Abstract: Lung cancer is one of the most commonly diagnosed cancers worldwide and remains the leading cause of cancer-related death in both men and women. In 2022, approximately 2.5 million new cases of lung cancer and 1.8 million deaths due to the disease were estimated. Historically, lung cancer has been more frequent in men, although the difference between sexes has been decreasing, with tobacco use remaining the main etiological factor. Survival rates vary considerably depending on the stage at diagnosis and other factors, and overall prognosis remains poor, with a relatively low five-year survival rate compared to other types of cancer. In this work, the objective is to present current approaches to lung cancer diagnosis through the study of multiple genetic alterations and biomarkers, mainly detected by next-generation sequencing (NGS), which has significantly transformed cancer diagnostics by enabling highthroughput and cost-effective genomic analysis. In the context of lung cancer, NGS plays a crucial role in improving molecular characterization, guiding targeted therapies, and supporting personalized medicine strategies. Specifically, its relevance lies in the ability to provide a comprehensive genomic profile of the tumor, identify driver mutations, predict treatment response, detect co-occurring alterations, and assist in therapeutic stratification. A real-world case study was conducted including 101 patients diagnosed with lung cancer between 2023 and 2025 in a reference laboratory, whose tumors were analyzed using NGS. The most frequently altered genes identified were KRAS, EGFR, and ALK, together with other less common but clinically actionable alterations, as well as the evaluation of programmed death-ligand 1 (PD-L1) expression by immunohistochemistry. In summary, next-generation sequencing represents a fundamental tool in the diagnostic workflow of lung cancer, enabling comprehensive molecular profiling that supports personalized treatment selection and contributes to improved clinical management of patients.

Abstract:

The G14R mutation in α-synuclein is associated with aggressive, early-onset Parkinson’s disease, yet its impact on the protein’s N-terminal regulatory domain remains poorly understood. As an intrinsically disordered protein, α-synuclein’s conformational landscape is highly sensitive to sequence perturbations and ligand interactions. This study investigates a hypothesized "allosteric tug-of-war" between pro-aggregatory zinc ions and inhibitory dopamine at the N-terminus. Using a Python-based physicochemical structural proxy model, we assessed residue-level charge, volume, and interaction heuristics for the first 20 residues of the G14R variant. Our results demonstrate that the substitution of glycine with arginine at residue 14 creates a localized "rigidity hotspot" characterized by enhanced electrostatic coordination with Zn²⁺ ions. Crucially, we found that dopamine competitively attenuates this stabilization at overlapping residues, suggesting a displacement-based mechanism. This modeling framework provides a mechanistic basis for the G14R phenotype, suggesting that dopamine depletion may permit persistent zinc-mediated structural stabilization, thereby promoting aggregation. These findings highlight the N-terminus as a critical switch for modulating α-synuclein pathology through small-molecule competition.

