Medicine and Pharmacology

Abstract: Localized lower respiratory tract infection including unilobar and round pneumonia can be associated with hypoxia and oxygen requirements. Previous explanations include shunting of deoxygenated blood, a systemic inflammatory response syndrome and vasoconstriction.This is unexplained.The alternative hypothesis is that spread of fluid absorption inhibiting cytokines in the alveolar spaces of the inflamed lung is cause of hypoxia in localized lower respiratory tract infection by spread of Cystic Fibrosis Transmembrane Conductance (CFTR) dysfunction in alveolar epithelial cells to more areas including those not infected. There is no evidence of pulmonary shunting to explain hypoxia in localized pneumonia. Systemic inflammatory response syndrome (SIRS) related generalized increase in alveolar capillary barrier or pulmonary vasoconstriction not visible on a chest x-ray cannot explain the hypoxia detected in most patients. Confirmation of the hypothesis could be achieved using pulmonary MRI or high resolution CT to confirm spread of alveolar fluid accumulation from the localized pneumonia focus as opposed to generalized SIRS related pulmonary oedema together with cytokine and chloride measurement in bronchoalveolar lavage samples from the lung segments near the affected lung segment and unaffected contralateral lung. Ventilation/perfusion scintigraphy could investigate for involvement of vasoconstriction or micro-emboli from intravascular coagulation.Should the posed hypothesis be confirmed adjuvant strategies including small molecule CFTR activators, CFTR activating combination of beta-agonists, phosphodiesterase inhibitors and steroids could be used to treat hypoxia and CFTR activating low-intensity ultrasound explored.

Abstract: In pregnancy physiologically based pharmacokinetic (PBPK) modelling within PK-Sim/Mobi, pregnancy stage is canonically parameterised on the fertilisation-age (FA) timescale, yet PK-Sim’s physiology database is indexed by chronological “Age”. The Open Systems Pharmacology (OSP) pregnancy framework therefore encodes FA on a dummy “Age” axis (30.00 years = FA 0 weeks; 30.75 years = FA 38 weeks) and generates pregnancy physiology vectors from FA 0 – 38 weeks discretised at 1-day intervals for database ingestion. Although the anchor points are publicly documented, an explicit closed-form transform and week-resolved lookup suitable for deterministic reproduction of daily physiology grids has not been routinely foregrounded in the literature or repository instructions. A unique affine mapping is derived, implied by the anchors, that provide forward and inverse equations in week- and day-space, quantifying rounding error in terms of FA-day misalignment, and supply a fertilization week (1-38) table for implementation-ready pregnancy virtual population creation in PK-Sim.

Abstract: Background: Gastrectomy for gastric cancer is associated with substantial metabolic, nutritional, and immunological disturbances that may significantly influence postoperative recovery. Increasing evidence suggests that perioperative immunonutritional status, particularly as assessed by the Controlling Nutritional Status (CONUT) score, represents an important predictor of surgical outcomes. However, prospective data evaluating sex-related differences in postoperative nutritional recovery after gastrectomy remain limited. Methods: This prospective observational cohort study included 150 consecutive patients undergoing curative-intent gastrectomy for gastric adenocarcinoma at a tertiary referral center between 2021 and 2024. Nutritional and immune status were longitudinally assessed using the CONUT score at predefined perioperative timepoints: preoperatively (T0), early postoperatively (T1), and at 3-month follow-up (T3). Functional recovery outcomes, postoperative complications, and mid-term functional parameters were compared between male and female patients. Multivariable logistic regression analysis was performed to identify independent predictors of delayed postoperative recovery. Results: The study population included 91 male patients (60.7%) and 59 female patients (39.3%). Significant postoperative deterioration of albumin level, lymphocyte count, total cholesterol, and CONUT score was observed in the entire cohort (p-time < 0.001 for all comparisons), followed by partial recovery during follow-up. No significant sex-related differences were identified regarding longitudinal immunonutritional evolution, postoperative complications, gastrointestinal recovery, or functional outcomes (p > 0.05). Overall postoperative complications occurred in 31.3% of patients, while 90-day mortality was 2.7%. Elevated baseline CONUT score ≥5 (OR 2.74, 95% CI 1.48–5.09, p = 0.001), postoperative CONUT score T1 ≥5 (OR 3.36, 95% CI 1.82–6.19, p < 0.001), ASA class III (OR 2.08, 95% CI 1.19–3.63, p = 0.010), and anastomotic leakage (OR 4.91, 95% CI 1.74–13.88, p = 0.003) independently predicted delayed functional recovery. Male sex was not independently associated with adverse postoperative recovery (OR 1.18, 95% CI 0.74–1.89, p = 0.44). Conclusions: Gastrectomy induces significant postoperative immunonutritional deterioration irrespective of sex. Although biological sex did not independently influence postoperative recovery trajectories, impaired perioperative immunonutritional status—particularly elevated postoperative CONUT score—was strongly associated with delayed functional recovery. Serial perioperative CONUT assessment may represent a valuable tool for individualized postoperative risk stratification and nutritional management in gastric cancer patients undergoing gastrectomy.

