Abstract: Background/Objectives: The current strategy for seasonal influenza prophylaxis relies on updating the vaccine components annually to account for the rapid antigenic drift of viruses and the low cross-protective efficacy of available vaccines. Mutant influenza viruses with truncated or deleted NS1 protein are known to stimulate cross-specific T-cell immune response and provide protection against heterosubtypic influenza A and B viruses. Methods: We generated NS1ΔC influenza A and B viruses with C-terminal NS1 deletions by reverse genetics. In a mouse model, we assessed the safety and immunogenicity of the B/Lee/NS1ΔC strain upon intranasal administration, as well as the mechanism of its cross-protective efficacy against sublethal B/Victoria and B/Yamagata challenge. We then investigated the potential of the intranasal Flu/UniVec vaccine–a trivalent formulation of NS1ΔC A/H1N1, A/H3N2, and B influenza viruses–to protect mice from lethal influenza infection with homologous, heterologous, and antigenically drifted influenza A and B viruses. Results: Intranasal immunization with the B/Lee/NS1ΔC strain was safe in mice. It activated cross-specific T-cell responses in the lungs and protected animals against heterologous challenge by reducing viral load, inflammation, and lung pathology. Immunization with the trivalent Flu/UniVec vaccine formulation improved survival and reduced weight loss and viral load upon challenge with A/H1N1pdm, A/H2N2, A/H5N1, and B/Victoria viruses. Conclusions: The trivalent intranasal replication-deficient Flu/UniVec influenza vaccine is a promising tool to improve seasonal influenza protection and preparedness for an influenza pandemic.

Abstract: Modern geroscience and demographic data suggest that humans possess a biological lifespan potential of approximately 120 years, supported by evolutionary biology, longevity demographics, and cellular aging models. Yet global life expectancy in developed nations remains only 78–80 years—roughly a 20–30% shortfall. This gap is driven not by “inevitable aging” but by preventable chronic diseases rooted in metabolic, toxic, endocrine, inflammatory, and micronutrient dysregulation. This article proposes a Two-Tier Anti-Aging Model. (1) Restorative medicine—the foundation—focuses on restoring existing cells, organs, and systems to youthful physiological function by removing biological stressors and replenishing deficiencies. This includes detoxification, orthomolecular repletion (vitamin C, D₃/K₂, B₃, Mg, minerals), metabolic repair via the insulin–cortisol–vitamin C (ICV) axis, mitochondrial support, NAD⁺ restoration, senolytics, hormonal optimization, and epigenetic stabilization. These interventions repair the internal terrain and can enable recovery of roughly the first 15–20 lost healthy years. (2) Regenerative (specific anti-aging) medicine—built only after restoration—applies targeted biological interventions such as stem cells, exosomes, platelet-rich plasma (PRP), regenerative peptides, gene and epigenetic reprogramming, and tissue/organ engineering to further extend human longevity toward the 100–120-year upper limit. A central flaw in today’s market-driven “anti-aging industry” is the obsession with isolated “magic anti-aging pills,” peptides, or gadgets that ignore underlying terrain dysfunction. Attempting regeneration in a milieu burdened by micronutrient deficiencies, metabolic chaos, mitochondrial decay, chronic inflammation, and toxic load yields short-lived or misleading outcomes, as repeatedly observed in commercial longevity products and failed rejuvenation trials. Integrative Orthomolecular Medicine (IOM) directly addresses this systemic gap by identifying ten root drivers of chronic disease and aging and systematically repairing the internal terrain through detoxification, targeted nutrient repletion, mitochondrial and metabolic optimization, and hormonal rhythm restoration. This systems-biology framework supports realistic goals of healthy, independent longevity into the 90s and beyond, aligning modern biogerontology with practical clinical outcomes.

