Search Results (778)

Major airway diseases, including chronic obstructive pulmonary disease (COPD), asthma, bronchiectasis and chronic rhinosinusitis without nasal polyps (CRSsNP), frequently coexist and share inflammatory, epithelial and remodeling features. However, whether these clinically distinct airway disorders are driven by a unified genetic liability and how this shared liability maps to disease-relevant tissues, genes and immune-regulatory programs remain incompletely understood. We integrated GWAS summary statistics for COPD, asthma, bronchiectasis and CRSsNP using linkage disequilibrium score regression, local genetic correlation analysis and Genomic structural equation modeling. A latent shared airway disease factor, termed gAirwayDisease, was constructed to capture common genetic liability across the four conditions. We then applied an integrative functional genomics framework, including gsMap spatial enrichment, PoPS gene prioritization, MAGMA gene-set enrichment, GTEx v8 lung MTWAS, OneK1K and DICE immune-cell MTWAS, scMORE regulon analysis and phenome-wide Mendelian randomization. All six airway disease pairs showed positive genetic correlations, with estimates ranging from 0.508 to 0.685. Genomic SEM supported a single shared factor, with positive standardized loadings for COPD, asthma, bronchiectasis and CRSsNP and excellent model fit. Spatial mapping localized gAirwayDisease-associated signals to airway- and epithelial-associated anatomical domains. PoPS prioritized immune and airway-relevant genes, including SMAD3, GATA3, IL1R1, RUNX3 and STAT6, while MAGMA enrichment highlighted B-cell activation, T-cell activation and transcriptional regulatory pathways. Lung MTWAS identified SLC9A2 and ORMDL3 as top genetically regulated expression signals. OneK1K immune-cell MTWAS highlighted recurrent IL18R1 associations across CD4 and CD8 T-cell subsets. scMORE further identified 36 significant regulon–cell type pairs across dendritic cells, B cells, monocytes, T cells and NK cells, including BCL11A, TCF4, KLF4, RUNX1 and STAT4 regulons. MR-PheWAS linked genetically predicted gAirwayDisease to respiratory, allergic, lung function and immune-related traits. This study defines gAirwayDisease as a genetically informed latent factor capturing shared liability across major airway diseases. Integrated functional genomic analyses highlight airway epithelial and immune regulatory programs associated with shared disease susceptibility and prioritize candidate genes and regulons for future experimental validation. Full article

Background/Objectives: Strongyloides stercoralis may persist through autoinfection and is clinically important before corticosteroid exposure, but its relationship with airway obstruction in children with sickle cell disease (SCD) is uncertain. We examined whether routine-detected S. stercoralis infection was associated with spirometry-defined airway obstruction in children with SCD in French Guiana. Methods: This multicentre cross-sectional secondary analysis used an availability-based sample from a routine respiratory screening database. Eligible children aged 5–17 years had SCD, spirometry, and stool parasitology documented during routine care. The primary outcome was FEV1/FVC < 80%. Logistic regression adjusted for age, sex, genotype, hydroxyurea treatment, previous acute chest syndrome, and atopy. Results: Stool parasitology was available for 160 children; 26 (16.2%) had S. stercoralis detected. Among 138 children with complete spirometry and covariate data, 45 (32.6%) had obstruction. S. stercoralis was not associated with obstruction in univariable analysis (OR 0.75, 95% CI 0.30–1.91) or after adjustment (adjusted OR 1.02, 95% CI 0.37–2.86; p = 0.964). Male sex was independently associated with obstruction (adjusted OR 2.32, 95% CI 1.11–4.83). Conclusions: Routine-detected S. stercoralis infection was not an independent correlate of airway obstruction. The wide confidence interval, limited exposure ascertainment, and small infected subgroup mean that clinically important protective or harmful associations cannot be excluded. Full article