Abstract: Chronic wounds are a persistent clinical and public health challenge. Natural polyphenols such as curcumin and resveratrol, alongside mesenchymal stem cell (MSC) secretome, have demonstrated complementary anti-inflammatory, antioxidant, and pro-angiogenic properties with potential for wound healing. This study reports two complementary in vitro investigations evaluating the release profiles of curcumin and resveratrol from two polymeric platforms: poly(vinyl alcohol)/sodium alginate/carboxymethylcellulose films (Study 1) and an acrylate copolymer-based hydrogel incorporating MSC secretome (Study 2). UV-Vis spectrophotometric analysis confirmed analytical selectivity with no interference from excipients. In Study 1, films containing curcumin alone exhibited low structural stability and early disintegration in aqueous medium, whereas resveratrol-only films (2% w/w) demonstrated sustained and reproducible release profiles. Combined formulations showed that curcumin compromised polymer matrix integrity and reduced resveratrol release efficiency. In Study 2, resveratrol exhibited progressive and consistent release from the hydrogel, reaching 14.31 µg/mL (isolated control) and 12.60 µg/mL (combined with curcumin) at 120 min. Curcumin showed unsatisfactory release in both systems, attributed to its low aqueous solubility. These results support resveratrol-loaded polymeric matrices as promising sustained-release platforms for bioactive wound dressings and highlight the need for nanoencapsulation strategies to improve curcumin bioavailability.

Abstract: Background/Objectives: Inflammatory and hematologic indices derived from routine blood tests have been increasingly investigated as prognostic biomarkers in multiple myeloma (MM). However, their clinical utility remains inconsistent, and data on novel composite indices, such as the mean corpuscular volume-to-lymphocyte ratio (MCVL) and the cumulative inflammatory index (IIC), are lacking in MM. Methods: We conducted a retrospective study including 122 patients with newly diagnosed MM. Hematologic and inflammatory indices were evaluated at baseline and after four cycles of induction therapy. Associations with progression-free survival (PFS) and overall survival (OS) were assessed using Kaplan–Meier analysis, Cox regression models, and receiver operating characteristic (ROC) curve analysis. Results: Baseline inflammatory biomarkers, including NLR, PLR, MLR, SII, as well as MCVL and IIC, were not significantly associated with PFS or OS. ROC analysis demonstrated poor discriminative ability for all evaluated markers at both baseline and post-induction timepoints (AUC values close to or below 0.50). In contrast, post-induction inflammatory indices, particularly PLR, MLR, AISI, and SIRI, were significantly associated with PFS in both univariable and multivariable Cox regression analyses. Neither baseline nor post-induction MCVL and IIC showed independent prognostic value. Conclusions: Baseline inflammatory and erythrocyte-derived indices, including the novel composite markers MCVL and IIC, have limited prognostic utility in MM. In contrast, dynamic changes in inflammatory biomarkers during treatment may provide more clinically relevant information regarding disease progression. These findings support the integration of longitudinal biomarker assessment into future risk stratification models in MM.

