Host heterogeneity in humoral bactericidal activity can be complement independent.

Background: Humoral bactericidal activity was first recognized nearly a century ago. However, the extent of inter-individual heterogeneity and the mechanisms underlying such heterogeneity beyond antibody or complement systems have not been well studied. Methods: The plasma bactericidal activity of five healthy volunteers were tested against 30 strains of Gram-negative uropathogens, Klebsiella pneumoniae and Escherichia coli, associated with bloodstream infections. IgG and IgM titers specific to K. pneumoniae strains KP13883 and KPB1 were measured by ELISA, and complement inhibitor was used to measure the contribution of complement-induced killing. Furthermore, MALDI-TOF mass spectrometry was conducted to determine the metabolomic components of plasma with bactericidal properties in 25 healthy individuals using Bayesian inference of Pearson correlation between peak intensity and colony counts of surviving bacteria. Results: Plasma bactericidal activity varied widely between individuals against various bacterial strains. While individual plasma with higher IgM titers specific to K. pneumoniae strain KP13883 showed more efficient killing of the strain, both IgM and IgG titers for K. pneumoniae strain KPB1 did not correlate well with the killing activity. Complement inhibition assays elucidated that the complement-mediated killing was not responsible for the inter-individual heterogeneity in either isolate. Subsequently, using MALDI-TOF mass spectrometry on plasmas of 25 healthy individuals, we identified several small molecules including gangliosides, pediocins, or saponins as candidates that showed negative correlation between peak intensities and colony forming units of the test bacteria. Conclusion: This is the first study to demonstrate the inter-individual heterogeneity of constitutive innate humoral bactericidal function quantitatively and that the heterogeneity can be independent of antibody or the complement system.

Baseline Characteristics Associated with Hypoglossal Nerve Stimulation Treatment Outcomes in Patients with Obstructive Sleep Apnea: A Systematic Review.

Hypoglossal nerve stimulation (HGNS) has emerged as an effective treatment for obstructive sleep apnea (OSA). Identifying baseline characteristics that prospectively could predict treatment outcomes even better is crucial for optimizing patient selection and improving therapeutic success in the future. A systematic review was conducted following PRISMA guidelines. Literature searches in Medline, Web of Science, and Cochrane databases identified studies assessing baseline characteristics associated with HGNS treatment outcomes. Inclusion criteria focused on studies with adult patients diagnosed with OSA, treated with HGNS, and assessed using full-night efficacy sleep studies. Risk of bias was evaluated using the NICE tool. Twenty-six studies met the inclusion criteria. Commonly reported baseline characteristics with predictive potential included BMI, site of collapse, and various pathophysiological endotypes. Most studies used the original Sher criteria to define treatment response, though variations were noted. Results suggested that lower BMI, absence of complete concentric collapse at the palatal level, and specific pathophysiological traits were associated with better HGNS outcomes. This review identified several baseline characteristics associated with HGNS outcomes, which may guide future patient selection. Importantly, patients were already preselected for HGNS. Standardizing response criteria is recommended to enhance the evaluation and effectiveness of HGNS therapy in OSA patients.

Choosing the right biologic treatment for individual patients with severe asthma - Lessons learnt from Picasso.

Severe asthma represents a true challenge for clinicians from two basic perspectives, i.e.: a rational assessment of the underlying endo/phenotype and the subsequent selection of the best fitted (personalized) and effective treatment. Even though asthma is a heterogeneous disease, in the majority of therapy-compliant patients, it is possible to achieve (almost) complete disease control or even remission through conventional and quite uniform step-based pharmacotherapy, even without phenotyping. However, the absence of deeper assessment of individual patients revealed its handicap to its fullest extent during the first years of the new millennium upon the launch of biological therapeutics for patients with the most severe forms of asthma. The introduction of differentially targeted biologics into clinical practice became a challenge in terms of understanding and recognizing the etiopathogenetic heterogeneity of the asthmatic inflammation, pheno/endotyping, and, consequently, to choose the right biologic for the right patient. The answers to the following three questions should lead to correct identification of the dominant pheno/endotype: Is it really (severe) asthma? Is it eosinophilic asthma? If eosinophilic, is it (predominantly) allergen-driven? The identification of the best achievable and relevant alliance between endotypes and phenotypes ("euphenotypes") should be based not only on the assessment of the actual clinical characteristics and laboratory biomarkers, but more importantly, on the evaluation of their development and changes over time. In the current paper, we present a pragmatic three-step approach to severe asthma diagnosis and management.

