Medicine and Pharmacology

Abstract: Long‑acting injectable (LAI) formulations have transformed adherence in several psychiatric conditions, yet no depot antidepressant currently exists. People with major depressive disorder (MDD) remain at risk of accidental overdose from prescribed oral medications, particularly during periods of cognitive impairment or crisis. Artificial intelligence (AI)–driven molecular modelling now enables the design of antidepressant compounds optimised for slow‑release, water‑based depot systems that avoid the fibromas and granulomatous reactions associated with oil‑based injectables. This study outlines an AI‑enabled workflow for generating a novel antidepressant molecule with favourable receptor‑binding properties, low toxicity, and compatibility with biodegradable, aqueous depot carriers. The resulting formulation has the potential to reduce overdose risk, improve adherence, and decrease the burden of frequent GP prescribing.

Abstract: Mitochondria regulate cellular energetics, redox balance, apoptosis, and inflammatory signaling in oral, airway, and systemic tissues. Hypoxia is a powerful modulator of mitochondrial function, with effects ranging from adaptive hormesis to overt injury. Cyclic altitude training, most delivered as intermittent hypoxic exposure or intermittent hypoxia training (IHT), has been proposed as a strategy to improve mitochondrial efficiency and exercise performance. By contrast, obstructive sleep apnea (OSA) exposes patients to uncontrolled chronic intermittent hypoxia (CIH), a pattern increasingly linked to endothelial dysfunction, ceramide-mediated mitochondrial dysfunction, insulin resistance, systemic inflammation, oral dysbiosis, and periodontitis. This narrative review covers intermittent hypoxia, mitochondrial biogenesis, hypoxia-inducible factor signaling, OSA, periodontitis, oral microbiome shifts, nitric oxide biology, and smoke-related mitochondrial injury. Appropriately dosed IHT can increase mitochondrial biogenesis, improve mitochondrial morphology, and augment oxidative capacity through pathways involving PGC-1alpha, hypoxia-inducible signaling, mitochondrial dynamics, and reactive oxygen species-dependent hormesis. In contrast, CIH in OSA promotes oxidative stress, sympathetic activation, endothelial injury, and inflammatory signaling and is associated with worse periodontal status and altered salivary microbiome profiles. Controlled IHT and OSA-related CIH, therefore, represent opposite ends of a hypoxia continuum, and mitochondrial health connects sleep-disordered breathing, periodontal inflammation, environmental exposures, and systemic cardiometabolic risk within a single conceptual frame. Sphingolipid signaling—particularly hypoxia- and toxicant-driven ceramide accumulation—connects CIH, inhaled environmental exposures, mitochondrial fragmentation, and the development of insulin resistance.

Abstract: Amplification of the mesenchymal–epithelial transition factor protooncogene (MET), fibroblast growth factor receptor 2 (FGFR2), and epidermal growth factor receptor (EGFR) genes has been identified in 2–24%, 2–9%, and 27–64% of patients with gastric cancer (GC), respectively. This study characterised carcinogenesis-related alterations and copy number variation (CNV) in 286 genes from four human GC cell lines and analysed differences in the susceptibility of these cells to treatment with pelitinib, tepotinib, and docetaxel. Using a targeted DNA sequencing, we evaluated alterations and CNV in 286 genes from four GC cell lines. We assessed the antitumour activity of pelitinib, tepotinib, and docetaxel in these GC cell lines and in a xenograft model. Docetaxel is a drug commonly used to treat gastric cancer and was used as a positive control in this study. The effects of pelitinib, tepotinib, and docetaxel on cell viability (half-maximal inhibitory concentration), apoptotic cell death, tumour volume, and hematoxylin and eosin staining were evaluated using MTS cell proliferation assays and flow cytometry. Antitumour efficacy was assessed in xenograft mice. Compared to tepotinib, pelitinib inhibited the growth of GC cells, showing dose-dependent amplification of EGFR (CNV > 3, without HRAS, KRAS, or NRAS mutations), MET (CNV > 30), and FGFR2 (CNV = 87), with concomitant cell death induction. In the murine xenograft model, tumour volumes were significantly reduced in the pelitinib, tepotinib, and docetaxel-treated groups when administered by daily oral gavage at doses of 10, 10, and 5 mg/kg/day, respectively. Histologically, necrosis was more pronounced in the pelitinib, tepotinib, and docetaxel groups than in the control group. Pelitinib demonstrated anti-tumour activity, with MET and FGFR2 amplified in all tested GCs and EGFR amplified in GCs without HRAS, KRAS, or NRAS mutations.

Abstract: Gender role beliefs shape healthcare interactions, particularly in societies with deeply rooted traditional norms. This study examined discrepancies between culturally inherited gender role ideologies and actual behavioural patterns within a diverse cohort involved in medical training and practice. Participants, aged 20–52, represented a wide range of clinical exposure, employment status and personal life circumstances, offering a complex sociocultural spectrum rather than a uniform academic group. Using an interpretative phenomenological approach, participants provided written and oral reflections on widely known Romanian gender role axioms. Results revealed endorsement of traditional beliefs—like male authority and female domestic responsibility—yet these convictions frequently contrasted with participants’ lived behaviours, including women serving as primary earners, engaging in advanced studies and balancing multiple roles, and men in caregiving professions. This misalignment suggests unconscious bias and limited self-awareness of one’s own nonconforming practices. These discrepancies have implications for clinical care, as rigid gender role beliefs may influence communication, empathy, the ability to provide equitable healthcare to gender-diverse patients. Findings indicate the need for structured gender-diversity education, reflexivity training and cultural competence development across medical curricula, workplace settings and continuing professional education. Overall, the study demonstrates how traditional gender representations persist despite behavioural change, potentially shaping healthcare attitudes and reinforcing bias unless explicitly addressed.