Abstract: Background: Transcatheter aortic valve implantation (TAVI) has transitioned from a therapy for inoperable or extreme-risk patients to a standard option across broader risk categories. How this evolution has reshaped patient selection, procedural practice, and early outcomes within a mature program over extended time remains incompletely described. Methods: We conducted a single-center retrospective observational cohort study including all consecutive patients undergoing TAVI for severe symptomatic aortic stenosis between 2012 and 2024. Patients were stratified into three temporal eras (2012–2015, 2016–2020, 2021–2024). Baseline clinical, imaging, and procedural variables were prospectively recorded. The primary endpoint was 1-month major adverse events (MAE), defined as a composite of all-cause death, stroke, myocardial infarction, major vascular complications, or major bleeding. Comparisons across eras used ANOVA and chi-square or Fisher exact tests, as appropriate; multivariable logistic regression was applied to identify independent predictors of MAE. Results: A total of 1,946 patients were included (n=230, 396, and 1,320 across the three eras). Mean age (~81 years) and sex distribution (~60% women) remained stable, whereas cardiovascular risk factors became more prevalent over time (dyslipidemia 46.4% to 89.9%, hypertension 90.9% to 97.7%, smoking 1.1% to 11.2%; all p<0.001). Functional status improved (NYHA III–IV 78.2% to 18.0%; p<0.001), and EuroSCORE II decreased (5.7±5.1 to 3.2±3.6; p<0.001). Angiographically significant coronary artery disease and bicuspid valves were more frequently treated in the most recent era. Transfemoral access under local anesthesia remained predominant, while fluoroscopy time, contrast volume, and procedural duration significantly decreased (all p≤0.003). Residual aortic regurgitation ≥moderate became rare, with none/trace regurgitation increasing from 57.8% to 91.3% (p<0.001). Hospital stay shortened (7.3±2.8 to 6.1±3.1 days; p<0.001). MAE declined from 17.4% to 7.2% (p<0.001), driven by marked reductions in major bleeding (10.0% to 0.7%; p<0.001) and stroke (2.6% to 0.3%; p=0.002), while 1-month mortality remained low (2.6% to 1.0%; p=0.087). The need for new permanent pacemaker implantation was frequent but stable (~17–19%; p=0.645). Conclusions: Over 12 years, this high-volume TAVI program has progressively shifted towards patients with more conventional cardiovascular risk profiles, lower surgical risk, and more complex coronary and valvular anatomy, while achieving shorter, more efficient procedures and improved early safety. These findings support the robustness of a structured Heart Team approach and underscore the importance of continuous optimization of TAVI pathways in an evolving and increasingly heterogeneous patient population.

Abstract: Human intelligence is strongly heritable, but the genes that fine-tune the brain's wiring are still being mapped. We re-examined the large IQ genome-wide association study by Savage et al. (2018; N = 269 867) with three complementary tools—partitioned SNP-heritability, MAGMA gene tests, and a transcriptome-wide association study (TWAS)—to ask whether synaptic pruning makes an independent contribution beyond classic glutamatergic signalling. Seven pre-registered gene sets were contrasted: two glutamate lists, two pruning lists, two negative-control lists (monoamine and housekeeping genes), and a "pruning-only" set that removed every glutamatergic gene.Heritability was significantly enriched in both glutamate and pruning sets, but the pruning-only panel still carried a clear signal (1.10-fold, P ≈ 5 × 10⁻¹⁵), showing that pruning effects are not simply spill-over from glutamate pathways. MAGMA supported this pattern, highlighting SEMA3F, RHOA, MAP1LC3B and TCF4 after Bonferroni correction. TWAS added tissue context: pruning genes showed the strongest over-representation (core set 1.38-fold, P ≈ 2 × 10⁻⁵), with RHOA down-regulated in caudate and SEMA3F up-regulated in anterior cingulate.Together, the results inspire a "Calibrated Pruning Framework." We propose that common variants adjust the timing of a multistep pruning cascade—TCF4 keeps critical periods open a little longer, SEMA3F–RHOA steers branch retraction, MAP1LC3B clears debris, and HLA tags mark synapses for removal—thereby fine-tuning network efficiency and, ultimately, cognitive ability. Limits of the work include the European bias of the base GWAS and reliance on adult-brain expression panels; future longitudinal imaging and multi-ancestry studies will be needed to test the model's predictions.

Abstract:

Background: We sought to analyze the geographic distribution of HFE p.C282Y (homeostatic iron regulator c.845G>A; rs1800562) allele frequencies in Iberia. Methods: We analyzed published population/control cohorts of 50 or more subjects in mainland Spain and mainland Portugal and determined whether or not the p.C282Y genotypes in each cohort deviated from Hardy-Weinberg equilibrium (HWE) proportions. We defined combined p.C282Y allele frequencies from Spain and Portugal as representative of Iberia. We computed linear regressions (Pearson’s correlations) of allele frequencies vs. latitudes and longitudes of cohort recruitment sites, defined significant regressions as allele frequency gradients, and mapped regional allele frequencies. Results: There were 33 Iberian cohorts: 24 Spanish (12,082 subjects; 10 autonomous communities) and 9 Portuguese (1024 subjects; five administrative regions). p.C282Y genotypes in one of 33 cohorts (3.0%) deviated significantly from HWE proportions. Aggregate allele frequency in Iberia was 0.0291 (762/26,212) [95% confidence interval: 0.0271, 0.0312]. The correlation of allele frequencies vs. latitudes in Iberia was significant (r₃₃ = 0.4129; p = 0.0152). The correlation of allele frequencies vs. longitudes was not significant (r₃₃ = -0.0118; p = 0.9552). The range of 15 regional allele frequencies in Iberia was 0.0068 (Murcia) to 0.5000 (Galicia). Frequencies were highest in regions adjacent to the north and northwest coasts (Cantabria, Galicia, Norte) and lowest in the south (Algarve, Murcia). Conclusions: There is a significant decreasing linear north-to-south gradient of HFE p.C282Y allele frequencies in Iberia. p.C282Y allele frequencies are highest in regions adjacent to the north and northwest coasts.

