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Asthma is a heterogeneous disease characterized by multiple phenotypes with varying risk factors and therapeutic responses. This Commentary describes research on biomarkers for T2-"high" and T2-"low" inflammation, a hallmark of the disease. Patients with asthma who exhibit an increase in airway T2 inflammation are classified as having T2-high asthma. In this endotype, Type 2 cytokines interleukins (IL)-4, IL-5, and IL-13, plus other inflammatory mediators, lead to increased eosinophilic inflammation and elevated fractional exhaled nitric oxide (FeNO). In contrast, T2-low asthma has no clear definition. Biomarkers are considered valuable tools as they can help identify various phenotypes and endotypes, as well as treatment response to standard treatment or potential therapeutic targets, particularly for biologics. As our knowledge of phenotypes and endotypes expands, biologics are increasingly integrated into treatment strategies for severe asthma. These treatments block specific inflammatory pathways or single mediators. While single or composite biomarkers may help to identify subsets of patients who might benefit from these treatments, only a few inflammatory biomarkers have been validated for clinical application. One example is sputum eosinophilia, a particularly useful biomarker, as it may suggest corticosteroid responsiveness or reflect non-compliance to inhaled corticosteroids. As knowledge develops, a meaningful goal would be to provide individualized care to patients with asthma. [ABSTRACT FROM AUTHOR]

Objective: To establish an irritant contact dermatitis (ICD) model induced by sodium dodecyl sulfate (SDS) in mice, and explore its endotype to provide an experimental and theoretical basis for subsequent precise treatment. Methods: Mice were randomly divided into two groups (model group and control group), 4%SDS was topically applied to induce ICD in mice, saline was used on control group, the dose and frequency were consistent with model group, and the skin lesions of mice were observed. Epidermal thickness and inflammatory cell infiltration were analyzed by HE staining, toluidine blue staining and immunofluorescence staining. Real-time quantitative PCR was performed to investigate mRNA expression levels of cytokines. Results: Compared with control group, mice in ICD model group showed epidermal thickness on the back of neck, and the numbers of inflammatory cells were increased in dermis. The number of neutrophils, macrophages and T cells were increased. Expressions of Il17a and Il17f mRNA levels were increased. Conclusion: SDS-induced ICD model is successfully established, with the elevated infiltration of neutrophils, macrophages and T cells, and secretion of type 17 cytokines . [ABSTRACT FROM AUTHOR]

Background Methods Results Conclusion Practical biomarkers for endotypic characterization of chronic rhinosinusitis (CRS) remain elusive, hindering clinical utility. Eosinophil peroxidase (EPX) is an enzyme released by activated eosinophils. The objective of this study was to evaluate a clinic EPX assay as a marker of eosinophilic CRS.Subjects with and without CRS presenting to a tertiary care rhinology clinic were prospectively enrolled, and nasal cytology brushings were collected from the middle meatus during in‐clinic nasal endoscopy. ELISA assay was used to quantify EPX levels, and a customized multiplex immunoassay was used to quantify inflammatory cytokine mediators. Findings were correlated with clinical data.Forty‐two subjects were enrolled, including 31 CRS subjects and 11 controls. Median EPX levels were 125.0 ng/mL (standard deviation [SD] 1745.8) and 6.5 ng/mL (SD 99.0) for CRS group and controls, respectively (p = 0.003). EPX levels were associated with history of asthma (p = 0.015), allergies (p = 0.028), polyps (p = 0.0006), smell loss (p = 0.006), and systemic eosinophilia or elevated immunoglobulin E (p ≤ 0.0001). Twenty‐eight subjects from both the CRS and control groups had prior pathology for comparison, with histologic confirmation of local tissue eosinophilia (>10 eosinophils/hpf) in 11 subjects. This subgroup had a median EPX level of 967.5 ng/mL compared to 10.6 ng/mL in 17 subjects without local tissue eosinophilia (p = 0.0008). EPX levels were positively correlated to interleukin‐5 levels (p = 0.0005).EPX levels can be measured via well‐tolerated in‐clinic collection of nasal mucus. EPX levels are associated with clinical markers of type 2 inflammation and tissue eosinophilia and may provide a valuable diagnostic tool to delineate eosinophilic CRS. [ABSTRACT FROM AUTHOR]

Objectives: Chronic rhinosinusitis (CRS) endotypes have demonstrated clinical value in guiding treatment decisions. Bacterial lysates are immunomodulators that have shown beneficial effects in various respiratory inflammatory diseases. This study aimed to evaluate the effect of postoperative bacterial lysate therapy on different CRS endotypes. Methods: Patients diagnosed with CRS who underwent endoscopic sinus surgery were recruited. Bacterial lysates were administered postoperatively for 10 days per month for 3 months to the experimental group comprising patients with a history of frequent upper respiratory infections without adverse reactions. The remaining participants were allocated to the control group. The results of the postoperative 3-, 6-, and 12-month assessments, including the modified Lund-Kennedy (mLK) endoscopic and Sinonasal Outcome Test (SNOT) 22 scores, for the groups were compared. The tissue samples obtained from the participants were evaluated to detect the presence of relevant inflammatory mediators. Results: Among the 92 participants, 47 started bacterial lysate therapy 2 weeks after the surgery. The tissue cytokine profiles and clinical parameters, such as the disease severity and blood eosinophil percentage, of the bacterial lysate and control groups were comparable before treatment. The mLK endoscopic and SNOT-22 scores did not differ after 3, 6, and 12 months of follow-up. The subgroup analysis revealed that the bacterial lysate group had significantly lower mLK endoscopic scores than the control group for CRS without nasal polyps, while there was a tendency toward significance for the interleukin (IL)-5 negative group after 6 months. Conclusion: Postoperative bacterial lysate therapy has some beneficial effects on the endoscopic findings of patients with CRS without nasal polyps or those who are negative for IL-5. [ABSTRACT FROM AUTHOR]

Abstract Preschool children with recurrent wheezing are a heterogeneous population with many underlying biological pathways that contribute to clinical presentations. Although the morbidity of recurrent wheezing in preschool children is significant, biological studies in this population remain quite limited. To address this gap, this study performed untargeted plasma metabolomic analyses in 68 preschool children with recurrent wheezing to identify metabolomic endotypes of wheezing. K-means cluster analysis was performed on metabolomic dataset including a total of 1382 named and unnamed metabolites. We identified three metabolomic clusters which differed in symptom severity, exacerbation occurrence, and variables associated with social disadvantage. Metabolites that distinguished the clusters included those involved in fatty acid metabolism, fatty acids (long chain monounsaturated fatty acids, long chain polyunsaturated fatty acids, and long chain saturated fatty acids), lysophospholipids, phosphatidylcholines, and phosphatidylethanolamines. Pathway analyses identified pathways of interest in each cluster, including steroid metabolism, histidine metabolism, sphingomyelins, and sphingosines, among others. This study highlights the biologic complexity of recurrent wheezing in preschool children and offers novel metabolites and pathways that may be amenable to future study and intervention.

Specific molecular and inflammatory endotypes have been identified for chronic respiratory disorders, including asthma and COPD (chronic obstructive pulmonary disease). These endotypes correspond with clinical aspects of disease, enabling targeted medicines to address certain pathophysiologic pathways, often referred to as “precision medicine”. With respect to bronchiectasis, many comorbidities and underlying causes have been identified. Inflammatory endotypes have also been widely studied and reported. Additionally, several genes have been shown to affect disease progression. However, the lack of a clear classification has also hampered our understanding of the disease’s natural course. The aim of this review is, thus, to summarize the current knowledge on biomarkers and actionable targets of this complex pathologic condition and to point out unmet needs, which are required in the design of effective diagnostic and therapeutic trials.

Abstract Atopic dermatitis (AD) is a chronic inflammatory skin condition. The pathogenesis involves genetic, environmental, and immunological factors as well as a barrier dysfunction of the epidermis. Biomarkers may play a significant role in diagnosis, severity assessment, and treatment monitoring of AD. They are categorizable into diagnostic and prognostic as well as severity and stratification biomarkers, offering the potential for a more personalized treatment approach. Although there have been tremendous therapeutic advancements with interleukin (IL) antagonists and Janus kinase (JAK) inhibitors, the domain of biomarkers still requires further research to clarify their place in the diagnosis and prognosis of AD to unravel a better scientific basis for personalized medical care for patients with AD. This article reviews the various biomarkers in relation to the different AD phenotypes and endotypes.