Metabolomic-derived endotypes of age-related macular degeneration (AMD): a step towards identification of disease subgroups.

Age-related macular degeneration (AMD) is a leading cause of blindness worldwide, with a complex pathophysiology and phenotypic diversity. Here, we apply Similarity Network Fusion (SNF) to cluster AMD patients into putative metabolomics-derived endotypes. Using a discovery cohort of 163 AMD patients from Boston, US, and a validation cohort of 214 patients from Coimbra, Portugal, we identified four distinct metabolomics-derived endotypes with varying retinal structural and functional characteristics, confirmed across both cohorts. Patients clustered into Endotype 1 exhibited a milder form of AMD and were characterized by low levels of amino acids in specific metabolic pathways. Meanwhile, patients clustered into both Endotype 3 and 4 were associated with more severe AMD and exhibited low levels of fatty acid metabolites and elevated levels of sphingomyelins and fatty acid metabolites, respectively. These preliminary findings indicate that metabolomics-derived endotyping may offer a refined strategy for categorizing AMD patients based on their specific pathophysiological underpinnings, rather than relying solely on traditional observational clinical indicators.

From biochemical markers to molecular endotypes of osteoarthritis: a review on validated biomarkers.

INTRODUCTION: 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. AREAS COVERED: 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. EXPERT OPINION: 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.

A novel TASK channel antagonist nasal spray reduces sleep apnea severity in physiological responders: a randomized, blinded, trial.

Preclinical and human physiological studies indicate that topical, selective TASK 1/3 K+ channel antagonism increases upper airway dilator muscle activity and reduces pharyngeal collapsibility during anesthesia and nasal breathing during sleep. The primary aim of this study was to determine the effects of BAY2586116 nasal spray on obstructive sleep apnea (OSA) severity and whether individual responses vary according to differences in physiological responses and route of breathing. Ten people (5 females) with OSA [apnea-hypopnea index (AHI) = 47 ± 26 events/h (means ± SD)] who completed previous sleep physiology studies with BAY2586116 were invited to return for three polysomnography studies to quantify OSA severity. In random order, participants received either placebo nasal spray (saline), BAY2586116 nasal spray (160 µg), or BAY2586116 nasal spray (160 µg) restricted to nasal breathing (chinstrap or mouth tape). Physiological responders were defined a priori as those who had improved upper airway collapsibility (critical closing pressure ≥2 cmH2O) with BAY2586116 nasal spray (NCT04236440). There was no systematic change in apnea-hypopnea index (AHI3) from placebo versus BAY2586116 with either unrestricted or nasal-only breathing versus placebo (47 ± 26 vs. 43 ± 27 vs. 53 ± 33 events/h, P = 0.15). However, BAY2586116 (unrestricted breathing) reduced OSA severity in physiological responders compared with placebo (e.g., AHI3 = 28 ± 11 vs. 36 ± 12 events/h, P = 0.03 and ODI3 = 18 ± 10 vs. 28 ± 12 events/h, P = 0.02). Morning blood pressure was also lower in physiological responders after BAY2586116 versus placebo (e.g., systolic blood pressure = 137 ± 24 vs. 147 ± 21 mmHg, P < 0.01). In conclusion, BAY2586116 reduces OSA severity during sleep in people who demonstrate physiological improvement in upper airway collapsibility. These findings highlight the therapeutic potential of this novel pharmacotherapy target in selected individuals.NEW & NOTEWORTHY Preclinical findings in pigs and humans indicate that blocking potassium channels in the upper airway with topical nasal application increases pharyngeal dilator muscle activity and reduces upper airway collapsibility. In this study, BAY2586116 nasal spray (potassium channel blocker) reduced sleep apnea severity in those who had physiological improvement in upper airway collapsibility. BAY2586116 lowered the next morning's blood pressure. These findings highlight the potential for this novel therapeutic approach to improve sleep apnea in certain people.

Macroarray expression analysis of cytokines and prostaglandin metabolism-related genes in chronic rhinosinusitis.

