Type 2 Research Articles

Eosinophilic Bronchiectasis: Prevalence, Severity, and Associated Features-A Cohort Study.

Background: Bronchiectasis (BE) has been traditionally associated with neutrophilic inflammation, but eosinophilic bronchiectasis (EB) has recently emerged. Data about prevalence, clinical features, and disease severity are lacking. This study aimed to assess the EB prevalence, compare EB with non-EB, evaluate the Type-2 (T2) high endotype in BE (T2-high EB) versus non-T2-high EB, and identify EB predictors. Methods: We conducted a prospective study involving 153 BE patients. The data collected included clinical, radiological, and microbiological findings. BE severity was assessed using the bronchiectasis severity index (BSI), FACED and E-FACED scores, and the bronchiectasis etiology and comorbidity index (BACI). EB was defined as a blood eosinophil count (BEC) ≥ 300 cells/μL, and T2-high EB as BEC ≥ 300 cells/μL with fractional exhaled nitric oxide (FeNO) ≥ 25 ppb. Results: Prevalence was 27% for EB and 20% for T2-high EB. EB patients exhibited poorer lung function and more severe radiologic features, with significantly higher severity scores [BSI, FACED, E-FACED, BACI (p < 0.05)], and a higher median exacerbation rate [4 (2-5) in EB vs. 2 (1-4) in non-EB, p = 0.0002], compared with non-EB patients. T2-high EB patients showed higher severity scores [BSI, FACED, E-FACED (p < 0.05)], as well as worse lung function parameters [FEV1%, FVC%, FEF 25-75% (p < 0.05)] compared with non-T2-high EB patients. In our study, patients with EB exhibited notably worsened lung function and higher BE severity scores compared with their non-EB counterparts, with exacerbations playing a major role in these differences. We found statistically significant positive correlations between BEC and disease severity scores, such as BSI, FACED, and mMRC, as well as an inverse relationship with pulmonary function. The likelihood of EB being present was significantly higher in association with mMRC ≥ 1 (OR = 2.53; 95% CI, 1.26-5.64), exacerbations/year ≥ 1 (OR = 1.27; 95% CI, 1.0-1.63), and chronic PA colonization (OR = 3.9; 95% CI, 1.08-15.8). Conclusions: EB is a distinct endotype. Dyspnea, exacerbations, and PA colonization may be predictive of EB, emphasizing the importance of early detection for improved outcomes. BEC could serve as a useful biomarker of disease severity to consider when diagnosing EB.

First-order rule partitions-based decomposition technique of type-1 and interval type-2 rule-based fuzzy systems for computational and memory efficiency

Rule-based fuzzy systems are widely adopted in various fields for their effectiveness in reducing uncertainties. However, large rule bases present significant computational and memory challenges, especially for real-time applications. To overcome this limitation, this paper introduces a novel first-order rule partitions-based decomposition technique (FORPs-DT) for type-1 (T1) and interval type-2 (IT2) fuzzy logic systems (FLSs). This method involves decomposing the universe of discourse, membership functions (MFs), and fuzzy sets (FSs) by defining conditions for non-zero firing levels (intervals). Significantly, this approach allows the construction of subfuzzy systems with separate knowledge bases while maintaining the input–output relationship. The paper provides detailed explanations and visual representations of FORPs-DT and proposes a case of identical FORPs to illustrate its simplicity and resource optimization benefits. Extensive experiments demonstrate the superiority of this technique, showcasing not only reduced execution time and memory usage but also enhanced performance through identical partitions, which allows an increase in the number of FSs without additional computational or memory overhead.

Increased SERPINB2 potentiates 15LO1 expression via STAT6 signalling in epithelial cells in eosinophilic chronic rhinosinusitis with nasal polyps.