Pediatric allergic and obstructive respiratory diseases are a leading cause of chronic childhood morbidity. Passive tobacco smoke exposure (TSE) is one of the most prevalent and preventable indoor pollutants affecting children, while oxidative stress is increasingly recognized as a key mechanism linking tobacco smoke exposure to airway inflammation. This systematic review critically evaluated the evidence connecting passive TSE to oxidative stress pathways in pediatric airway disease and integrated it into a “second oxidative hit” hypothesis. Following PRISMA 2020 guidelines, PubMed and MEDLINE were searched to identify studies assessing passive TSE, oxidative or antioxidant biomarkers, and respiratory outcomes in children. Of the 77 records identified, four studies met the inclusion criteria. Across the available evidence, passive TSE was associated with increased lipid peroxidation, NOX2 activation, oxidative–inflammatory signaling, depletion of antioxidant defenses, oxidative DNA damage, and impairment of redox-sensitive corticosteroid-response pathways, although findings were not uniform across studies. Clinically, passive TSE children showed persistent allergic rhinitis, greater wheezing severity, poorer asthma control and reduced corticosteroid responsiveness. Despite limited and heterogeneous evidence, the findings provide a biological rationale for a testable “second oxidative hit” hypothesis, whereby passive TSE, combined with a pre-existing inflammatory environment in the airways associated with the underlying disease, could produce an additional oxidative burden. Further prospective studies integrating standardized oxidative biomarkers and objective exposure assessment are needed to validate this hypothesis, and establish temporal and causal relationships, potentially supporting more targeted preventive and personalized strategies. Full article

Airborne microplastics and nanoplastics (MNPs) are increasingly reported in indoor, outdoor, and occupational air, but their aerobiological significance remains incompletely defined. This narrative review proposes the aeroplastic exposome as a cautious, testable framework for evaluating airborne MNPs as interfaces among aerosol transport, biological and chemical loading, aeroallergen co-exposure, inhalation, respiratory deposition, clearance, and airway immune response. Evidence from environmental monitoring, indoor and occupational exposure studies, and human respiratory-sample and lung-tissue detection studies supports the occurrence of airborne MNPs, the plausibility of inhalation exposure, reported detection in human respiratory samples, and experimental hazard under selected conditions. However, evidence that airborne plastic particles routinely carry bioaerosols or aeroallergens remains insufficient or model-dependent. The aeroplastic exposome is therefore not proposed as a disease entity, validated exposure metric, or established explanation for asthma, chronic obstructive pulmonary disease, fibrosis, infection, or cancer. Instead, it is a framework for organizing testable questions about polymer identity, aerodynamic fraction, morphology, aging state, biological loading, co-exposure context, deposition, clearance, epithelial–immune responses, and host susceptibility. Priority research needs to include standardized airborne sampling, same-particle polymer–bioaerosol–allergen characterization, exposure-relevant aerosol systems, factorial co-exposure experiments, and prospective human studies with repeated personal exposure assessment. Full article

Background: Asthma is a chronic inflammatory airway disease characterized by variable airflow obstruction and tissue remodeling. Alamandine (ALA), a renin–angiotensin system (RAS) peptide with anti-inflammatory properties, remains poorly explored in allergic respiratory disease. Objectives: This study evaluated prophylactic (33 days) and therapeutic (21 days) subcutaneous ALA (50 µg/kg/day) administration in an ovalbumin (OVA)-induced rat asthma model. Methods: Twenty male Wistar rats were assigned to four groups: control (CO), OVA with prophylactic ALA (ALA-P; days 1–33), OVA with therapeutic ALA (ALA-T; days 12–33), and OVA-only control (OVA). Rats were sensitized (days 1–3) and challenged with aerosolized OVA (days 6–33). On day 34, ventilatory mechanics were assessed via FlexiVent, including methacholine challenge (12.5 mg/mL). Pulmonary inflammation was evaluated by eosinophil quantification; MrgD/Mas and AT1 receptor expression by immunohistochemistry and Western blot, respectively. Results: OVA animals exhibited elevated baseline airway resistance and bronchoconstriction, and eosinophil infiltration. ALA-T significantly attenuated the respiratory symptoms, restoring airway resistance and eosinophil infiltration to CO-group levels, whereas ALA-P exhibited only a partial reduction. MrgD and Mas expression were elevated in OVA, reflecting compensatory RAS activation, but normalized in both ALA-treated groups. No significant differences in AT1 expression were observed. Conclusions: ALA likely exerts bronchoprotective and anti-allergic effects in this model via MrgD/Mas modulation. The ALA–MrgD/Mas axis represents a potential therapeutic target for allergic airway diseases, particularly when conventional treatments are insufficient. Full article