Rationale: Idiopathic pulmonary fibrosis (IPF) causes irreversible fibrosis of the lung parenchyma. Although antifibrotic therapy can slow IPF progression, treatment response is variable. There exists a critical need to develop a precision medicine approach to IPF. Objectives: To identify and validate biologically driven molecular endotypes of IPF. Methods: Latent class analysis (LCA) was independently performed in prospectively recruited discovery (n = 875) and validation (n = 347) cohorts. Twenty-five plasma biomarkers associated with fibrogenesis served as class-defining variables. The association between molecular endotype and 4-year transplant-free survival was tested using multivariable Cox regression adjusted for baseline confounders. Endotype-dependent differential treatment response to future antifibrotic exposure was then assessed in a pooled cohort of patients naive to antifibrotic therapy at the time of biomarker measurement (n = 555). Measurements and Main Results: LCA independently identified two latent classes in both cohorts (P < 0.0001). WFDC2 (WAP four-disulfide core domain protein 2) was the most important determinant of class membership across cohorts. Membership in class 2 was characterized by higher biomarker concentrations and a higher risk of death or transplant (discovery, hazard ratio [HR], 2.02; 95% confidence interval [CI], 1.64–2.48; P < 0.001; validation, HR, 1.95; 95% CI, 1.34–2.82; P < 0.001). In pooled analysis, significant heterogeneity in treatment effect was observed between endotypes (P = 0.030 for interaction), with a favorable antifibrotic response in class 2 (HR, 0.64; 95% CI, 0.45–0.93; P = 0.018) but not in class 1 (HR, 1.19; 95% CI, 0.77–1.84; P = 0.422). Conclusions: In this multicohort study, we identified two novel molecular endotypes of IPF with divergent clinical outcomes and responses to antifibrotic therapy. Pending further validation, these endotypes could enable a precision medicine approach for future IPF clinical trials. [ABSTRACT FROM AUTHOR]

Background: Asthma is the most common chronic respiratory disease in childhood. Aspergillus fumigatus sensitivity may be involved in the pathogenesis of asthma by leading to different clinical presentations. Objective: To investigate the demographic, clinical, laboratory, and radiological characteristics of A. fumigatus sensitivity in childhood asthma and identify associated risk factors and diagnostic parameters. Methods: A total of 259 children with asthma were included in the study, 7 (2.7%) with allergic bronchopulmonary aspergillosis (ABPA), 84 (32.4%) with A. fumigatus‐sensitized asthma (Af‐SA), and 168 (64.9%) with A. fumigatus‐unsensitized asthma (Af‐UA). Results: Aspergillus sensitivity was associated with early asthma onset and longer asthma duration. Total IgE level and asthma severity are highest in ABPA and higher in Af‐SA. Absolute eosinophil count was higher, and FEV1 was lower in Af‐SA and ABPA. Aspergillus fumigatus was associated with greater odds of being male (odds ratio [OR], 2.45), having atopic dermatitis (OR, 3.159), Alternaria sensitivity (OR, 10.37), and longer asthma duration (OR, 1.266). The best cut‐off values for detecting A. fumigatus positivity were 363.5 IU/mL for total IgE and 455 cells/μL for absolute eosinophil count. In Af‐SA compared to Af‐UA, centrilobular nodules and peribronchial thickening were more common, and the bronchoarterial ratio was higher. Conclusions: Aspergillus sensitivity is a strong allergic stimulus in asthma, leading to laboratory, structural, clinical, and functional consequences. Af‐SA is a distinct asthma endotype independent of ABPA that is characterized by increased risk of severe clinical presentations and impaired lung function. [ABSTRACT FROM AUTHOR]

Background: Gene expression can provide distinct information compared to clinical biomarkers in the context of longitudinal clinical outcomes in asthma patients. Objective: This study examined the association between the gene expression levels of upstream (IL-25, IL-33, and TSLP) and downstream cytokines (IL-5, IL-4, and IL-13) in the T2 inflammatory pathway with a 12-month follow-up of exacerbation, lung function, and steroid use. Methods: Transcriptomic sequencing analysis was performed on peripheral blood mononuclear cells from 279 adult asthmatics. Survival analysis and linear mixed-effect models were used to investigate potential differences between the high-level and low-level gene expression groups and the clinical outcomes. Analysis was performed separately for the upstream, downstream, and all 6 cytokines. Results: In general, T2 inflammatory cytokine gene expression showed a weak correlation with blood eosinophil counts (all r < 0.1) and clinical outcomes. Among moderate-to-severe eosinophilic asthma (MSEA) patients, individuals with elevated levels of downstream cytokines were at increased risk of time-to-first exacerbation (p = 0.044) and a greater increase of inhaled corticosteroid use over time (p = 0.002) compared to those with lower gene expression. There was no association between baseline T2 inflammatory cytokine gene expression and the longitudinal changes in lung function over time among MSEA patients. Conclusion: These findings suggest that, among MSEA patients, the gene expression levels of downstream cytokines in the T2 inflammatory pathway may serve as indicators for endotyping asthma. [ABSTRACT FROM AUTHOR]

Although substantial progress has been made in our understanding of asthma pathogenesis and phenotypes over the nearly 60-year history of the Aspen Lung Conferences on asthma, many ongoing challenges exist in our understanding of the clinical and molecular heterogeneity of the disease and an individual patient's response to therapy. This report summarizes the proceedings of the 2023 Aspen Lung Conference, which was organized to review the clinical and molecular heterogeneity of asthma and to better understand the impact of genetic, environmental, cellular, and molecular influences on disease susceptibility, heterogeneity, and severity. The goals of the conference were to review new information about asthma phenotypes, cellular processes, and cellular signatures underlying disease heterogeneity and treatment response. The report concludes with ongoing gaps in our understanding of asthma pathobiology and provides some recommendations for future research to better understand the clinical and basic mechanisms underlying disease heterogeneity in asthma and to advance the development of new treatments for this growing public health problem. [ABSTRACT FROM AUTHOR]

Background: Sepsis poses a grave threat, especially among children, but treatments are limited owing to heterogeneity among patients. We sought to test the clinical and biological relevance of pediatric septic shock subclasses identified using reproducible approaches. Methods: We performed latent profile analyses using clinical, laboratory, and biomarker data from a prospective multi-center pediatric septic shock observational cohort to derive phenotypes and trained a support vector machine model to assign phenotypes in an internal validation set. We established the clinical relevance of phenotypes and tested for their interaction with common sepsis treatments on patient outcomes. We conducted transcriptomic analyses to delineate phenotype-specific biology and inferred underlying cell subpopulations. Finally, we compared whether latent profile phenotypes overlapped with established gene-expression endotypes and compared survival among patients based on an integrated subclassification scheme. Results: Among 1071 pediatric septic shock patients requiring vasoactive support on day 1 included, we identified two phenotypes which we designated as Phenotype 1 (19.5%) and Phenotype 2 (80.5%). Membership in Phenotype 1 was associated with ~ fourfold adjusted odds of complicated course relative to Phenotype 2. Patients belonging to Phenotype 1 were characterized by relatively higher Angiopoietin-2/Tie-2 ratio, Angiopoietin-2, soluble thrombomodulin (sTM), interleukin 8 (IL-8), and intercellular adhesion molecule 1 (ICAM-1) and lower Tie-2 and Angiopoietin-1 concentrations compared to Phenotype 2. We did not identify significant interactions between phenotypes, common treatments, and clinical outcomes. Transcriptomic analysis revealed overexpression of genes implicated in the innate immune response and driven primarily by developing neutrophils among patients designated as Phenotype 1. There was no statistically significant overlap between established gene-expression endotypes, reflective of the host adaptive response, and the newly derived phenotypes, reflective of the host innate response including microvascular endothelial dysfunction. However, an integrated subclassification scheme demonstrated varying survival probabilities when comparing patient endophenotypes. Conclusions: Our research underscores the reproducibility of latent profile analyses to identify pediatric septic shock phenotypes with high prognostic relevance. Pending validation, an integrated subclassification scheme, reflective of the different facets of the host response, holds promise to inform targeted intervention among those critically ill. [ABSTRACT FROM AUTHOR]