SERPINB2, a biomarker of Type-2 (T2) inflammatory processes, has been described in the context of asthma. Chronic rhinosinusitis with nasal polyps (CRSwNP) is also correlated with T2 inflammation and elevated 15LO1 induced by IL-4/13 in nasal epithelial cells. The aim of this study was to evaluate the expression and location of SERPINB2 in nasal epithelial cells (NECs) and determine whether SERPINB2 regulates 15LO1 and downstream T2 markers in NECs via STAT6 signalling. SERPINB2 gene expression in bulk and single-cell RNAseq database was analysed by bioinformatics analysis. SERPINB2, 15LO1 and other T2 markers were evaluated from CRSwNP and HCs NECs. The colocalization of SERPINB2 and 15LO1 was evaluated by immunofluorescence. Fresh NECs were cultured at an air-liquid interface with or without IL-13, SERPINB2 Dicer-substrate short interfering RNAs (DsiRNAs) transfection, exogenous SERPINB2, 15-HETE recombinant protein and pSTAT6 inhibitors. 15LO1, 15-HETE and downstream T2 markers were analysed by qRT-PCR, western blot and ELISA. SERPINB2 expression was increased in eosinophilic nasal polyps compared with that in noneosinophilic nasal polyps and control tissues and positively correlated with 15LO1 and other downstream T2 markers. SERPINB2 was predominantly expressed by epithelial cells in NP tissue and was colocalized with 15LO1. In primary NECs invitro, SERPINB2 expression was induced by IL-13. Knockdown or overexpression SERPINB2 decreased or enhanced expression of 15LO1 and 15-HETE in NECs, respectively, in a STAT6-dependent manner. SERPINB2 siRNA also inhibited the expression of the 15LO1 downstream genes, such as CCL26, POSTN and NOS2. STAT6 inhibition similarly decreased SERPINB2-induced 15LO1. SERPINB2 is increased in NP epithelial cells of eosinophilic CRSwNP (eCRSwNP) and contributes to T2 inflammation via STAT6 signalling. SERPINB2 could be considered a novel therapeutic target for eCRSwNP.

Difficult-to-treat chronic rhinosinusitis-when thestandard treatment is not effective and biologics are not available

In recent years, significant improvements have been made in the treatment options for uncontrolled chronic rhinosinusitis (CRS) refractory to standard medical and surgical therapy. This is the result of abetter understanding of the pathophysiology and the resulting development of biologicals for CRS with nasal polyps (CRSwNP). However, biologics are not (yet) available for all patients in Europe. Based on the session "Difficult-to-treat CRS, when biologics are not available" at the 29thCongress of the European Rhinologic Society (ERS) 2023 in Sofia, Bulgaria, the treatment options for uncontrolled CRS with the exclusion of biologics will be discussed. The content of the presentations "Is there aplace for antibiotics?" "Indications for revision surgery," "Novel systemic treatment options," "Novel local treatment options," and "Phototherapy for nasal polyps" are outlined and supported by areview of the literature. Various treatment options are available for managing uncontrolled CRS, even if biologic treatments are unavailable. Treatment options for type‑2 (T2)CRS include steroid rinses, repeated short-term oral steroids, steroid-eluting stents, and extended sinus surgery. In the case of nonsteroidal anti-inflammatory drug (NSAID)-exacerbated respiratory disease (NERD), acetylsalicylic acid (ASA) desensitization can be considered. Non-T2 endotypes or CRS without nasal polyps (CRSsNP) may benefit from several weeks of macrolides and xylitol rinses. To accurately assess the efficacy of second-line therapies for treatment of difficult-to-treat CRS within an endotype-specific framework, additional controlled clinical trials are needed that take into account the heterogeneity of CRS endotypes.

Increased glycolysis and cellular crosstalk in eosinophilic chronic rhinosinusitis with nasal polyps.

Chronic rhinosinusitis (CRS) is a chronic inflammatory disease of the sinonasal mucosa with distinct endotypes including type 2 (T2) high eosinophilic CRS with nasal polyps (eCRSwNP), T2 low non-eosinophilic CRS with nasal polyps (neCRSwNP), and CRS without nasal polyps (CRSsNP). Given the heterogeneity of disease, we hypothesized that assessment of single cell RNA sequencing (scRNA-seq) across this spectrum of disease would reveal connections between infiltrating and activated immune cells and the epithelial and stromal populations that reside in sinonasal tissue. Here we find increased expression of genes encoding glycolytic enzymes in epithelial cells (EpCs), stromal cells, and memory T-cell subsets from patients with eCRSwNP, as compared to healthy controls. In basal EpCs, this is associated with a program of cell motility and Rho GTPase effector expression. Across both stromal and immune subsets, glycolytic programming was associated with extracellular matrix interactions, proteoglycan generation, and collagen formation. Furthermore, we report increased cell-cell interactions between EpCs and stromal/immune cells in eCRSwNP compared to healthy control tissue, and we nominate candidate receptor-ligand pairs that may drive tissue remodeling. These findings support a role for glycolytic reprograming in T2-elicited tissue remodeling and implicate increased cellular crosstalk in eCRSwNP.