Background and Objectives: Oxidative stress and nitric oxide (NO)-related inflammatory activity contribute to chronic obstructive pulmonary disease (COPD), particularly during acute exacerbation of COPD (AECOPD). Myeloperoxidase (MPO) reflects neutrophil-related oxidative activity, whereas NO is involved in airway inflammation, endothelial regulation, and systemic inflammatory responses. This study compared serum MPO and NO levels among patients with AECOPD, patients with stable COPD, and healthy controls, and explored their discriminatory performance for distinguishing AECOPD from stable COPD. Materials and Methods: This cross-sectional comparative observational study prospectively enrolled 90 participants: 30 patients with AECOPD, 30 patients with stable COPD, and 30 healthy adult controls. COPD was confirmed by post-bronchodilator spirometry. Serum MPO and NO levels were measured using commercially available enzyme-linked immunosorbent assay kits. Group comparisons, exploratory subgroup analyses, correlation analyses, regression models, and receiver operating characteristic (ROC) curve analyses were performed. Results: Serum NO and MPO levels increased stepwise from healthy controls to stable COPD and AECOPD. Median serum NO levels were 109.79, 170.05, and 227.95 µmol/L, respectively, and median serum MPO levels were 4.14, 8.00, and 9.98 ng/mL, respectively (both p < 0.001). GOLD stage 3–4 disease was associated with higher levels of both biomarkers than GOLD stage 1–2 disease (both p < 0.001). In COPD-only exploratory logistic regression, serum NO and MPO were associated with AECOPD status. ROC analysis showed AUC values of 0.911 for serum NO and 0.811 for serum MPO, with no significant AUC difference by DeLong’s test (p = 0.187). Conclusions: Serum MPO and NO levels were progressively higher across healthy control, stable COPD, and AECOPD states. These exploratory findings suggest that systemic oxidative and NO-associated inflammatory activity may reflect COPD clinical state; however, sample-specific ROC cut-offs require external validation before diagnostic use. Full article

Chronic respiratory diseases, including asthma, chronic obstructive pulmonary disease (COPD), bronchiectasis, cystic fibrosis, and chronic bronchitis, are characterized by persistent airway inflammation and mucus hypersecretion, leading to airway remodeling and progressive pulmonary dysfunction. Although current therapies improve disease control, they often fail to adequately target the complex molecular mechanisms underlying chronic airway diseases and may cause adverse effects during long-term use. Natural products have therefore emerged as promising multitarget therapeutic agents because they simultaneously regulate oxidative stress, inflammatory signaling, epithelial dysfunction, and mucus production. Recent evidence demonstrates that marine-derived bioactive compounds and plant-derived phytochemicals modulate key signaling pathways, including nuclear factor-kappa B (NF-κB), mitogen-activated protein kinases (MAPKs), phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt), Janus kinase/signal transducer and activator of transcription (JAK/STAT), the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome, and nuclear factor erythroid 2-related factor 2 (Nrf2), thereby suppressing airway inflammation, oxidative stress, goblet cell differentiation, and MUC5AC overexpression. Advances in nanoformulation, pulmonary drug delivery, multi-omics, artificial intelligence-assisted drug discovery, and network pharmacology are expected to accelerate clinical translation. Collectively, natural products represent promising candidates for the development of evidence-based functional foods, nutraceuticals, and novel therapeutic strategies for chronic respiratory diseases. Full article

Background/Objectives: Obstructive sleep apnea (OSA) is a prevalent chronic disorder whose first-line treatment, continuous positive airway pressure (CPAP), is effective only if the patient maintains sufficient adherence. Early predictions of the risk of low adherence would make it possible to personalize follow-up and optimize healthcare resources. The aim of this study was to develop and evaluate a machine-learning-based clinical decision support system to predict CPAP adherence after one year of treatment. Methods: A cohort of 200 patients with OSA from the Sleep-Disordered Breathing Unit of Hospital Álvaro Cunqueiro in Vigo was used. The cohort was split into a training set (n = 160) and an independent test set (n = 40). Two scenarios were defined: Scenario A, with pre-treatment variables, and Scenario B, which also includes early adherence metrics. In each scenario, variables were selected through recursive feature elimination. The selected variables were apnea-hypopnea index (AHI), 3% oxygen desaturation index (ODI3%), chronic obstructive pulmonary disease and neck circumference in Scenario A, and first-month adherence, ODI3% and AHI in Scenario B. Once these subsets were defined, several classifiers were analyzed. Results: Random Forest was the model selected in both scenarios. On the test set, Scenario A reached an area under the curve (AUC) of 0.71 (sensitivity 0.83; specificity 0.45) and Scenario B an AUC of 0.91 (sensitivity 0.90; specificity 0.82). Conclusions: Early prediction of CPAP adherence using machine learning is feasible; incorporating real first-month use markedly improves discriminative ability. The system was integrated into a web prototype as a proof of concept. Given the modest sample size and the absence of external validation, these results should be interpreted as preliminary, corresponding to an exploratory, feasibility study. For future implementation, an extensive clinical validation process will be required, along with the expansion of the database, which will likely contribute to improving the system’s robustness and generalization capacity. Full article

