Cancer immunotherapy is increasingly used in clinical practice, but its success rate is reduced by tumor escape from the immune system. This may be due to the genetic instability of tumor cells, which allows them to adapt to the immune response and leads to intratumoral immune heterogeneity. The study investigated spatial immune heterogeneity in the tumor microenvironment and its possible drivers in a mouse model of tumors induced by human papillomaviruses (HPV) following immunotherapy. Gene expression was determined by RNA sequencing and mutations by whole exome sequencing. A comparison of different tumor areas revealed heterogeneity in immune cell infiltration, gene expression, and mutation composition. While the mean numbers of mutations with every impact on gene expression or protein function were comparable in treated and control tumors, mutations with high or moderate impact were increased after immunotherapy. The genes mutated in treated tumors were significantly enriched in genes associated with ECM metabolism, degradation, and interactions, HPV infection and carcinogenesis, and immune processes such as antigen processing and presentation, Toll-like receptor signaling, and cytokine production. Gene expression analysis of DNA damage and repair factors revealed that immunotherapy upregulated Apobec1 and Apobec3 genes and downregulated genes related to homologous recombination and translesion synthesis. In conclusion, this study describes the intratumoral immune heterogeneity, that could lead to tumor immune escape, and suggests the potential mechanisms involved.

• MeSH
• Immunotherapy * methods   MeSH
• Papillomavirus Infections immunology   virology   MeSH
• Humans MeSH
• Disease Models, Animal * MeSH
• Mutation * MeSH
• Mice, Inbred C57BL MeSH
• Mice MeSH
• Tumor Microenvironment * immunology   MeSH
• Gene Expression Regulation, Neoplastic MeSH
• Exome Sequencing MeSH
• Tumor Escape genetics   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Mice MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

INTRODUCTION: A variable proportion of non-responders to cardiac resynchronization therapy (CRT) warrants the search for new approaches to optimize the position of the left ventricular (LV) lead and the CRT device programming. CineECG is a novel ECG modality proposed for the spatial visualization and quantification of myocardial depolarization and repolarization sequences. OBJECTIVE: The present study aimed to evaluate CineECG-derived parameters in different pacing modes and to test their associations with acute hemodynamic responses in CRT patients. METHODS AND RESULTS: CineECG was used to construct the average electrical path within the cardiac anatomy from the 12-lead ECG. CineECG and LV dP/dt max were tested in 15 patients with nonischemic dilated cardiomyopathy and left bundle branch block (QRS: 170 ± 17 ms; LVEF: 26 ± 5.5%) under pacing protocols with different LV lead localizations. The CineECG-derived path directions were computed for the QRS and ST-T intervals for the anteroposterior (Xh), interventricular (Yh), and apicobasal (Zh) axes. In a multivariate linear regression analysis with adjustment for the pacing protocol type, the ST-T path direction Yh was independently associated with the increase in dP/dt max during CRT, [regression coefficient 639.4 (95% confidence interval: 187.9-1090.9), p = 0.006]. In ROC curve analysis, the ST-T path direction Yh was associated with the achievement of a 10% increase in dP/dt max (AUC: 0.779, p = 0.002) with the optimal cut-off > 0.084 (left-to-right direction) with sensitivity 0.67 and specificity 0.92. CONCLUSION: The acute hemodynamic response in CRT patients was associated with specific CineECG repolarization sequence parameters, warranting their further testing as potential predictors of clinical outcomes.

• MeSH
• Action Potentials MeSH
• Bundle-Branch Block * physiopathology   therapy   diagnosis   MeSH
• Time Factors MeSH
• Cardiomyopathy, Dilated physiopathology   therapy   diagnosis   MeSH
• Electrocardiography * MeSH
• Ventricular Function, Left * MeSH
• Hemodynamics * MeSH
• Middle Aged MeSH
• Humans MeSH
• Predictive Value of Tests * MeSH
• Cardiac Resynchronization Therapy Devices MeSH
• Aged MeSH
• Heart Rate MeSH
• Cardiac Resynchronization Therapy * MeSH
• Heart Failure physiopathology   therapy   diagnosis   MeSH
• Stroke Volume MeSH
• Treatment Outcome MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