Investigation analysis of the acute asthma risk factor and phenotype based on relational analysis with outdoor air pollutants in Xi'an, China.

Asthma is a common chronic heterogeneous disease. Outdoor air pollutants are an important cause of acute asthma. Until now, the association between the risk of acute asthma and outdoor air pollutants is unclear. And the relationship between the different phenotypes of asthma and outdoor air pollutants has not been reported. Thus, an analysis of the association between outdoor air pollutants and daily acute asthma inpatient and outpatient visits in Xi'an, China, from January 1 to December 31, 2018, was conducted. A total of 3395 people were included in the study. The statistical analysis and relational analysis based on the logistic regression were used for illustrating the relatedness of the acute asthma risk factor and phenotype with outdoor air pollutants, while the age, gender, pollen peak and non-pollen peak periods, high type 2 (T2) asthma and non-high T2 asthma were also stratified. Results showed that particulate matter with particle size below 10μm and 2.5μm (PM10 and PM2.5), sulfur dioxide(SO2), nitrogen dioxide(NO2), and carbon monoxide(CO) increase the risk of acute asthma and that air pollutants have a lagged effect on asthma patients. PM10, NO2, CO, and Ozone (O3) are associated with an increased risk of acute attacks of high T2 asthma. PM10, PM2.5, SO2, NO2 and CO are associated with an increased risk of acute asthma in males of 0-16years old. PM10 and PM2.5 are more harmful to asthma patients with abnormal lung function.

Interval Type-2 Mutual Subsethood Cauchy Fuzzy Neural Inference System (IT2MSCFuNIS)

An interval type-2 (IT2) mutual subsethood Cauchy fuzzy neural inference system has been proposed in this paper. The network architecture consists of 3-layers with all connection weights being IT2 Cauchy fuzzy membership functions (CMFs). The crisp inputs to the system are fuzzified into IT2CMFs with fixed centers and uncertain spreads. The hidden layer represents the rule-based knowledge. The firing degree of the antecedent part of each rule at the hidden layer is computed by aggregating the product of the mutual subsethood similarity measures between the inputs and the connection weights. A volume defuzzification is used to compute the numeric output. A gradient descent back-propagation algorithm is used to train the model. The novelty of the proposed model is threefold. First, is enriching the theory of the mutual subsethood fuzzy neural models by adopting the Cauchy membership function (CMF) as another powerful fuzzy basis function (FBF) rather than the classical choice of Gaussian fuzzy membership functions (GMFs). Second, is the success of computing the mutual subsethood similarity measure between the IT2CMFs and all the model parameters’ updating equations in analytic closed-form formulas, not numerically or approximately. Third, is the ability to extract the type-1 (T1) mutual subsethood Cauchy fuzzy neural inference system (T1MSCFuNIS) with all its analytic closed-form formulas directly as a special case from the general formulas of IT2MSCFuNIS model. Such a novelty makes the proposed model a concrete and effective development of the theory of mutual subsethood fuzzy neural models. Both IT2MSCFuNIS and T1MSCFuNIS models have been tested using different examples from the domains of function approximation, classification, and prediction. The results ensure the efficacy of both models compared with other models reported in the literature.

Role of serum eosinophil cationic protein in distinct endotypes of chronic rhinosinusitis.