Background: Chronic rhinosinusitis (CRS) can be divided into endotypes by functional or pathophysiologic findings. Objective: The aim of this study was to analyze the expression of cytokines, prostaglandin (PG) synthases, and their receptors related to the pathogenesis of CRS, especially those contributing to nasal polyp (NP) formation. Methods: NPs and uncinate tissue (UT) samples were collected from 90 patients who underwent endoscopic sinus surgery. They included 75 patients with CRS (including 45 with eosinophilic CRS [eCRS] and 30 with non-eCRS) and 15 patients without CRS. A total of 30 genes were selected for our original DNA array plate to analyze the levels of expression of 10 cytokines (IFN-γ, IL-4, IL-5, IL-10, IL-13, IL-17A, IL-22, IL-25, IL-33, and TSLP), 4 prostaglandin synthases (prostaglandin D2 [PGD2] synthase, prostaglandin E2 synthase, COX-1, and COX-2), and their 16 receptors. Clustering analysis was performed according to the expression results, and clinical findings of patients from each cluster were investigated. Results: The samples could be divided into 3 clusters. Cluster 1 showed elevated levels of expression of IL4, IL5, IL13, TSLP, IL1RL1 (ST2 [an IL-33 receptor]), HPGDS, and GPR44 (CRTH2, a PGD2 receptor); cluster 2 showed elevated levels of expression of IL17A and PTGES; and cluster 3 showed an elevated level of expression of IL25. Regarding clinical features, the main characteristics of each cluster were as follows: NPs from patients with eCRS for cluster 1, NPs and/or UT samples from patients with non-eCRS for cluster 2, and UTs from patients with non-CRS for cluster 3. Conclusion: The results suggest that there are associations between type 2 inflammation/PGD2 and eCRS and also between type 3 inflammation/prostaglandin E2 and non-eCRS.

Phenotypes, Etiotypes, and Endotypes of Exacerbations of Chronic Obstructive Pulmonary Disease.

Chronic obstructive pulmonary disease is a major health problem with a high prevalence, a rising incidence, and substantial morbidity and mortality. Its course is punctuated by acute episodes of increased respiratory symptoms, termed exacerbations of chronic obstructive pulmonary disease (ECOPD). ECOPD are important events in the natural history of the disease, as they are associated with lung function decline and prolonged negative effects on quality of life. The present-day therapy for ECOPD with short courses of antibiotics and steroids and escalation of bronchodilators has resulted in only modest improvements in outcomes. Recent data indicate that ECOPD are heterogeneous, raising the need to identify distinct etioendophenotypes, incorporating traits of the acute event and of patients who experience recurrent events, to develop novel and targeted therapies. These characterizations can provide a complete clinical picture, the severity of which will dictate acute pharmacological treatment, and may also indicate whether a change in maintenance therapy is needed to reduce the risk of future exacerbations. In this review we discuss the latest knowledge of ECOPD types on the basis of clinical presentation, etiology, natural history, frequency, severity, and biomarkers in an attempt to characterize these events.

A Scoping Review of Artificial Intelligence Research in Rhinology.

BACKGROUND: A considerable volume of possible applications of artificial intelligence (AI) in the field of rhinology exists, and research in the area is rapidly evolving. OBJECTIVE: This scoping review aims to provide a brief overview of all current literature on AI in the field of rhinology. Further, it aims to highlight gaps in the literature for future rhinology researchers. METHODS: OVID MEDLINE (1946-2022) and EMBASE (1974-2022) were searched from January 1, 2017 until May 14, 2022 to identify all relevant articles. The Preferred Reporting Items for Systematic Reviews and Meta-analyses Extension for Scoping Reviews checklist was used to guide the review. RESULTS: A total of 2420 results were identified of which 62 met the eligibility criteria. A further 17 articles were included through bibliography searching, for a total of 79 articles on AI in rhinology. Each year resulted in an increase in the number of publications, from 3 articles published in 2017 to 31 articles published in 2021. Articles were produced by authors from 22 countries with a relative majority coming from the USA (19%), China (19%), and South Korea (13%). Articles were placed into 1 of 5 categories: phenotyping/endotyping (n = 12), radiological diagnostics (n = 42), prognostication (n = 10), non-radiological diagnostics (n = 7), surgical assessment/planning (n = 8). Diagnostic or prognostic utility of the AI algorithms were rated as excellent (n = 29), very good (n = 25), good (n = 7), sufficient (n = 1), bad (n = 2), or was not reported/not applicable (n = 15). CONCLUSIONS: AI is experiencing an increasingly significant role in rhinology research. Articles are showing high rates of diagnostic accuracy and are being published at an almost exponential rate around the world. Utilizing AI in radiological diagnosis was the most published topic of research, however, AI in rhinology is still in its infancy and there are several topics yet to be thoroughly explored.

