed risk of bias. Furthermore, none of the included studies recorded adverse events. Therefore, further high-quality studies are warranted to confirm the potential health benefits of MAK and to determine its optimal dosage and duration of use.

Periprosthetic Joint Infection (PJI) is a significant contributor to patient morbidity and mortality, and it can be addressed through a range of surgical interventions coupled with antibiotic therapies. Following surgical intervention(s), prolonged administration of oral antibiotics is recommended to cure PJI. There is a lack of reports on the adverse events (AEs) associated with oral antibiotics, particularly rifampin. This investigation sought to elucidate the occurrence of antibiotic-related AEs after an initial regimen of intravenous antibiotic administration, supplemented by an extended course of oral antibiotics. A prospective study of patients diagnosed with PJI of the hip, knee, or shoulder who underwent single-stage exchange arthroplasty (SSE) (10%), two-stage exchange arthroplasty (TSE) (81%), or debridement, antibiotics, and implant retention (DAIR) (6%) was performed. The primary outcome of interest was the detection of AEs, the secondary outcome the detection of a correlation between rifampin use and the incidence of AEs, and the tertiary outcome was whether oral antibiotic treatment needed to be adjusted or discontinued due to AEs. In addition, subjective tolerability was monitored throughout the study. A total of 336 events were identified for 73 out of 80 patients. The most frequently used antibiotics were rifampin and co-trimoxazole. Most AEs occurred in the gastrointestinal tract (46%). The most frequent AEs were nausea, inappetence, diarrhea, and skin rash. In 6% of cases, the AEs led to antibiotic discontinuation, and in 29% of cases, a dose adjustment of the oral therapy occurred, mainly with amoxicillin or co-trimoxazole. The majority of patients (55%) rated the subjective tolerability as good. In conclusion, AEs during antibiotic treatment for PJI are common. They mainly affect the gastrointestinal tract. Rifampin use might be a reason for the higher incidence of AEs compared to non-rifampin antibiotic treatment.

Primary care gynecologists play an important role in setting the course for coping with an increased genetic cancer risk. The suggested 90 min psychosocial training module enables primary care gynecologists to expand their competence in dealing with familial breast and ovarian cancer burden. It may contribute to a sustainable improvement in the care of women with an increased risk of familial breast and ovarian cancer.Abstract Primary care gynecologists are increasingly integrated into the care of patients with hereditary breast and ovarian cancer (HBOC) risks. These physicians should not only have basic genetic knowledge; they should also feel able to sensitively address an increased HBOC risk and deal with emotional, stressful situations in this context. Our project aimed at developing a training module, 'iKNOWgynetics', addressing psychosocial challenges in the context of HBOC care for primary care gynecologists. We developed the psychosocial training module in three phases: first, we conducted an online survey with n = 35 women with a family history of breast or ovarian cancer to assess patients' experiences and needs. Second, based on the results of the needs assessment, we developed the training module. Third, we evaluated the training by assessing physicians' (n = 109) self-efficacy with regard to communication skills in the context of HBOC before and after the training. In the needs assessment, seven psychosocial themes emerged. These themes, complementing a review of the literature, informed the training curriculum. The training was divided into two parts: (1) communicating with women before genetic testing and (2) care co-management for women with HBOC after genetic testing. After the training, participants reported a significant increase in self-efficacy in three domains: communicating empathetically, educating patients in a comprehensible way and dealing with emotionally challenging situations. Our results highlight the relevance of psychosocial issues for patients with HBOC. A genetic literacy training module that integrates aspects of psychosocial care increases physicians' confidence in dealing with emotionally challenging situations before and after their patients' genetic testing. Thus, such trainings may improve the care of women with hereditary cancer risks.

Background Chronic hand eczema (CHE) is a burdensome disease, and new well‐documented, safe and efficacious treatments are warranted. In a recent CHE phase IIa trial, the pan‐Janus kinase (JAK) inhibitor delgocitinib in an ointment formulation was found to be efficacious and well tolerated.

Objectives This trial assessed the dose response, efficacy and safety of delgocitinib cream in CHE.

Methods In this double‐blind, phase IIb dose‐ranging trial, adults with CHE and a recent history of inadequate response or contraindication to topical corticosteroids were randomized to delgocitinib cream 1, 3, 8, 20 mg g–1 or vehicle treatment twice daily for 16 weeks. The primary endpoint was the Investigator’s Global Assessment for CHE (IGA‐CHE) treatment success [0 (clear) or 1 (almost clear) with a ≥ two‐point improvement from baseline to week 16]. Secondary endpoints were the time to IGA‐CHE treatment success and changes in Hand Eczema Severity Index (HECSI); other endpoints were itch and pain numerical rating scale (NRS) scores, and Patient’s Global Assessment (PaGA) at week 16.