Abstract: Background: Comorbid obsessive-compulsive symptoms in bipolar disorder often prove highly resistant to standard treatments, with serotonergic agents carrying substantial risk of mood destabilisation. Recent interest has focused on glutamatergic modulation as an alternative pathway, inspired by the rapid effects of ketamine, though oral regimens require careful attention to pharmacokinetics for clinical success.Methods: This retrospective case report describes a 23-year-old woman with previously stabilised bipolar disorder who, following treatment discontinuation, presented with severe moral scrupulosity and compulsive reassurance-seeking refractory to mood stabilisation alone. In routine outpatient care, valproate was combined with dextromethorphan (NMDA antagonism) and piracetam (AMPA positive allosteric modulation), with subsequent addition of a mild CYP2D6 inhibitor (Deanxit). Progress was monitored through clinical interviews and standardized questionaires.Results: Dextromethorphan 30–45 mg nocte plus piracetam 600–1200 mg nocte on a background of valproate 500 mg produced only modest reduction in ruminations. Marked and sustained improvement—near-complete resolution of obsessive thoughts and reassurance-seeking, with PHQ-9 falling from 16 to 8 and GAD-7 from 19 to 7—occurred only after introduction of Deanxit 1 tablet nocte, providing CYP2D6 inhibition via melitracen.Discussion: The stepwise response pattern underscores the critical role of sustained dextromethorphan exposure in achieving therapeutic NMDA blockade sufficient to drive downstream AMPA-mediated plasticity. This observation aligns with emerging clinical experience suggesting that pharmacokinetic optimisation is essential for translating ketamine-like mechanisms into reliable oral efficacy, particularly in complex bipolar-OCD presentations where conventional options are limited.

Abstract:

Background: Robotic-assisted surgery (RAS) is increasingly used for colorectal cancer (CRC), but its clinical and oncologic advantages over conventional laparoscopy (LS) remain uncertain. Prior meta-analyses have included overlapping RCTs but vary in methodology, scope, and analytical transparency. This review aims to provide an updated, independently re-analyzed synthesis of RCTs published from 2015–2025, with full PRISMA compliance, explicit analytic reproducibility, and expanded evaluation of bias and evidence certainty. Methods: A systematic review and meta-analysis was conducted according to PRISMA guidelines. The protocol was retrospectively registered in PROSPERO (Registration ID: CRD420251237158). PubMed, Embase, and Cochrane CENTRAL were searched (January 1, 2015–January 31, 2025). Full reproducible search strings, PICOS criteria, and inclusion/exclusion rules were predefined. Only RCTs comparing RAS vs LS for malignant colorectal disease were included. Data extraction was performed independently by two reviewers. Meta-analyses used DerSimonian–Laird random-effects models; standardized procedures were applied for converting medians/IQRs into means/SDs and for continuity corrections in zero-event trials. Risk of bias was assessed using Cochrane RoB 2.0, and evidence certainty was graded using GRADE. Results: A total of 12 RCTs encompassing 3,107 patients met the inclusion criteria. RAS resulted in significantly lower conversion-to-open rates (OR 0.42; 95% CI 0.28–0.63; I²=18%) compared with LS. Operative time was consistently longer with RAS (MD +23.8 minutes; 95% CI 14.2–33.4; I²=67%). Overall postoperative complications (Clavien–Dindo ≥II) were comparable (OR 0.91; 95% CI 0.76–1.13; I²=22%). Length of stay showed a small but significant reduction with RAS (MD −0.8 days; 95% CI −1.3 to −0.2; I²=49%). Pathologic outcomes showed lower circumferential resection margin (CRM) positivity with RAS (OR 0.59; 95% CI 0.41–0.85). Lymph node retrieval was slightly higher with RAS (MD +0.71 nodes; 95% CI 0.25–1.18). Distal margins and TME completeness were equivalent. No RCT reported mature long-term oncologic outcomes; evidence remains limited to short-term surrogates. Conclusions: In contemporary RCTs, RAS provides fewer conversions and slightly better pathologic surrogates, while maintaining similar morbidity compared to LS. The main trade-off remains longer operative time and higher resource use. True oncologic equivalence cannot be confirmed until long-term RCT data mature. Advanced imaging (e.g., SOMATOM Force CT), age-specific MIS evidence, and the emergence of endoluminal robotic systems are likely to shape future refinements in technique and patient selection.

Abstract: Background: Over the past century, numerous pharmacological regimens have been developed for multiple myeloma (MM), yet relapse remains inevitable. Although these regimens prolong overall survival (OS), repetitive treatment cycles and cumulative toxicity progressively impair quality of life (QoL). This study aimed to compare conventional stepwise therapies with CAR-T cell therapy in terms of QoL, toxicity, cost, and ethical value.Methods: Kaplan-Meier survival curves were analyzed to estimate overall (OS) and progression-free survival (PFS). Based on these durations, treatment costs were calculated. A simple and transparent utility-based model was developed to enable clinicians, researchers, and health policy authorities to easily estimate quality-adjusted life years (QALY) and incremental cost-effectiveness ratios (ICER).Results: Among heavily pretreated patients, CAR-T therapy approximately doubled OS and PFS compared with other late-line regimens and provided markedly better quality of life with lower overall treatment burden. While daratumumab-based combinations improved survival and patient well-being, they were associated with very high treatment costs (~USD 1 million per patient). Carfilzomib-based regimens remained essential for managing high-risk disease despite their expense. In contrast, VMP represented a practical and accessible option, especially for transplant-ineligible or resource-limited patients.Conclusion: CAR-T therapy provided significant improvements in survival and quality of life compared with conventional regimens among patients who had received three or more prior lines of therapy. Its earlier use appears promising. However, the limited availability of CAR-T across only a few countries raises ethical concerns regarding treatment accessibility. Contrary to common assumptions, CAR-T can be less expensive than many traditional therapies, though its single-payment structure poses barriers for patients with limited financial means. Further analyses are needed to refine toxicity management and optimize its broader clinical application in multiple myeloma.