Abstract: Background: Admission-based risk stratification in acute decompensated heart failure (ADHF) remains challenging, particularly in cohorts enriched for cardiorenal syndrome type 1 (CRS1). B-type natriuretic peptide (BNP) is the most extensively validated admission biomarker in ADHF, yet its independent contribution alongside heart failure (HF) phenotype and serum albumin within a prespecified multivariable mortality prediction model has not been formally established in CRS-enriched populations. Methods: In a retrospective cohort of consecutive index ADHF admissions (N=220 complete cases) at a single center enriched for CRS1, we developed a prespecified multivariable logistic regression model to predict in-hospital death using: age, sex, HF phenotype (HFpEF/HFmrEF/HFrEF), systolic blood pressure (SBP), estimated glomerular filtration rate (eGFR), serum albumin, and log-transformed BNP [ln(BNP)]. Discrimination was assessed by the area under the receiver operating characteristic curve (AUC) with 200-iteration bootstrap optimism correction. Calibration was assessed across risk deciles, and clinical utility was evaluated by decision curve analysis. Reporting followed the TRIPOD statement. Results: Seventeen patients (7.7%) died during the index hospitalization. ln(BNP) was the sole statistically significant independent predictor of in-hospital mortality (OR 2.39 per ln-unit; 95% CI 1.25–4.59; p=0.009). Albumin and eGFR showed consistent directional associations with mortality. The model demonstrated good apparent discrimination (AUC 0.81), with an optimism-corrected AUC of 0.73. Decision curve analysis indicated net benefit at threshold probabilities of 5–30%. A prespecified two-variable sensitivity model (albumin + ln[BNP]) yielded AUC 0.77, confirming the robustness of these two markers. Conclusions: This exploratory, internally validated model incorporating BNP, albumin, eGFR, and HF phenotype demonstrated promising discrimination for in-hospital mortality in a CRS-enriched ADHF cohort. The principal contribution is the application of a formally prespecified, TRIPOD-reported admission model in a CRS-enriched population, rather than identifying BNP as a novel prognostic marker. ln(BNP) was the sole statistically significant independent predictor. These findings are hypothesis-generating and require external validation before any clinical deployment.

Abstract: The coagulation cascade depends on the active participation of several elements present in the blood as well as signals arising from the endothelial cells. A platelet plug is a temporary, fast-response seal formed by platelets at the site of a damaged blood vessel to initiate hemostasis. It acts as the first step in primary hemostasis, where platelets stick to exposed collagen, activate, and aggregate to create a plug that temporarily prevents blood loss. Among changes platelets undergo is the degranulation step. Platelet degranulation is the process where activated platelets release stored chemical mediators from their internal alpha and dense granules into the bloodstream to promote hemostasis and immune responses. Platelet degranulation results in the release of substances like ADP, serotonin, fibrinogen, and zinc. In the present work we provide evidence that the high local concentration of zinc is intended to target junctional adhesion molecule A (JAM-A) that remains inactive (inhibited cell-adhesion and cytoskeleton dynamics) when coagulation is not needed and platelets move through the blood stream as single units. Zinc-activated JAM-A leads the platelets to aggregate. Our experimentation includes work with platelets, and a synthetic biology small peptide to quench the effects of zinc. We suggest that further exploring this mechanism of zinc-activated JAM-A can be advantageous for better understanding hemostasis, its role in antithrombotic therapy, coagulation inhibition, or thrombosis prevention.