Positional OSA (POSA) is a recognized subtype of OSA that exhibits distinct endotypic characteristics when compared with nonpositional OSA (NPOSA). The basis for the disparity in endotypes between these subtypes remains poorly understood. (1) Do individuals with NPOSA and POSA have different underlying OSA endotypes? (2) Which endotypic characteristics are critical in determining NPOSA and POSA severity? Within the Shanghai Sleep Health Study cohort, individuals with OSA were recruited and classified as having POSA or NPOSA. Endotypes were calculated using polysomnography. Endotype analysis was conducted in 1,036 individuals with OSA. Compared with individuals with NPOSA, those with POSA had lower loop gain calculated during all sleep stages and all sleep positions (0.55; interquartile range [IQR], 0.46-0.66 vs 0.68, IQR, 0.52-0.90; P <.001), lower arousal threshold calculated during all sleep stages and all sleep positions (ArTH All) (138.67; IQR, 118.94-180.87 percentage of the eupneic ventilation [%Veupnea] vs 189.00; IQR, 129.71-257.76 %Veupnea; P <.001), lower pharyngeal collapsibility calculated during all sleep stages and all sleep positions (Vpassive All) (91.85; IQR, 83.13-95.15 %Veupnea vs 76.38; IQR, 23.77-92.08 %Veupnea; P <.001), and higher muscle compensation calculated during all sleep stages and all sleep positions (6.50; IQR, −6.77 to 16.39 %Veupnea vs 3.65; IQR, −10.47 to 12.14 %Veupnea; P =.003). Logistic regression analyses indicated that higher Vpassive All was associated with increased odds of POSA vs NPOSA. In NPOSA, fully adjusted linear regression analyses indicated that Vpassive All (β = −0.55; 95% CI, −0.68 to −0.42; P <.001) and lower loop gain calculated during all sleep stages and all sleep positions (β = 0.19; 95% CI, 0.08-0.30; P <.001) were significant independent predictors of the apnea hypopnea index, with Vpassive All being the most critical factor. In contrast, in POSA, collapsibility appeared to be less influential (β = −0.09; 95% CI, −0.21 to 0.03; P =.138). Nonanatomic endotypic characteristics (LG All : β = 0.29; 95% CI, 0.18-0.41; P <.001; arousal threshold in all sleep stages and all sleep positions: β = 0.15; 95% CI, 0.01-0.28; P =.031; muscle compensation in all sleep stages and all sleep positions: β = −0.21; 95% CI, −0.29 to −0.12; P <.001) were significant in determining the severity of POSA, with loop gain being the most crucial factor. This study highlights the differences in endotypes between NPOSA and POSA. In Chinese individuals, anatomic factors were more significant in determining the severity of NPOSA, whereas nonanatomic traits were more likely to determine the severity of POSA. Future research should focus on developing personalized management strategies for individuals with NPOSA and POSA based on their endotypes. Chinese Clinical Trial Registry; No.: ChiCTR1900025714; URL: https://www.chictr.org.cn/indexEN.html. [ABSTRACT FROM AUTHOR]

Atopic dermatitis (AD) is a chronic inflammatory skin condition. The pathogenesis involves genetic, environmental, and immunological factors as well as a barrier dysfunction of the epidermis. Biomarkers may play a significant role in diagnosis, severity assessment, and treatment monitoring of AD. They are categorizable into diagnostic and prognostic as well as severity and stratification biomarkers, offering the potential for a more personalized treatment approach. Although there have been tremendous therapeutic advancements with interleukin (IL) antagonists and Janus kinase (JAK) inhibitors, the domain of biomarkers still requires further research to clarify their place in the diagnosis and prognosis of AD to unravel a better scientific basis for personalized medical care for patients with AD. This article reviews the various biomarkers in relation to the different AD phenotypes and endotypes. [ABSTRACT FROM AUTHOR]

Objective: Structured histopathology (SHP) is a method of analyzing sinonasal tissue to characterize endotypes of chronic rhinosinusitis with nasal polyps (CRSwNP). Allergic fungal rhinosinusitis (AFRS) shares several features with certain endotypes of CRSwNP. Our objective was to compare the histopathology of AFRS and eosinophilic CRSwNP to further understand whether they are separate endotypes or disease entities altogether. Methods: A retrospective review of AFRS and CRSwNP patients undergoing endoscopic sinus surgery was performed. Data were collected on demographics, comorbidities, subjective and objective severity scores, and 13‐variable SHP reports. CRSwNP patients with >10 eosinophils per high‐power field (eCRSwNP) were included. Chi‐squared and t‐tests were used for statistical analysis. Results: A total of 29 AFRS and 108 eCRSwNP patients were identified. AFRS patients were younger and more often Black. Symptom severity scores (SNOT‐22, Lund‐MacKay, and Lund‐Kennedy) were uniform between groups. AFRS patients had a higher rate of Charcot–Leyden crystals (41.4% vs. 10.2%; p < 0.001). Severe degree of inflammation, eosinophilic inflammatory predominance, eosinophil aggregates, subepithelial edema, and basement membrane thickening were common in both groups, and their rates were not statistically significantly different between groups. Metaplasia, ulceration, fibrosis, and hyperplastic/papillary change rates were low (<30%) and similar between groups. Conclusion: The SHP of eCRSwNP and AFRS are highly consistent, which suggests AFRS is a severe subtype of CRSwNP overall rather than a separate disease entity. This also lends credence to AFRS belonging on the endotypic spectrum of CRSwNP. Level of Evidence: 3 Laryngoscope, 134:2617–2621, 2024 [ABSTRACT FROM AUTHOR]

Necrotizing enterocolitis (NEC) remains a devastating disease in preterm and term neonates. Despite significant progress made in understanding NEC pathogenesis over the last 50 years, the inability of current definitions to discriminate the various pathophysiological processes underlying NEC has led to an umbrella term that limits clinical and research progress. In this mini review, we provide a historical perspective on how NEC definitions and pathogenesis have evolved to our current understanding of NEC endotypes. We also discuss how artificial intelligence-based approaches are influencing our knowledge of risk-factors, classification and prognosis of NEC and other neonatal intestinal injury phenotypes.

This document is an editorial titled "Musculoskeletal pain phenotypes and personalised pain medicine" published in the journal Frontiers in Pain Research. The editorial discusses the concept of phenotypes in personalized medicine and its application to musculoskeletal pain. It highlights four articles within the research topic that explore different approaches to personalized pain medicine. These articles cover topics such as pain stratification options, sex differences in musculoskeletal pain, personalized diagnosis of non-specific back pain, and considerations for optimizing antidepressant use in pain management. The editorial also mentions the potential role of artificial intelligence in advancing personalized pain medicine. [Extracted from the article]

BackgroundEpithelial remodeling is a histopathologic feature of chronic inflammatory airway diseases including chronic rhinosinusitis (CRS). Cell-type shifts and their relationship to CRS endotypes and severity are incompletely described.ObjectiveWe sought to understand the relationship of epithelial cell remodeling to inflammatory endotypes and disease outcomes in CRS.MethodsUsing cell-type transcriptional signatures derived from epithelial single-cell sequencing, we analyzed bulk RNA-sequencing data from sinus epithelial brushings obtained from patients with CRS with and without nasal polyps in comparison to healthy controls.ResultsThe airway epithelium in nasal polyposis displayed increased tuft cell transcripts and decreased ciliated cell transcripts along with an IL-13 activation signature. In contrast, CRS without polyps showed an IL-17 activation signature. IL-13 activation scores were associated with increased tuft cell, goblet cell, and mast cell scores and decreased ciliated cell scores. Furthermore, the IL-13 score was strongly associated with a previously reported activated ("polyp") tuft cell score and a prostaglandin E2 activation signature. The Lund-Mackay score, a computed tomographic metric of sinus opacification, correlated positively with activated tuft cell, mast cell, prostaglandin E2, and IL-13 signatures and negatively with ciliated cell transcriptional signatures.ConclusionsThese results demonstrate that cell-type alterations and prostaglandin E2 stimulation are key components of IL-13-induced epithelial remodeling in nasal polyposis, whereas IL-17 signaling is more prominent in CRS without polyps, and that clinical severity correlates with the degree of IL-13-driven epithelial remodeling.

