Search Results (6,255)

Pyrazole derivatives have attracted considerable interest in medicinal chemistry as adaptable frameworks for developing cholinesterase inhibitors, owing to their advantageous physicochemical properties and structural flexibility. The heteroaromatic characteristics of the pyrazole core allow for various substitution patterns, promoting selective interactions with both the catalytically active site (CAS) and the peripheral anionic site (PAS) of cholinesterase enzymes. These attributes enable pyrazole-based drugs to be viable candidates for the therapy of cognitive disorders, especially Alzheimer’s disease. This study aims to systematically describe medicinal chemistry studies on pyrazole-based cholinesterase inhibitors conducted from 2020 to 2025. The focus is on structural alterations of the pyrazole core and their impact on the inhibitory action against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) using structure–activity relationship (SAR) analysis. Recent advancements in in vitro enzymatic inhibition studies, molecular docking, kinetic analysis, ADME predictions, and multi-target-directed ligand (MTDL) techniques are rigorously evaluated to elucidate trends in potency, selectivity, and drug-like characteristics based on information retrieved from three search engines: Scopus, PubMed, and Google Scholar. This review addresses significant challenges in pharmacokinetics, blood–brain barrier permeability, and safety while delineating prospects for integrating rational design, computational modeling, and biological validation to expedite the development of clinically relevant pyrazole-based cholinesterase inhibitors for Alzheimer’s disease. Full article

Hypertension is a prevalent disorder that results in millions of deaths worldwide. In this regard, timely diagnosis and effective treatment are paramount for maintaining optimal blood pressure levels in the early stages of the disease. The objective of the present study was to synthesize and assess the effect of peptides derived from chia seeds that had undergone fermentation with Lacticaseibacillus paracasei strain 2501 (hereinafter referred to as LPDP, i.e., L. paracasei-derived products from this fermentation) on the angiotensin-converting enzyme (ACE) and the spontaneously hypertensive rat model (SHR). LPDP exhibited competitive inhibition, as evidenced by the identification of seven peptides in the <1 kDa fraction by HPLC-QToF-MS. The LPDP exhibited an IC₅₀ of 11.1 μg/mL on ACE. The oral administration of 50 mg/kg body weight (BW) to SHR over a 14-day period resulted in a significant reduction in systolic pressure from 152 to 87 mmHg, accompanied by a substantial decrease in diastolic pressure from 117 to 74 mmHg. It is noteworthy that doses of 500 mg/kg BW led to a significant reduction in systolic pressure, from 154 to 68 mmHg and diastolic pressure, from 117 to 42 mmHg under identical experimental conditions. The hematological profiling of the assayed animals revealed that LPDP has no adverse effects at the cellular or biochemical level. These findings indicate the anti-hypertensive properties of LPDP and its possible application in the treatment of blood pressure. Full article

Age-associated metabolic dysfunction is commonly defined by abnormalities in adiposity, glucose regulation, lipid metabolism, and blood pressure. Although clinically useful, these criteria do not fully capture the biological heterogeneity that explains why older adults with similar metabolic profiles may follow divergent trajectories toward type 2 diabetes, cardiovascular disease, metabolic dysfunction-associated steatotic liver disease, frailty or multimorbidity. This narrative Review summarizes clinical, translational, and mechanistic evidence on the biological processes that shape metabolic aging, with particular emphasis on inflammaging, immunosenescence, cellular senescence, oxidative stress, mitochondrial dysfunction, adipose tissue dysfunction, endothelial injury, and inflammation-related microRNAs. We first discuss how chronic low-grade inflammation and immune remodeling alter the interpretation of conventional metabolic syndrome components in older adults. We then review redox imbalance and mitochondrial stress as amplifiers of insulin resistance, lipid injury, vascular dysfunction, and tissue remodeling. The review also examines inflammation-related microRNAs, including circulating and extracellular-vesicle-associated miRNAs, as post-transcriptional regulators that may connect inflammatory, metabolic, and redox pathways. Finally, we discuss how conventional metabolic markers may be integrated with inflammatory mediators, oxidative-stress indicators, adipokines, endothelial and senescence-related markers, and miRNA profiles to improve biological interpretation of metabolic risk. Within this context, we present the Inflammaging–Redox–InflammamiR Axis as a conceptual framework for organizing these overlapping mechanisms rather than as an established diagnostic or causal model. The proposed biomarker tiers and candidate risk phenotypes are author-derived, hypothesis-generating constructs intended to guide future longitudinal and interventional research. Clinical translation will require standardized assays, longitudinal validation, external replication, and intervention studies. Full article