Dynamic activity in cis-regulatory elements of leukocytes identifies transcription factor activation and stratifies COVID-19 severity in ICU patients.

Transcription factor programs mediating the immune response to coronavirus disease 2019 (COVID-19) are not fully understood. Capturing active transcription initiation from cis-regulatory elements such as enhancers and promoters by capped small RNA sequencing (csRNA-seq), in contrast to capturing steady-state transcripts by conventional RNA-seq, allows unbiased identification of the underlying transcription factor activity and regulatory pathways. Here, we profile transcription initiation in critically ill COVID-19 patients, identifying transcription factor motifs that correlate with clinical lung injury and disease severity. Unbiased clustering reveals distinct subsets of cis-regulatory elements that delineate the cell type, pathway-specific, and combinatorial transcription factor activity. We find evidence of critical roles of regulatory networks, showing that STAT/BCL6 and E2F/MYB regulatory programs from myeloid cell populations are activated in patients with poor disease outcomes and associated with COVID-19 susceptibility genetic variants. More broadly, we demonstrate how capturing acute, disease-mediated changes in transcription initiation can provide insight into the underlying molecular mechanisms and stratify patient disease severity.

Advancing Precision Medicine for the Diagnosis and Treatment of Acute Respiratory Distress Syndrome.

Acute respiratory distress syndrome (ARDS) is a common and life-threatening cause of respiratory failure. Despite decades of research, there are no effective pharmacologic therapies to treat this disease process and mortality remains high. The shortcomings of prior translational research efforts have been increasingly attributed to the heterogeneity of this complex syndrome, which has led to an increased focus on elucidating the mechanisms underlying the interpersonal heterogeneity of ARDS. This shift in focus aims to move the field towards personalized medicine by defining subgroups of ARDS patients with distinct biology, termed endotypes, to quickly identify patients that are most likely to benefit from mechanism targeted treatments. In this review, we first provide a historical perspective and review the key clinical trials that have advanced ARDS treatment. We then review the key challenges that exist with regards to the identification of treatable traits and the implementation of personalized medicine approaches in ARDS. Lastly, we discuss potential strategies and recommendations for future research that we believe will aid in both understanding the molecular pathogenesis of ARDS and the development of personalized treatment approaches.

Advances and Highlights of miRNAs in Asthma: Biomarkers for Diagnosis and Treatment.

Asthma is a heterogeneous inflammatory disease of the airways that causes breathing difficulties, episodes of cough and wheezing, and in more severe cases can greatly diminish quality of life. Epigenetic regulation, including post-transcriptional mediation of microRNAs (miRNAs), is one of the mechanisms behind the development of the range of asthma phenotypes and endotypes. As in every other immune-mediated disease, miRNAs regulate the behavior of cells that shape the airway structure as well as those in charge of the defense mechanisms in the bronchi and lungs, controlling cell survival, growth, proliferation, and the ability of cells to synthesize and secrete chemokines and immune mediators. More importantly, miRNAs are molecules with chemical and biological properties that make them appropriate biomarkers for disease, enabling stratification of patients for optimal drug selection and thereby simplifying clinical management and reducing both the economic burden and need for critical care associated with the disease. In this review, we summarize the roles of miRNAs in asthma and describe how they regulate the mechanisms of the disease. We further describe the current state of miRNAs as biomarkers for asthma phenotyping, endotyping, and treatment selection.

Topical Potassium Channel Blockage Improves Pharyngeal Collapsibility: A Translational, Placebo-Controlled Trial.

