Type 2 Research Articles

Variation in laboratory testing for patients with long-term conditions: a longitudinal cohort study in UK primary care.

Use of laboratory testing has increased in the UK over the past few decades, with considerable geographical variation. To evaluate what laboratory tests are used to monitor people with hypertension, type 2 (T2) diabetes, or chronic kidney disease (CKD) and assess variation in test use in UK primary care. Longitudinal cohort study of people registered with UK general practices between June 2013 and May 2018 and previously diagnosed with hypertension, T2 diabetes, or CKD. Clinical Practice Research Datalink (CPRD) primary care data linked to ethnic group and deprivation was used to examine testing rates over time, by GP practice, age, sex, ethnic group, and socioeconomic deprivation, with age-sex standardisation. Nearly 1 million patients were included, and more than 27 million tests. The most ordered tests were for renal function (1463 per 1000 person-years), liver function (1063 per 1000 person-years), and full blood count (FBC; 996 per 1000 person-years). There was evidence of undertesting (compared with current guidelines) for HbA1c and albumin:creatinine ratio (ACR) or microalbumin, and potential overtesting of lipids, FBC, liver function, and thyroid function. Some GP practices had up to 27 times higher testing rates than others (HbA1c testing among patients with CKD). Testing rates are no longer increasing, but they are not always within the guidelines for monitoring long-term conditions (LTCs). There was considerable variation by GP practice, indicating uncertainty over the most appropriate testing frequencies for different conditions. Standardising the monitoring of LTCs based on the latest evidence would provide greater consistency of access to monitoring tests.

Transition from paediatric to adult care in young people with diabetes; A structured programme from a regional diabetes service, Auckland, New Zealand.

To assess participation with a structured transition programme for adolescents with diabetes. Data from a regional cohort aged less than 16 years of age with type 1 (T1) and type 2 diabetes (T2D) in Auckland, New Zealand (2006-2016). Participation was defined as opting into a structured transition programme. Five hundrend and twelve adolescents who were to be transferred to adult care (476 type 1 (T1D) and 36 type 2 (T2D)), overall participation rate of 83%, 86% (408/476) with T1D compared to 47% (17/36) with T2D. Within the cohort of T1D, participation rates for Māori and Pacific were lower (74% and 77%, respectively) than New Zealand Europeans (88%, p= 0.020 and p= 0.039, respectively). Lower socio-economic status was associated with reduced participation (77%) compared to higher socio-economic status (90%, p= 0.002). Of the 476 T1D who participated, 408 (96%) subsequently attended at least one adult service clinic ("capture"). 42% attended an adult clinic within the planned 3 months, 87% at 6 months and retention in adult clinics over 5 years of follow-up was 78%. By contrast, the 68 young people with T1D who did not participate in the structured transition had a capture rate of 78% (p< 0.001) and retention of 63% (p= 0.036). In adolescents with diabetes, a formal transition from a paediatric service was associated with high rates of adult capture and subsequent retention in adult care over a 5-year follow-up period. Low socio-economic status, Māori or Pacific ethnicity and T2D were associated with reduced participation in the structured transition programme.

Allergic Reaction: Etiology, Pathogenesis with Advanced Vision in Therapeutics Modalities

Immunity is the cornerstone of the strenthening performance of the body health system. the immune system is the defense system of the body against any pathogens. Regulation of the immune system through the sympathetic and parasympathetic arms of The autonomic nervous system. Allergic reaction is an inappropriate immune response to antigen. Allergy is not a disease itself, but a mechanism leading to a disease. Allergic inflammation is a key contributor to several common diseases, including allergic asthma, allergic rhinosinusitis, atopic dermatitis and eosinophilic esophagitis, multiple sclerosis, rheumatoid arthritis, bullous pemphigoid and various types of cancer, which characterized by coordination between the innate and adaptive immune systems to promote type 2 (T2) inflammatory responses. Dietary habit and gut microbium considered the blamed factors contributing to this allergy.