Serum eosinophil cationic protein (ECP) levels affect the surgical outcome of chronic rhinosinusitis (CRS) with nasal polyps. Primary CRS can be classified into type 2 (T2) and non-T2. We aimed to differentiate the role of serum ECP levels in surgical outcomes between the distinct endotypes of primary CRS. We prospectively enrolled patients with bilateral primary CRS who underwent surgical treatment with postoperative follow-up for at least 12 months. Endotyping and serum parameter measurements were completed within 1 week before surgery. In total, 113 patients were enrolled, including 65 with T2 CRS and 48 with non-T2 CRS. Patients in the T2 CRS group with uncontrolled CRS had significantly higher serum ECP levels than those in patients in the non-T2 CRS group. An optimal cut-off value was obtained at 17.0 μg/L using the receiver operating characteristic curve, attaining a sensitivity of 91.7% and specificity of 56.6%. Multivariate logistic regression analysis showed that a higher serum ECP level was an independent factor for postoperative uncontrolled disease. The hazard ratio was 11.3 for the T2 group, with serum ECP levels over 17.0 μg/L. In the non-T2 group, no parameters were significantly correlated with postoperative uncontrolled CRS. Serum ECP levels appear to be a feasible predictor of postoperative uncontrolled disease in patients with T2 CRS as preoperative serum ECP levels &gt;17.0 μg/L in these patients have an approximately 16.7-fold increased risk of postoperative uncontrolled disease and should be closely monitored.

Genetic and T2 biomarkers linked to the efficacy of HDM sublingual immunotherapy in asthma

BackgroundHypersensitivity to house dust mite (HDM) allergens is a common cause of allergic asthma symptoms and can be effectively treated with allergy immunotherapy (AIT).ObjectiveTo investigate whether genetic and type 2...

Personalized Medicine in Severe Asthma: From Biomarkers to Biologics.

Severe asthma is a complex and heterogeneous clinical condition presented as chronic inflammation of the airways. Conventional treatments are mainly focused on symptom control; however, there has been a shift towards personalized medicine. Identification of different phenotypes driven by complex pathobiological mechanisms (endotypes), especially those driven by type-2 (T2) inflammation, has led to improved treatment outcomes. Combining biomarkers with T2-targeting monoclonal antibodies is crucial for developing personalized treatment strategies. Several biological agents, including anti-immunoglobulin E, anti-interleukin-5, and anti-thymic stromal lymphopoietin/interleukin-4, have been approved for the treatment of severe asthma. These biological therapies have demonstrated efficacy in reducing asthma exacerbations, lowering eosinophil count, improving lung function, diminishing oral corticosteroid use, and improving the quality of life in selected patients. Severe asthma management is undergoing a profound transformation with the introduction of ongoing and future biological therapies. The availability of novel treatment options has facilitated the adoption of phenotype/endotype-specific approaches and disappearance of generic interventions. The transition towards precision medicine plays a crucial role in meticulously addressing the individual traits of asthma pathobiology. An era of tailored strategies has emerged, allowing for the successful targeting of immune-inflammatory responses that underlie uncontrolled T2-high asthma. These personalized approaches hold great promise for improving the overall efficacy and outcomes in the management of severe asthma. This article comprehensively reviews currently available biological agents and biomarkers for treating severe asthma. With the expanding repertoire of therapeutic options, it is becoming increasingly crucial to comprehend the influencing factors, understand the pathogenesis, and track treatment progress in severe asthma.

Real-World Characteristics of Patients with Severe Asthma prior to Starting Dupilumab: The ProVENT Study

Introduction: Dupilumab is approved for the treatment of severe type 2 (T2) asthma; however, the characteristics of patients receiving dupilumab in routine clinical practice are incompletely understood. This study describes the characteristics of patients with severe asthma before dupilumab treatment in a real-world setting. Methods: This interim analysis of an ongoing real-life study of dupilumab assessed baseline characteristics of the first patient cohort enrolled in the ProVENT study. Results: A total of 99 patients (59% females) were analyzed (17% received another biologic before dupilumab treatment and 15% were on maintenance oral corticosteroid treatment). Adult-onset asthma (>18 years) and an allergic phenotype were documented in 58% and 48% of patients, respectively. Median (interquartile range) age was 54 (40–61) years; the median number of exacerbations in the last 24 months was 1 (0–3); median fractional exhaled nitric oxide (FeNO) value was 38 (23–64) ppb; and median blood eosinophils (bEOS) count was 184 (8–505) cells/µL. According to the United Kingdom Severe Asthma Registry classification, 53% of patients had T2 intermediate asthma (bEOS ≥150 cells/µL or FeNO ≥25 ppb), 17% had T2 high asthma (bEOS ≥150 cells/µL and FeNO ≥25 ppb), and 4% had T2 low asthma (bEOS <150 cells/µL and FeNO <25 ppb). At least one GINA criterion for T2 airway inflammation was documented in 70% of patients. T2 comorbidities were observed in 64% of patients. Conclusions: This analysis suggests that patients eligible for dupilumab treatment display various clinical and biochemical characteristics rather than one clear-cut phenotype.