Abstract: Emerging evidence indicates that the genetics of substance-use disorders (SUDs) extend beyond canonical dopaminergic and metabolic pathways. To evaluate neurodevelopmental contributors, we re-examined summary statistics from a multivariate genome-wide association study of 1,025,550 individuals of European ancestry. Gene-based analysis with MAGMA, partitioned heritability with stratified LD-score regression, and transcriptome-wide association with S-PrediXcan were applied to bespoke gene sets: glutamatergic signalling, three synaptic-pruning variants (core, expanded, and pruning-exclusive sets), and negative controls.MAGMA identified a significant competitive enrichment for the expanded pruning set (Bonferroni-corrected p = 0.036) that remained after removing genes overlapping glutamatergic pathways (false-discovery-rate p = 0.033). Stratified LD-score regression corroborated this signal, showing a 1.06-fold enrichment of heritability (Bonferroni-corrected p ≈ 0.002). S-PrediXcan produced a concordant, albeit weaker, pattern; the top association was RHOA, a cytoskeletal regulator of pruning (p ≈ 3 × 10⁻⁹). Directionality of effects implied that risk alleles favour excessive pruning. We propose that such variants exaggerate adolescent synaptic elimination within reward circuitry, leaving networks hyper-responsive to dopaminergic and alcohol-related stimuli. This neurodevelopmental perspective aligns SUD onset during adolescence with its frequent comorbidity patterns, positioning synaptic pruning as a new, actionable target for prevention and intervention.

Abstract: Background: Schizophrenia is driven by many common variants, and two biological themes—excessive synaptic pruning and reduced glutamatergic transmission—feature prominently in current models. Yet these mechanisms do not fully account for the early-emerging, severe cognitive difficulties seen in affected individuals. To examine how pruning and plasticity signals diverge or overlap with cognition, we contrasted their genetic footprints in schizophrenia and in general intelligence.Methods: Using identical analytic steps, we processed summary statistics from the Psychiatric Genomics Consortium Wave 3 schizophrenia genome-wide association study and a large-scale intelligence study. The pipeline combined three approaches: (1) MAGMA for competitive gene-set enrichment, (2) stratified LD-score regression to partition heritability, and (3) S-PrediXcan to infer transcriptome-wide associations. Seven predefined gene panels anchored the work: three capturing pruning biology, two plasticity and two controls.Results: All three methods converged on a robust enrichment of pruning genes in schizophrenia. For the shortened pruning panel, MAGMA yielded a Bonferroni-corrected p = 1.3 × 10⁻⁵ and LD-score regression indicated extreme enrichment (p ≈ 10⁻¹⁷⁹). Signal persisted after glutamatergic genes were removed, and S-PrediXcan suggested up-regulated expression of key complement components such as C4A. In contrast, glutamatergic pathways showed only modest schizophrenia involvement.Conclusions: A double dissociation emerges. Schizophrenia risk aligns mainly with overactive pruning, whereas successful cognitive performance depends more on balanced glutamatergic-driven plasticity. We outline a “prune-without-repair” model in which unchecked complement activity, combined with weak glutamatergic stabilization, progressively undermines cognitive circuits in schizophrenia.