Abstract:

Background: Interventions targeting the gut–brain axis offer potential for mitigating Subjective Cognitive Decline (SCD), a critical window for Alzheimer’s prevention. This study evaluated the effects of a novel probiotic supplement, ExoBDNF, on cognitive function, sleep, and emotional distress in adults with SCD. Methods: In this 9-week open-label study, participants received ExoBDNF supplementation. Efficacy was assessed using the SCD-Questionnaire (SCD-Q), DASS-21, PSQI, MoCA, and a computerized cognitive battery measuring inhibition (Go/No-Go), flexibility (Task Switching), and working memory. Results: Post-intervention analyses revealed significant improvements in subjective cognition (SCD-Q, p < 0.001), sleep quality (PSQI, p < 0.001), and emotional distress (DASS-21, p < 0.001). Objective cognitive performance also improved, with significant gains in MoCA scores (p = 0.047) and executive function metrics. Spearman correlation analysis indicated a significant link between cognitive and emotional changes: longitudinal reductions in SCD scores correlated with concurrent reductions in emotional distress (rho = 0.471, p = 0.009). Furthermore, higher baseline SCD scores predicted greater improvement in emotional outcomes (rho = -0.540, p = 0.002). Conclusion: ExoBDNF supplementation significantly enhanced cognitive performance, sleep quality, and emotional well-being. The findings demonstrate that improvements in subjective cognition are closely tied to alleviated emotional distress, supporting the gut–brain axis as a viable therapeutic target for early-stage cognitive decline.

Abstract: Tuberculosis (TB) remains one of the leading causes of death from a single infectious agent worldwide, particularly aggravated by HIV co-infection and the increasing burden of drug-resistant strains. This review provides a comprehensive overview of current la-boratory diagnostic methods for active and latent TB, emphasizing their clinical applica-bility across different healthcare settings, diagnostic performance, and implementation in integrated testing workflows. Conventional methods, such as smear microscopy and cul-ture, are discussed alongside modern diagnostic approaches, including automated nucle-ic acid amplification tests (NAATs), loop-mediated isothermal amplification (LAMP), line probe assays (LPA), next-generation sequencing (NGS), and lateral flow assays for the di-agnosis of TB in specific clinical contexts. The strengths and limitations of each method are critically evaluated according to infrastructure level, resource availability, and epide-miological scenario. While traditional techniques remain useful in selected settings, mo-lecular technologies provide higher sensitivity, shorter turnaround times, and expanded capacity for drug resistance detection. The integration of complementary diagnostic strat-egies into hybrid testing algorithms is essential to optimize resource use, ensure diagnos-tic accuracy, promote equitable access, and enable early treatment initiation, thereby sup-porting effective TB control.

Abstract:

Background/Objectives: Periprosthetic joint infections (PJIs) remain one of the most challenging complications after arthroplasties due to the ability of pathogens to form biofilms on implant surfaces. Although staphylococci predominate, Gram-negative bacilli, have increasingly been associated with more aggressive clinical courses and diagnostic failure. This study aimed to evaluate the structural characteristics and maturation of E. coli and P. aeruginosa biofilms and to assess the effectiveness of a standardized sonication protocol in disrupting these biofilms and releasing viable cells. Methods: Biofilms of E. coli (ATCC 25922) and P. aeruginosa (ATCC 53278) were grown on polyethylene catheter segments for 24, 48, and 72 hours. Morphological and structural features were assessed by scanning electron microscopy. A standardized sonication protocol was then applied to evaluate its ability to disrupt the extracellular polymeric matrix. Viability of released cells was confirmed by culturing aliquots of the sonication fluid on BHI agar. Biofilms were produced in triplicate for each time point. Results: Both species formed increasingly dense and structured biofilms over time. Mature biofilms exhibited markedly thicker EPS layers compared to 24-h biofilms. P. aeruginosa developed highly complex, multilayered matrices, while E. coli produced characteristic but less elaborate biofilm structures. Sonication consistently disrupted immature and mature biofilms of both organisms, fragmenting the matrix and releasing individual or small clusters of bacterial cells. Cultures from the sonication fluid demonstrated that bacterial cells remained viable following the procedure. Conclusions: The standardized sonication protocol effectively disrupted Gram-negative biofilms at different maturation stages and released viable microorganisms, reinforcing its value as a complementary diagnostic tool for PJIs, especially in chronic or low-grade infections where conventional culture methods show reduced sensitivity.