Oxidative stress contributes to retinal neurovascular injury through inflammation, mitochondrial dysfunction, blood–retinal barrier (BRB) disruption, microcirculatory impairment, and regulated cell death. Hydroxysafflor yellow A (HSYA), a water-soluble quinochalcone C-glycoside derived from safflower (Carthamus tinctorius L.), modulates oxidative and inflammatory signaling, apoptosis, mitochondrial injury, endothelial barrier dysfunction, and neurovascular damage in experimental ischemic, inflammatory, and metabolic disorders. This review critically evaluates the direct ocular evidence for HSYA in diabetic retinopathy and examines the systemic-to-ocular pharmacokinetic and delivery barriers that constrain its ophthalmic translation. Current ocular evidence is limited and concentrated mainly in DR models, in which HSYA attenuates oxidative stress, inflammation, BRB disruption, and apoptosis, potentially through Nrf2/HO-1 signaling. Evidence in retinal photic injury is limited, whereas the proposed relevance of HSYA to retinal ischemia–reperfusion injury, glaucoma, and AMD remains largely hypothesis-generating. The principal translational challenge is whether HSYA can achieve pharmacologically relevant exposure in ocular target tissues. Future studies should integrate dose, plasma and ocular exposure, target engagement, retinal structure, local safety, and visual function in disease-specific models. Accordingly, evidence from non-DR models is discussed primarily to define mechanistic hypotheses and experimental priorities rather than to establish ophthalmic efficacy. Full article

Cardiometabolic residual risk in type 2 diabetes mellitus (T2D) persists despite major advances in glucose-lowering therapy, lipid management, blood pressure control, weight reduction, and organ-protective strategies. This residual burden should not be interpreted solely as the consequence of incomplete achievement of conventional therapeutic targets, but rather as the clinical expression of persistent molecular activity involving multiple interconnected organs and pathways. Insulin resistance, metaflammation, oxidative stress, mitochondrial dysfunction, lipotoxicity, endothelial impairment, hepatic metabolic dysregulation, renal inflammation, fibrotic remodeling, and metabolic memory interact within a dynamic network linking adipose tissue, liver, kidney, immune cells, and vasculature. In this review, we discuss the biochemical and molecular drivers of cardiometabolic residual risk in T2D, with particular emphasis on impaired insulin receptor substrate/PI3K/Akt signaling, stress-kinase activation, NLRP3 inflammasome priming and assembly, MASLD-related lipotoxicity and fibrogenesis, podocyte and tubular injury, endothelial nitric oxide synthase uncoupling, AGE-RAGE signaling, and thrombo-inflammatory vascular injury. These pathways explain why biological vulnerability may persist even when conventional clinical parameters appear adequately controlled. We also examine the role of translational biomarkers and simple clinical indices, including TyG-derived indices, adiposity markers, hepatic steatosis and fibrosis scores, albuminuria, eGFR, and lipid-related markers, as accessible windows into active biological pathways. Finally, we review how contemporary therapeutic strategies may modulate selected components of this residual-risk network. A pathway-centered interpretation of T2D may support more precise residual-risk phenotyping and help move cardiometabolic care beyond isolated target control toward mechanism-based prevention. This review further links these mechanisms to the contemporary cardiovascular–kidney–metabolic (CKM) framework, as defined by the 2026 AHA/ACC/ADA/ASN CKM Guideline, and disaggregates the underlying molecular network into organ-specific pathway cascades that make the causal relationships between metabolic, inflammatory, hepatic, renal, and vascular injury more explicit. Full article