Abstract: Exporting food products from the European Union (EU) to the United States of America (USA) involves navigating complex regulations and procedural barriers that hinder market access. Italian food businesses (FBs), particularly small and medium-sized enter-prises (SMEs), often face difficulties accessing clear guidance, as national procedures are scattered across multiple sources. This paper proposes a structured four-step analytical framework to support EU FBs: product-specific analysis, identification of relevant EU and USA legislation, comparative legislative analysis via concordance tables, and identifica-tion of procedures to integrate into the Food Safety Management System. The framework was applied to an Italian medium-sized FB exporting pork-based pasta sauce to the USA. Beyond the specific case study, the proposed framework was designed to be replicable and adaptable to different food products and third-country destinations. As such, it can support both FBs and Competent Authorities in conducting risk-based assessments of regulatory equivalence and export compliance. Results indicated the need for Sanitation Standard Operating Procedures, thermal process validation, direct verification activities, and pre-shipment review. Findings emphasize that operational and procedural barriers disproportionately affect SMEs, highlighting the importance of targeted support to facil-itate market access and strengthen certification systems.

Abstract: Background/Objectives: Angiosarcoma of the thorax is a very rare and malignant disease. We studied the incidence and survival of thoracic angiosarcomas with special focus on primary and secondary angiosarcoma. Methods: We analyzed data from the population-based cancer registry North Rhine-Westphalia (NRW), Germany, of the years 2008–2023. We included primary and secondary angiosarcoma of the thorax (ICD-O-3: morphology 9120/3, topography C34, C38, C44.51, C49.3, C50) and report age-standardized (Old European Standard population) incidence rates and survival (Kaplan-Meier Curves). Results: We analyzed 421 cases of thoracic angiosarcoma. 90.0% were female (n = 379). The age-standardized incidence rates of angiosarcoma of the thorax were 0.25 per million and year for male patients (SE 0.0) and 1.5 per million and year for female patients (SE 0.1). All male patients had primary angiosarcoma (n = 42). The majority of thoracic angiosarcoma among females were second primary tumors (n=262, 69.1%). The 5-year overall survival (OS) was 38.5% (SE 2.6). OS for women was 41.4% (SE 2.8) and for men was 12.0% (SE 5.4). OS for female patients was 40.9% (SE 4.1) and 41.8% (SE 3.8) for primary and second primary angiosarcoma respectively. The worst OS had patients with angiosarcoma of the lung (men 20.0% (SE 12.7) and mediastinum, heart and pleura (men 4.7% (SE 4.5). The OS for women was 0%, all females died within 2.2 years after diagnosis of angiosarcoma with these topographies. Conclusions: Angiosarcoma of the thorax is a rare condition with poor prognosis. Irrespective of the classification into primary and second primary, women with angiosarcoma have a better prognosis than men. Topography seems to be the most determining prognostic factor in this disease.

Abstract: Background: Chronological age does not always accurately reflect biological matura-tion in children, particularly in the presence of systemic diseases. Dental age assess-ment is widely used as a biological maturity indicator; however, the effect of juvenile diabetes mellitus on dental maturation remains insufficiently clarified, with incon-sistent findings reported across populations. Objective: This study aimed to compare dental age estimated using the Demirjian method with chronological age in children with juvenile diabetes and in age- and sex-matched healthy controls. Materials and Methods: This observational comparative study included panoramic radiographs from 30 children aged 8–15 years: 15 patients diagnosed with juvenile diabetes mellitus and 15 systemically healthy controls, all presenting Angle Class I malocclusion. Dental age was assessed using the Demirjian method and compared with chronological age. Ap-propriate parametric or non-parametric statistical tests were applied based on data distribution. Results: Children with juvenile diabetes exhibited a statistically signifi-cant advancement in dental age relative to chronological age, with a mean DA–CA difference of 1.36 years (p = 0.0066). No statistically significant differences between dental and chronological age were observed in the control group. Sexual dimorphism was evident from crown completion stages onward, with females demonstrating earli-er dental maturation. Conclusions: Juvenile diabetes mellitus is associated with accel-erated dental maturation. These findings have clinical implications for orthodontic treatment timing and growth assessment and indicate a potential risk of age overesti-mation in forensic contexts. Dental age should therefore be interpreted alongside skel-etal and chronological indicators, particularly in pediatric patients with systemic metabolic conditions.