Abstract:

Parkinson’s disease (PD) is a progressive neurodegenerative disorder lacking approved therapies that slow or halt its underlying pathology. Despite decades of research, disease-modifying trials have faced persistent challenges, including patient heterogeneity, insensitive endpoints, and confounding symptomatic effects. Recent advances in biomarker science and adaptive trial frameworks offer strategies to overcome these limitations. Enrichment designs using α-synuclein seed amplification assays, dopamine transporter imaging, and genetic stratification for GBA1 or LRRK2 variants improve mechanistic alignment and statistical power in early-phase studies. Concurrently, platform trials and master protocols enable simultaneous evaluation of multiple interventions under a unified infrastructure, reducing resource waste compared to traditional sequential designs. However, gaps remain in defining sensitive outcomes, mitigating symptomatic confounders, and ensuring equitable access to biomarker-driven strategies. Future directions emphasize precision medicine approaches integrating multi-omics, digital biomarkers, and AI-driven prognostic models to optimize patient selection and endpoint sensitivity. Equity and diversity must be prioritized to address underrepresentation of racial and ethnic minorities, while ethical frameworks for genetic testing and biomarker disclosure are essential. Regulatory agencies increasingly support qualification of enrichment biomarkers, digital endpoints, and adaptive designs, alongside accelerated approval pathways. The aim of this review is to synthesize current challenges, lessons learned, and emerging strategies to guide the design of efficient, inclusive, and mechanistically aligned disease-modifying trials in PD.

Abstract: Endophytic and marine-derived fungi represent prolific and structurally innovative sources of steroidal natural products. In recent years, extensive chemical investigations of diverse fungal taxa—including Aspergillus, Penicillium, and numerous other genera—have revealed an extraordinary variety of steroids and steroid-like metabolites featuring unprecedented carbon skeletons, unusual ring rearrangements, heterocyclic fusions, and hybrid architectures. These metabolites encompass ergostane-, lanostane-, pregnane-, and abeo-type derivatives; secosteroids; polyoxygenated and polycyclic frameworks; meroterpenoid–steroid hybrids; and rare Diels–Alder adducts. Many of these compounds exhibit significant biological activities, including cytotoxic, anti-inflammatory, antimicrobial, antiviral, immunosuppressive, antioxidant, enzyme-inhibitory, larvicidal, neuroprotective, and herbicidal effects. Several metabolites, such as cordycepsterols, citristerones, rubensteroid A, anicequol, and various hybrid steroidal structures, demonstrate potent inhibition of key molecular targets (e.g., COX-2, NF-κB, PTP1B, AChE, NO production) and show promise as leads for anticancer, anti-infective, anti-neuroinflammatory, and metabolic disease therapeutics. Collectively, the rapidly expanding diversity of fungal steroids underscores the remarkable biosynthetic capabilities of fungi and highlights their continued potential as reservoirs of structurally novel and biologically valuable natural products. This review summarizes recent discoveries and structural classes of fungal-derived steroids, emphasizing their chemical diversity, biosynthetic features, and bioactivity profiles.

Abstract:

Background/Objectives: Triple-negative breast cancer (TNBC) is an aggressive subtype, with limited diagnostic options and no targeted early detection tools. Liquid biopsy represents a minimally invasive approach for detecting tumor-derived molecular alterations in body fluids. This scoping review aimed to comprehensively synthesize all liquid biopsy–derived molecular biomarkers evaluated for the diagnosis of TNBC in adults. Methods: This review followed the Arksey and O’Malley framework and PRISMA-ScR guidelines. Systematic searches of PubMed, Scopus, Embase, and Web of Science identified primary human studies evaluating circulating molecular biomarkers for TNBC diagnosis. Non-TNBC, non-human, hereditary, treatment-response, and non-molecular studies were excluded. Data on study design, patient characteristics, biospecimen type, analytical platforms, biomarker class, and diagnostic performance were extracted and synthesized descriptively by biomolecule class. Results: Thirty-two studies met inclusion criteria, comprising 15 protein-based, 11 RNA-based, and 6 DNA-based studies (one reporting both protein and RNA). In total, 1532 TNBC cases and 3137 participants in the comparator group were analyzed. Protein biomarkers were the most frequently studied, although only APOA4 appeared in more than one study, with conflicting results. RNA-based biomarkers identified promising candidates, particularly miR-21, but validation cohorts were scarce. DNA methylation markers showed promising diagnostic accuracy yet lacked replication. Most studies were small retrospective case–control designs with heterogeneous comparators and inconsistent diagnostic reporting. Conclusions: Evidence for liquid biopsy–derived biomarkers in TNBC remains limited, heterogeneous, and insufficiently validated. No biomarker currently shows reproducibility suitable for clinical implementation. Robust, prospective, and standardized studies are needed to advance liquid biopsy–based diagnostics in TNBC.