Background/Objectives: Preoperative discrimination of complicated appendicitis in children remains challenging but crucial for timely surgical decision-making and perioperative management. We aimed to develop a simple, clinically applicable scoring system for preoperative risk stratification of complicated appendicitis in children. Methods: This retrospective single-center study included children aged 5 to <16 years who underwent emergency appendectomy between 2015 and 2024. Complicated appendicitis was defined as gangrene, perforation, or intra-abdominal abscesses on intraoperative or pathological evaluation. Literature-based prespecified predictors included body temperature ≥ 38.0 °C, presence of periappendicular fluid, serum sodium level < 135 mEq/L, white blood cell (WBC) count > 12,000/μL, and C-reactive protein (CRP) level ≥ 3.0 mg/dL. A multivariable logistic regression model using Firth’s penalized likelihood was developed and internally validated using bootstrap resampling. An additive scoring system was derived from the final model. Results: Among 301 patients, 102 (33.9%) had complicated appendicitis. Based on the Firth penalized multivariable model, integer point values were assigned in proportion to the regression coefficients. Serum sodium level < 135 mEq/L and CRP level ≥ 3.0 mg/dL assigned 2 points each; body temperature ≥ 38.0 °C, presence of periappendicular free fluid, and WBC count > 12,000/μL assigned 1 point each. The scoring system (range, 0–7) demonstrated good discrimination (area under the receiver operating characteristic curve, 0.880; 95% confidence interval, 0.840–0.920), minimal optimism, and good calibration. Stratification into low-, intermediate-, and high-risk categories showed an increasing prevalence of complicated appendicitis. Conclusions: This simple preoperative scoring system enables reliable and clinically interpretable risk stratification for complicated appendicitis in children aged 5 to <16 years and may support early decision-making in routine pediatric surgical practice. Full article

Background: Biomarkers are increasingly used in sport science and sports medicine to monitor training load, recovery, metabolic stress, nutritional status, and potential clinical risk in athletes. However, their interpretation is often limited by overreliance on isolated values, population reference ranges, and simplified thresholds. This narrative review aims to provide a contextual and metabolically informed framework for interpreting routine and emerging biomarkers in athletes. Methods: A critical narrative synthesis was conducted across key physiological domains relevant to athlete monitoring, including exercise intensity, metabolic flexibility, muscle damage, protein catabolism, hydration, hematological and iron status, micronutrient and bone–muscle health, inflammation, endocrine stress, sport-specific interpretation, and emerging metabolomics. The review integrated routine laboratory markers with pathway-level metabolomic interpretation and practical decision-making principles. Results: Routine markers such as lactate, creatine kinase, urea/blood urea nitrogen (BUN), creatinine, electrolytes, ferritin, C-reactive protein, cortisol, testosterone, and vitamin D are useful only when interpreted in relation to individual baseline, sampling conditions, recent workload, nutrition, hydration, sleep, illness, sex-specific physiology, and performance. Metabolomics expands interpretation by identifying pathway-level signatures involving glycolysis, β-oxidation, amino acid turnover, purine degradation, ketone bodies, acylcarnitines, bile acids, oxylipins, kynurenine metabolites, and exercise-induced signaling molecules such as lactate, β-aminoisobutyric acid (BAIBA), and N-lactoyl-phenylalanine (Lac-Phe). However, omics-derived markers require careful standardization and validation before routine applied use. Conclusions: Biomarkers should refine, not replace, clinical reasoning and athlete monitoring. A BASE framework (Baseline, Analytical standardization, Sport-specific context, and Evidence of functional change) may support more precise and proportionate interpretation of both routine blood tests and emerging metabolomic tools in athletes. Full article