Abstract: Background/Objectives: There are well-established sex differences in the epidemiology of stroke, but current data does not provide a clear mechanism to explain this phenomenon. This study asked if relationships between circulating sex hormone levels and stroke incidence could explain the sex differences in stroke rates. Methods: 393,158 participants from the UK Biobank aged were followed for a mean duration of 13.2 years. The incidence of ischemic stroke (IS) and intracerebral haemorrhage (ICH) was analysed in relation to baseline and changing levels of testosterone, sex hormone binding globulin (SHBG) and oestradiol. Results: A total of 3,844 participants experienced an IS and/or ICH, with incidence higher in men than women. In both sexes, a U-shaped association between total testosterone and ICH was found, independent of common cerebrovascular disease risk factors (P=0.006). Higher SHBG levels were associated with higher risk of IS (Q4 hazard ratio=1.18; P&lt;0.001) in both men and women, independent of common cerebrovascular risk factors. No significant associations were observed between oestradiol levels and stroke events after making demographic adjustments. Conclusions: These data highlight the nuanced roles that sex hormones play in the epidemiology of stroke between sexes. Whilst sex hormones are implicated in modulating stroke risk, this study demonstrated the complexity of this relationship.

Abstract: Background: Pirtobrutinib has recently emerged as a promising first-line treatment option for chronic lymphocytic leukemia (CLL). Unlike currently established regimens, which are generally based on doublet combinations, pirtobrutinib can be administered as monotherapy. Because no head-to-head trials comparing pirtobrutinib with contemporary first-line combinations are currently available, indirect comparative evidence may help define its potential role. Methods: A non-anchored indirect comparison based on reconstructed individual patient data (IPD) was conducted using published Kaplan-Meier curves from randomized controlled trials evaluating first-line treatments for CLL. Progression-free survival (PFS) was the endpoint of interest. Reconstructed IPD were generated using WebPlotDigitizer and the IPDfromKM algorithm. Pirtobrutinib monotherapy was compared indirectly with acalabrutinib plus obinutuzumab, venetoclax plus obinutuzumab, and venetoclax plus ibrutinib. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using univariate Cox models. Results: The analysis included four randomized trials. Compared with pirtobrutinib monotherapy, HRs for PFS were 0.5544 (95%CI, 0.2696-1.1397) versus venetoclax plus obinutuzumab, 0.4583 (95%CI, 0.2066-1.0200) versus venetoclax plus ibrutinib, and 1.4453 (95%CI, 0.6684-3.1240) versus acalabrutinib plus obinutuzumab. Confidence intervals were wide and crossed unity in all comparisons, indicating substantial statistical uncertainty. Visual inspection of reconstructed Kaplan-Meier curves did not suggest inferior PFS for pirtobrutinib relative to established doublet regimens. Conclusions: This exploratory non-anchored analysis suggests that pirtobrutinib monotherapy may provide PFS outcomes broadly comparable to current first-line combination regimens for CLL. Given the methodological limitations inherent to indirect comparisons, prospective head-to-head studies are needed to clarify the optimal positioning of pirtobrutinib in treatment-naïve CLL.

Abstract: Nano-engineering strategies have been increasingly applied to enhance the biological performance of calcium silicate–based materials; however, the optimal concentration of nano-hydroxyapatite (HANP) remains unclear. This study evaluated the bone-healing response to different concentrations of HANP incorporated into mineral trioxide aggregate (MTA) and bioceramic (BC) sealers in an experimental rabbit model. Thirty adult New Zealand white rabbits were allocated into two experimental groups according to sealer type: HANP-modified MTA and HANP-modified BC (n = 15 each). Two standardized circular intrabony defects were created bilaterally in the maxillary diastema of each rabbit. In the MTA group, the right-side defects were filled with 2% and 4% HANP-modified MTA, while on the left side one defect received 6% HANP-modified MTA and the adjacent defect was left as control. The same protocol was followed for the BC group using corresponding HANP concentrations. Five rabbits per group were sacrificed at 2, 4, and 8 weeks postoperatively for histopathological hematoxylin and eosin (H&E) and Masson trichrome staining. The results demonstrated significant differences among groups at all-time points, with 4% HANP showing the most favorable biological response, including reduced inflammatory cell infiltration, increased new bone formation, and improved collagen organization compared with lower and higher concentrations. Pairwise comparisons at matched HANP concentrations revealed no statistically significant differences between HANP-modified MTA and BC groups. These findings indicate that HANP incorporation enhances the biological performance of calcium silicate–based sealers in a concentration-dependent manner, with 4% representing an optimal formulation for promoting bone regeneration.