Should Airway Hyper-Responsiveness Be Included in the Definition of Clinical Remission With Biologic Therapy in Severe Asthma

Airway hyper-responsiveness (AHR) is a tenet of the persistent asthma phenotype along with reversible airway obstruction and type 2 (T2) inflammation. Indirect acting challenges such as mannitol are more closely related to the underlying T2 inflammatory process as compared with direct challenges. In this review article, we summarise the current literature and explore the future role of mannitol AHR in clinical remission with biologics.

Forsythia velutina Nakai extract: A promising therapeutic option for atopic dermatitis through multiple cell type modulation.

Atopic dermatitis (AD) is a complex condition characterized by impaired epithelial barriers and dysregulated immune cells. In this study, we demonstrated Forsythia velutina Nakai extract (FVE) simultaneously inhibits basophils, macrophages, keratinocytes, and T cells that are closely interrelated in AD development. We analyzed the effect of FVE on nitric oxide and reactive oxygen species (ROS) production in macrophages, basophil degranulation, T cell activation, and tight junctions in damaged keratinocytes. Expression of cell-type-specific inflammatory mediators was analyzed, and the underlying signaling pathways for anti-inflammatory effects of FVE were investigated. The anti-inflammatory effects of FVE were validated using a DNCB-induced mouse model of AD. Anti-inflammatory activity of compounds isolated from FVE was validated in each immune cell type. FVE downregulated the expression of inflammatory mediators and ROS production in macrophages through TLR4 and NRF2 pathways modulation. It significantly reduced basophil degranulation and expression of type 2 (T2) and pro-inflammatory cytokines by perturbing FcεRI signaling. Forsythia velutina Nakai extract also robustly inhibited the expression of T2 cytokines in activated T cells. Furthermore, FVE upregulated the expression of tight junction molecules in damaged keratinocytes and downregulated leukocyte attractants, as well as IL-33, an inducer of T2 inflammation. In the AD mouse model, FVE showed superior improvement in inflammatory cell infiltration and skin structure integrity compared to dexamethasone. Dimatairesinol, a lignan dimer, was identified as the most potent anti-inflammatory FVE compound. Forsythia velutina Nakai extract and its constituent compounds demonstrate promising efficacy as a therapeutic option for prolonged AD treatment by independently inhibiting various cell types associated with AD and disrupting the deleterious link between them.

Classification of longitudinal strain curves measured by speckle-tracking echocardiography in normal and pathological myocardial segments

Abstract Background Two-dimensional speckle-tracking echocardiography (2D-STE) provides a quantitative tool to evaluate LV function at the regional level. The purpose of this study was to classify the types of regional longitudinal strain curves (LSC). Moreover, we propose a novel longitudinal strain curve index (LSCI) which we compared to the wall motion score index (WMSI). Methods We enrolled 100 healthy volunteers and 50 patients with prior myocardial infarction (MI). Each LSC was classified considering the positive peak (peak P), peak maximum strain (PMS), and time to maximum peak strain (TPMS) as follows: Type 1 (Peak P&lt;6%, PMS&gt;6%, TPMS before aortic valve closure [AVC]); Type 2 (Peak P&lt;6%, PMS≥6%, TPMS after AVC); Type 3 (Peak P≥6%, PMS≥6%, TPMS before AVC); Type 4 (Peak P≥6%, PMS≥6%, TPMS after AVC); Type 5 (Peak P&lt;6%, PMS≥6%, TPMS first third of systole); Type 6 (Peak P&lt;6%, PMS&lt;6%); and Type 7 (Peak P≥6%, PMS&lt;6%). The longitudinal curve score index (LCSI) was obtained (sum of LSC type/18 segments). Results A total of seven types of LSC were identified. In the healthy subjects, LSC Type 1 (T1) and Type 2 (T2) were the most frequent. Type 3 (T3) and Type 4 (T4) were found in insignificant percentages while Type 5 (T5), Type 6 (T6), and Type 7 (T7) were not identified. When analyzed for the entire population, LSCI correlated strongly with WMSI (r=0.83, p&lt;0.01). Conclusions Analysis of LSC may provide a substantial support to visual assessment of regional LV function and the LCSI represents an index that is highly reproducible, independent of the examiner’s experience.