Pediatric obstructive sleep apnea (OSA) is a common disorder associated with significant neurocognitive, behavioral, cardiovascular, and metabolic consequences. Although adenotonsillectomy remains first-line therapy for many children, residual OSA is common, particularly among those with obesity, craniofacial abnormalities, genetic syndromes, neuromuscular disease, or other forms of medical complexity. Continuous positive airway pressure (CPAP) is the standard non-surgical treatment; however, long-term effectiveness is frequently limited by poor tolerance and adherence. Heated high-flow nasal cannula (HFNC) therapy has emerged as a potential alternative for selected children with sleep-disordered breathing, particularly those who are unable to tolerate conventional positive airway pressure therapy. Unlike CPAP, HFNC delivers heated, humidified gas through an open nasal interface and may improve sleep-disordered breathing through a combination of flow-dependent positive airway pressure generation, dead-space washout, improved ventilatory efficiency, enhanced gas conditioning, and reductions in inspiratory resistance. However, the relative contribution of these mechanisms during sleep remains incompletely understood. Current clinical evidence consists primarily of physiological studies, retrospective cohorts, case series, and a limited number of prospective comparative studies. Collectively, these data suggest that HFNC can reduce obstructive respiratory events and improve oxygenation in selected pediatric populations, including children with persistent OSA, CPAP intolerance, medical complexity, and syndromic conditions. Nevertheless, important uncertainties remain regarding optimal patient selection, titration strategies, patient monitoring, long-term adherence and comparative effectiveness relative to CPAP. This review summarizes the physiological basis of HFNC therapy, critically appraises the current clinical evidence, discusses practical considerations related to adherence and implementation, and highlights key knowledge gaps and future research priorities. Overall, HFNC should be viewed as an alternative for selected children who cannot tolerate CPAP, rather than as a universal substitute for pressure-based therapy. Full article

Background: Asthma and chronic obstructive pulmonary disease (COPD) are heterogeneous chronic airway disorders characterized by complex interactions among inflammation, immune dysregulation, environmental exposures, and tissue remodeling. Conventional clinical classifications based on symptoms, lung function, and exacerbation history often fail to fully capture the biological mechanisms underlying disease progression and therapeutic variability. Methods: This narrative review summarizes current evidence regarding the biological and clinical significance of YKL-40, mannose-binding lectin (MBL), and epigenetic remodeling in asthma and COPD, with particular emphasis on the inflammation–epigenetic axis and its potential role in disease phenotyping and precision medicine. Results: Available evidence suggests that YKL-40, MBL, and epigenetic signatures represent complementary biomarker layers reflecting tissue remodeling, innate immune variability, and cumulative inflammatory adaptation, respectively. Chronic inflammatory signaling, oxidative stress, and epigenetic remodeling may contribute to persistent molecular memory and phenotypic stabilization, providing a mechanistic framework for understanding disease heterogeneity and progression. Advances in multi-omics technologies, artificial intelligence, and machine learning are further supporting the development of integrated multimarker models. Conclusions: YKL-40, MBL, and epigenetic signatures should currently be considered complementary research variables rather than validated clinical tools. Their translation requires disease-specific assay standardization, prospective evaluation against prespecified outcomes, external validation, and evidence that biomarker-guided decisions improve patient care. Full article