Abstract: Chronic Mycobacterium tuberculosis (M.tb) infection reflects failure of sterilizing immunity and persistent pulmonary bacterial burden. While CD4+ T cells and IFN-γ are central to protection, the role of CD8+ T cells in chronic disease remains unclear. This study examined whether CD8+ T cells contribute to immune dysregulation during chronic tuberculosis through IL-10 production. Susceptible CBA/J and resistant C57BL/6 mice were infected with a low-dose aerosol of M.tb Erdman and followed for 150 days. Lung bacterial burden, cytokine responses, and T-cell populations were assessed using high-purity CD8+ T-cell isolation (>97%), ELISA, ELISPOT, and in vivo CD8+ depletion. In susceptible CBA/J mice, chronic infection was associated with progressive pulmonary accumulation of CD8+ T cells, reduced CD4:CD8+ ratios, increased IL-10 levels, and impaired bacterial control. Antigen-experienced CD8+ T cells were a major source of IL-10, which correlated with reduced IFN-γ responses and higher bacterial burden. CD8+ depletion during chronic infection was associated with reduced bacterial burden and increased IFN-γ responses. Resistant C57BL/6 mice showed limited expansion of IL-10-associated CD8+ responses and better bacterial control. These findings support a model in which chronic M.tb infection is associated with expansion of IL-10-producing CD8+ T cells in susceptible hosts and altered immune control. CD8+ T-cell modulation during chronic disease is associated with changes in bacterial burden, suggesting a contributory role in disease outcome. These results highlight CD8+ T-cell functional polarization as a factor to consider in tuberculosis pathogenesis and vaccine design.

Abstract: Paediatric rhinosinusitis (RS), particularly chronic rhinosinusitis (CRS), is a common inflammatory condition with a significant impact on quality of life and a well-recognized association with asthma within the framework of united airway disease. This review aims to evaluate the impact of RS on asthma control in children and explore its role as a modifiable determinant. Mechanistically, RS and asthma share key pathophysiological features, including type 2 inflammation, epithelial barrier dysfunction, and airway microbiome dysbiosis, supporting the concept of a unified inflammatory process across the respiratory tract. Clinically, epidemiological data demonstrate a high prevalence of coexisting RS and asthma, with consistent associations with poorer asthma control, increased disease severity, and higher exacerbation burden, even in cases of subclinical sinonasal inflammation. Emerging evidence suggests that appropriate management of CRS, including medical therapy and, in selected cases, surgical intervention, may improve asthma outcomes such as symptom control and lung function. However, the current evidence base remains limited, with a predominance of small, heterogeneous, and observational studies. RS therefore represents a potentially treatable trait in paediatric asthma, warranting systematic evaluation in children with difficult-to-treat disease. Further prospective and interventional studies are needed to clarify causality and define its impact on long-term outcomes.

Abstract: Objectives: To evaluate the impact of Point-of-Care Ultrasound (POCUS) performed by family physicians on the management of abdominal pain in the emergency department, assessing its effect on length of stay, performance of complementary diagnostic tests, diagnostic concordance, and patient satisfaction. Methods: Quasi-experimental pilot study with a control group conducted in a hospital emergency department. A total of 222 adult patients with abdominal pain were included and allocated according to the attending professional (with or without ultrasound training). Clinical, care-related, and patient-satisfaction variables (SERVPERF questionnaire) were analyzed. Non-parametric statistical tests were used, and multiple linear regression analyses were performed. Results: The POCUS group showed a shorter length of stay (3.46 vs. 4.41 hours; p=0.022) and a lower number of plain radiographies (16.8% vs. 69.9%; p<0.001) and CT scans (p=0.034). Diagnostic concordance was significantly higher in the experimental group (99.2% vs. 75.7%; p<0.001). Overall satisfaction with received care was also higher in the intervention group (p<0.001), with significant differences observed across all evaluated dimensions. The multivariate model explained 26.6% of the variability, with patient satisfaction emerging as a positive predictor. Conclusions: POCUS improves the quality of care in emergency departments by reducing length of stay and the use of complementary diagnostic tests while increasing diagnostic accuracy and patient satisfaction. Its implementation can be considered an effective and potentially cost-effective strategy; however, further studies with greater methodological robustness are required to validate the development of standardized composite indexes.