Abstract: Background: The clinical-radiological paradox in multiple sclerosis (MS) underscores the need for biomarkers that better reflect neurodegenerative pathology. Serum neurofilament light chain (sNfL) is a dynamic marker of neuroaxonal injury, while brain volumetry provides structural assessment of disease impact. However, the precise link between sNfL and regional atrophy patterns, and their combined utility for patient stratification and prediction, remains underexplored. Objective: To establish a multimodal biomarker framework by integrating sNfL with comprehensive volumetric MRI to define neurodegenerative endophenotypes and predict neuroaxonal injury using Bayesian inference and machine learning. Methods: In a cohort of 57 MS patients, sNfL levels were measured using single-molecule array (Simoa) technology. Brain volumes for 42 regions were quantified via automated deep-learning segmentation (mdbrain software). We employed: 1) Bayesian correlation to quantify evidence for sNfL-volumetric associations; 2) mediation analysis to test whether gray matter atrophy mediates the EDSS–sNfL relationship; 3) unsupervised K-means clustering to identify patient subtypes based on combined sNfL-volumetric profiles; and 4) supervised machine learning (Elastic Net and Random Forest regression) to predict sNfL from volumetric features. Results: Bayesian analysis revealed strong evidence linking sNfL to total gray matter volume (r = -0.449, BF₁₀ = 0.022) and lateral ventricular volume (r = 0.349, BF₁₀ = 0.285). Mediation confirmed that gray matter atrophy significantly mediates the relationship between EDSS and sNfL (indirect effect = 0.45, 95% CI [0.20, 0.75]). Unsupervised clustering identified three distinct endophenotypes: "High Neurodegeneration" (elevated sNfL, severe atrophy, high disability), "Moderate Injury," and "Benign Volumetry" (low sNfL, preserved volumes, mild disability). Supervised models predicted sNfL with high accuracy (R² = 0.65), identifying total gray matter volume, ventricular volume, and age as top predictors. Conclusions: This integrative multi-method analysis demonstrates that sNfL is robustly associated with global gray matter and ventricular volumes, and that these measures define clinically meaningful neurodegenerative subtypes in MS. Machine learning confirms that a concise set of volumetric features can effectively predict neuroaxonal injury. These findings advance a pathobiology-driven subtyping framework and provide a validated model for using routine MRI volumetry to assess neuroaxonal health, with implications for prognosis and personalized therapeutic strategies.

Abstract: Desmoplastic melanoma (DM) is a rare, aggressive melanoma subtype with high local recurrence rates (20-60%) following surgical excision. This systematic review evaluated the efficacy of adjuvant radiotherapy (RT) in improving local control and survival outcomes in DM patients. Following Preferred reporting items for systematic review and meta-analyses (PRISMA) guidelines, we searched PubMed/MEDLINE, ScienceDirect, Scopus, CINAHL, and EBSCO databases from inception through December 2025.. Thirteen studies (10 retrospective cohorts, 3 prospective trials) met the inclusion criteria. quality assessment using JBI tools revealed 69% high quality and 31% moderate quality studies. Adjuvant RT significantly reduced local recurrence rates from 17.2% (surgery alone) to 7.6% (surgery plus RT), representing a 56% relative risk reduction. All hypofractionated RT (e.g. 30 Gy/5 fractions) achieved comparable local control rates (90-95% at 5 years). High-risk features including positive margins, Breslow depth ˃4 mm, and neurotropism identified patients deriving greatest benefits from RT. Adjuvant radiotherapy significantly improves local control in DM following surgical excision and should be considered standardized of care for high-risk patients. Future randomized trials are needed to established definitive treatment.