Abstract Background Previously, fragments from Sirtuin 1 (SIRT1) were identified in preclinical and clinical samples to display an increase in serum levels for N-terminal (NT) SIRT1 vs. C-terminal (CT) SIRT1, indicative of early signs of OA. Here we tested NT/CT SIRT1 levels as well as a novel formulated sandwich assay to simultaneously detect both domains of SIRT1 in a manner that may inform us about the levels of full-length SIRT1 in the circulation (flSIRT1) of clinical cohorts undergoing knee joint distraction (KJD). Methods We employed an indirect ELISA assay to test NT- and CT-SIRT1 levels and calculated their ratio. Further, to test flSIRT1 we utilized novel antibodies (Ab), which were validated for site specificity and used in a sandwich ELISA method, wherein the CT-reactive served as capture Ab, and its NT-reactive served as primary detection Ab. This method was employed in human serum samples derived from a two-year longitudinal study of KJD patients. Two-year clinical and structural outcomes were correlated with serum levels of flSIRT1 compared to baseline. Results Assessing the cohort, exhibited a significant increase of NT/CT SIRT1 serum levels with increased osteophytes and PIIANP/CTX-II at baseline, while a contradictory increase in NT/CT SIRT1 was associated with less denuded bone, post-KJD. On the other hand, flSIRT1 exhibited an upward trend in serum level, accompanied by reduced denuded bone for 2-year adjusted values. Moreover, 2 year-adjusted flSIRT1 levels displayed a steeper linear regression for cartilage and bone-related structural improvement than those observed for NT/CT SIRT1. Conclusions Our data support that increased flSIRT1 serum levels are a potential molecular endotype for cartilage-related structural improvement post-KJD, while NT/CT SIRT1 appears to correlate with osteophyte and PIIANP/CTX-II reduction at baseline, to potentially indicate baseline OA severity.

Nobuyuki Hizawa Department of Pulmonary Medicine, Institute of Medicine, University of Tsukuba, Ibaraki, JapanCorrespondence: Nobuyuki Hizawa, Email nhizawa@md.tsukuba.ac.jpAbstract: Neither asthma nor chronic obstructive pulmonary disease (COPD) is a single disease consisting of a uniform pathogenesis; rather, they are both syndromes that result from a variety of basic distinct pathogeneses. Many of the basic pathogeneses overlap between the two diseases, and multiple basic pathogeneses are simultaneously involved at varying proportions in individual patients. The specific combination of different basic pathogeneses in each patient determines the phenotype of the patient, and it varies widely from patient to patient. For example, type 2 airway inflammation and neutrophilic airway inflammation may coexist in the same patient, and quite a few patients have clinical characteristics of both asthma and COPD. Even in the same patient, the contribution of each pathogenesis is expected to differ at different life stages (eg, childhood, adolescence, middle age, and older), during different seasons (eg, high seasons for hay fever and rhinovirus infection), and depending on the nature of treatments. This review describes several basic pathogeneses commonly involved in both asthma and COPD, including chronic non-type 2 inflammation, type 2 inflammation, viral infections, and lung development. Understanding of the basic molecular pathogeneses in individual patients, rather than the use of clinical diagnosis, such as asthma, COPD, or even asthma COPD overlap, will enable us to better deal with the diversity seen in disease states, and lead to optimal treatment practices tailored for each patient with less disease burden, such as drug-induced side effects, and improved prognosis. Furthermore, we can expect to focus on these molecular pathways as new drug discovery targets.Keywords: Asthma, chronic obstructive pulmonary disease (COPD), endotype, precision medicine, treatable traits approach

ABSTRACTPaediatric Mycoplasma pneumoniae pneumonia (MPP) is a heterogeneous disease with a diverse spectrum of clinical phenotypes. No studies have demonstrated the relationship between underlying endotypes and clinical phenotypes as well as prognosis about this disease. Thus, we conducted a multicentre prospective longitudinal study on children hospitalized for MPP between June 2021 and March 2023, with the end of follow-up in August 2023. Blood samples were collected and processed at multiple time points. Multiplex cytokine assay was performed to characterize serum cytokine profiles and their dynamic changes after admission. Cluster analysis based on different clinical phenotypes was conducted. Among the included 196 patients, the levels of serum IL-17A and IL-6 showed remarkable variabilities. Four cytokine clusters based on the two cytokines and four clinical groups were identified. Significant elevation of IL-17A mainly correlated with diffuse bronchiolitis and lobar lesion by airway mucus hypersecretions, while that of IL-6 was largely associated with lobar lesion which later developed into lung necrosis. Besides, glucocorticoid therapy failed to inhibit IL-17A, and markedly elevated IL-17A and IL-6 levels may correlate with lower airway obliterans. Our study provides critical relationship between molecular signatures (endotypes) and clustered clinical phenotypes in paediatric patients with MPP.

ABSTRACTAsthma is a heterogenous disease characterized by airway inflammation and variable expiratory airflow limitation resulting in variable respiratory symptoms. Characterization of airway inflammation is important to choose the optimal treatment for severe asthma patients eligible for biological treatment. However, counting cells in induced sputum samples are a time-consuming process, highly dependent on personal skills. Replacing eosinophil and neutrophil cell counting with qPCR for transcripts of selected mast cell, and basophil genes may provide more reproducible results.Aims The objective of this study was to compare qPCR with microscopy in asthma endotyping.Methods A qPCR method measuring five mast cell/basophil genes was applied on induced sputum samples from 30 severe asthma patients and compared with microscopy. Target gene Ct-values (CPA3, GATA2, HDC, MS4A2, TPSAB1/TPSB2) were referenced to household β-actin Ct values as a measure of relative mRNA abundance of the target in each sample. Target/β-actin-ratios in eosinophilic and non-eosinophilic groups determined by microscopy with an eosinophil threshold of 3% in 400 cells were compared using Mann–Whitney U Test. Spearman´s correlations were used to test for correlation between targets vs. FENO and targets vs. blood eosinophil counts.Results The study demonstrated a statistical difference in relative mRNA abundance for four mast cell/basophil specific genes. CPA3, GATA2, HDC and MS4A2 were elevated in eosinophilic asthma versus non-eosinophilic asthma patients. The study found that GATA2, CPA3, MS4A2 and TPSAB1/TPSB2 transcripts are positively correlated with FENO. Neither the five mast cell genes nor the five-gene signature correlated with blood eosinophils. The five-gene signature with a target/β-actin-ratio cut-off ≥2 generated sensitivity = 87%, specificity = 94%, NPV = 88% and PPV = 92% compared to microscopy.Conclusion This study confirms the contribution of mast cells in the pathogenesis of EA and suggests that mast cell mRNA markers could be one of the biomarkers used to identify EA

BACKGROUND: While Alzheimers disease (AD) pathology is associated with altered brain structure, it is not clear whether gene expression changes mirror the onset and evolution of pathology in distinct brain regions. Deciphering the mechanisms which cause the differential manifestation of the disease across different regions has the potential to help early diagnosis. OBJECTIVE: We aimed to identify common and unique endotypes and their regulation in tangle-free neurons in sporadic AD (SAD) across six brain regions: entorhinal cortex (EC), hippocampus (HC), medial temporal gyrus (MTG), posterior cingulate (PC), superior frontal gyrus (SFG), and visual cortex (VCX). METHODS: To decipher the states of tangle-free neurons across different brain regions in human subjects afflicted with AD, we performed analysis of the neural transcriptome. We explored changes in differential gene expression, functional and transcription factor target enrichment, and co-expression gene module detection analysis to discern disease-state transcriptomic variances and characterize endotypes. Additionally, we compared our results to tangled AD neuron microarray-based study and the Allen Brain Atlas. RESULTS: We identified impaired neuron function in EC, MTG, PC, and VCX resulting from REST activation and reversal of mature neurons to a precursor-like state in EC, MTG, and SFG linked to SOX2 activation. Additionally, decreased neuron function and increased dedifferentiation were linked to the activation of SUZ12. Energetic deficit connected to NRF1 inactivation was found in HC, PC, and VCX. CONCLUSIONS: Our findings suggest that SAD manifestation varies in scale and severity in different brain regions. We identify endotypes, such as energetic shortfalls, impaired neuronal function, and dedifferentiation.