Abstract: Background/Objectives: The anticoagulant used for blood collection is a fundamental but underexplored variable in platelet-rich plasma (PRP) preparation. Ethylenediaminetetraacetic acid (EDTA) and sodium citrate act on platelets through distinct calcium chelation mechanisms with potentially different consequences for PRP quality. Our group has previously demonstrated that biological and demographic variables independently modulate platelet composition in PRP; the present study extends this analysis to the pre-analytical anticoagulant variable. No prospective paired clinical study has systematically compared the effects of EDTA and sodium citrate on platelet morphological parameters in a real clinical setting. This study aimed to characterise these differences and evaluate their implications for orthobiologic therapy. Methods: A prospective within-subject paired-sample study was conducted at Instituto Cugat – Quirónsalud Barcelona (November 2025–April 2026). Twenty-six consecutive adult patients undergoing routine blood extraction prior to orthopaedic procedures had blood drawn simultaneously into K₂-EDTA and sodium citrate (3.2%) tubes. Full haematological analysis was performed on a Sysmex XN automated analyser within 30 minutes. Primary outcomes were mean platelet volume (MPV), platelet distribution width (PDW), large platelet ratio (P-LCR), large platelet cell count (P-LCC), and plateletcrit (PCT). Statistical comparisons used the paired t-test or Wilcoxon signed-rank test; effect sizes were quantified as Cohen's d. Results: Seven of eight platelet-related parameters differed significantly between anticoagulants (all p<0.001). Compared to sodium citrate, EDTA produced systematically higher MPV (+10.1%, d=2.81), P-LCR (+25.8%, d=2.41), P-LCC (+24.3%, d=1.70), PDW (+13.5%, d=1.33), PCT (+7.3%, d=0.78), RDW-CV (+2.0%, d=0.83), and RDW-SD (+2.6%, d=0.80). MPV was higher with EDTA in all 26/26 paired samples without exception. Total platelet count did not differ significantly (p=0.135). Effect sizes for all morphological parameters were large (d≥0.78). Conclusions: EDTA induces large, reproducible, and universal platelet morphological changes consistent with calcium chelation-induced swelling, not genuine platelet hypertrophy. These artefactual changes systematically overestimate platelet size and large platelet indices by up to 26%, with direct implications for PRP quality assessment in orthobiologic medicine. Sodium citrate should remain the anticoagulant of choice for PRP preparation. Clinicians using EDTA must recognise that morphological parameters do not reflect functional platelet capacity.

Abstract: Thymosin beta-4 (TB4) and the related compound commonly referred to as TB-500 are widely discussed in tissue healing and musculoskeletal medicine, but the scope and nature of the supporting literature remain unclear. We conducted a scoping review to map the evidence on TB4 and TB-500 in tissue healing, regeneration, and musculoskeletal repair. PubMed, Europe PMC, and ClinicalTrials.gov were searched through March 2026. English-language in vitro, animal, human, and registered clinical trial sources directly evaluating TB4, TB-500, or included derivatives in repair-related contexts were eligible. Of 1772 records identified, 80 studies were included. The evidence base was weighted toward mixed and in vitro designs, and most studies evaluated TB4 rather than TB-500. The most common tissue categories were wound/skin/soft tissue, vascular/endothelial, ocular/cornea, and bone. Direct musculoskeletal tissue categories such as tendon, ligament, muscle, cartilage, and spine/intervertebral disc were comparatively sparse. Human evidence was concentrated in ocular/cornea and wound/skin/soft tissue settings, whereas direct TB-500 evidence was limited to a single included study. Overall, the mapped literature supports the popular interest in several repair-related pathways but remains unevenly distributed and largely preclinical, with limited human evidence directly relevant to musculoskeletal applications.