Abstract: Traumatic brain injury (TBI) and malignancies, despite their distinct nature, are characterized by similar immune responses, including the development of local and systemic inflammation and T-cell exhaustion. This article compares the role of immune checkpoints in the development of immune dysfunction in cancer and TBI, examines the contribution of the sympathetic nervous system to these changes, and discusses the relationship between local and systemic inflammation in these two conditions. Particular attention is paid to approaches to pharmacological modulation of inflammation and the impact on exhausted T-cells in these conditions. Comparison of inflammation and T-cell exhaustion in cancer and TBI highlights existing gaps in our understanding of immune regulation in TBI and points to areas requiring further investigation. Clarification of the immune mechanisms underlying the pathogenesis of TBI may facilitate the search for new diagnostic markers and lay the groundwork for the development of new therapeutic approaches for TBI treatment.

Abstract: Peptides are short chains of amino acids with a unique pharmacological niche between small-molecule drugs and large proteins. Their use in sports medicine is rapidly expanding, driven by patient demand for accelerated injury recovery and performance enhancement. While numerous peptide drugs have undergone a rigorous approval process that evaluates both safety and efficacy, a parallel "gray market" of unapproved compounds has emerged, operating largely outside regulatory oversight. Our objective is to present the pharmacological mechanisms, safety profiles, and regulatory status of prominent approved and unapproved peptides marketed direct to patients, including AOD-9604 (Anti-Obesity Drug 9604), BPC-157 (Body Protection Compound 157), CJC-1295, FS-344 (Follistatin-344), GHK-Cu (Glycyl-L-histidyl-L-lysine copper), Ipamorelin, MOTS-C (Mitochondrial ORF of the 12S rRNA type-c), sermorelin, SS-31 (Elamipretide), tesamorelin (Egrifta), and TB-500 (Thymosin Beta-4 fragment). Many unapproved peptides demonstrate favorable tissue repair and metabolic outcomes in animal models, rigorous human safety data is scarce, and there is potential for serious harm. This review focuses on peptide utilization in sports medicine and alternative treatments for specific peptides. We provide a framework to navigate patient discussions about peptides to better facilitate evidence-based practices for musculoskeletal healing and athletic performance. We also discuss the placebo effect as a mediator of peptide efficacy, and how social media amplifies this effect.