Abstract: Cadmium (Cd) is a ubiquitous environmental pollutant that enters the circulation from the lungs and gastrointestinal tract. For most people, staple foods form the main route of Cd exposure. Current evidence suggests that Cd may increase the prevalence of iron deficiency and anemia in environmentally exposed people. Concerningly, intravenous iron administration to treat iron deficiency anemia has resulted in adverse bone outcomes in a higher-than-expected frequency; for which reasons remain unclear. The bone-derived hormone, fibroblast growth factor 23 (FGF23), the regulator of vitamin D and phosphate homeostasis, has been speculatively implicated, given that anemia, iron deficiency and inflammatory conditions all are known to increase FGF23 expression levels in osteoblasts. Additionally, early studies demonstrated that Cd increased FGF23 expression by osteoblast-like cells and suppressed FGF23 cleavage leading to an abrupt rise in serum FGF23, which, in turn, mediated an effect of Cd on tubular phosphate reabsorption. In this review, experimental breakthrough studies showing Cd-induced iron deficiency, and a reduction in iron absorption by Cd are summarized together with intestinal absorption of Cd, and an increment of Cd uptake and Cd body burden in those with low body iron stores. Potential contributions of Cd, anemia and iron deficiency in the context of hypophosphatemic osteomalacia development after intravenous iron supplementation, are discussed. Mechanism of Cd-induced ferroptosis in pathogenesis of osteoporosis, emphasizing heme oxygenase-1 (HO-1)/bilirubin axis and zinc deficiency are presented.

Abstract: Background: There is paucity of information concerning automatic mitral valve apparatus analysis of patients with mitral valve prolapse (MVP). Objectives: We aimed to study with an automatic three-dimensional transesophageal echocardiography (TEE) dedicated software patients with moderate and severe mitral regurgitation when compared to patients with no structural cardiac chamber alterations (patients with patent foramen ovale (PFO) who underwent TEE) . Methods: We employed a TEE software dedicated to automatic analysis of 34 parameters of the mitral valve apparatus comparing MVP patients with moderate and severe mitral regurgitation and patients with PFO without cardiac chamber structural alterations. Mitral valve effective regurgitant orifice (ERO) and regurgitant volume were correlated to automatic MVP parameters. Results: 59 MVP patients and 43 PFO patients were analysed. All MVP patients presented P2 mitral valve prolapse, 15 (25.4 % ) with both posterior and anterior prolapse. Twenty-seven automatic parameters (79%) were different concerning MVP and PFO patients (p< 0.05): diameters, area, perimeter, height, angle, coaptation width, lenght, closure line lenght, annulus. ERO was 0.43 + 0.11 cm2 , and regurgitant volume: 62.2 + 14.9 ml/beat. Automatic analysis correlated to 75 percentile ERO MVP patients (ERO> 0.48 cm2): Posterior Leafltet Area (r:0.74, p:0.031); Posterior Leafltet Lenght (r:0.73, p:0.032); Tenting area (r:0,41, p:0.048). Conclusions: Automatic mitral valve parameters analysis were different concerning MVP and no structural cardiac chamber (PFO) patients. 75 percentile ERO MVP patients (ERO> 0.48 cm2) correlated to posterior leaflet parameters.This anatomic information could be useful to planning and surgical treatment of mitral valve prolapse patients.

Abstract: Prostate cancer is one of the most prevalent and deadly neoplasias in the male population. Despite the availability of therapies that increase the long-term survival of patients with localized tumors, metastatic prostate cancer is challenging to treat. A previous study revealed that the 2-aminopyridine derivative (named Neq0440) inhibited the PI3K-AKT-mTOR pathway and presented selective cytotoxicity toward the metastatic prostate cancer cell line PC-3. Here, we further analyzed the mechanism of action of these molecules by using cell-based colorimetric, fluorometric, epifluorescence microscopy, and Western blot assays. Mitochondrial depolarization increased the AMPK level at 24 h inhibition with Neq0440, which led to the PI3K-AKT-mTOR pathway downregulation after 48 h. The phosphorylation was inhibited for AKT and the downstream quinases (S6RP and 4EBP1) from the PI3K-AKT-mTOR pathway, which can work together with the mitochondrial depolarization, lowering the pH of the medium, increasing ROS levels, and translocating the lysosomes toward the nucleus to trigger cell death. Therefore, Neq0440 can be used as a lead compound to obtain derivatives with a novel anticancer mechanism of action.