Abstract: Major depressive disorder (MDD) is increasingly understood as a disorder of integrated immune, endocrine, metabolic, neurovascular and synaptic regulation rather than a disease reducible to a single neurotransmitter deficit. Lipidomic studies have repeatedly identified glycerophospholipid abnormalities in MDD, but their mechanistic meaning remains unresolved because changes in bulk lipid abundance do not explain how a metabolic disturbance becomes a receptor-level neural signal. This review argues that the lysophosphatidylcholine (LPC)-autotaxin (ATX)-lysophosphatidic acid (LPA)-LPA receptor (LPAR) axis offers a chemically and biologically coherent route for addressing that gap. LPC is not merely a readout of phospholipid remodeling; it is the direct ATX substrate from which receptor-active LPA can be generated. LPA receptors, in turn, regulate neural excitability, synaptic balance, hippocampal plasticity and stress-related behavior. Human studies report lower serum and cerebrospinal-fluid ATX in MDD, lower CSF LPA 22:6 in MDD and schizophrenia, and negative total-LPA findings that caution against biomarker oversimplification. Experimental studies show that ATX/LPA/LPAR perturbation alters hippocampal function, emotional behavior, stress resilience and synaptic physiology. These findings do not establish a completed depression pathway. They support a more specific hypothesis: depression-relevant ATX-LPA biology may be molecular-species resolved, compartment dependent, regionally organized and shaped by local production-inactivation balance. Reproductive endocrine transitions provide a biologically informative setting for testing this hypothesis because mood vulnerability, systemic lipid remodeling and steroid-sensitive regulation of pathway-adjacent nodes converge in the same clinical context. The decisive unresolved issue is spatial and biochemical: no depression-relevant study has yet demonstrated that defined brain-accessible LPC species, catalytically active ATX, locally generated LPA, local LPA inactivation capacity and receptor-specific circuit output coexist within a single mood-relevant CNS microenvironment. Future work should therefore move from fluid-level association toward pathway closure through targeted and spatial lipidomics, anatomical ATX activity mapping, LPA inactivation assays, BBB/interface analysis, LPAR perturbation and matched circuit or behavioral readouts.

Abstract: This study investigates the comparative effects of traditional cigarettes and e-cigarettes on lung health in male Rattus norvegicus over 8 and 12 weeks. Following ARRIVE 2.0 guidelines, 30 rats were divided into six groups to evaluate the impact of nicotine and ascorbic acid aerosols on tracheal and alveolar structures, as well as systemic inflammatory markers (IL-6, TNF-α, SOD-3, MDA). Results indicate that long-term cigarette exposure (12 weeks) and nicotine vaping (8 weeks) significantly stunted weight gain, whereas ascorbic acid vaping caused less growth inhibition. Histological analysis revealed that 8-week cigarette exposure (K3) increased tracheal mucosal thickness and antioxidant activity (SOD-3), while cigarette smoke generally decreased goblet cell counts and induced early emphysema. In contrast, long-term exposure significantly elevated IL-6 and caused severe alveolar wall damage. Notably, vaping ascorbic acid (K6) offered protective benefits, preserving the basement membrane and reducing septal thickening compared to nicotine groups. The findings conclude that while short-term smoking triggers immediate tracheal damage, long-term exposure escalates systemic inflammation and permanent alveolar destruction. Phytochemical-based aerosols, such as ascorbic acid, reduce pulmonary injury compared with nicotine-based products.