How Does Mild Asthma Differ Phenotypically from Difficult-to-Treat Asthma?

Despite most of the asthma population having mild disease, the mild asthma phenotype is poorly understood. Here, we aim to address this gap in knowledge by extensively characterising the mild asthma phenotype and comparing this with difficult-to-treat asthma. We assessed two real-world adult cohorts from the South of England using an identical methodology: the Wessex AsThma CoHort of difficult asthma (WATCH) (n=498) and a mild asthma cohort from the comparator arm of the Epigenetics Of Severe Asthma (EOSA) study (n=67). Data acquisition included detailed clinical, health and disease-related questionnaires, anthropometry, allergy and lung function testing, plus biological samples (blood and sputum) in a subset. Mild asthma is predominantly early-onset and is associated with type-2 (T2) inflammation (atopy, raised fractional exhaled nitric oxide (FeNO), blood/sputum eosinophilia) plus preserved lung function. A high prevalence of comorbidities and multimorbidity was observed in mild asthma, particularly depression (58.2%) and anxiety (56.7%). In comparison to difficult asthma, mild disease showed similar female predominance (>60%), T2-high inflammation and atopy prevalence, but lower peripheral blood/airway neutrophil counts and preserved lung function. Mild asthma was also associated with a greater prevalence of current smokers (20.9%). A multi-component T2-high inflammatory measure was comparable between the cohorts; T2-high status 88.1% in mild asthma and 93.5% in difficult asthma. Phenotypic characterisation of mild asthma identified early-onset disease with high prevalence of current smokers, T2-high inflammation and significant multimorbidity burden. Early comprehensive assessment of mild asthma patients could help prevent potential later progression to more complex severe disease.

Long-term outcome of patients presenting with myocardial injury or myocardial infarction.

Patients with acute or chronic myocardial injury are frequently identified in the context of suspected myocardial infarction (MI). We aimed to investigate their long-term follow-up. We prospectively enrolled 2714 patients with suspected MI and followed them for all-cause mortality and a composite cardiovascular endpoint (CVE; cardiovascular death, MI, unplanned revascularization) for a median of 5.1years. Final diagnoses were adjudicated by two cardiologists according to the Fourth Universal Definition of MI, including 143 (5.3%) ST-elevation MI, 236 (8.7%) non-ST-elevation MI (NSTEMI) Type 1 (T1), 128 (4.7%) NSTEMI T2, 86 (3.2%) acute and 677 (24.9%) with chronic myocardial injury, and 1444 (53.2%) with other reasons for chest pain (reference). Crude event rates per 1000 patient-years for all-cause mortality were highest in patients with myocardial injury (81.6 [71.7, 92.3]), and any type of MI (55.9 [46.3, 66.7]), compared to reference (12.2 [9.8, 15.1]). Upon adjustment, all diagnoses were significantly associated with all-cause mortality. Moreover, patients with acute (adj-HR 1.92 [1.08, 3.43]) or chronic (adj-HR 1.59 [1.16, 2.18]) myocardial injury, and patients with NSTEMI T1 (adj-HR 2.62 [1.85, 3.69]) and ST-elevation MI (adj-HR 3.66 [2.41, 5.57]) were at increased risk for cardiovascular events. Patients with myocardial injury are at a similar increased risk for death and cardiovascular events compared to patients with acute MI. Further studies need to determine appropriate management strategies for patients with myocardial injury. Clinicaltrials.gov (NCT02355457).