Enhanced type-2 Wang-Mendel Approach

ABSTRACT The Wang-Mendel Approach (WMA) focuses on combining the numerical as well as linguistic information for achieving greater explainability for inference models. The standard WMA models the linguistic information using type-1 (T1) fuzzy sets (FSs), which have a reduced capability to model the semantics of linguistic information. Therefore, we propose a novel Enhanced WMA, which models the linguistic information using the type-2 (T2) FSs. Further, our Enhanced T2 FS-based WMA can be modified to reflect the use of interval type-2 (IT2) FSs, for modelling linguistic uncertainty. IT2 FSs are suitable when better uncertainty handling capabilities are required compared to T1 FSs, however, at a computational cost lesser than the T2 FSs. Performance of Enhanced WMA is demonstrated through a real-world crop-yield prediction problem in smart agriculture and an additional exemplar application on users’ satisfaction ratings. Further, we have compared our approach with the performance obtained from the T1 FS-based WMA and the original estimations given in the original data. We found that our Enhanced WMA provides more precise estimates than the other two with 95% confidence level. To the best of our knowledge, this is the first proposal of a T2 FSs method for enhancing the modeling of linguistic uncertainty in the WMA.

Abstract 10860: Limb and Cardiovascular Event Risk in Type 1 and 2 Diabetic Patients With Peripheral Artery Disease

Introduction: Peripheral artery disease (PAD) is a risk factor for adverse limb events (LE) and cardiovascular events (CVE) that often coexists with type 1 (T1) and type 2 (T2) diabetes mellitus (DM), which differ mechanistically. There is a paucity of data on comparative risk of LE and CVE in T1DM and T2DM patients with PAD. Methods: We queried our database of 40,144 patients ≥18y old who underwent ankle brachial index (ABI) measurement from 01/1996-02/2020. We isolated patients with T1DM or T2DM and with PAD diagnosed by ABI (low [&lt;1.0] or elevated [&gt;1.4]). We retrieved demographics including hemoglobin A1c (A1c). Primary outcomes were LE (critical limb ischemia or vascular amputation) and CVE (myocardial infarction or ischemic stroke). All-cause mortality was a secondary outcome. Multivariable Cox proportional regression yielded hazard ratios (HR) with 95% confidence intervals (CI) after adjusting for age, sex, A1c, hypertension, hyperlipidemia, coronary artery disease (CAD), chronic kidney disease (CKD), and tobacco use. Results: Our study found 9,271 patients with PAD and DM (36% T1DM, 64% T2DM) with median follow-up time 34 mo (interquartile range [IQR] 85 mo). T1DM patients were younger than T2DM (mean age 67 vs 70y), with higher median A1c (7.7 [IQR 1.9] vs 6.7% [IQR 1.6]), and higher prevalence of hypertension, hyperlipidemia, CAD, and CKD. Antiplatelet and statin use did not differ. Elevated ABI was more common in T1DM (47 vs 27%). LE occurred in 23% and CVE in 12% of patients. LE risk was higher in T1DM patients than T2DM (HR 1.59[95% CI 1.45,1.74], p&lt;0.0001), but CVE and all-cause mortality did not differ significantly. Conclusions: PAD patients with T1DM had a higher LE risk than those with T2DM, even after adjustment for A1c and pertinent risk factors, but CVE risk and all-cause mortality were equivocal. These data suggest a potential role for more intensive LE risk modification in PAD patients with T1DM, but further investigation is needed to minimize limb morbidity.

Local Allergic Rhinitis: A Different Rhinitis Endotype? Literature Overview

Chronic rhinitis (CR) is commonly divided into allergic rhinitis (AR) and nonallergic rhinitis (NAR). AR is triggered by the immunoglobulin E (IgE)-mediated response to allergens, whereas NAR is characterized by the absence of allergic sensitization. Previous studies have demonstrated the presence of local IgE in the nasal mucosa of patients suffering from typical allergic rhinitis (AR) symptoms but without a history of atopy and a positive response to a nasal allergen challenge (NAC). This condition was recently defined as local allergic rhinitis (LAR), which is supposed to be a different CR characterized by a type 2 (T2) inflammation response with the release of typical T2 mediators. LAR is defined as a phenotype of AR characterized by a localized nasal allergic response that is negative skin prick testing to allergens in the absence of serum-specific IgE. Diagnosis is based on a positive response to NAC. This review is an update of LAR literature, focusing on the definition of LAR as an independent endotype. LAR, AR, and NAR are characterized by the same clinical symptoms, although there are some differences between these three subtypes. However, the literature data are not yet univocal in defining LAR as an independent endotype.