The formation of memories is a complex, multi-scale phenomenon, especially when it involves integration of information from various brain systems. We have investigated the differences between a novel and consolidated association of spatial cues and amphetamine administration, using an in situ hybridisation method to track the short-term dynamics during the recall testing. We have found that remote recall group involves smaller, but more consolidated groups of neurons, which is consistent with their specialisation. By employing machine learning analysis, we have shown this pattern is especially pronounced in the VTA; furthermore, we also uncovered significant activity patterns in retrosplenial and prefrontal cortices, as well as in the DG and CA3 subfields of the hippocampus. The behavioural propensity towards the associated localisation appears to be driven by the nucleus accumbens, however, further modulated by a trio of the amygdala, VTA and hippocampus, as the trained association is confronted with test experience. Moreover, chemogenetic analysis revealed central amygdala as critical for linking appetitive emotional states with spatial contexts. These results show that memory mechanisms must be modelled considering individual differences in motivation, as well as covering dynamics of the process.

• MeSH
• Amphetamine pharmacology   MeSH
• Amygdala physiology   MeSH
• Hippocampus * physiology   MeSH
• Memory Consolidation * physiology   MeSH
• Rats MeSH
• Brain physiology   MeSH
• Neurons physiology   metabolism   MeSH
• Nucleus Accumbens * physiology   MeSH
• Reward * MeSH
• Memory physiology   MeSH
• Cues MeSH
• Prefrontal Cortex physiology   MeSH
• Mental Recall * physiology   MeSH
• Machine Learning MeSH
• Ventral Tegmental Area * physiology   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

Hepatitis B (VHB) and C (VHC) are significant global public health issues, particularly for certain risk groups. In the Czech Republic, individuals who inject drugs (IDUs), incarcerated people, and those with high-risk sexual behaviours are especially susceptible. This research investigates the epidemiology, risk factors, and effects of both diseases on these groups. It analyzes the incidence of VHB and VHC in Czechia over the last twenty years in the post-vaccine era, compares their occurrence, and identifies factors influencing their rates. A total of 28,160 VHB and VHC cases reported in the Czech Republic from 2000 to 2021 were analyzed, categorized into acute and chronic forms. Specifically, there were 8,762 cases of VHB and 19,398 cases of VHC. The research employed quantitative methods and descriptive data analysis. A spatial visualization of disease occurrence per 100,000 inhabitants in Czech districts was conducted for the years 2000, 2010, and 2020 to compare disease development and the risk group of IDUs across districts. For VHB, transmission primarily occurs through intravenous drug use or risky sexual behaviour, with IDUs, men who have sex with men, and promiscuous individuals being the most at-risk groups. For VHC, sexual transmission is less common, with IDUs being the most at-risk group. Many VHC cases have been recorded in prisons, often due to shared razors or amateur tattooing and piercing. This discovery underscores the necessity for focused interventions and thorough strategies to address both diseases in high-risk communities.

• MeSH
• Adult MeSH
• Hepatitis B * epidemiology   MeSH
• Hepatitis C * epidemiology   MeSH
• Incidence MeSH
• Substance Abuse, Intravenous epidemiology   MeSH
• Middle Aged MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Risk-Taking MeSH
• Risk Factors MeSH
• Prisoners statistics & numerical data   MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Geographicals
• Czech Republic MeSH

BACKGROUND: This study aimed to assess the mid-term effects of focused extracorporeal shockwave therapy (ESWT) on clinical symptoms and tendon structure in patellar tendinopathy. Ultrasound (US) evaluation and an innovative in vivo analysis of intra-tendinous morphology using validated spatial frequency analysis (SFA) software were employed to quantify the organization and density of collagen fascicles. METHODS: This prospective cohort study included 21 recreational athletes (mean age 29.9 ± 9.3 years) with chronic unilateral symptomatic patellar tendinopathy. ESWT was applied as monotherapy over four weekly sessions. Pain was assessed using the Numeric Rating Scale (NRS) and disease severity with the Victorian Institute of Sports Assessment - Patella (VISA-P) questionnaire. Morphological parameters, such as tendon diameter (TD), were assessed with US and analyzed using SFA software. The asymptomatic tendons served as controls. Follow-up assessments were conducted at the end of the treatment period and 3 months posttreatment. RESULTS: Baseline evaluations revealed increased TD in proximal part of the tendon ( P = 0.001) and decreased organization of collagen fascicles ( P = 0.013) in symptomatic tendons compared to asymptomatic controls. At the 3-month follow-up, symptomatic tendons showed significant reductions in TD ( P < 0.001) and improvements in both organization and density of collagen fascicles throughout various parameters - peak spatial frequency radius (PSFR) ( P = 0.024), P6 ( P = 0.05), Q6 ( P = 0.016), PPP ( P = 0.003). No significant morphological changes were observed in asymptomatic tendons. Clinical evaluations demonstrated significant reductions in NRS ( P < 0.001) and increases in Victorian Institute of Sports Assessment - Patella (VISA-P) scores ( P < 0.001) at all time points. CONCLUSION: The study suggests that ESWT may have the potential to induce positive structural changes in patellar tendinopathy, including improved organization and density of collagen fascicles. These findings indicate that ESWT could be a promising noninvasive approach to managing patellar tendinopathy, with observed improvements in clinical symptoms and tendon structure. However, further high-quality research is needed to confirm these results and establish their long-term efficacy.