Critical illness syndromes including sepsis, acute respiratory distress syndrome, and acute kidney injury (AKI) are associated with high in-hospital mortality and long-term adverse health outcomes among survivors. Despite advancements in care, clinical and biological heterogeneity among patients continues to hamper identification of efficacious therapies. Precision medicine offers hope by identifying patient subclasses based on clinical, laboratory, biomarker and 'omic' data and potentially facilitating better alignment of interventions. Within the previous two decades, numerous studies have made strides in identifying gene-expression based endotypes and clinico-biomarker based phenotypes among critically ill patients associated with differential outcomes and responses to treatment. In this state-of-the-art review, we summarize the biological similarities and differences across the various subclassification schemes among critically ill patients. In addition, we highlight current translational gaps, the need for advanced scientific tools, human-relevant disease models, to gain a comprehensive understanding of the molecular mechanisms underlying critical illness subclasses. [ABSTRACT FROM AUTHOR]

[Display omitted] Type 2 (T2) inflammation plays a pathogenic role in chronic rhinosinusitis (CRS). The effects of endoscopic sinus surgery (ESS) on T2 inflammation are unknown. The aim of this study was to compare T2 inflammatory biomarkers from middle meatal (MM) mucus for distinguishing patients with CRS from CRS-free patients, identifying major phenotypes (CRS without nasal polyps [CRSsNP] and CRS with nasal polyps [CRSwNP]), assessing endotypic change, and establishing cross-sectional and longitudinal outcomes in patients undergoing ESS. MM mucus samples were collected from patients with CRSsNP and patients with CRSwNP before and 6 to 12 months after ESS and compared with samples from CRS-free control patients. T2 biomarkers were evaluated both continuously and using threshold-based definitions of T2 endotype to identify relationships with patient-reported (based on the 22-Item Sinonasal Outcomes Test and Chronic Rhinosinusitis Patient-Reported Outcomes Measure) and clinician-reported (radiographic and endoscopic) severity. Linear mixed models were developed to analyze clinical variables associated with T2 biomarker levels. A total of 154 patients with CRS (89 with CRSsNP and 65 with CRSwNP) were enrolled, with a mean interval of 9 months between ESS and follow-up. An analysis of pre-ESS MM mucus samples revealed elevated levels of T2 mediators in patients with CRSwNP versus in patients with CRSsNP and CRS-free controls. Temporally stable correlations between levels of IL-13 and IL-5, levels of periostin and complement 5a, and levels of eosinophil cationic protein (ECP) and eotaxin-3 were observed. On this basis and on the basis of pathologic significance, levels of IL-13, periostin and ECP were further analyzed. After ESS, levels of IL-13 and periostin decreased significantly, whereas ECP levels remained unchanged. Across pre- and post-ESS evaluation, the T2 endotype was associated with radiographic severity but did not predict outcomes. CRSwNP status and African American race were associated with higher levels of IL-13 and periostin, whereas ECP level was higher in patients undergoing extensive surgery. ESS decreased levels of IL-13 and periostin in the middle meatus. T2 inflammation after ESS was correlated with patient- and clinician-reported severity across phenotypes. Pre-ESS T2 inflammation did not predict post-ESS outcomes. [ABSTRACT FROM AUTHOR]

Introduction: In adult-onset asthma, two major endotypes have been proposed: T2 with eosinophilia and non-T2 characterised by neutrophils and interleukin (IL)-17. The objective of the study was to examine the endotype marker profile in patients with severe asthma who were hospitalized for exacerbations, with a focus on differentiating between viral and non-viral triggers. Material and methods: Forty-nine patients with asthma, admitted for exacerbations, and 51 healthy controls (HCs) were recruited. We further categorized the exacerbated asthma patients into two groups: non-viral infected (n = 38) and viral infected (n = 11) groups. Blood was drawn and a nasopharyngeal swab taken at the time of admission and eosinophil numbers, eosinophil cationic protein (ECP), immunoglobulin E (IgE), tryptase and viral infection were determined. Additionally, levels of IL-17, IL-33 and IL-31 were assessed. Results: The majority of patients had adult onset asthma (age of diagnosis, 42.8 ±16.1) with a duration of 7.7 ±10.8 years, 24.5% being atopic. Patients had higher levels of eosinophils, ECP and IgE than healthy controls (eosinophils, p = 0.003; ECP and IgE, p = 0.0001). Immunohistochemistry confirmed eosinophils as a source of ECP. Tryptase (p = 0.0001), IL-17 (p = 0.0005), IL-31 (p = 0.0001) and IL-33 (p = 0.0002) were also higher in patients than controls. ECP correlated with tryptase (r = 0.08, p = 0.62). IL-17 showed the best correlation with other mediators, including ECP (r = 0.35, p = 0.24), tryptase (r = 0.69, p = 0.0001), IgE (r = 0.50, p = 0.0001), IL-33 (r = 0.95, p = 0.0001) and IL-31 (r = 0.89, p = 0.0001). IgE, IL-17, and IL-31 had a high AUC when differentiating those with severe and non-severe asthma. The group with exacerbated viral infection showed elevated levels of serum IL-17 and IL-31 compared to the non-infected group. Conclusions: Patients with asthmatic exacerbations were found to have higher levels of both T2 and non-T2 inflammatory markers than healthy controls. In the study, levels of IgE, IL-17, and IL-31 differentiated between patients with severe and non-severe asthma. The last two cytokines were also able to distinguish between exacerbated asthma caused by viral infection and exacerbated asthma caused by non-viral infection. [ABSTRACT FROM AUTHOR]

Background: It is unclear whether chronic rhinosinusitis (CRS) endotypes show a differential response to endoscopic sinus surgery (ESS). We explored patient mucous inflammatory cytokine expression and associations with patient‐reported and clinically measured post‐operative outcome measures. Methods: Patients with CRS were prospectively recruited between 2016 and 2021 into a national multicenter, observational study. Mucus was collected from the olfactory cleft preoperatively and evaluated for 26 biomarkers using cluster analysis. Patient‐reported outcome measures included the 22‐item Sino‐Nasal Outcome Test (SNOT‐22) and Questionnaire of Olfactory Dysfunction (QOD). Additional clinical measures of disease severity included threshold, discrimination, and identification (TDI) scores using "Sniffin' Sticks" testing and Lund–Kennedy endoscopic score (LKES). Results: A total of 115 patients were clustered into type 2 inflammatory, non–type 2 inflammatory, noninflammatory, and two indeterminate clusters based on individual protein levels. Overall, the type 2 inflammatory cluster was found to have the highest mean improvement in both SNOT‐22 (−28.3 [standard deviation, ±16.2]) and TDI (6.5 [standard deviation, ±7.9]) scores 6 months after ESS. However, on average, all endotype clusters demonstrated improvement in all outcome measures after ESS without statistically significant between‐group differences in SNOT‐22 (p = 0.738), QOD (p = 0.306), TDI (p = 0.358), or LKES (p = 0.514) measures. Conclusions: All CRS endotype clusters responded favorably to surgery and showed improvements in patient‐reported and objective outcome measures. Thus, ESS should be considered a more generalized CRS therapy, and benefits appear to not be limited to specific endotypes. [ABSTRACT FROM AUTHOR]

Chronic rhinosinusitis (CRS) is heterogeneous and contains diverse pathogenesis including type 1, type 2, and/or type 3 inflammation. For severe type 2 CRS especially CRS with nasal polyps (CRSwNP), biologics that target inflammatory molecules have recently been applied along with further changes in the treatment algorithm for CRS. Currently, a completed phase 3 clinical trial for biologics for severe CRSwNP with inadequate response to surgery and/or intranasal corticosteroids, including omalizumab (anti-IgE), mepolizumab (anti-IL-5), benralizumab (anti-IL-5Rα), and dupilumab (anti-IL-4Rα), have all shown efficacy. Similar phase 3 clinical trials for tezepelumab (anti-TSLP) and etokimab (anti-IL-33) are now underway and completed, respectively. Further studies need to evaluate how to optimally and cost-effectively use biologics for CRS and determine if any biomarkers are indicative of which biologics should be administered. A definition of complete and/or clinical remission of CRS is also needed to determine when to reduce or discontinue biologics. In addition, more precise basic research on CRS, such as endotyping and genotyping, will need to be undertaken in order to determine novel targets for biologics. [ABSTRACT FROM AUTHOR]