Abstract:

Background. Both primary hyperparathyroidism (PHPT) and chronic hypoparathyroidism (HypoPT) are associated with the onset and development of cardiovascular diseases (CVDs). Especially PHPT is accompanied by the presence of elevated atherothrombotic risk, while the importance of traditional and new anthropometric indices to reflect the cardiovascular risk remains uncertain in this condition. This study aims to investigate whether novel and traditional anthropometric indices distinguish PHPT and their correlation with atherothrombotic risk. Methods. 40 Subjects with HypoPT, 40 PHPT and 40 age- and sex-matched control subjects were consecutively enrolled for the evaluation of flow-mediated vasodilation (FMD) and carotid intimal-media thickness (IMT). A blood sample was collected for calcium-phosphate metabolism, PTH, TSH and 25-hydroxy vitamin D evaluation. Physical examination was performed to obtain traditional anthropometric parameters and derived indices of adiposity and cardiometabolic risk (waist height ratio (WHtR) and waist hip ratio (WHR) and conicity index (CI)). Results. The PHPT group showed higher central adiposity indices (WHtR p=0.002, and CI p=0.008). Among patients with parathyroid disorders, PHPT subjects display the highest reduction of FMD (p<0.001) and a marked increase of IMT (p<0.001). In the Ctrl group, WHtR showed a weak-to-moderate positive association with IMT (r=0.381, p=0.018). In the PHPT group, no anthropometric index was significantly correlated with IMT or FMD (all p>0.05). Conclusions. WHtR and CI provide evidence of increased central fat adiposity in PHPT but do not account for impaired atherothrombotic risk, indicating that anthropometric indices may lack relevance to cardiovascular risk in this condition and emphasising the importance of a specific assessment profile.

Abstract: Background Hospitalizations for hepatocellular carcinoma (HCC) increasingly involve a complex interaction of chronic liver disease, cardiometabolic comorbidities, and systemic complications, which now exert greater influence than tumor-specific factors alone. However, contemporary data on how the evolving comorbidity burden affects inpatient resource utilization and procedural care are limited. This study evaluates national trends in inpatient characteristics, procedural utilization, and outcomes among patients hospitalized with HCC from 2018 to 2022. Methods A retrospective, cross-sectional analysis of adult hospitalizations was performed using the National Inpatient Sample (NIS) from 2018 to 2022. Hospitalizations involving HCC were identified through ICD-10 diagnosis codes, encompassing both principal and secondary diagnoses. Survey-weighted analyses were used to estimate national prevalence, in-hospital mortality, length of stay (LOS), and total hospital charges. Temporal trends were evaluated using survey-weighted logistic or linear regression, with calendar year as a continuous variable. Multivariable survey-weighted logistic regression models were constructed to identify adjusted predictors of inpatient mortality and procedural utilization, including liver transplantation, hepatic resection, and transjugular intrahepatic portosystemic shunt (TIPS) placement. Results During the study period, an estimated 275,000 HCC-related hospitalizations occurred nationwide. The prevalence of cardiometabolic comorbidities increased significantly over time (all p< 0.001), including MASLD (6.6% to 8.7%), obesity (10.6% to 13.7%), diabetes (36.0% to 38.9%), and dyslipidemia (26.4% to 34.4%). In-hospital mortality rose from 8.82% (95% CI, 8.40-9.24%) in 2018 to 9.23% (95% CI, 8.81-9.65%) in 2022, with the highest rate in 2020 (9.42%). In parallel, inpatient resource utilization rose, as reflected by longer lengths of stay and higher hospitalization charges. Utilization of diagnostic endoscopic procedures, such as esophagogastroduodenoscopy and endoscopic retrograde cholangiopancreatography, increased, whereas rates of definitive inpatient oncologic and portal hypertension–directed interventions—including liver transplantation, hepatic resection, and TIPS—remained low and stable. In-hospital mortality was independently associated with markers of hepatic decompensation and systemic illness, including hepatic encephalopathy, acute kidney injury, sepsis, and hepatorenal syndrome. These associations were stronger than those observed for tumor-directed procedures, as reflected by inpatient procedural utilization patterns. Conclusions Between 2018 and 2022, inpatient resource utilization among patients hospitalized with hepatocellular carcinoma increased in parallel with rising cardiometabolic comorbidity and was driven primarily by the management of hepatic decompensation and systemic illness rather than oncologic intervention. These findings characterize the evolving complexity of HCC hospitalizations in the contemporary inpatient setting.