Abstract: Lipedema affects an estimated 11–12% of women worldwide and is characterized by bilateral, symmetric adipose deposition in the lower extremities, disproportionate pressure pain, spontaneous bruising, and resistance to conventional dietary interventions. Despite its prevalence, lipedema lacks a unifying mechanistic framework. Current descriptions treat it as a fat storage disorder with secondary vascular and inflammatory features, leaving critical observations mechanistically unexplained: a highly characteristic quantitative sensory testing (QST) pattern with no published alternative mechanistic explanation, a paradoxical immunological profile, a 35–40% comorbidity with fibromyalgia, a 1.42 relative risk for ADHD, estrogen-dependent onset, and asymmetric expression in the presence of local vascular triggers.We propose the gfWAT-IIT2 framework, which posits that lipedema is fundamentally a syndrome of polarization of the gluteofemoral white adipose tissue (gfWAT) microenvironment toward innate type 2 immunity (IIT2), amplified by estrogen via mast cell estrogen receptors, and generating neuropathic pain through selective histaminergic sensitization of Aδ/C fibers (H1/H4 receptors, PPT↓) and inhibition of Aβ fibers (H3 receptor, VDT↑), with thermal thresholds remaining normal: a triad that is mechanistically explained by histaminergic peripheral sensitization.The gfWAT-IIT2 framework integrates reported clinical, sensory, immunological, and depot-specific observations into a testable mechanistic cascade, generates fourteen falsifiable predictions, and repositions the therapeutic target from adipocyte to mast cell. The framework further proposes that asymmetric lipedema (where one limb expresses the disease more severely due to an identifiable local trigger) constitutes a natural controlled experiment suggesting that local trigger removal may be disease-modifying in selected patients with documented triggers.

Abstract: Background: Plyometric training has been proposed as an effective strategy for improving neuromuscular performance in climbing. However, its specific effects on upper-body explosive capacity and rate of force development (RFD) in advanced boulder climbers remain unclear. The objective was to determine the effect of a 10-week plyometric training program on neuromuscular performance in advanced boulder climbers. Methods: Eighteen male climbers participated, divided into a plyometric training group (n = 9; 31.33 ± 5.63 years) and a control group (n = 9; 29.67 ± 4.50 years). Maximal strength and rate of force development (RFD) of the finger flexor muscles were assessed, and RFD was analyzed in time intervals from 0 to 200 ms and in a relative range of 20–80% of maximal strength. Maximal pulling strength (isometric pull-ups) was assessed using a load cell in a standardized pull-up position. Lower-body power was assessed using the counter-movement jump (CMJ) test, and upper-body specific power using the Power Slap test on a campus board. The plyometric training program was conducted over ten weeks (two sessions of 45 to 60 minutes each). Results: Significant differences were observed between groups in pull-ups (Δ difference = +3.89 repetitions; 95% CI:-7.48,0,30, p=0.036; η²p=0.248), push-up power (Δ difference = +174.5 W; 95% CI: 5.05,–343. 46, p=0.044; η²p=0.128) and isometric pull-up RFD at 200 ms (Δ difference = +107.85 kg/s; 95% CI: 27.54, -188.16; p=0.012; η²p=0.336), and in the 20–80% range (Δ difference = +261.78 kg/s; 95% CI: 23.09–500.47; p=0.034; η²p=0.194). No differences were observed between groups in Power Slap (p=0.409) or in CMJ height (p=0.122). Conclusion: A 10-week plyometric training program produced specific neuromuscular adaptations in advanced boulder climbers, improving pull-up performance, upper body explosive power, and isometric pull-up RFD. The absence of transfer to finger strength, Power Slap, and CMJ confirms the high specify of neuromuscular adaptations to the trainer movement pattern.

Abstract: The study considers the hypothesis (supported by a compatible theory) that the vibratory test (SVIN) corresponds to unilateral weakness (UW) in caloric tests and that the head-shaking test (HST) is directly proportional to directional preponderance (DP). A group of 76 patients with vestibular deficits at various stages of compensation, confirmed by bithermal tests using the Fitzgerald-Hallpike technique and evaluated with Jongkees' formulas, was studied and compared with SVIN and HST results. The statistical study shows a marked correlation between SVIN and UW and between HST and DP. At the same time, the cross-correlations between SVIN and DP, and between HST and UW, are significantly weaker, confirming the hypothesis. It is concluded that, in cases where caloric testing is not considered necessary, these two bedside functional tests can give a precise idea of the results of caloric testing and that this interpretation can highlight the great clinical potential of SVIN and HST performed in combination.