BACKGROUND: Potassium (K+) channel inhibition has been identified in animal models as a potential target to increase pharyngeal dilator muscle activity and to treat OSA. However, these findings have not yet been translated to humans. RESEARCH QUESTION: Does a novel, potent, tandem of P domains in a weak inward rectifying K+ channel (TWIK)-related acid-sensitive K+ (TASK) 1/3 channel antagonist, BAY2586116, improve pharyngeal collapsibility in pigs and humans, and secondarily, what is the optimal dose and method of topical application? STUDY DESIGN AND METHODS: In the preclinical study, pharyngeal muscle activity and upper-airway collapsibility via transient negative pressure application was quantified in 13 anesthetized pigs during administration of placebo, 0.3 µg, 3 µg, and 30 µg nasal drops of BAY2586116. In the clinical study, 12 people with OSA instrumented with polysomnography equipment, an epiglottic pressure catheter, pneumotachograph, and nasal mask to monitor sleep and breathing performed up to four detailed upper airway sleep physiology studies. Participants received BAY2586116 (160 µg) or placebo nasal spray before sleep via a double-masked, randomized, crossover design. Most participants also returned for three additional overnight visits: (1) nasal drops (160 µg), (2) half-dose nasal spray (80 µg), and (3) direct endoscopic application (160 µg). The upper-airway critical closing pressure (Pcrit) during sleep was quantified at each visit. RESULTS: Consistent and sustained improvements in pharyngeal collapsibility to negative pressure were found with 3 and 30 µg of BAY2586116 vs placebo in pigs. Similarly, BAY2586116 improved pharyngeal collapsibility by an average of approximately 2 cm H2O vs placebo, regardless of topical application method and dose (P < .008, mixed model) in participants with OSA. INTERPRETATION: Acute topical application of BAY2586116 improves upper-airway collapsibility in anesthetized pigs and sleeping humans with OSA. These novel physiologic findings highlight the therapeutic potential to target potassium channel mechanisms to treat OSA. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT04236440; URL: www. CLINICALTRIALS: gov.

Obesity affects type 2 biomarker levels in asthma.

OBJECTIVE: Type 2 (T2) inflammation offers a therapeutic target for biologics. Previous trials suggest obesity influences T2-biomarker levels in asthma, though have not accounted for key variables, e.g. inhaled (ICS)/oral corticosteroid (OCS) use. We hypothesized that body mass index (BMI) would affect T2-biomarker levels, after adjusting for covariates. METHODS: A retrospective analysis of data from two recent local trials of 153 participants with asthma (102 difficult-to-treat, 51 mild). Measurements included BMI, fractional exhaled nitric oxide (FeNO) and eosinophils. Correlation and regression analysis were performed for each biomarker to describe their relationship with BMI. Data was analyzed overall, and by asthma severity, T2-status and BMI tertile. RESULTS: Increasing BMI was associated with reduction in FeNO when stratified by BMI tertile (25 ppb lowest tertile, 18 ppb highest tertile; p = 0.014). Spearmans rank showed a negative correlation between BMI and FeNO in difficult-to-treat asthma (ρ= -0.309, p = 0.002). Linear regression adjusting for sex, age, smoking, atopy, allergic/perennial rhinitis, ICS and OCS confirmed BMI as a predictor of FeNO overall (ß= -2.848, p = 0.019). Eosinophils were reduced in the highest BMI tertile versus lowest in difficult-to-treat asthma (0.2x109/L, 0.3x109/L respectively; p = 0.02). CONCLUSIONS: Increasing BMI is associated with lower FeNO in asthma when adjusted for relevant covariates, including steroid use. There also appears to be an effect on eosinophil levels. Obesity, therefore, affects T2 biomarker levels with implications for disease endotyping and determination of eligibility for biologic therapy. Whether this is due to masking of underlying T2-high status or development of a truly T2-low endotype requires further research.

Pharmacometabolomics of Asthma as a Road Map to Precision Medicine.

Pharmacometabolomics applies the principles of metabolomics to therapeutics in order to elucidate the biological mechanisms underlying the variation in responses to drugs between groups and individuals. Asthma is associated with broad systemic effects and heterogeneity in treatment response and as such is ideally suited to pharmacometabolomics. In this chapter, we discuss the state of the emerging field of asthma pharmacometabolomics, with a particular focus on studies of steroids, bronchodilators, and leukotriene inhibitors. We also consider those studies concerned with subtyping cases to better understand the pharmacology of those groups and those looking to leverage pharmacometabolomics for asthma prevention. We finish with a discussion of the challenges and opportunities of asthma pharmacometabolomics and reflect upon where this field must go next in order to realize its precision medicine potential.

The Respiratory Microbiome in Paediatric Chronic Wet Cough: What Is Known and Future Directions.