Orthopedic procedures trigger a complex inflammatory response that plays a central role in tissue repair and postoperative recovery. However, excessive or dysregulated inflammation may contribute to complications such as periprosthetic joint infection, thromboembolic events, delayed healing, or systemic organ dysfunction. Therefore, accurate perioperative monitoring of inflammatory activity has become increasingly important in orthopedic surgery. Evidence discussed in this review was identified through a literature search of PubMed, Scopus, and Web of Science databases covering publications from 2000 to 2026. This narrative review summarizes the current evidence regarding both traditional inflammatory biomarkers, including C-reactive protein (CRP), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), procalcitonin (PCT), and D-dimers, as well as emerging biomarkers derived from complete blood count (CBC), such as the neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), platelet-to-lymphocyte ratio (PLR), systemic immune-inflammation index (SII), systemic inflammatory response index (SIRI), and aggregate index of systemic inflammation (AISI). Particular attention is devoted to the clinical utility of these biomarkers in orthopedic trauma, fracture healing, total joint arthroplasty, and the early detection of postoperative complications. Increasing evidence suggests that composite CBC-derived indices may provide a practical and cost-effective approach for perioperative risk stratification and prognosis assessment. Nevertheless, their interpretation remains challenging due to the lack of standardized cutoff values and the influence of multiple patient-related factors. Current evidence indicates that assessing biomarker kinetics and interpreting multiple inflammatory indices together may be more clinically valuable than isolated measurements. Future research should focus on standardization, validation in prospective studies, and integration of inflammatory biomarkers into personalized perioperative care pathways in orthopedic surgery. Full article

This paper presents a unified comparative study of various controllers, including proportional–integral–derivative (PID), Fractional-Order PID (FOPID), Internal Model Control (IMC) controllers, and Tilt–Integral–Derivative (TID) controllers, for the regulation of mean arterial blood pressure (MABP). The controllers are optimally tuned by using a single metaheuristic approach, namely the Pelican Optimization Algorithm (POA), ensuring a fair and consistent comparison. The POA optimizes the objective function using standard error indices (ITAE, IAE, and ISE) along with transient characteristics. The aforementioned controllers are then evaluated under varying patient conditions for different patient categories, including sensitive, nominal, and insensitive, and their performance is systematically compared with one another and with the reported methods from the existing literature. The simulation results demonstrate that IMC offers fast settling with minimal overshoot, FOPID improves robustness through fractional dynamics, and the TID controller provides the smoothest transient response and disturbance rejection across all patient categories. The results confirm the effectiveness of advanced control strategies over conventional PID and highlight the potential of POA-tuned TID control for reliable and patient-specific MABP regulation in critical care applications. Full article

Background: Electrolyte disturbances are common in critically ill patients with acute kidney injury (AKI) and often require urgent intervention. Arterial blood gas (ABG) analyzers provide rapid point-of-care electrolyte measurements, but their agreement with central laboratory analyzers in critically ill patients with AKI remains uncertain. This study evaluated the agreement between ABG and central laboratory measurements of sodium (Na⁺), potassium (K⁺), and chloride (Cl⁻). Methods: We conducted a retrospective observational study of adult critically ill patients with AKI admitted to a tertiary university hospital ICU between January 2013 and June 2024. Patients with paired electrolyte measurements obtained from an ABG analyzer (ABL800 Basic, Radiometer) and a central laboratory analyzer (Abbott Alinity) within 10 min were included. Agreement was assessed using Bland–Altman analysis and Passing–Bablok regression. Results: A total of 1870 critically ill patients with AKI were included. The mean bias (95% limits of agreement [LOA]) between ABG and central laboratory measurements was −0.68 mmol/L (−11.41 to 10.06) for sodium, −0.17 mmol/L (−1.46 to 1.12) for potassium, and 7.18 mmol/L (−4.15 to 18.51) for chloride. Potassium showed the narrowest LOA. Pearson correlation coefficients were 0.736, 0.642, and 0.728 for sodium, potassium, and chloride, respectively. Clinically meaningful discrepancies were observed in 7.0% of sodium, 14.1% of potassium, and 31.4% of chloride measurements. Conclusions: ABG-derived sodium and potassium measurements showed relatively good agreement with central laboratory measurements, particularly for potassium. However, clinically meaningful discrepancies occurred in a subset of measurements, suggesting that preanalytical factors and specimen quality may influence measurement reliability. ABG-derived electrolyte measurements may support rapid bedside assessment, whereas central laboratory measurements remain the reference standard. Full article