• MeSH
• Adult MeSH
• Extracorporeal Shockwave Therapy * methods   MeSH
• Humans MeSH
• Patellar Ligament * diagnostic imaging   pathology   MeSH
• Young Adult MeSH
• Prospective Studies MeSH
• Tendinopathy * therapy   diagnostic imaging   pathology   MeSH
• Ultrasonography MeSH
• Treatment Outcome MeSH
• Check Tag
• Adult MeSH
• Humans MeSH
• Young Adult MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

Protein misfolding diseases, including α1-antitrypsin deficiency (AATD), pose substantial health challenges, with their cellular progression still poorly understood1-3. We use spatial proteomics by mass spectrometry and machine learning to map AATD in human liver tissue. Combining Deep Visual Proteomics (DVP) with single-cell analysis4,5, we probe intact patient biopsies to resolve molecular events during hepatocyte stress in pseudotime across fibrosis stages. We achieve proteome depth of up to 4,300 proteins from one-third of a single cell in formalin-fixed, paraffin-embedded tissue. This dataset reveals a potentially clinically actionable peroxisomal upregulation that precedes the canonical unfolded protein response. Our single-cell proteomics data show α1-antitrypsin accumulation is largely cell-intrinsic, with minimal stress propagation between hepatocytes. We integrated proteomic data with artificial intelligence-guided image-based phenotyping across several disease stages, revealing a late-stage hepatocyte phenotype characterized by globular protein aggregates and distinct proteomic signatures, notably including elevated TNFSF10 (also known as TRAIL) amounts. This phenotype may represent a critical disease progression stage. Our study offers new insights into AATD pathogenesis and introduces a powerful methodology for high-resolution, in situ proteomic analysis of complex tissues. This approach holds potential to unravel molecular mechanisms in various protein misfolding disorders, setting a new standard for understanding disease progression at the single-cell level in human tissue.

• MeSH
• alpha 1-Antitrypsin metabolism   MeSH
• Single-Cell Analysis MeSH
• alpha 1-Antitrypsin Deficiency * pathology   metabolism   genetics   MeSH
• Phenotype MeSH
• Hepatocytes metabolism   pathology   MeSH
• Liver Cirrhosis pathology   metabolism   MeSH
• Liver pathology   metabolism   MeSH
• Humans MeSH
• Disease Progression MeSH
• Proteome * analysis   metabolism   MeSH
• Proteomics * methods   MeSH
• Unfolded Protein Response MeSH
• Machine Learning MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

This study aimed to directly compare electroencephalography (EEG) whole-brain patterns of neural dynamics with concurrently measured fMRI BOLD data. To achieve this, we aim to derive EEG patterns based on a spatio-spectral decomposition of band-limited EEG power in the source-reconstructed space. In a large dataset of 72 subjects undergoing resting-state hdEEG-fMRI, we demonstrated that the proposed approach is reliable in terms of both the extracted patterns as well as their spatial BOLD signatures. The five most robust EEG spatio-spectral patterns not only include the well-known occipital alpha power dynamics, ensuring consistency with established findings, but also reveal additional patterns, uncovering new insights into brain activity. We report and interpret the most reproducible source-space EEG-fMRI patterns, along with the corresponding EEG electrode-space patterns, which are better known from the literature. The EEG spatio-spectral patterns show weak, yet statistically significant spatial similarity to their functional magnetic resonance imaging (fMRI) blood oxygenation level-dependent (BOLD) signatures, particularly in the patterns that exhibit stronger temporal synchronization with BOLD. However, we did not observe a statistically significant relationship between the EEG spatio-spectral patterns and the classical fMRI BOLD resting-state networks (as identified through independent component analysis), tested as the similarity between their temporal synchronization and spatial overlap. This provides evidence that both EEG (frequency-specific) power and the BOLD signal capture reproducible spatio-temporal patterns of neural dynamics. Instead of being mutually redundant, these only partially overlap, providing largely complementary information regarding the underlying low-frequency dynamics.