Abstract: Borderline personality disorder (BPD) produces severe problems with mood regulation, relationships and impulse control, yet its molecular basis has remained unclear because early genomic screens were too small to yield stable signals. Building on the most recent meta-analysis of genome-wide association data, with a cohort with schizophrenia and bipolar cases excluded, we re-examined the data with three complementary tools: (i) MAGMA for gene-set enrichment, (ii) linkage-disequilibrium score regression for partitioned heritability and (iii) transcriptome-wide association studies for imputed brain expression. Two a priori biological themes were tested through custom gene panels: glutamatergic synaptic plasticity and complement-mediated synaptic pruning.Across all three analytic layers, glutamate-related plasticity genes showed reproducible enrichment—1.2- to 1.5-fold increases in heritability and false-discovery-rate-adjusted p values below 0.05. Directionally, risk alleles tended to raise expression of excitatory receptor subunits (for example, GRIA1, GRIN3B) while lowering expression of scaffolding or trophic genes (for example, DLG2, NGF). In contrast, pruning panels, including a refined set with glutamatergic overlap removed, displayed no comparable signal.Taken together, the findings argue against a primary role for excessive synaptic pruning in BPD and instead point to bidirectionally disrupted NMDA/AMPA-dependent plasticity within limbic–prefrontal circuits. A model centred on malleability—rather than elimination—of synapses may account for the emotional learning deficits and interpersonal hypersensitivity that typify the disorder. This framework generates testable predictions for imaging-genetics work and suggests that therapies aimed at normalizing glutamatergic plasticity could prove beneficial.

Abstract: Background: Adult growth hormone deficiency (GHD) is linked to increased cardio-vascular and metabolic risk due to oxidative stress (OS), endothelial dysfunction, and adverse body composition. Long-term systemic effects of recombinant human growth hormone (rhGH) therapy remain insufficiently defined. This study assessed the impact of 24-month rhGH replacement on OS, vascular markers, body composition, and bone mineral density (BMD) in adults with severe GHD. Methods: Fifteen adults with confirmed GHD received rhGH for 24 months. Serum insulin-like growth factor -1 (IGF-1), oxidized LDL (Ox-LDL), thioredoxin (Trx), 8-oxoguanine DNA glycosylase (OGG1), E-selectin, ICAM-1, and VCAM-1 were meas-ured at baseline, 12, and 24 months. Body composition and BMD were evaluated by DXA. Results: IGF-1 increased significantly at 12 and 24 months (p < 0.001). Ox-LDL decreased markedly (p < 0.00001), while Trx and OGG1 increased (p < 0.05). Levels of E-selectin, ICAM-1, and VCAM-1 declined, indicating improved endothelial function. Lean body mass and BMD (lumbar spine and femoral neck) increased, whereas body fat percentage decreased. Lipid profiles were unchanged. Significant correlations were observed be-tween vascular markers and adiposity, and between BMD, triglycerides, and IGF-1. Conclusion: A 24-month rhGH therapy improves redox balance, vascular function, and body composition in adults with severe GHD, supporting the use of redox and vascular biomarkers to monitor treatment efficacy.