Chronic wet cough for longer than 4 weeks is a hallmark of chronic suppurative lung diseases (CSLD), including protracted bacterial bronchitis (PBB), and bronchiectasis in children. Severe lower respiratory infection early in life is a major risk factor of PBB and paediatric bronchiectasis. In these conditions, failure to clear an underlying endobronchial infection is hypothesised to drive ongoing inflammation and progressive tissue damage that culminates in irreversible bronchiectasis. Historically, the microbiology of paediatric chronic wet cough has been defined by culture-based studies focused on the detection and eradication of specific bacterial pathogens. Various 'omics technologies now allow for a more nuanced investigation of respiratory pathobiology and are enabling development of endotype-based models of care. Recent years have seen substantial advances in defining respiratory endotypes among adults with CSLD; however, less is understood about diseases affecting children. In this review, we explore the current understanding of the airway microbiome among children with chronic wet cough related to the PBB-bronchiectasis diagnostic continuum. We explore concepts emerging from the gut-lung axis and multi-omic studies that are expected to influence PBB and bronchiectasis endotyping efforts. We also consider how our evolving understanding of the airway microbiome is translating to new approaches in chronic wet cough diagnostics and treatments.

Endotyping of Cholesteatoma: Which Molecular Biomarkers? A Systematic Review.

BACKGROUND: So far, no medical treatment is available for cholesteatoma (C) and the only effective therapy is complete surgical removal, but recurrence is common even after surgical treatment. While C is classically divided into two clinical phenotypes, congenital and acquired, only a few studies have focused on its potential biomarkers. This study aims to revise the literature to identify which biomarkers can define the endotype of C. METHODS: We conducted a systematic review in accordance with the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) process to identify published experimental articles about molecular biomarkers in C. RESULTS: KGF and its receptor, MMP-9, KRT-1, KRT-10, and MIF might be considered biomarkers of recurrence, whereas Ki-67, TLR-4, RANKL, IL17, MMP-2, MMP-9, IL6, TNF-α, should be considered more specifically as biomarkers of bony erosion. CONCLUSIONS: These results are interesting especially from a prognostic point of view, nevertheless more studies are needed to search new biomarkers of C that could completely change not only the therapeutic standards of the disease, but also the clinical history of C itself in the era of precision medicine.

Phenotype clustering in health care: A narrative review for clinicians.

Human pathophysiology is occasionally too complex for unaided hypothetical-deductive reasoning and the isolated application of additive or linear statistical methods. Clustering algorithms use input data patterns and distributions to form groups of similar patients or diseases that share distinct properties. Although clinicians frequently perform tasks that may be enhanced by clustering, few receive formal training and clinician-centered literature in clustering is sparse. To add value to clinical care and research, optimal clustering practices require a thorough understanding of how to process and optimize data, select features, weigh strengths and weaknesses of different clustering methods, select the optimal clustering method, and apply clustering methods to solve problems. These concepts and our suggestions for implementing them are described in this narrative review of published literature. All clustering methods share the weakness of finding potential clusters even when natural clusters do not exist, underscoring the importance of applying data-driven techniques as well as clinical and statistical expertise to clustering analyses. When applied properly, patient and disease phenotype clustering can reveal obscured associations that can help clinicians understand disease pathophysiology, predict treatment response, and identify patients for clinical trial enrollment.

[The development of a personalized approach in the treatment of chronic rhinosinusitis with nasal polyps]. / Razvitie personalizirovannogo podkhoda v lechenii polipoznogo rinosinusita.

Due to the high recurrence rate and the variety of complex pathogenesis mechanisms, chronic rhinosinusitis with nasal polyps is difficult to treat. In addition, the disease reduces the quality of life of patients and carries a large financial burden on the healthcare system, therefore, a personalized approach to the treatment of this pathology is becoming popular today. In order to determine which drug route would be most rational for a particular patient, key concepts such as phenotyping, endotyping and genotyping of chronic rhinosinusitis with nasal polyps were introduced. This approach has expanded the understanding of the etiological aspects of the disease and the pathogenetic mechanisms of the formation of nasal polyps. In this regard, immunotherapy of chronic rhinosinusitis with nasal polyps began to develop, consisting in the use of monoclonal antibodies to the substrates of the immune system, which are key figures in the development of certain types of inflammatory reactions of the mucous membrane of the nasal cavity and paranasal sinuses. The use of biological agents represents the first steps in targeted therapy, which is a transition to personalized treatment of patients with chronic rhinosinusitis with nasal polyps. Further studies in the field of immunological mechanisms of the formation of various phenotypes of chronic rhinosinusitis with nasal polyps from the standpoint of proteinomics, transcriptomics and epigenetics give hope for the development of a new drug-based treatment for this disease, which can significantly reduce the need for surgical treatment of patients with this pathology.