Parasitic infections related to anti-type 2 immunity monoclonal antibodies: a disproportionality analysis in the food and drug administration's adverse event reporting system (FAERS).

Introduction: Monoclonal antibodies (mAbs) targeting immunoglobulin E (IgE) [omalizumab], type 2 (T2) cytokine interleukin (IL) 5 [mepolizumab, reslizumab], IL-4 Receptor (R) α [dupilumab], and IL-5R [benralizumab]), improve quality of life in patients with T2-driven inflammatory diseases. However, there is a concern for an increased risk of helminth infections. The aim was to explore safety signals of parasitic infections for omalizumab, mepolizumab, reslizumab, dupilumab, and benralizumab. Methods: Spontaneous reports were used from the Food and Drug Administration's Adverse Event Reporting System (FAERS) database from 2004 to 2021. Parasitic infections were defined as any type of parasitic infection term obtained from the Standardised Medical Dictionary for Regulatory Activities® (MedDRA®). Safety signal strength was assessed by the Reporting Odds Ratio (ROR). Results: 15,502,908 reports were eligible for analysis. Amongst 175,888 reports for omalizumab, mepolizumab, reslizumab, dupilumab, and benralizumab, there were 79 reports on parasitic infections. Median age was55 years (interquartile range 24-63years) and 59.5% were female. Indications were known in 26 (32.9%) reports; 14 (53.8%) biologicals were reportedly prescribed for asthma, 8 (30.7%) for various types of dermatitis, and 2 (7.6%) for urticaria. A safety signal was observed for each biological, except for reslizumab (due to lack of power), with the strongest signal attributed to benralizumab (ROR = 15.7, 95% Confidence Interval: 8.4-29.3). Conclusion: Parasitic infections were disproportionately reported for mAbs targeting IgE, T2 cytokines, or T2 cytokine receptors. While the number of adverse event reports on parasitic infections in the database was relatively low, resulting safety signals were disproportionate and warrant further investigation.

NSTEMI MINOCA: clinical-instrumental characterization of a heterogeneous clinical enigma

Abstract Background The nosology of angiographically non-critical coronary myocardial infarction (MINOCA) with the presentation of NSTEMI represents a challenge for the clinician due to the lack of a clear definition of this entity, which is often interpreted as a transitional diagnosis awaiting a more precise investigation. Purpose The aim of the study was to investigate the epidemiological, clinical and prognostic characteristics of MINOCA with NSTEMI presentation, comparing it with a population of type 2 (T2) NSTEMI to identify significant clinical-instrumental and outcome predictors. Methods In this single-centre retrospective observational study, 18223 undergoing invasive coronary angiography were screened from 2005 to 2022. After a review of angiographic data and clinical presentation, 538 patients were included, of which 301 were classified as MINOCA and 237 as T2 NSTEMI following guidelines. The primary outcome was defined as a composite of death, non-fatal AMI, non-fatal transitory ischemic attack or stroke, and hospitalization for heart failure. Results After stratification by diagnosis, patients with MINOCA were younger than those with T2 NSTEMI (66.33 ± 11.67 vs 70.55 ± 10.94 years, respectively, p&amp;lt;0.0001), tended to be less hypertensive (SBP 137.34 ± 18.98 vs 144.68 ± 30.32, respectively, p=0.001), with lower diastolic pressure (81.1 ± 16.95 vs 78.28 ± 10.35, respectively, p=0.018). The MINOCA group had a lower incidence of typical risk factors such as diabetes (p=0.001), hypertension (p=0.002), atherosclerotic disease (p&amp;lt;0.0001) and sedentary lifestyle (p=0.002) but was more frequently smokers (p&amp;lt;0.0001). Atypical cardiovascular risk factors such as adverse events during pregnancy (p=0.013) were more frequent in the MNOCA group. At logistic regression analysis, typical chest pain (p&amp;lt;0.0001), the absence of palpitations (p&amp;lt;0.0001), lower heart rate (p=0.012), sinus rhythm (p=0.001), advanced age (p=0.015), absence of ST-segment changes (p=0.002), absence of diastolic dysfunction (p=0.001) and hypo/akinesia with non-coronary distribution at echocardiography (p&amp;lt;0.0001), and postmenopausal status (p=0.009) were independent predictors of MINOCA. During a median follow-up time of 61.1 [34.2 – 100.34] months, 135 patients met the primary endpoint. The Kaplan-Meier analysis indicated that patients with MINOCA were less likely to experience the composite endpoint than NSTEMI T2 (p&amp;lt;0.0001). Conclusions The MINOCA group was associated with a more subtle clinical-instrumental presentation and unconventional risk factors that account for the greater diagnostic difficulty. Moreover, in the MINOCA group, the absence of elements that classically characterize the AMI-CAD predicts the occurrence of the event with high accuracy. Finally, the MINOCA subgroup had a better prognosis for the major cardiac adverse events than T2 NSTEMI, the latter is therefore comparable to the classic MI-CAD.Nomogram for MINOCA predictors