Obstructive sleep apnea (OSA) is a highly prevalent sleep-related breathing disorder affecting an estimated 1.36 billion people worldwide. It is associated with excessive daytime sleepiness, impaired quality of life, cardiovascular and cerebrovascular disease, and increased all-cause mortality, and is a substantial economic burden. Although positive airway pressure (PAP) remains the gold-standard therapy, its effectiveness is limited by suboptimal tolerance and adherence, leading to interest in pharmacological alternatives. Among emerging options, AD109, a combination of the selective noradrenergic reuptake inhibitor atomoxetine (75 mg) and the antimuscarinic aroxybutynin (2.5 mg), taken once daily, represents a mechanistically targeted approach that acts on the neuromuscular roots of OSA. Preclinical work demonstrated that pharyngeal dilator tone is suppressed in sleep through withdrawal of noradrenergic excitation and active muscarinic inhibition at the hypoglossal motor nucleus, providing the rationale for combining a noradrenergic agent with an antimuscarinic to augment hypoglossal motor output and preserve upper-airway patency. Building on a series of smaller precursor trials of noradrenergic–antimuscarinic combinations, AD109 has demonstrated consistent efficacy across phase 2 and two large phase 3 trials (SynAIRgy and LunAIRo), with meaningful reductions in the apnea–hypopnea index, improvements in nocturnal oxygenation, and a generally favorable tolerability profile. These findings position AD109 as a promising oral option, particularly for adults with mild to severe OSA who cannot tolerate or decline PAP. However, its effect on long-term cardiovascular, neurocognitive, and mortality outcomes remains to be established. This commentary reviews the mechanism of action and clinical trial evidence for AD109 and related combinations. Full article

Obstructive sleep apnea (OSA) is associated with increased cardiovascular, respiratory, and all-cause mortality, yet the long-term survival impact of continuous positive airway pressure (CPAP) remains contested, and treatment is usually analysed as a binary exposure rather than by the quality of the response achieved. In a single-centre cohort of 4368 adults referred for polysomnography and followed for 8–20 years (prespecified subgroup with apnea–hypopnea index [AHI] ≥ 15, n = 2304), we applied cause-specific Cox and Fine–Gray competing-risks models, together with machine-learning classifiers, to characterise all-cause, cardiovascular, and pulmonary mortality. CPAP was associated with reduced all-cause (hazard ratio [HR] 0.75), cardiovascular (HR 0.75), and pulmonary mortality (HR 0.54), with the benefit confined to severe OSA (HR 0.66) and absent in moderate disease (HR 0.95). Good responders showed a significant 34% reduction in all-cause mortality (HR 0.66), whereas poor responders showed no significant reduction. Nocturnal desaturation (time with oxygen saturation < 90%) was the dominant independent predictor of pulmonary mortality, and baseline features predicted response category only moderately (macro-averaged AUC 0.76). Long-term CPAP confers a severity- and response-dependent survival benefit; nocturnal hypoxaemia is a key, modifiable driver of respiratory death. Full article

Background and Clinical Significance: Anti–myelin-associated glycoprotein (MAG) antibody polyneuropathy is a rare, chronic IgM-mediated demyelinating peripheral neuropathy predominantly affecting sensory nerves in older adults, commonly in association with monoclonal gammopathy of undetermined significance. Reports describing anesthetic management in patients with this condition remain extremely limited, and no specific guidelines currently exist regarding neuromuscular blocking agent (NMBA) use or neuromuscular monitoring in this population. Case Presentation: A 79-year-old man with anti-MAG antibody polyneuropathy (diagnosed in 2007) and IgM monoclonal gammopathy of undetermined significance developed disproportionate progressive lower-extremity weakness and became wheelchair-dependent following COVID-19 infection in 2020. Preoperative evaluation revealed mildly reduced left ventricular function (ejection fraction 49%), mild chronic kidney disease, and marked intrinsic hand muscle atrophy with absent deep tendon reflexes. He was scheduled for robot-assisted radical cystectomy with ileal conduit diversion under combined general and thoracic epidural anesthesia. Before NMBA administration, neuromuscular monitoring was systematically attempted at the ulnar nerve (electromyography and acceleromyography, up to 60 mA/300 μs) and the corrugator supercilii; despite visible muscle contractions following peripheral nerve stimulation, neither modality produced reliable responses at either site. Given the inability to establish reliable monitoring, the administration of NMBAs was considered to carry an unacceptable risk of a prolonged, undetectable blockade. Anesthesia was maintained with deep sevoflurane (2.0–2.5% end-tidal) and remifentanil infusion without NMBAs, titrated to a bispectral index of 40–60. Tracheal intubation was accomplished via video laryngoscopy without NMBA. The 7 h and 30 min surgery was completed without patient movement or surgical compromise. Postoperatively, the patient developed transient upper airway obstruction attributed to glossoptosis, managed successfully with head elevation and nasopharyngeal airway insertion; supplemental oxygen was required until postoperative day 3, and the patient was discharged from the high-dependency unit on postoperative day 5. Conclusions: No measurable quantitative neuromuscular response could be obtained in this patient with advanced anti-MAG antibody neuropathy, despite appropriate application of electromyography- and acceleromyography-based monitoring and the presence of visible muscle contractions following peripheral nerve stimulation. In such circumstances, avoiding NMBA administration in favor of deep volatile or intravenous anesthesia with opioid supplementation may represent a reasonable, hypothesis-generating approach in carefully selected patients; this observation does not establish the general superiority of an NMBA-free strategy, and caution is warranted before generalizing it to procedures such as robotic surgery, in which profound neuromuscular blockade is often considered desirable. Full article