Results Patients (n = 258) were randomized 1 : 1 : 1 : 1 : 1 to delgocitinib cream 1, 3, 8, 20 mg g–1 or vehicle. A significant dose–response relationship was established for IGA‐CHE (P < 0.025). IGA‐CHE treatment success at week 16 was achieved in 21.2% (1 mg g–1), 7.8% (3 mg g–1), 36.5% (8 mg g–1), 37.7% (20 mg g–1) and 8.0% (vehicle) of patients. Delgocitinib 8 and 20 mg g–1 showed a treatment effect against vehicle (P < 0.001). Similarly, there were improvements in HECSI, itch and pain NRS scores, and PaGA. Delgocitinib cream was well tolerated with the majority of adverse events being mild or moderate and considered unrelated to treatment. The most frequently reported adverse events were nasopharyngitis (17.3–29.4% in delgocitinib groups vs. 40% in vehicle group), eczema (5.8–11.3% in delgocitinib groups vs. 16.0% in vehicle group) and headache (3.8–11.5% in delgocitinib groups vs. 4.0% in vehicle group).

Conclusions In this trial, delgocitinib cream showed a dose–response relationship in terms of efficacy and was well tolerated.

Objective To analyse the efficacy and safety of focal prostate-specific membrane antigen positron emission tomography (PSMA-PET)- and multiparametric magnetic resonance imaging (mpMRI)-guided single-fraction stereotactic body radiotherapy (SBRT) for the treatment of prostate cancer (PCa) local recurrences.

Patients and Methods Patients with PSMA-PET-positive PCa local recurrences treated with single-fraction SBRT between 2016 and 2020 were included. Identification for subsequent recurrences or metastatic spread based on increasing prostate-specific antigen (PSA) levels were evaluated using PSMA-PET imaging.

Results A total of 64 patients were identified. Patients received various treatments before SBRT (31 patients with radical prostatectomy [RP], 18 external beam radiotherapy [EBRT] with RP, five EBRT, and the remaining 10 other combinations). The median follow-up was 21.6 months. The median PSA level before SBRT was 1.47 ng/mL. All patients received a single-fraction treatment with a median prescription dose and isodose line of 21 Gy and 65%, respectively. At the time of SBRT, six patients (9%) received an androgen deprivation therapy (ADT). PSA levels decreased after SBRT (P = 0.03) and three local recurrences were detected during the follow-up. The progression-free survival after 1-, 2-, and 3-years was 85.3%, 65.9%, and 51.2%, respectively. Six patients (9%) started ADT after SBRT due to disease progression. The rates of newly started ADT after 1-, 2-, and 3-years were 1.8%, 7.3%, and 22.7%, respectively. Grade 1 or 2 toxicities occurred in six patients (9%); no high-grade toxicity was observed.

Conclusion While the available data for SBRT in the PCa local recurrence setting describe outcomes for fractionated irradiations, the findings of this first analysis of single-fraction, PSMA-PET- and mpMRI-guided focal SBRT are encouraging. Such treatment appears to be a safe, efficient, and time-saving therapy even in intensively pretreated patients. Recurrence-directed treatments can delay the use of ADT and could avoid prostate bed irradiation in selected patients.

Background Childhood asthma is a result of a complex interaction of genetic and environmental components causing epigenetic and immune dysregulation, airway inflammation and impaired lung function. Although different microarray based EWAS studies have been conducted, the impact of epigenetic regulation in asthma development is still widely unknown. We have therefore applied unbiased whole genome bisulfite sequencing (WGBS) to characterize global DNA-methylation profiles of asthmatic children compared to healthy controls.

Methods Peripheral blood samples of 40 asthmatic and 42 control children aged 5–15 years from three birth cohorts were sequenced together with paired cord blood samples. Identified differentially methylated regions (DMRs) were categorized in genotype-associated, cell-type-dependent, or prenatally primed. Network analysis and subsequent natural language processing of DMR-associated genes was complemented by targeted analysis of functional translation of epigenetic regulation on the transcriptional and protein level.

Results In total, 158 DMRs were identified in asthmatic children compared to controls of which 37% were related to the eosinophil content. A global hypomethylation was identified affecting predominantly enhancer regions and regulating key immune genes such as IL4, IL5RA, and EPX. These DMRs were confirmed in n = 267 samples and could be linked to aberrant gene expression. Out of the 158 DMRs identified in the established phenotype, 56 were perturbed already at birth and linked, at least in part, to prenatal influences such as tobacco smoke exposure or phthalate exposure.

Conclusion This is the first epigenetic study based on whole genome sequencing to identify marked dysregulation of enhancer regions as a hallmark of childhood asthma.

Background Drugs are a frequent cause of severe anaphylactic reactions. Here, we analyze a large dataset on drug induced anaphylaxis regarding elicitors, risk factors, symptoms, and treatment.

Methods Data from the European Anaphylaxis Registry (2007–2019) with 1815 reported cases of drug-induced anaphylaxis were studied accordingly.

Results Drugs are the third most frequent cause of anaphylaxis reported in the Anaphylaxis Registry. Among the eliciting groups of drugs analgesics and antibiotics were far most often reported. Female and senior patients were more frequently affected, while the number of children with DIA was low. DIA patients had symptoms affecting the skin and mucous membranes (n = 1525, 84.02%), the respiratory (n = 1300, 71.63%), the cardiovascular (n = 1251, 68.93%) and the gastrointestinal system (n = 549, 30.25%). Drugs caused significant more severe reactions, occurred more often in medical facilities and led to increased hospitalization rates in comparison to food and insect venom induced anaphylaxis. Adrenaline was used more often in patients with DIA than in anaphylaxis due to other causes. Patients with skin symptoms received more antihistamines and corticosteroids in the acute treatment, while gastrointestinal symptoms led to less adrenaline use.