Dual inhibition of airway inflammation and fibrosis by common β cytokine receptor blockade

BackgroundSevere asthmatics can present with eosinophilic type 2 (T2), neutrophilic or mixed inflammation that drives airway remodeling and exacerbations and represents a major treatment challenge. The common beta (βc) receptor signals for three cytokines GM-CSF, IL-5 and IL-3, that collectively mediate T2 and neutrophilic inflammation. ObjectivesTo determine the pathogenesis of βc receptor mediated inflammation and remodeling in severe asthma, and to investigate βc antagonism as a therapeutic strategy for mixed granulocytic airway disease. Methodsβc gene expression was analysed in bronchial biopsies from mild/moderate and severe asthmatics. House dust mite extract (HDM) and Aspergillus fumigatus extract (ASP) models were used to establish asthma-like pathology and airway remodeling in human βc transgenic mice. Lung tissue gene expression was analysed by RNA-sequencing. The monoclonal antibody CSL311 targeting the shared cytokine binding site of βc was used to block βc signaling. Resultsβc gene expression was increased in severe asthmatics. CSL311 potently reduced lung neutrophils, eosinophils and interstitial macrophages, and improved airway pathology and lung function in the acute steroid resistant HDM model. Chronic intranasal ASP exposure induced airway inflammation and fibrosis and impaired lung function that was inhibited by CSL311. CSL311 normalised the ASP-induced fibrosis-associated extracellular matrix gene expression network and strongly reduced signatures of cellular inflammation in the lung. Conclusionsβc cytokines drive steroid-resistant mixed myeloid cell airway inflammation and fibrosis. The anti-βc antibody CSL311 effectively inhibits mixed T2/neutrophilic inflammation and severe asthma-like pathology and reverses fibrosis gene signatures induced by exposure to commonly encountered environmental allergens.

Regulatory ILC2-Role of IL-10 Producing ILC2 in Asthma.

Over the past two decades, a growing body of evidence observations have shown group two innate lymphoid cells (ILC2) to be critical drivers of Type 2 (T2) inflammatory responses associated with allergic inflammatory conditions such as asthma. ILC2 releases copious amounts of pro-inflammatory T2 cytokines-interleukin (IL)-4, IL-5, IL-9, and IL-13. This review provides a comprehensive overview of the newly discovered regulatory subtype of ILC2 described in murine and human mucosal tissue and blood. These KLRG1+ILC2 have the capacity to produce the anti-inflammatory cytokine IL-10. Papers compiled in this review were based on queries of PubMed and Google Scholar for articles published from 2000 to 2023 using keywords "IL-10" and "ILC2". Studies with topical relevance to IL-10 production by ILC2 were included. ILC2 responds to microenvironmental cues, including retinoic acid (RA), IL-2, IL-4, IL-10, and IL-33, as well as neuropeptide mediators such as neuromedin-U (NMU), prompting a shift towards IL-10 and away from T2 cytokine production. In contrast, TGF-β attenuates IL-10 production by ILC2. Immune regulation provided by IL-10+ILC2s holds potential significance for the management of T2 inflammatory conditions. The observation of context-specific cues that alter the phenotype of ILC warrants examining characteristics of ILC subsets to determine the extent of plasticity or whether the current classification of ILCs requires refinement.