The therapeutic goals related to chronic airway diseases are evolving from short-term symptom control toward sustained suppression of disease activity and prevention of future risk. In severe asthma, this shift has been captured by the concept of clinical remission, generally defined by absence of exacerbations, no need for oral corticosteroids, symptom control, and stable or improved lung function. In chronic obstructive pulmonary disease (COPD), the analogous concept has more often been described as disease stability. Although remission in asthma and stability in COPD have developed within different biological and clinical frameworks, they may reflect disease-specific expressions of the same therapeutic ambition. Recent studies support COPD stability as a measurable and clinically meaningful state, associated with reduced exacerbation risk and mortality. Evidence from optimized inhaled triple therapy, particularly with fluticasone furoate/umeclidinium/vilanterol, indicates that multidimensional stability can be achieved and maintained in a proportion of patients, while real-world studies reinforce its applicability beyond randomized trials. The emergence of biologic therapies for selected patients with eosinophilic or type 2 COPD further strengthens the rationale for considering stability as an ambitious treatment target. In this narrative review, informed by a structured literature search, we discuss the conceptual relationship between asthma remission and COPD stability, and summarize the evidence supporting disease stability as an attainable and prognostically relevant outcome. In addition, we propose a pragmatic multidimensional definition based on symptom stability, absence of moderate or severe exacerbations, no systemic corticosteroid use, and maintained lung function over 12 months. COPD stability should not be viewed as a weaker goal than asthma remission, but rather as the most appropriate COPD-specific expression of sustained low disease activity. Full article

Background/Objectives: Obstructive sleep apnea (OSA) is traditionally diagnosed via polysomnography (PSG) using the apnea–hypopnea index (AHI). However, AHI alone may inadequately reflect the clinical heterogeneity, symptom burden, and cardiometabolic consequences of the disease. The Baveno classification incorporates symptom severity and comorbidity burden into a multidimensional framework. We aimed to evaluate the agreement between PSG-staging and the Baveno classification, to investigate the impact of reclassification on positive airway pressure (PAP) treatment recommendations. Methods: This retrospective study included 395 adults with OSA diagnosed via PSG between January 2016 and June 2024. Patients were categorized according to PSG severity (mild, moderate, and severe) and Baveno phenotypes (A, B, C, D). PAP therapy indication was defined as AHI ≥ 15 events/hour in the PSG-based classification and as Baveno groups B-D in the multidimensional approach. Agreement between the systems was assessed using Cohen’s kappa coefficient. Results: PAP therapy was indicated in 252 patients (63.8%) via PSG and in 268 patients (67.8%) via the Baveno classification. Overall agreement between the systems was 63.5%, (κ = 0.191) and increased with disease severity, reaching 87.1% with severe OSA. Overall, 144 patients (36.5%) were reclassified, including 80 patients newly identified as candidates for PAP therapy and 64 patients reclassified as not requiring PAP therapy according to the Baveno framework. BMI showed only a weak correlation with AHI overall and no significant association in women. Conclusions: Combined use of PSG and the Baveno approach provides more individualized PAP treatment decisions, particularly among clinically heterogeneous patients and those within intermediate severity categories. Full article