DUPILUMAB IMPROVES CHRONIC RHINOSINUSITIS WITH NASAL POLYPS DISEASE OUTCOMES IRRESPECTIVE OF TYPE 2 SIGNATURE DEFINITION

<h3>Introduction</h3> Chronic rhinosinusitis with nasal polyps (CRSwNP) is a disease of the nasal cavity and paranasal sinuses characterized by type 2 (T2) inflammation. Different algorithms that identify T2 inflammation in CRSwNP have been suggested. This analysis aims to evaluate dupilumab clinical efficacy by these definitions. <h3>Methods</h3> Efficacy was assessed by baseline T2 signature definition (1. ≥150 eosinophils/μL or total ≥IgE 100 IU/mL or any coexisting T2 condition; 2. ≥150 eosinophils/μL or total ≥IgE 100 IU/mL; 3. ≥150 eosinophils/µL; 4. ≥250 eosinophils/μL or total IgE ≥100 IU/mL; 5. asthma or ≥300 eosinophils/μL; 6. any coexisting T2 condition) by least squares (LS) mean differences (dupilumab versus placebo) in change from baseline in nasal polyps score (NPS), nasal congestion/obstruction (NC) score, and loss of smell (LoS) score at Weeks 24 and 52 in the intention-to-treat populations of SINUS-24 and SINUS-52 (NCT02912468/NCT02898454), respectively. <h3>Results</h3> At Week 24, LS mean differences for dupilumab versus placebo by baseline T2 signatures ranged from −2.32 to −2.14 for NPS, −1.10 to −0.92 for NC, and −1.20 to −1.07 for LoS (all <i>P</i> < 0.0001). Similar results were observed at Week 52: −2.64 to −2.40 for NPS, −1.12 to −1.01 for NC, and −1.28 to −1.12 for LoS (all <i>P</i> < 0.0001). <h3>Conclusion</h3> Dupilumab demonstrated robust efficacy across all definitions (combinations and permutations) of T2 inflammation consistent with its profile as an inhibitor of IL-4 and IL-13 signaling, key and central drivers of type 2 inflammation in CRSwNP.

Distribution of type 2 biomarkers and association with severity, clinical characteristics and comorbidities in the BREATHE real-life asthma population.

Type 2 (T2) high asthma is recognised as a heterogenous entity consisting of several endotypes; however, the prevalence and distribution of the T2 biomarkers in the general asthma population, across asthma severity, and across compartments is largely unknown. The objective of the present study was to describe expression and overlaps of airway and systemic T2 biomarkers in a clinically representative asthma population. Patients with asthma from the real-life BREATHE cohort referred to a specialist centre were included and grouped according to T2 biomarkers: blood and sputum eosinophilia (≥0.3×109 cells·L-1 and 3% respectively), total IgE (≥150 U·mL-1), and fractional exhaled nitric oxide (≥25 ppb). Patients with mild-to-moderate asthma were younger (41 versus 49 years, p<0.001), had lower body mass index (25.9 versus 28.0 kg·m-2, p=0.002) and less atopy (47% versus 58%, p=0.05), higher forced expiratory volume in 1 s (3.2 versus 2.8 L, p<0.001) and forced vital capacity (4.3 versus 3.9 L, p<0.001) compared with patients with severe asthma, who had higher blood (0.22×109 versus 0.17×109 cells·L-1, p=0.01) and sputum (3.0% versus 1.5%, p=0.01) eosinophils. Co-expression of all T2 biomarkers was a particular characteristic of severe asthma (p<0.001). In patients with eosinophilia, sputum eosinophilia without blood eosinophilia was present in 45% of patients with mild-to-moderate asthma and 35% with severe asthma. Severe asthma is more commonly associated with activation of several T2 pathways, indicating that treatments targeting severe asthma may need to act more broadly on T2 inflammatory pathways. Implementation of airway inflammometry in clinical care is of paramount importance, as the best treatable trait is otherwise is overlooked in a large proportion of patients irrespective of disease severity.

Calculation of Resonance Raman Spectra and Excited State Properties for Blue Copper Protein Model Complexes

Laccase enzymes have been investigated for their potential as eco-friendly biofuel cell cathode catalysts. In these applications, electrons transfer from the electrode directly to the so-called Type 1 (T1) redox site within the enzyme. Over the years, resonance Raman (RR) spectroscopy has been utilized to probe the nature of ligand interactions with the Cu2+ center at the T1 site of the resting, oxidized form of laccases and related blue copper proteins. Spectral interpretation has been guided by parallel studies of small molecule T1 site mimics. Reported herein are results of time-dependent density functional theory (TDDFT) calculations performed on a series of experimentally well-studied T1 site mimics based on Cu2+ thiolate complexes stabilized by either a tridentate tris(pyrazolyl)hydroborate ligand or a bidentate β-diketiminate ligand. Vertical excitation energies were computed for the first 10 doublet states of each complex. The electronic absorption and RR spectra derived show excellent agreement with the experiment. RR spectra were dominated by a strong Cu–S stretching transition near 400 cm–1, which is sensitive to molecular conformation within the thiolate ligand. The results provide a foundation to build from in advancing models of laccase catalytic active sites in support of sustainable technologies.