Background/Objectives: Lipid peroxidation is a relevant oxidative–inflammatory mechanism in essential hypertension and cardiovascular disease. Plasma thiobarbituric acid reactive substances (TBARS), commonly reported as malondialdehyde-equivalent values, provide an operational index of lipid peroxidation-related aldehydic reactivity, but blood-based assessment is limited by venipuncture and preanalytical handling requirements. Urine is an attractive non-invasive matrix for redox biomarker development, although whether urinary TBARS reflect plasma lipid peroxidation in hypertensive patients remains insufficiently characterized. This study aimed to evaluate whether matrix-specific normalization—total cholesterol for plasma TBARS and creatinine for urinary TBARS—reveals a measurable intra-individual relationship between these matrices in essential hypertension. Methods: In this paired observational study, plasma and urine samples were obtained from 39 treated patients with essential hypertension under standardized fasting conditions. TBARS were quantified using a colorimetric thiobarbituric acid reaction assay. Plasma TBARS were normalized to total cholesterol and expressed as TBARSp, while urinary TBARS were normalized to creatinine and expressed as TBARSu. Associations were assessed using Spearman’s rank correlation, exploratory receiver operating characteristic (ROC) analyses based on internally derived plasma TBARS percentile thresholds, and Bayesian bootstrap inference. Results: Cholesterol-normalized plasma TBARS and creatinine-normalized urinary TBARS showed a moderate-to-strong positive monotonic association (Spearman’s ρ = 0.717, p < 0.001). Bayesian bootstrap analysis supported this relationship, with a 95% credible interval of 0.57–0.83 and a Bayes factor > 300 for ρ ≥ 0.5. Urinary TBARS showed exploratory within-cohort discriminatory capacity for identifying elevated plasma TBARS using internally derived thresholds, with an AUC of 0.892 for the median-based classification. Conclusions: Creatinine-normalized urinary TBARS showed a moderate-to-strong association with cholesterol-normalized plasma TBARS in treated essential hypertension. These findings provide hypothesis-generating paired-sample evidence that urinary TBARS may serve as a low-burden, non-invasive proxy of plasma lipid peroxidation-related redox alterations. Further validation in larger and clinically diverse cohorts, ideally including more specific lipid peroxidation markers and renal-function-aware analyses, is required to define their translational and clinical utility. Full article

Background: Depression is a severe disorder associated with hypothalamic–pituitary–adrenal (HPA) axis dysregulation and neuroinflammation, and which restrains the efficacy of conventional antidepressants. Vortioxetine is a multimodal antidepressant with potential immunomodulatory properties. Glycyrrhizic acid (GA) is a natural compound derived from licorice root that exhibits anti-inflammatory activity and modulates glucocorticoid signaling. We hypothesized that a supramolecular complex of vortioxetine with GA (Vort:Na₂GA) would exert synergistic effects on inflammatory and glucocorticoid pathways. Methods: Vortioxetine compositions with Na₂GA were prepared using a mechanochemical method. Cytotoxicity, anti-inflammatory property, and glucocorticoid receptor (GR) signaling pathway modulation of the complex were evaluated in vitro using SIM-A9 microglial cells. Additionally, a 7-day oral administration study in intact female C57BL/6 mice was conducted to evaluate the effects on peripheral blood cells. Results: The Vort:Na₂GA complex improves the solubility of the parent drug while increasing its stability and permeability. Furthermore, the resulting complex exhibits reduced cytotoxicity, particularly under glucocorticoid challenge. In SIM-A9 microglial cells, the Vort:Na₂GA complex upregulated expression of Nr3c1 and Nr1d1 genes without activating canonical GR target genes (Fkbp5 and Gilz) and partially reversed dexamethasone-induced glucocorticoid resistance. In vivo, the complex reduced the percentage of inflammatory Ly6C^high monocytes and preserved dexamethasone-induced Gilz expression in peripheral blood cells, indicating protection against stress-induced glucocorticoid resistance. Conclusions: The Vort:Na₂GA supramolecular complex enhances the physicochemical and pharmacological profile of vortioxetine, reduces inflammation-associated myeloid cell populations, and preserves glucocorticoid sensitivity. These findings support its further evaluation as a potential therapeutic agent for depressive disorders with inflammatory and HPA axis-related components. Full article