Chronic rhinosinusitis (CRS) is a heterogenic disease characterized by persistent mucosal inflammation of the upper airway. Researches of CRS have progressed from phenotype-based to endotype-based, looking more deeply into molecular biomarkers, signaling pathways, and immune microenvironment. Single-cell RNA sequencing is an effective tool in analyzing composition, function, and interaction of cells in disease microenvironment at transcriptome level, showing great advantage in analyzing potential biomarkers, pathogenesis, and heterogeneity of chronic airway inflammation in an unbiased manner. In this article, we will review the latest advances in scRNA-seq studies of CRS to provide new perspectives for the diagnosis and treatment of this heterogeneous disease. [ABSTRACT FROM AUTHOR]

Objective: Clinical and prognostic features of Anti-MDA5-Positive Dermatomyositis (MDA5+ DM) are diverse. This study aimed to examine the peripheral immune cell profiles of patients with MDA5+ DM, identify disease endotypes related to the heterogeneous manifestations and prognosis, and guide individualized therapy regimen. Methods: This inpatient cohort included 123 patients with MDA5+ DM. Unsupervised hierarchical clustering analysis was used to derive disease endotypes from the circulating immune cell profiles on admission. Clinical symptoms, laboratory test results, inpatient treatments, and disease outcomes were then analyzed among the identified endotypes. Results: Three disease endotypes in MDA5+ DM were identified from peripheral immune cell profiles. Endotype1 had the highest percentages of CD4+ T cells and monocytes, and the lowest percentage of neutrophils; Endotype2 had the highest percentage of B cells; Endotype3 had the highest percentage of CD8+ T cells and NK cells. Clinical and prognostic heterogeneity of the endotypes were revealed. Endotype1 had the lowest 3-month mortality with the high incidence of periungual capillary changes. Endotype2 and Endotype3 had higher prevalence of rapidly progressive interstitial lung disease (RPILD) and mortality at 3 months than Endotype1. Meanwhile, Endotype3 had higher pneumocystis jiroveci and CMV viremia cases with significantly elevated of activated CD8+ T cells and multiple cytokines than Endotype1. Conclusion: Clustering analysis of peripheral immune cell profiles identified three different endotypes in MDA5+ dermatomyositis. Endotpye2 and 3 showed higher RPILD, 3-month mortality, pneumocystis jiroveci and CMV viremia. [ABSTRACT FROM AUTHOR]

Approximately 60% of veterans living with posttraumatic stress disorder (PTSD) experience obstructive sleep apnoea (OSA). Why OSA is so prevalent in individuals with PTSD remains unknown, though PTSD may influence the underlying endotypes known to cause OSA. We examined whether these endotypes (upper airway collapsibility, muscle compensation, loop gain, and the arousal threshold) differ between those with comorbid OSA and PTSD relative to their counterparts with OSA-only. Using the ventilatory flow pattern from diagnostic polysomnography, the OSA endotypes were measured in a retrospective cohort of 21 OSA patients with PTSD and 27 OSA-only patients. All participants were trauma exposed elderly male Australian Vietnam War veterans with mild-to-severe OSA (median Apnoea-Hypopnea index: 20.2 vs. 23.6 events/h). Age and BMI were similar between groups (70.7 vs. 71.7 years, and 28.4 vs. 28.4 kg/m2). There were no significant differences in the OSA endotype traits between PTSD + OSA and OSA-only patients for upper airway collapsibility (76.68 [71.53–83.56] vs. 78.35 [72.81–83.82] %V eupnea, median [IQR]), muscle compensation (4.27 [0.34–9.18] vs. 5.41 [1.83–7.21] %V eupnea), loop gain (0.56(0.17) vs. 0.60(0.14)), and arousal threshold (135.76 [126.59–147.54] vs. 146.95 [128.64–151.28] %V eupnea). The OSA endotypes in veterans with PTSD were similar to their trauma exposed OSA-only counterparts. PTSD appears to exert little influence on the OSA endotypes beyond the effect that age and trauma exposure may have. The aetiology of increased prevalence of OSA in PTSD remains unclear. Further work examining OSA endotypes using larger and more diverse samples is needed before robust conclusions can be made. • This study investigated whether PTSD influences the OSA endotype traits among older, male veterans. • We found the OSA endotype traits were similar between veteran OSA patients with and without PTSD. • PTSD may have little influence on the OSA endotype traits in elderly veterans. • The reason why OSA is so prevalent in older individuals with PTSD remains unclear. • Similar research needs to be conducted in younger and more diverse samples with PTSD. [ABSTRACT FROM AUTHOR]

BACKGROUND: Regulator of G protein signaling (RGS) 2 terminates bronchoconstrictive Gαq signaling; murine RGS2 knockout demonstrate airway hyperresponsiveness. While RGS2 promoter variants rs2746071 and rs2746072 associate with a clinical mild asthma phenotype, their impact on human airway smooth muscle (HASM) contractility and asthma severity outcomes is unknown. OBJECTIVE: We sought to determine whether reductions in RGS2 expression seen with these 2 RGS2 promoter variants augment HASM contractility and associate with an asthma severity phenotype. METHODS: We transfected HASM with a range of RGS2-specific small interfering RNA (siRNA) concentrations and determined RGS2 protein expression by Western blot analysis and intracellular calcium flux induced by histamine (a Gαq-coupled H1 receptor bronchoconstrictive agonist). We conducted regression-based genotype association analyses of RGS2 variants from 611 patients from the National Heart, Lung, and Blood Institute Severe Asthma Research Program 3. RESULTS: RGS2-specific siRNA caused dose-dependent increases in histamine-stimulated bronchoconstrictive intracellular calcium signaling (2-way ANOVA, P < .0001) with a concomitant decrease in RGS2 protein expression. RGS2-specific siRNA did not affect Gαq-independent ionomycin-induced intracellular calcium signaling (P = .42). The minor allele frequency of rs2746071 and rs2746072 was 0.46 and 0.28 among African American/non-Hispanic Black patients and was 0.28 and 0.27 among non-Hispanic White patients, among whom these single nucleotide polymorphisms were in stronger linkage disequilibrium (r2 = 0.97). Among non-Hispanic White patients, risk allele homozygotes for rs2746072 and rs2746071 each had nearly 2-fold greater asthma exacerbation rates relative to alternative genotypes with wild-type alleles (Padditive = 2.86 × 10-5/Precessive = 5.22 × 10-6 and Padditive = 3.46 × 10-6/Precessive = 6.74 × 10-7, respectively) at baseline, which was confirmed by prospective longitudinal exacerbation data. CONCLUSION: RGS2 promoter variation associates with a molecular and clinical phenotype characterized by enhanced bronchoconstrictive stimulation in vitro and higher asthma exacerbations rates in non-Hispanic White patients.