Abstract: Background/Objectives: The delayed effects of subchronic and chronic organophosphate poisoning may manifest years after exposure, often masked by age-related diseases. The aim of this retrospective cohort study was to identify the biochemical "trace" that could remain in the patients decades after the poisoning. To achieve this goal, we determined a wide range of biochemical parameters, along with the spectrum of esterified and non-esterified fatty acids (EFA and NEFA, respectively), in the blood plasma of a cohort of elderly patients diagnosed with occupational pathology (OP) due to subacute or (sub)chronic exposure to organophosphates in the 1980s. Methods: Elderly patients with and without a history of exposure to organophosphates were retrospectively divided into two groups: controls (n=59, aged 73±4, men 29% and women 71%) and having the OP (n=84, aged 74±4, men 29% and women 71%). The period of neurological examination and blood sampling for subsequent analysis was approximately one and a half years - from mid-2022 to the end of 2023. Determination of the content of biomarkers of metabolic syndrome, NEFA and EFA in blood plasma was performed by HPLC-MS/MS and GC-MS. Results: The medical history of the examined elderly individuals with OP and the aged control group includes common age-related diseases. However, patients with OP more often have hepatitis (33 vs 7%, p<0.001) and other gastrointestinal diseases (54 vs 32%, p<0.05), total with diagnosis of polyneuropathy (87 vs 66%, p<0.01) and polyneuropathy of the upper and lower extremities (29 vs 12%, p<0.05), impaired distal sensitivity (83 vs 56%, p<0.001), increased body mass index (30.0±4.6 vs 28.4±4.1, p<0.05), and also they have an increased drug load (5 vs 4, p<0.001). Patients with OP more often have balance problems (84 vs 69%, p<0.05) and difficulties in performing daily activities (75 vs 49%, p<0.01). No differences were found between the groups when assessing cognitive function using the MMSE (mini mental state examination), SAGE (self-administered gerocognitive exam), and “Clock” tests. Of the 34 basic biochemical parameters determined on the biochemical analyzer, statistically significant changes were found for only 11, with their median values not going beyond the reference range (clinical norm), and the differences being due to significant individual deviations. Analysis of some metabolic biomarkers with HPLC-MS/MS revealed in the OP group a 1.4-fold decrease in the concentration of 3-hydroxybutyrate (p<0.05, AUC=0.62) and 1.6-fold decrease in the concentration of 2-hydroxybutyrate (p<0.0001, AUC=0.72). In the OP group, a 26% decrease in acetyl-L-carnitine concentration was found (p<0.001, AUC=0.69). An additional study of the esterase profile of patients revealed a decrease in the activity of butyrylcholinesterase (BChE) by 14% (p<0.05, AUC=0.62) though increase in the esterase activity of albumin by 29% (p<0.05, AUC=0.62) in the OP group. Correlation analysis revealed the most significant relationships between albumin esterase activity and arachidonic acid concentration in the OP group (0.64, p<0.0001). A study of a wide range of fatty acids in patients with OP revealed reciprocal relationships between EFA and NEFA. A decrease in concentration was shown for esters of margaric (p<0.01, AUC=0.65), stearic (p<0.01, AUC=0.65), eicosadienoic (p<0.01, AUC=0.63), eicosatrienoic (p<0.01, AUC=0.66), arachidonic (p<0.001, AUC=0.67), eicosapentaenoic (p<0.05, AUC=0.60), and docosahexaenoic (p<0.0001, AUC=0.74) fatty acids. An increase in the concentration was shown for free (non-esterified) fatty acids: heptadecenoic (p<0.0001, AUC=0.72), eicosapentaenoic (p<0.05, AUC=0.62), eicosatrienoic (p<0.001, AUC=0.68), docosahexaenoic (p<0.01, AUC=0.66), γ-linolenic (p<0.01, AUC=0.66), myristic (p<0.0001, AUC=0.71), eicosenoic (p<0.01, AUC=0.65), arachidonic (p<0.01, AUC=0.66), eicosadienoic (p<0.001, AUC=0.67), oleic (p<0.01, AUC=0.66), linoleic (p<0.01, AUC=0.65), palmitic (p<0.001, AUC=0.68), linoelaidic (p<0.01, AUC=0.65), stearic (p<0.01, AUC=0.64), palmitoleic (p<0.05, AUC=0.61), pentadecanoic (p<0.05, AUC=0.61), and margaric (p<0.01, AUC=0.64). Decrease in the ratios of omega-3 to other unsaturated fatty acids were observed only for the esterified forms: by 29% for n3/n6 (p<0.0001, AUC=0.70), by 33% for n3/(n6+n9) (p<0.0001, AUC=0.72), and by 26% for n3/(all fatty acids) (p<0.0001, AUC=0.72). Finally, we have found out how the most reliable indicators correlate with each other. The esterified docosahexaenoic acid – lactate dehydrogenase (LDH) (0.67, p <0.0001) and LDH – total antioxidant status (TAS) (-0.61, p <0.0001) correlations are stronger in the OP group compared to the correlation in the overall sample and lose their strength and statistical significance in the control group. In the OP group, esterified docosahexaenoic fatty acid, LDH activity, and TAS concentration have a moderate correlation with calcium concentration (-0.66, p <0.0001; -0.67, p <0.0001; 0.63, p <0.0001, respectively). In the control group, this correlation is significantly weakened. Esterified docosahexaenoic acid in the OP group also demonstrated strong positive correlations with a row of other esterified fatty acids, though these correlations were not significantly weakened in the control group. Conclusions: The data obtained allow us to consider an increased level of NEFA as one of the main cytotoxic factors for the vascular endothelium, which can determine the specificity of age-related diseases. Modification of albumin properties by arachidonic acid decreased bioavailability of docosahexaenoic acid could be molecular links that cause specific manifestations of OP-induced pathology at late stages after exposure. Epigenetic changes, the contribution of dietary patterns and intestinal microbiota to the spectrum of EFA and NEFA require additional research.

Abstract: Vascular dysfunction lies at the core of cardiovascular diseases—the leading cause of global morbidity and mortality. Despite their prevalence, therapeutic options remain limited, in part due to an incomplete understanding of the molecular mechanisms driving vascular pathology. The Integrated Stress Response (ISR), an evolutionarily conserved signaling network activated by di-verse stressors, represents a critical but underexplored mechanism in vascular biology. This re-view examines the dual roles of the core ISR kinases—PERK, GCN2, HRI and PKR—in vascular homeostasis and pathology, including atherosclerosis, pulmonary hypertension, and angiogenesis. We advance a conceptual framework in which the ISR functions as a context-dependent, double-edged sword: while PERK and PKR promote inflammation, apoptosis, and vascular re-modeling, GCN2 mediates protective effects. The outcome of ISR activation is shaped by cell type, stress duration and intensity, and downstream signaling bias (e.g., ATF4 vs. CHOP dominance). We further discuss pharmacological ISR modulators—including 2-aminopurine, C16, salubrinal, halofuginone, GSK2606414, and GSK2656157—which have demonstrated beneficial effects in preclinical models by suppressing inflammation, reducing apoptosis, and attenuating disease progression. Collectively, the ISR emerges as a critical regulatory node in vascular pathophysiology, and its selective, context-aware modulation represents a promising avenue for therapeutic intervention.