Background/Objectives: Reliable biomarkers for longitudinal surveillance of neuroendocrine tumors (NETs) remain an unmet clinical need. Chromogranin A (CgA), the most widely used circulating biomarker, is limited by low sensitivity, substantial biologic variability, and poor concordance with radiologic progression. NETest2.0^® is a blood-based multigene transcriptomic liquid biopsy designed to dynamically assess NET biologic activity. This study compared serial NETest2.0^® measurements with CgA for monitoring disease progression in a real-world registry cohort. Methods: Patients with histologically confirmed NETs enrolled in the RegisterNET program (NCT02270567) who had paired blood samples and contemporaneous clinical assessment were included. NETest2.0^® scores were derived from quantitative RT-PCR analysis of a 51-gene transcript panel and expressed on a 0–100 scale. Serum CgA levels were measured using standard clinical immunoassays. Imaging-based disease assessment was performed using CT, MRI, and/or ⁶⁸Ga-somatostatin receptor PET/CT with RECIST 1.1 criteria applied where appropriate. Longitudinal percentage changes (Δ) between sequential measurements were evaluated using predefined NETest2.0^® thresholds and compared with the conventional CgA threshold (>50%). NETest2.0 Δ thresholds of >0% and >5% were evaluated a priori: >0% as a high-sensitivity threshold capturing any upward transcriptomic drift, and >5% as a more conservative threshold intended to reduce minor biological or analytical fluctuation. Receiver operating characteristic (ROC) analysis, operating characteristics, multivariable analysis (MVA), and logistic regression analysis (LRA) were performed. Results: A total of 191 patients were analyzed. Exploratory ROC analysis demonstrated superior discrimination for progression using serial NETest2.0^® changes compared with changes in CgA (AUC: 0.893 vs. 0.538; p < 0.0001). In the primary surveillance analysis, NETest2.0^® thresholds of >0% and >5% achieved AUCs of 0.860 (95% CI: 0.803–0.906) and 0.822 (95% CI: 0.760–0.873), respectively, both significantly superior to CgA (AUC: 0.553, 95% CI: 0.480–0.625; both p < 0.0001). NETest2.0^® >0% demonstrated the highest sensitivity (86.4%), whereas NETest2.0^® >5% achieved the optimal balance of sensitivity (70.5%), specificity (93.9%), and overall accuracy (88.5%). In multivariable and logistic regression analyses, changes in NETest2.0^® were the strongest independent predictor of progression (all p < 0.0001; odds ratios: 52.99–61.26), whereas CgA did not significantly contribute to progression prediction. Conclusions: Serial NETest2.0^® assessment significantly outperformed CgA for monitoring NET disease activity and progression. These findings support the integration of NETest2.0^®into molecularly informed surveillance strategies to complement imaging and improve longitudinal monitoring of patients with NETs. Full article