Yu Chen,1 Ru Gao,1 Honghui Liu,1 Maoyu Ye,1 Ling Chu,2 Tiansheng Wang1 1Department of Otolaryngology-Head and Neck Surgery, the Third Xiangya Hospital, Central South University, Changsha, Hunan, People’s Republic of China; 2Department of Pathology, the Third Xiangya Hospital, Central South University, Changsha, Hunan, People’s Republic of ChinaCorrespondence: Tiansheng Wang, Department of Otolaryngology-Head and Neck Surgery, the Third Xiangya Hospital, Central South University, 138 Tongzipo Road, Yuelu District, Changsha, People’s Republic of China, Email 600923@csu.edu.cnBackground: Individuals with eosinophilic chronic rhinosinusitis with nasal polyps(eCRSwNP) exhibited worse outcomes and higher postoperative recurrence rates. This study aimed to identify biomarkers that can aid in the early differentiation of eCRSwNP and enhance our comprehension of its pathophysiology.Methods: We recruited two independent cohorts. In the discovery cohort, CRSwNP was categorized into eCRSwNP and non-eosinophilic CRSwNP(neCRSwNP), and serum proteomics was performed to identify differentially expressed proteins between the two groups. These candidate proteins were chosen and confirmed in the validation cohort using an enzyme-linked immunosorbent assay (ELISA), Western blot (WB), quantitative real time-polymerase chain reaction (qRT-PCR), immunofluorescence (IF), and their predictive values and associations with tissue eosinophilic pathophysiology were evaluated.Results: We identified a total of 39 differential proteins between the two groups, including 20 proteins upregulated and 19 downregulated in the eCRSwNP group. Further validation was conducted on the top 5 proteins that were up or down-regulated. Results from the ELISA showed that levels of serum MRC1, CDH13, and MMP2 were significantly higher, TRIM28 was lower in the eCRSwNP group compared to the neCRSwNP group (all P< 0.05), and serum MRC1 (AUC=0.742, P< 0.001) and MMP2 (AUC=0.766, P< 0.001) levels exhibited promising predicting values for eCRSwNP. Moreover, qRT-PCR and WB analysis found that MMP2 and MRC1 expressions were enhanced in the eCRSwNP group compared to the neCRSwNP group (all P< 0.01), and their levels were positively correlated with the number and percentages of tissue eosinophils (all P< 0.01). The IF suggested that MMP2 and MRC1 were overexpressed in the nasal polyps tissues of eCRSwNP patients, and MMP2 was mainly located on eosinophils.Conclusion: Circulating proteins identified by proteomics could serve as potential preoperative biomarkers for distinguishing eCRSwNP. Among them, MMP2 was enhanced in eCRSwNP and correlated with tissue eosinophilia, which provided valuable insights into the pathophysiology of eCRSwNP.Keywords: chronic rhinosinusitis with nasal polyps, endotype, eosinophilic, proteomics

Precision medicine is the current approach to managing chronic respiratory diseases, especially asthma and chronic obstructive pulmonary disease (COPD). It involves the evaluation of genetic, environmental, and lifestyle variations for each patient. It requires valid and specific biomarkers obtained through genetic studies, biomolecular technology, and omics-based technology to determine targeted therapies. Asthma and COPD have heterogeneous clinical phenotype variations, and giving one standard treatment for asthma and COPD may not necessarily provide the same effectiveness to other patients. The endotype, a specific molecular mechanism in disease pathogenesis, is essential in phenotype variation. The role of precision medicine in asthma and COPD is to determine endotypes through specific biomarkers and to provide specific targeted therapy for achieving personalized treatment in each patient. The application of precision medicine not only provides precise diagnosis and treatment but also enables early detection in individuals at risk and prevention of progression and exacerbation in asthma and COPD.

Abstract Background As treatment strategies differ according to endotype, rhinologists must accurately determine the endotype in patients affected by chronic rhinosinusitis with nasal polyps (CRSwNP) for the appropriate management. In this study, we aim to construct a novel deep learning model using paranasal sinus computed tomography (CT) to predict the endotype in patients with CRSwNP. Methods We included patients diagnosed with CRSwNP between January 1, 2020, and April 31, 2023. The endotype of patients with CRSwNP in this study was classified as eosinophilic or non-eosinophilic. Sinus CT images (29,993 images) were retrospectively collected, including the axial, coronal, and sagittal planes, and randomly divided into training, validation, and testing sets. A residual network-18 was used to construct the deep learning model based on these images. Loss functions, accuracy functions, confusion matrices, and receiver operating characteristic curves were used to assess the predictive performance of the model. Gradient-weighted class activation mapping was performed to visualize and interpret the operating principles of the model. Results Among 251 included patients, 86 and 165 had eosinophilic or non-eosinophilic CRSwNP, respectively. The median (interquartile range) patient age was 49 years (37–58 years), and 153 (61.0%) were male. The deep learning model showed good discriminative performance in the training and validation sets, with areas under the curves of 0.993 and 0.966, respectively. To confirm the model generalizability, the receiver operating characteristic curve in the testing set showed good discriminative performance, with an area under the curve of 0.963. The Kappa scores of the confusion matrices in the training, validation, and testing sets were 0.985, 0.928, and 0.922, respectively. Finally, the constructed deep learning model was used to predict the endotype of all patients, resulting in an area under the curve of 0.962. Conclusions The deep learning model developed in this study may provide a novel noninvasive method for rhinologists to evaluate endotypes in patients with CRSwNP and help develop precise treatment strategies.

The ongoing COhort for Childhood Origin of Asthma and allergic diseases (COCOA) study is a prospective birth cohort investigating the origin and natural courses of childhood allergic diseases, including atopic dermatitis, food allergy, allergic rhinitis and asthma, with long-term prognosis. Initiated under the premise that allergic diseases result from a complex interplay of immune development alterations, environmental exposures, and host susceptibility, the COCOA study explores these dynamic interactions during prenatal and postnatal periods, framed within the hygiene and microbial hypotheses alongside the developmental origins of health and disease (DOHaD) hypothesis. The scope of the COCOA study extends to genetic predispositions, indoor and outdoor environmental variables affecting mothers and their offsprings such as outdoor and indoor air pollution, psychological factors, diets, and the microbiomes of skin, gut, and airway. We have embarked on in-depth investigations of diverse risk factors and the pathophysiological underpinnings of allergic diseases. By employing multi-omics approaches—proteomics, transcriptomics, and metabolomics—we gain deeper insights into the distinct pathophysiological processes across various endotypes of childhood allergic diseases, incorporating the exposome using extensive resources within the COCOA study. Integration with large-scale datasets, such as national health insurance records, enhances robustness and mitigates potential limitations inherent to birth cohort studies. As part of global networks focused on childhood allergic diseases, the COCOA study fosters collaborative research across multiple cohorts. The findings from the COCOA study are instrumental in informing precision medicine strategies for childhood allergic diseases, underpinning the establishment of disease trajectories.

Chronic rhinosinusitis (CRS) is a persistent inflammatory disease of the nasal cavity and paranasal sinuses. Traditional classification is denoted by the presence (CRSwNP) or absence of nasal polyps (CRSsNP). Particularly, CRSwNP is distinguished by the presence of infiltrating cells and inflammatory markers in the nasal mucosa. Patients with CRSwNP in Western countries predominantly display a type 2 endotype, whereas those in Asian regions display a mixed type 2 endotype. Nevertheless, recent transcriptome analyses have revealed two types of nasal polyps - type 2 and non-type 2 polyps, suggesting that geographical differences in endotypes likely resulted from the different proportions of each endotype. Moreover, various endotypes of CRSsNP have been identified, making phenotype a crucial factor for predicting treatment efficacy. Type 2 endotypes, designated as eosinophilic CRS (ECRS) in Japan, are characterized by severe eosinophilic infiltration into the paranasal sinus tissue and are particularly refractory. In this review, we discuss the latest developments in ECRS. We also provide recent findings on the involvement of nasal epithelial cells in pathogenesis. [ABSTRACT FROM AUTHOR]

Background: As treatment strategies differ according to endotype, rhinologists must accurately determine the endotype in patients affected by chronic rhinosinusitis with nasal polyps (CRSwNP) for the appropriate management. In this study, we aim to construct a novel deep learning model using paranasal sinus computed tomography (CT) to predict the endotype in patients with CRSwNP. Methods: We included patients diagnosed with CRSwNP between January 1, 2020, and April 31, 2023. The endotype of patients with CRSwNP in this study was classified as eosinophilic or non-eosinophilic. Sinus CT images (29,993 images) were retrospectively collected, including the axial, coronal, and sagittal planes, and randomly divided into training, validation, and testing sets. A residual network-18 was used to construct the deep learning model based on these images. Loss functions, accuracy functions, confusion matrices, and receiver operating characteristic curves were used to assess the predictive performance of the model. Gradient-weighted class activation mapping was performed to visualize and interpret the operating principles of the model. Results: Among 251 included patients, 86 and 165 had eosinophilic or non-eosinophilic CRSwNP, respectively. The median (interquartile range) patient age was 49 years (37–58 years), and 153 (61.0%) were male. The deep learning model showed good discriminative performance in the training and validation sets, with areas under the curves of 0.993 and 0.966, respectively. To confirm the model generalizability, the receiver operating characteristic curve in the testing set showed good discriminative performance, with an area under the curve of 0.963. The Kappa scores of the confusion matrices in the training, validation, and testing sets were 0.985, 0.928, and 0.922, respectively. Finally, the constructed deep learning model was used to predict the endotype of all patients, resulting in an area under the curve of 0.962. Conclusions: The deep learning model developed in this study may provide a novel noninvasive method for rhinologists to evaluate endotypes in patients with CRSwNP and help develop precise treatment strategies. [ABSTRACT FROM AUTHOR]