Proposal for Structured Histopathology of Nasal Secretions for Endotyping Chronic Rhinosinusitis: An Exploratory Study

Background: The EPOS guidelines promote cellular analysis as a primary goal in endotyping chronic rhinosinusitis (CRS). Current analysis is mainly based on biopsy or operative tissue collection, whereas the use of sinonasal secretions for inflammatory endotyping is not advocated in clinical practice. Early endotyping is crucial though, especially regarding the increasing evidence of patient-tailored therapy. We aimed to investigate the diagnostic value and reproducibility of sinonasal secretions sampling. Methods: First, preoperative secretion analysis of 53 Caucasian CRS patients was compared to subsequent operative tissue analysis. Second, secretion analysis at two different time points was compared for 10 postoperative Caucasian CRS patients with type 2 (T2) inflammation and 10 control participants. Secretions were collected by both endoscopic aspiration and nasal blown secretions in all participants. Results: The sensitivity to detect T2 inflammation was higher in nasal aspiration samples (85%) compared to nasal blow secretions (32%). A specificity of 100% for both techniques was obtained. A 90% reproducibility for T2 eosinophil detection was found by sampling at different time points regardless of the technique. Of the T2 patients, 60% showed no T2 inflammatory pattern more than one year after endoscopic sinus surgery. Conclusions: Nasal secretion sampling, especially aspiration of nasal secretions, is useful in the detection of T2 inflammation in CRS pathology. We proposed a structured histopathology analysis to be useful in daily clinical practice, which includes Congo red staining sensitive for eosinophilic cells and free eosinophil granules. Analysis of nasal secretions enables endotyping in an early stage, allowing more directed therapy.

An Analysis of Biologic Therapies in Patients With Asthma and Chronic Rhinosinusitis.

BackgroundAsthma, Allergic rhinitis (AR), Chronic Obstructive Pulmonary Disease (COPD), Eczema, and Chronic Rhinosinusitis with Sinonasal Polyposis (CRSwNP) are illnesses often characterized by type 2 (T2) inflammation, wherein T helper (Th) cells release pro-inflammatory cytokines such as IL (interleukin)-4, IL-5, IL-9, and IL-13. This response may also promote the production of IgE and an increase in/activation of serum eosinophils. In the aforementioned type 2 inflammatory diseases, this immune response can cause excess mucous production, inflammation of the airways, other atopic responses when patients are exposed to certain environmental allergic triggers. Relatively new biologic monoclonal antibody therapies such as dupilumab (blocks IL-4 and IL-13), benralizumab (blocks IL-5), mepolizumab (blocks IL-5), and omalizumab (blocks IgE Fc/fragment of crystallization region) offer novel therapeutic targets that more specifically and directly block type 2 inflammatory responses.MethodsTo examine the effect of monoclonal antibody biologic therapies on patient indicators of type 2 inflammation, a retrospective analysis of 193 patients on biologic therapy was conducted, and these patients were compared to 48 control patients with type 2 inflammatory diseases who did not initiate biologic therapy. Total Lund-MacKay radiographic score, FEV1 (forced expiratory volume in the first second), FEF25-75 (forced expiratory flow from 25-75% of the forced vital capacity curve), annualized pulmonary exacerbations, oral corticosteroid dose, and serum eosinophils were recorded at baseline (zero months), and at three, six, nine, and twelve months after initiation of biologic therapy. Least squares mean data and the percent change from the baseline of least squares mean for the biologic and control groups were compared.ResultsOmalizumab was the most common biologic therapy prescribed. Control patients were younger than patients who initiated biologic therapy. Patients on biologic therapy had statistically significant reductions in Lund-MacKay score, improvements in FEV1 and FEF25-75, reductions in serum IgE levels, and reductions in serum Eosinophils. Patients on biologic therapy also had statistically significant reductions in annualized pulmonary exacerbations and oral corticosteroid dose compared to controls.ConclusionsPatients with a variety of type 2 inflammatory conditions appear to have significant improvements in lung function, radiographic sinusitis, and serum markers of type 2 inflammation after initiation of biologic therapy versus controls. These therapeutic medications appear to significantly improve type 2 inflammatory disease course in patients who can tolerate these medications.