Abstract: Patients with End-Stage Renal Disease on hemodialysis (HD) are at high risk for severe influen-za, and their underlying immune dysfunction may limit the magnitude of vaccine-induced pro-tection. This observational study evaluated the immune response in 93 hemodialysis patients vaccinated with the seasonal inactivated influenza vaccine (IIV) across the 2019-2020 (n=22) and 2023-2024 (n=71) seasons. Immune response was comprehensively assessed by measuring hemagglutina-tion inhibition (HAI) and neutralizing antibody titers and by analyzing the frequencies of key immune cells, including plasmablasts, T-follicular helper cells (Tfh), and effector memory T cells (Tem). The results of observation in 2019-2020 showed that the antibody response in HD patients was comparable to that of healthy volunteers, including both younger (18-60) and older (over 60) age groups. By day 7, there was a pronounced increase in activated Tfh1 cells, a corresponding surge in plasmablasts, and a rise in antigen-specific B-cells. A T-cell response followed, mediated by IFNγ-producing and polyfunctional CD4+ effector memory T cells. Subsequent vaccination in 2023-2024 season determined a higher baseline level of the antibody response but did not affect its further dynamics in case of A/H1N1pdm, A/H3N2, B/Yamagata virus antigens. The response to B/Victoria was higher in the revaccinated group throughout the entire observation period. Our findings confirm that standard-dose IIV vaccination is beneficial for HD patients, inducing a robust and compliant humoral and T-cell immune response that is not inferior to that of the general population.

Abstract: Background/Objectives: Flexible bronchoscopy (FB) enables airway exploration and diagnosis of various respiratory pathologies, but the sedation and instru-mentation required during the procedure raise oxygen demand while reducing ventilation, which can lead to hypoxemia. Conventional oxygen therapy (COT) may not adequately prevent desaturations in high-risk groups, as patients with moderate respiratory deficiency. High-flow nasal cannula (HFNC) can deliver heated, humidified oxygen at high flow rates, generating low-level positive airway pressure, improving oxygenation, reducing dead-space and enhancing procedure tolerance. Prior studies have shown that HFNC can improve gas exchange and reduce desaturations during bronchoscopy. However, evidence remains limited for patients with moderate respiratory deficiency, who are particularly vulnerable. Evaluating feasibility and safety of HFNC in this population is essential to guide safe procedural practice. Methods: Prospective observational study including patients undergoing FB with HFNC support between January and May 2025. Inclusion criteria were BMI between 18 to 30; age >18 years old; moderate respiratory dysfunction, defined by pulse oximetry, Pulmonary Functional Tests (PFTs) and Arterial Blood Gas (ABG) analysis. Exclusion criteria were intolerance/contraindication to HFNC. Procedures were performed under basic monitoring. Primary outcome was occurrence of severe hypoxemia (spO2 < 90%). Secondary outcomes were need for rescue maneuvers, interruption for conversion to other ventilatory strategies, hemodynamic instability. Results: No severe desaturations were recorded, and all procedures were completed without rescue maneuvers or other ventilatory strategies; no hypotensive have occurred. Mean duration of the procedure was 9 minutes. Vital parameters were maintained into the normal ranges, with a mean SpO2 during bronchoscopy of 98%. Conclusions: HFNC enables oxygenation and ventilation without adverse events in sedations for FB in patients with moderate respiratory deficiency.

Abstract: CD80 and CD86 molecules are key costimulatory ligands expressed primarily on the surface of antigen-presenting cells (APCs). However, the presence of these molecules on T cells is currently uncommon and may be associated with various immunopathologies, such as allergic diseases. Literature data demonstrate that the presence of these molecules on T cells can polarize the immune response toward Th2, thereby enhancing inflammation. In our study, we found that all Type 2-dependent diseases we examined (atopic dermatitis, bronchial asthma) were associated with increased CD80 expression by immune cells. One of the modern and effective treatments for these diseases is genetically engineered biological therapy (GEBT). In this study, we found that in patients with severe allergy pathology, GEBT-associated cells exhibit changes in the percentage of cells expressing CD80 and CD86 on both monocytes and T cells.