Sarcoidosis is a chronic granulomatous disorder characterized by unknown etiology, undetermined mechanisms, and non-specific therapies except TNF blockade. To improve our understanding of the pathogenicity and to predict the outcomes of the disease, the identification of new biomarkers and molecular endotypes is sorely needed. In this study, we systematically evaluate the biomarkers identified through Omics and non-Omics approaches in sarcoidosis. Most of the currently documented biomarkers for sarcoidosis are mainly identified through conventional “one-for-all” nonOmics targeted studies. Although the application of machine learning algorithms to identify biomarkers and endotypes from unbiased comprehensive Omics studies is still in its infancy, a series of biomarkers, overwhelmingly for diagnosis to differentiate sarcoidosis from healthy controls have been reported. In view of the fact that current biomarker profiles in sarcoidosis are scarce, fragmented and mostly not validated, there is an urgent need to identify novel sarcoidosis biomarkers and molecular endotypes using more advanced Omics approaches to facilitate disease diagnosis and prognosis, resolve disease heterogeneity, and facilitate personalized medicine. [ABSTRACT FROM AUTHOR]

Type 1 diabetes is caused by a deficiency of insulin secretion which has been considered traditionally as the outcome of a precipitous decline in the viability of β-cells in the islets of Langerhans, brought about by autoimmune-mediated attack. Consistent with this, various classes of lymphocyte, as well as cells of the innate immune system have been found in association with islets during disease progression. However, analysis of human pancreas from subjects with type 1 diabetes has revealed that insulitis is often less intense than in equivalent animal models of the disease and can affect many fewer islets than expected, at disease onset. This is especially true in subjects developing type 1 diabetes in, or beyond, their teenage years. Such studies imply that both the phenotype and the number of immune cells present within insulitic lesions can vary among individuals in an age-dependent manner. Additionally, the influent lymphocytes are often mainly arrayed peripherally around islets rather than gaining direct access to the endocrine cell core. Thus, insulitis remains an enigmatic phenomenon in human pancreas and this review seeks to explore the current understanding of its likely role in the progression of type 1 diabetes. [ABSTRACT FROM AUTHOR]

Since atopic dermatitis (AD) is a heterogeneous condition, the subtyping of AD is a crucial issue. The classical subtypes of AD are represented by extrinsic and intrinsic subtypes, European–American and Asian subtypes, and adult and pediatric subtypes. While the subtyping of AD was historically conducted based on the phenotype, recent findings on the mechanisms of AD have revealed the importance of the endotype, which can characterize individual patients more accurately. Considering the current development of AD therapies, AD endotyping is a prerequisite for a personalized therapeutic choice. Endotypes of AD can be stratified from different viewpoints, including cytokine expression patterns, allergen properties, epidermal barrier conditions, ceramide variation, the involvement of innate immunity, and serum biomarkers. Among them, the cytokine-based endotype seems to be the most useful one and is categorized into type 2 cytokine (IL-4, IL-13 and IL-31)-high, type 1 cytokine (IFN-γ)-high, and/or type 3 cytokine (IL-22 and IL-17)-high, or mixed subtypes. Recently proposed biomarker endotyping aims at individualized treatment options, although the daily clinical use of endotypes is a future issue. To better understand the endotypes for clinicians, attempts to adjust each of the classical subtypes to endotypes are required. This review will discuss the correspondence of the classical subtypes to the various endotypes that have recently been proposed. [ABSTRACT FROM AUTHOR]

The ongoing COhort for Childhood Origin of Asthma and allergic diseases (COCOA) study is a prospective birth cohort investigating the origin and natural courses of childhood allergic diseases, including atopic dermatitis, food allergy, allergic rhinitis and asthma, with long-term prognosis. Initiated under the premise that allergic diseases result from a complex interplay of immune development alterations, environmental exposures, and host susceptibility, the COCOA study explores these dynamic interactions during prenatal and postnatal periods, framed within the hygiene and microbial hypotheses alongside the developmental origins of health and disease (DOHaD) hypothesis. The scope of the COCOA study extends to genetic predispositions, indoor and outdoor environmental variables affecting mothers and their offsprings such as outdoor and indoor air pollution, psychological factors, diets, and the microbiomes of skin, gut, and airway. We have embarked on in-depth investigations of diverse risk factors and the pathophysiological underpinnings of allergic diseases. By employing multi-omics approaches—proteomics, transcriptomics, and metabolomics—we gain deeper insights into the distinct pathophysiological processes across various endotypes of childhood allergic diseases, incorporating the exposome using extensive resources within the COCOA study. Integration with large-scale datasets, such as national health insurance records, enhances robustness and mitigates potential limitations inherent to birth cohort studies. As part of global networks focused on childhood allergic diseases, the COCOA study fosters collaborative research across multiple cohorts. The findings from the COCOA study are instrumental in informing precision medicine strategies for childhood allergic diseases, underpinning the establishment of disease trajectories. [ABSTRACT FROM AUTHOR]

Key points: Elevated IL‐5, IL‐13, IL‐33, and CCL2 correlate with lower UPSIT scores in CRS and AERD patients.Elevated IL‐5, IL‐13, TNF‐α, CCL2, and CXCL‐8 correlate with higher SNOT‐22 scores in CRS and AERD patients. [ABSTRACT FROM AUTHOR]

BACKGROUND: Delirium, a common syndrome with heterogeneous etiologies and clinical presentations, is associated with poor long‐term outcomes. Recording and analyzing all delirium equally could be hindering the field's understanding of pathophysiology and identification of targeted treatments. Current delirium subtyping methods reflect clinically evident features but likely do not account for underlying biology. METHODS: The Delirium Subtyping Initiative (DSI) held three sessions with an international panel of 25 experts. RESULTS: Meeting participants suggest further characterization of delirium features to complement the existing Diagnostic and Statistical Manual of Mental Disorders Fifth Edition Text Revision diagnostic criteria. These should span the range of delirium‐spectrum syndromes and be measured consistently across studies. Clinical features should be recorded in conjunction with biospecimen collection, where feasible, in a standardized way, to determine temporal associations of biology coincident with clinical fluctuations. DISCUSSION: The DSI made recommendations spanning the breadth of delirium research including clinical features, study planning, data collection, and data analysis for characterization of candidate delirium subtypes. Highlights: Delirium features must be clearly defined, standardized, and operationalized.Large datasets incorporating both clinical and biomarker variables should be analyzed together.Delirium screening should incorporate communication and reasoning. [ABSTRACT FROM AUTHOR]

Osteoarthritis (OA) affects over 500 million people worldwide. OA patients are symptomatically treated, and current therapies exhibit marginal efficacy and frequently carry safety-risks associated with chronic use. No disease-modifying therapies have been approved to date leaving surgical joint replacement as a last resort. To enable effective patient care and successful drug development there is an urgent need to uncover the pathobiological drivers of OA and how these translate into disease endotypes. Endotypes provide a more precise and mechanistic definition of disease subgroups than observable phenotypes, and a panel of tissue- and pathology-specific biochemical markers may uncover treatable endotypes of OA. We have searched PubMed for full-text articles written in English to provide an in-depth narrative review of a panel of validated biochemical markers utilized for endotyping of OA and their association to key OA pathologies. As utilized in IMI-APPROACH and validated in OAI-FNIH, a panel of biochemical markers may uncover disease subgroups and facilitate the enrichment of treatable molecular endotypes for recruitment in therapeutic clinical trials. Understanding the link between biochemical markers and patient-reported outcomes and treatable endotypes that may respond to given therapies will pave the way for new drug development in OA. [ABSTRACT FROM AUTHOR]