Abstract: Stereotactic body radiation therapy (SBRT) for localized prostate cancer delivers high doses per fraction, making dose constraints to the rectum and other organs at risk critical during treatment planning. This study evaluated the association between prostate-rectum separation achieved with a biodegradable balloon rectal spacer at different anatomical levels and corresponding organ-at-risk dose patterns. Thirty-three patients underwent transperineal balloon spacer implantation followed by SBRT to 36.25 Gy in five fractions. Prostate-rectum separation at the apex, midgland, and base was measured on CT and/or MRI and categorized as < 10 mm, 10-14 mm, or ≥14 mm. Rectal dose-volume parameters and mean doses to the rectum, bladder, and penile bulb were assessed using linear regression analyses and group comparisons at 14 mm separation. Mean prostate-rectum separation was 16.6 mm overall, with minimal high-dose rectal exposure observed. Increasing separation was associated with reduced rectal dose-volume parameters at the apex and midgland, while greater base separation corresponded primarily to lower bladder mean dose. Increased apical separation was also associated with reduced penile bulb mean dose. No acute gastrointestinal toxicity was observed, and genitourinary toxicity was limited to low-grade events. These findings indicate that prostate-rectum separation varies by anatomical level and is associated with distinct organ-at-risk dose relationships in prostate SBRT.

Abstract:

Background/Objectives: Considering the excretion pathways and gadolinium concentrations of gadolinium-based contrast agents (GBCAs), our institution has developed a tailored administration protocol for patients with renal impairment to facilitate more rapid elimination and minimal retention of gadolinium. This study aims to evaluate the 8-year clinical outcomes and safety of this institutional protocol. Methods: This single-center retrospective study included patients with renal impairment who underwent GBCA-enhanced MRI between January 2015 and December 2022. The protocol recommended specific GBCAs and adjusted doses based on chronic kidney disease (CKD) stage and serum bilirubin levels: gadoxetate disodium was used for normal serum bilirubin level due to its dual excretion pathway, while macrocyclic agents were used for those with elevated serum bilirubin levels. During the follow-up period, occurrence of nephrogenic systemic fibrosis (NSF) and evidence of gadolinium deposition in brain tissues were evaluated. Results: A total of 288 patients (age, 64.6 ± 11.7 years; male, 64.9%) underwent 716 GBCA-enhanced MRI examinations in accordance with the institutional protocol. The cohort included 62 patients with CKD stage 4 and 131 patients with CKD stage 5 or undergoing hemodialysis. In patients with CKD stage 4 and 5 and those undergoing hemodialysis, 597 examinations were performed using gadoxetate disodium, and 119 used macrocyclic agents. No cases of NSF or gadolinium deposition in brain tissues were identified over mean follow-up intervals of 27.5 and 27.8 months, respectively. Conclusions: The tailored GBCA administration protocol, considering the excretion pathways and gadolinium concentrations, appears to be safe with respect to NSF and gadolinium deposition in brain tissues for patients with renal impairment.

Abstract: This study aims to characterizing both the pre-existing conditions that increase susceptibility and the long-term, post-acute sequelae ("long flu") following influenza. A longitudinal cohort study was conducted using data from the FinnGen cohort of 429,209 individuals including 9,204 influenza cases. A disease-wide association study (DWAS) framework was employed, using Cox proportional hazards models adjusted for age and sex to analyze 110 influenza-comorbid clinical endpoints. Pre-existing conditions, most notably cardiovascular diseases such as heart failure, coronary atherosclerosis, atrial fibrillation, and stroke, were significantly associated with an increased likelihood of a subsequent influenza diagnosis. Following influenza, individuals had a substantially elevated risk for a durable, multi-system "long flu" syndrome. The most robust and persistent risks were for new-onset cardiovascular and neurological diseases. Risks for thromboembolic events, heart failure, atrial fibrillation, stroke, and myocardial infarction remained significantly elevated for one to five years following influenza. Similarly, influenza was associated with a long-term increased incidence of neurodegenerative disorders, including migraine (with and without aura), Alzheimer's disease, and dementia. These findings underscore the urgent need to intensify preventive strategies, particularly through targeted vaccination of at-risk individuals, and to develop integrated care pathways to manage the multi-organ sequelae of long flu.