The evolving understanding of the regulation of allergic airway inflammation has offered new approaches for asthma therapy. For example, our understanding of the role of alarmins, Th2 cytokines and eosinophils has allowed the development of biologics that have revolutionized therapy for severe asthma. However, many questions remain and several of our patients are still not controlled with the current available therapies. Many immune cells have been implicated in asthma pathophysiology, but one cell that is missing from these studies is the monocyte. Monocytes (Mos) are bone marrow-derived cells that circulate in the blood and develop into macrophages and/or dendritic cells following migration to peripheral tissues. Macrophages (Møs) and dendritic cells have been implicated in the development and progression, of allergic airway inflammation, but also in tissue repair after inflammation. Recent studies in animal models suggest a major role for Mos in allergic airway inflammation, primarily through their ability to mediate recruitment of eosinophils and/or neutrophils to the airways. However, there is little information regarding the role of monocytes in human asthma. Here we review the literature regarding the presence and functions of peripheral blood and airway Mos in human asthma and suggest further work that needs to be done to consolidate the information on Mo functions. Studies show changes in Mo numbers and activation status in the peripheral blood of patients with asthma, changes that in many cases correlate with disease severity and/or activity. Studies also show altered phenotype of Mos present in the airways of patients with asthma. Detailed human studies need to be performed, if possible, studies that include therapeutic interventions, to allow for a full understanding of the role of Mos in asthma. Full article

Background: Chronic obstructive pulmonary disease (COPD) is associated with substantial long-term morbidity and mortality. Peripheral blood flow cytometry may provide exploratory information regarding immune-cell distributions and activation-related markers. However, careful interpretation is required when flow cytometry outputs are derived from lymphocyte-gated percentages rather than marker-specific mean fluorescence intensity or sequential lineage-confirmed gating. We investigated whether specific lymphocyte-gated flow cytometry parameters are associated with mortality during follow-up in COPD patients. Methods: In this single-center observational cohort study, 51 consecutive clinically stable outpatients with COPD were enrolled in November 2023 and followed for 24 months. Baseline peripheral blood flow cytometry results were verified against archived original instrument reports. The principal exploratory flow cytometry-derived variables were CD45/SSC-defined lymphocyte-gate percentage and lymphocyte-gated CD138+ events; HLA-DR positivity was evaluated as a secondary exploratory variable. Group comparisons and descriptive receiver operating characteristic (ROC) analyses were performed. Multiplicity was assessed using a hierarchical Benjamini–Hochberg false discovery rate (FDR) framework that separated the two biologically prioritized principal variables from the remaining exploratory screening variables. For transparency, a more conservative pooled FDR correction across all ten flow cytometry-derived variables was also reported. A two-variable analysis was performed only as exploratory signal aggregation, with descriptive internal assessment using leave-one-out cross-validation (LOO-CV) and bootstrap optimism correction. Results: During the 24-month follow-up, 13 of 51 patients died (25.5%). In unadjusted analyses, non-survivors had lower arterial oxygen tension and nominally lower CD45/SSC-defined lymphocyte-gate percentages (median 13.08% vs. 22.63%, p = 0.008) and lymphocyte-gated CD138+ event percentages (median 0.07% vs. 0.39%, p = 0.026) than survivors. Within the hierarchical analytical-family framework, both CD45/SSC-defined lymphocyte-gate percentage and lymphocyte-gated CD138+ events retained significance in the principal-variable family (within-family q = 0.016 and 0.026), whereas no secondary-family parameter, including HLA-DR (within-family q = 0.50), did; significance was not retained under a single correction across all ten parameters (CD45 q = 0.081; CD138 q = 0.129). Descriptive AUCs were 0.749 for CD45/SSC-defined lymphocyte-gate percentage and 0.710 for CD138+ events. The two-variable signal-aggregation analysis yielded an apparent AUC of 0.858, an LOO-CV AUC of 0.796, and a bootstrap optimism-corrected AUC of 0.832. NLR was available for all 51 patients; NLR-adjusted analyses did not establish clinical incremental utility. Conclusions: Lower CD45/SSC-defined lymphocyte-gate percentage and lower lymphocyte-gated CD138+ event percentage showed within-cohort associations with 24-month mortality in this small COPD cohort. These observations should be regarded solely as hypothesis-generating signals. Neither principal finding was retained after pooled correction across all ten flow cytometry-derived parameters, and no incremental prognostic value beyond routine inflammatory indices or established clinical predictors was demonstrated. External validation was absent; prospective replication in larger, appropriately adjusted cohorts is required. Full article