Abstract: Background: Skin grafts including split-thickness skin grafts (SSG) and full-thickness skin grafts (FTSG) are widely used in reconstructive surgery. Infection following grafting can compromise graft take and prolong hospitalisation, yet contemporary cohort data describing incidence, microbiology and graft-specific risk factors remain limited. Methods: We conducted a retrospective observational cohort study of 977 consecutive skin graft procedures performed in 116 patients at two hospitals in New South Wales, Australia, between 1 July 2021 and 13 August 2024. Post-graft infection was defined as a clinician-diagnosed graft site infection with microbiological confirmation. Infection incidence was estimated with exact 95% confidence intervals. Associations between graft characteristics and infection were explored using chi-square testing and binomial regression to estimate relative risks. Length of stay (LOS) was assigned to the index admission corresponding to each procedure and analysed using negative binomial regression to account for overdispersion. Results: Among 977 graft procedures, 66 infections occurred, giving an overall infection incidence of 6.8% (95% CI 5.3–8.5%). Median LOS was substantially longer in infected cases than non-infected cases (34 vs 3 days, p < 0.001). Full-thickness grafts to the face (RR 0.083, 95% CI 0.008–0.827) and nose (RR 0.038, 95% CI 0.004–0.378) were associated with a reduced incidence of infection, although estimates were imprecise because of sparse data. Among infections, Staphylococcus aureus accounted for approximately 47% of cases and Pseudomonas aeruginosa for approximately 20%. In a nested antimicrobial audit cohort of 111 split-thickness skin graft procedures, peri-operative prophylaxis was common, postoperative antibiotics were frequently prescribed, and postoperative antibiotic prescribing was not associated with reduced infection, although the analysis was underpowered. Conclusions: Post-graft infection occurred in 6.8% of procedures. This rate is comparable with contemporary literature and was associated with substantial morbidity. S. aureus and P. aeruginosa predominated. These findings support consideration of targeted preventive strategies, microbiology-informed empiric therapy and antimicrobial stewardship, while highlighting the need for prospective studies with more comprehensive risk adjustment.

Abstract: Point-of-care testing (POCT) for cardiac troponin is increasingly used to support rapid clinical decision-making, particularly in resource-limited settings. However, while many central laboratories, including those in Sri Lanka, now use high-sensitivity cardiac troponin I (hs-cTnI) assays, commonly available POCT platforms continue to use conventional methodologies with different analytical characteristics and decision thresholds. We evaluated the analytical agreement and clinical concordance of two POCT troponin assays against a central laboratory hs-cTnI assay using paired samples obtained during routine clinical care in a Sri Lankan hospital. Both POCT devices demonstrated strong correlation with the laboratory assay (Pearson r ≈ 0.90). However, Bland–Altman analysis showed substantial positive bias and wide limits of agreement, indicating poor interchangeability at the individual sample level, with proportional bias observed in one device. Clinically relevant discordance was also identified, with 26.9% and 30.4% of samples classified as negative by POCT despite being positive by the reference assay. Regression-based recalibration did not significantly improve concordance. These findings highlight that strong correlation does not ensure diagnostic agreement, emphasizing the need for local validation before integrating POCT troponin assays into established hs-cTnI diagnostic pathways.

Abstract: Background: Neuroinflammation contributes to etiopathology and symptom severity in neurodegenerative and neuropsychiatric disorders. Glial cells, especially microglia and astrocytes, play a crucial role in neuroinflammation. It has been reported that ginseng and its bioactive component ginsenoside Rg1 exhibit anti-inflammatory effects and improve cognitive performance in various models. However, the exact underlying mechanisms remain unclear. Methods: An astrocyte-microglia co-culture model simulating physiological (M5, 5-10% microglia) and pathological/inflammatory (M30, 30-40% microglia) conditions was treated with different concentrations of ginsenoside Rg1 (15, 30, 45 µM), ginseng extract (derived from Korean red ginseng) at low-dose (12.5, 25, 37.5 µg/ml) or high-dose (125, 250, 375 µg/ml) for 24 hours. Cell viability was assessed by MTT assay. Microglial reactivity was examined by immunocytochemistry. Astrocytic gap-junctional coupling was investigated using scrape loading method and connexin 43 (Cx43) expression was analyzed by immunocytochemistry and Western blot. Results: Both Rg1 and low-dose ginseng extract reduced microglial activation under inflammatory conditions by promoting a phenotypic shift from activated to homeostatic (resting) microglia. Rg1 preserved astrocytic gap-junctional function by preventing the inflammation-induced downregulation of Cx43 expression and enhancing Cx43-mediated gap-junctional intercellular communication. Rg1 caused a significant reduction of glial cell viability only at high concentrations (30 and 45 µM) under inflammatory conditions. High-dose ginseng extract showed significant concentration-dependent cytotoxicity, reducing glial cell viability under physiological and pathological conditions, without comparable anti-inflammatory benefits. Conclusions: This study suggests that low-dose ginseng and its active compound Rg1 exert anti-inflammatory effects by modulation of astrocytic coupling and microglial reactivity. These results provide a novel therapeutic perspective for ginseng in the treatment of neurodegenerative and neuropsychiatric diseases related to neuroinflammation.

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.