Conclusion The study contributes to a better understanding of DIA, with a large number of cases from Europe supporting previous data, e.g., analgesics and antibiotics being the most frequent culprits for DIA. Female gender and higher age are relevant risk factors and despite clear recommendations, the emergency treatment of DIA is not administered according to the guidelines.

Chronic spontaneous urticaria (CSU) is a debilitating skin disease characterized by intensely itchy wheals, angioedema, or both. Symptoms recur spontaneously, on a near-daily basis, over >6 weeks; many patients experience flare-ups over several years and, consequently, reduced quality of life. Differences between the inflammatory profiles of the skin of CSU patients (wheals and nonlesional sites) and healthy controls indicate that key drivers such as mast cells, eosinophils, and basophils interact, release vasoactive mediators, and prime the skin, leaving patients predisposed to symptoms. Many cytokines and chemokines involved in these inflammatory networks and their corresponding intracellular signaling cascades have been identified. These insights informed the development of therapies such as omalizumab, dupilumab, and Bruton's tyrosine kinase (BTK) inhibitors, marking a renewed focus on pathogenesis in CSU clinical research. Despite progress, current therapies provide symptomatic control but do not appear to redress the inflammatory balance in the skin permanently. A deeper understanding of CSU pathogenesis will permit a more targeted approach to developing novel treatments with curative intent. Here, we review what is known about the pathogenesis of CSU and consider how this can be used to identify rational targets to improve patient care further.

Background Chronic inducible urticaria (CIndU) is characterized by mast cell (MC)-mediated wheals in response to triggers: cold in cold urticaria (ColdU) and friction in symptomatic dermographism (SD). KIT receptor activation by stem cell factor (SCF) is essential for MC function. Barzolvolimab (CDX-0159) is a humanized antibody that inhibits KIT activation by SCF and was well tolerated in healthy volunteers with dose-dependent plasma tryptase suppression indicative of systemic mast cell ablation.

Methods This is an open-label, trial in patients with antihistamine refractory ColdU or SD, receiving one IV dose of barzolvolimab (3 mg/kg), with a 12-week follow-up. Primary endpoint was safety/tolerability; pharmacodynamic (PD)/clinical endpoints included serum tryptase, plasma SCF, skin MC histology, provocation tests, urticaria control test (UCT), and dermatology life quality index (DLQI).

Results Analysis populations were safety (n = 21) and pharmacodynamics/clinical activity (n = 20). Barzolvolimab was well tolerated; most adverse events were mild and resolved. Treatment resulted in significant depletion of skin MCs, decreased tryptase (<limit of detection), and increased soluble SCF through Week 12. Complete responses (negative provocation test) occurred in 95% (n = 19/20) of patients (n = 10/10 ColdU; n = 9/10 SD), and all (n = 20/20) showed improvement in urticaria control (UCT ≥ 12). The kinetics of clinical activity mirrored that of MC and tryptase reduction. DLQI-measured impairment significantly decreased to minimal/none in 93% of patients on study.

Conclusion In CIndU patients, barzolvolimab was well tolerated, demonstrated marked, rapid, durable depletion of skin MCs, circulating tryptase, and reductions in clinical activity with significant improvements in disease control and quality of life (QoL) demonstrating potential therapeutic effects for MC-mediated disorders.

Introduction Data from mHealth apps can provide valuable information on rhinitis control and treatment patterns. However, in MASK-air®, these data have only been analyzed cross-sectionally, without considering the changes of symptoms over time. We analyzed data from MASK-air® longitudinally, clustering weeks according to reported rhinitis symptoms.

Methods We analyzed MASK-air® data, assessing the weeks for which patients had answered a rhinitis daily questionnaire on all 7 days. We firstly used k-means clustering algorithms for longitudinal data to define clusters of weeks according to the trajectories of reported daily rhinitis symptoms. Clustering was applied separately for weeks when medication was reported or not. We compared obtained clusters on symptoms and rhinitis medication patterns. We then used the latent class mixture model to assess the robustness of results.

Results We analyzed 113,239 days (16,177 complete weeks) from 2590 patients (mean age ± SD = 39.1 ± 13.7 years). The first clustering algorithm identified ten clusters among weeks with medication use: seven with low variability in rhinitis control during the week and three with highly-variable control. Clusters with poorly-controlled rhinitis displayed a higher frequency of rhinitis co-medication, a more frequent change of medication schemes and more pronounced seasonal patterns. Six clusters were identified in weeks when no rhinitis medication was used, displaying similar control patterns. The second clustering method provided similar results. Moreover, patients displayed consistent levels of rhinitis control, reporting several weeks with similar levels of control.

Conclusions We identified 16 patterns of weekly rhinitis control. Co-medication and medication change schemes were common in uncontrolled weeks, reinforcing the hypothesis that patients treat themselves according to their symptoms.