Allergic Sensitization Is Crucial for the Suppressive Role of Streptococcus pneumoniae in the Acute Exacerbation of Asthma

Introduction: Allergic sensitization is an important factor in the development, severity, and exacerbation of asthma, which is attributed to type 2 (T2) inflammation. Evidence suggests that respiratory bacterial pathogens (e.g., Streptococcus pneumoniae) exert suppressive effects on airway T2 inflammation. To clarify the role of allergic inflammation in bacterial colonization in asthma based on allergic sensitization, we investigated pharyngeal bacterial colonization, biomarkers (e.g., serum eosinophil cationic protein (ECP) and cytokines/chemokines), and symptoms in the acute exacerbation of childhood asthma. Methods: Pharyngeal samples were collected from 53 children (mean/median age 2.7/2.5 years). Serum levels of total and allergen-specific IgE against aeroallergens, ECP, and 17 cytokines/chemokines were measured. Results: Allergic sensitization was recognized in 62.2% patients. S. pneumoniae, Moraxella catarrhalis, Haemophilus influenzae, and other bacteria were detected in 47.1%, 11.3%, 11.3%, and 30.1% of all patients, respectively. Patients with S. pneumoniae had a significantly shorter duration of wheezing than those without (4.7 ± 3.6 vs. 7.1 ± 3.5 days, p = 0.024). In patients with allergic sensitization, patients with S. pneumoniae had a significantly shorter duration of wheezing than those without (4.0 ± 3.6 vs. 7.7 ± 4.0 days, p = 0.003). Serum total IgE was significantly lower in patients with S. pneumoniae than in those without (81.9 [7.8–894] vs. 287 [4.4–1,840] IU/mL, p = 0.014). Serum ECP was significantly higher (33.1 [2–109] vs. 7.8 [3–35] ng/mL, p = 0.042), and IFN-γ was significantly lower (5.6 [4–10] vs. 16.4 [7–28] pg/mL, p = 0.032) in patients with allergic sensitization than those without. Discussion/Conclusion: Our results suggested that the suppressive effects of S. pneumoniae colonization were observed only in patients with allergic sensitization, wherein serum total IgE, ECP, and IFN-γ may have an important role on acute exacerbation of asthma.

Type 1 and Type 2 Epstein-Barr viruses induce proliferation, and inhibit differentiation, in infected telomerase-immortalized normal oral keratinocytes.

Differentiated epithelial cells are an important source of infectious EBV virions in human saliva, and latent Epstein-Barr virus (EBV) infection is strongly associated with the epithelial cell tumor, nasopharyngeal carcinoma (NPC). However, it has been difficult to model how EBV contributes to NPC, since EBV has not been shown to enhance proliferation of epithelial cells in monolayer culture in vitro and is not stably maintained in epithelial cells without antibiotic selection. In addition, although there are two major types of EBV (type 1 (T1) and type 2 (T2)), it is currently unknown whether T1 and T2 EBV behave differently in epithelial cells. Here we inserted a G418 resistance gene into the T2 EBV strain, AG876, allowing us to compare the phenotypes of T1 Akata virus versus T2 AG876 virus in a telomerase-immortalized normal oral keratinocyte cell line (NOKs) using a variety of different methods, including RNA-seq analysis, proliferation assays, immunoblot analyses, and air-liquid interface culture. We show that both T1 Akata virus infection and T2 AG876 virus infection of NOKs induce cellular proliferation, and inhibit spontaneous differentiation, in comparison to the uninfected cells when cells are grown without supplemental growth factors in monolayer culture. T1 EBV and T2 EBV also have a similar ability to induce epithelial-to-mesenchymal (EMT) transition and activate canonical and non-canonical NF-κB signaling in infected NOKs. In contrast to our recent results in EBV-infected lymphoblastoid cells (in which T2 EBV infection is much more lytic than T1 EBV infection), we find that NOKs infected with T1 and T2 EBV respond similarly to lytic inducing agents such as TPA treatment or differentiation. These results suggest that T1 and T2 EBV have similar phenotypes in infected epithelial cells, with both EBV types enhancing cellular proliferation and inhibiting differentiation when growth factors are limiting.

Impact of dysglycemia and obesity on the brain in adolescents with and without type 2 diabetes: A pilot study.

Both diabetes and obesity can affect the brain, yet their impact is not well characterized in children with type 2 (T2) diabetes and obesity. This pilot study aims to explore differences in brain function and cognition in adolescents with T2 diabetes and obesity and nondiabetic controls with obesity and lean controls. Participants were 12-17 years old (5 T2 diabetes with obesity [mean HgbA1C 10.9%], 6 nondiabetic controls with obesity and 10 lean controls). Functional MRI (FMRI) during hyperglycemic/euglycemic clamps was performed in the T2 diabetes group. When children with obesity, with and without diabetes, were grouped (mean BMI 98.8%), cognitive scores were lower than lean controls (BMI 58.4%) on verbal, full scale, and performance IQ, visual-spatial and executive function tests. Lower scores correlated with adiposity and insulin resistance but not HgbA1C. No significant brain activation differences during task based and resting state FMRI were noted between children with obesity (with or without diabetes) and lean controls, but a notable effect size for the visual-spatial working memory task and resting state was observed. In conclusion, our pilot study suggests that obesity, insulin resistance, and dysglycemia may contribute to relatively poorer cognitive function in adolescents with T2 diabetes and obesity. Further studies with larger sample size are needed to assess if cognitive decline in children with obesity, with and without T2 diabetes, can be prevented or reversed.

EFFICACY OF DUPILUMAB IN CHILDREN WITH UNCONTROLLED TYPE 2 ASTHMA RECEIVING HIGH/MEDIUM DOSES OF INHALED CORTICOSTEROIDS AT BASELINE: THE LIBERTY ASTHMA VOYAGE STUDY

EFFICACY OF DUPILUMAB IN CHILDREN WITH UNCONTROLLED TYPE 2 ASTHMA RECEIVING HIGH/MEDIUM DOSES OF INHALED CORTICOSTEROIDS AT BASELINE: THE LIBERTY ASTHMA VOYAGE STUDY

Phenotyping, Precision Medicine, and Asthma.

The traditional one-size-fits all approach based on asthma severity is archaic. Asthma is a heterogenous syndrome rather than a single disease entity. Studies evaluating observable characteristics called phenotypes have elucidated this heterogeneity. Asthma clusters demonstrate overlapping features, are generally stable over time and are reproducible. What the identification of clusters may have failed to do, is move the needle of precision medicine meaningfully in asthma. This may be related to the lack of a straightforward and clinically meaningful way to apply what we have learned about asthma clusters. Clusters are based on both clinical factors and biomarkers. The use of biomarkers is slowly gaining popularity, but phenotyping based on biomarkers is generally greatly underutilized even in subspecialty care. Biomarkers are more often used to evaluate type 2 (T2) inflammatory signatures and eosinophils (sputum and blood), fractional exhaled nitric oxide (FeNO) and serum total and specific immunoglobulin (Ig) E reliably characterize the underlying inflammatory pathways. Biomarkers perform variably and clinicians must be familiar with their advantages and disadvantages to accurately apply them in clinical care. In addition, it is increasingly clear that clinical features are critical in understanding not only phenotypic characterization but in predicting response to therapy and future risk of poor outcomes. Strategies for asthma management will need to leverage our knowledge of biomarkers and clinical features to create composite scores and risk prediction tools that are clinically applicable. Despite significant progress, many questions remain, and more work is required to accurately identify non-T2 biomarkers. Adoption of phenotyping and more consistent use of biomarkers is needed, and we should continue to encourage this incorporation into practice.

101 Differentiating Type 1 from Type 2 Acute Myocardial Infarction in the Emergency Department Using the N-terminal Pro B-type Natriuretic Peptide/High-sensitivity Cardiac Troponin T Ratio

Acute myocardial infarction (AMI) is currently further diagnosed as being a type 1 (T1), caused by coronary artery atherosclerosis with thrombosis or a type 2 (T2), resulting from cardiac oxygen supply and demand imbalance. It is hypothesized that patients with T2 might develop earlier and increased cardiac wall stressing before the development of AMI as compared to those with T1, resulting in higher N- terminal pro B-type natriuretic peptide (NT-proBNP)/high sensitivity cardiac troponin T (hs-cTnT) ratios.

An Integrated Analysis of Inflammatory Endotypes and Clinical Characteristics in Chronic Rhinosinusitis with Nasal Polyps.

ObjectiveChronic rhinosinusitis with nasal polyps (CRSwNP) is mainly characterised by type 1 (T1), type 2 (T2) and type 3 (T3) inflammatory endotypes. However, correlations between inflammatory endotypes and clinical features in CRSwNP have not been demonstrated sufficiently. This study aimed to determine the endotype-phenotype associations in CRSwNP.MethodsClinical data of 31 control subjects and 106 CRSwNP patients were analysed. Interferon (IFN)-γ (T1), Charcot-Leyden crystal galectin (CLC) (T2) and Interleukin (IL)-17A (T3) were used as biomarkers to identify the inflammatory endotypes.ResultsThe mRNA expression level of IFN-γ was positively correlated with IL-17A (r = 0.817; P < 0.0001). Headache/facial pain (P = 0.039) was associated with T1 endotype. Smell loss (P = 0.025) was associated with T2 endotype. Purulent rhinorrhea (P = 0.001) was associated with T3 endotype. Atopy (P = 0.030), asthma (P = 0.005) and recurrence (P = 0.022) were more frequent in T2 endotype. Total Symptom Scores (TSS) of T2 (P < 0.001) and T3 (P = 0.009) endotype were higher than non-T2 and non-T3, respectively. Sino Nasal Outcome Test-22 (SNOT-22) total scores of T3 (P = 0.054) endotype were higher than non-T3.ConclusionIdentifications of endotype-phenotype associations are useful in clinical diagnoses and targeted therapies for patients with CRSwNP.

IL1RAP expression and the enrichment of IL-33 activation signatures in severe neutrophilic asthma.

Interleukin (IL)-33 is an upstream regulator of type 2 (T2) eosinophilic inflammation and has been proposed as a key driver of some asthma phenotypes. To derive gene signatures from in vitro studies of IL-33-stimulated cells and use these to determine IL-33-associated enrichment patterns in asthma. Signatures downstream of IL-33 stimulation were derived from our in vitro study of human mast cells and from public datasets of in vitro stimulated human basophils, type 2 innate lymphoid cells (ILC2), regulatory T cells (Treg) and endothelial cells. Gene Set Variation Analysis (GSVA) was used to probe U-BIOPRED and ADEPT sputum transcriptomics to determine enrichment scores (ES) for each signature according to asthma severity, sputum granulocyte status and previously defined molecular phenotypes. IL-33-activated gene signatures were cell-specific with little gene overlap. Individual signatures, however, were associated with similar signalling pathways (TNF, NF-κB, IL-17 and JAK/STAT signalling) and immune cell differentiation pathways (Th17, Th1 and Th2 differentiation). ES for IL-33-activated gene signatures were significantly enriched in asthmatic sputum, particularly in patients with neutrophilic and mixed granulocytic phenotypes. IL-33 mRNA expression was not elevated in asthma whereas the expression of mRNA for IL1RL1, the IL-33 receptor, was up-regulated in the sputum of severe eosinophilic asthma. The mRNA expression for IL1RAP, the IL1RL1 co-receptor, was greatest in severe neutrophilic and mixed granulocytic asthma. IL-33-activated gene signatures are elevated in neutrophilic and mixed granulocytic asthma corresponding with IL1RAP co-receptor expression. This suggests incorporating T2-low asthma in anti-IL-33 trials.

Design and application of Nagar-Bardini structure-based interval type-2 fuzzy logic systems optimized with the combination of backpropagation algorithms and recursive least square algorithms

This paper designs a kind of Nagar-Bardini structure based on interval type-2 (IT2) fuzzy logic systems for permanent magnetic drive uncertain parameter forecasting. For each fuzzy rule, the consequent, antecedent and input measurement of IT2 membership functions (MFs) are selected as the Gaussian type-2 MFs with uncertain standard deviations. Backpropagation algorithms and recursive least square algorithms are used to optimize the antecedent, input measurement and consequent parameters of fuzzy logic system (FLS) forecasters, respectively. Compared with the corresponding singleton and non-singleton type-1 (T1) FLSs, two Monte Carlo simulation instances on the basis of data of PMD process show the effectiveness and superiority of non-singleton IT2 FLSs according to the convergence analysis.