• Publication type
• Journal Article MeSH

This paper describes a compact video-ophthalmoscope (VO) designed for capturing retinal video sequences of the optic nerve head (ONH) under flicker light stimulation. The device uses an OLED display and a fiber optic-coupled LED light source, enabling high-frame-rate video at low illumination intensity (12 μW/cm2). Retinal responses were recorded in 10 healthy subjects during flicker light exposure with a pupil irradiance of 2 μW/cm2. Following 20 s of stimulation, all subjects displayed changes in retinal reflectance and pulsation attenuation, linked to blood flow and volume variations. These findings suggest that increased blood volume leads to decreased retinal reflectance. Temporal analysis confirmed the ability to capture flicker-induced retinal reflectance changes, indicating its potential for spatial and temporal analysis. Overall, this device offers a portable approach for investigating dynamic retinal responses to light stimuli, which can aid the diagnosis of retinal diseases like diabetic retinopathy, glaucoma, or neurodegenerative diseases affecting retinal blood circulation.

• MeSH
• Video Recording * instrumentation   MeSH
• Adult MeSH
• Humans MeSH
• Young Adult MeSH
• Ophthalmoscopes * MeSH
• Retina * radiation effects   physiology   MeSH
• Photic Stimulation * MeSH
• Light * MeSH
• Check Tag
• Adult MeSH
• Humans MeSH
• Young Adult MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

Background: Lesbian, gay, bisexual, transgender, and queer (LGBTQ+) older adults experience long-term minority stress due to societal norms that lead to discrimination and stigma. The purpose of the research was to compare the differences in subjective psychological well-being among LGBTQ+ older adults according to their living environment. Methods: A purposive sample comprising 318 LGBTQ+ older adults was recruited for the quantitative survey. In the initial stage, exploratory factor analysis (EFA) was conducted. To examine the aim of the study, a one-way analysis of variance (ANOVA) was employed, followed by a post hoc analysis to identify any variations in the perception of well-being based on the living environment. Results: Significant differences in well-being among LGBTQ+ older adults across living environments were observed for three items (p < 0.05): WB1 - ... I feel cheerful and in good spirits, WB2 - ... I feel calm and relaxed and WB4 - ... I wake up feeling fresh and rested. With post hoc analysis, we showed statistically significant differences in the perception of subjective psychological well-being according to the three living environments. Conclusion: Our findings indicate significant variations in subjective psychological well-being among LGBTQ+ older adults across different residential settings in Slovenia. While these findings may not generalise to other settings, further research using larger samples and in other EU countries should explore the role of living environments on LGBTQ+ older adults' subjective psychological well-being.

• MeSH
• Adult MeSH
• Quality of Life MeSH
• Middle Aged MeSH
• Humans MeSH
• Urban Population statistics & numerical data   MeSH
• Surveys and Questionnaires MeSH
• Aged MeSH
• Sexual and Gender Minorities * psychology   statistics & numerical data   MeSH
• Rural Population statistics & numerical data   MeSH
• Environment * MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Aged MeSH
• Geographicals
• Slovenia MeSH

PURPOSE: Focused ultrasound-induced blood-brain barrier (BBB) opening is a promising method for neurotherapeutic delivery. The standard for quantifying induced BBB permeability is the Ktrans$$ {K}^{\mathrm{trans}} $$ parameter, which reflects both permeability and plasma flow. The influence of plasma flow can be eliminated by estimating the PS parameter. However, this parameter has been largely unexplored in this application. This study aims to compare permeability estimates based on Ktrans$$ {K}^{\mathrm{trans}} $$ and PS in focused ultrasound-induced BBB opening experiments. METHODS: We used the extended Tofts model (ETM) and the two-compartment exchange model (2CXM) to estimate Ktrans$$ {K}^{\mathrm{trans}} $$ and PS parameters, respectively. Permeability estimates were compared using simulated concentration curves, simulated DCE-MRI data, and real datasets. We explored the influence of spatially-regularized model fitting on the results. RESULTS: For opened BBB, Ktrans$$ {K}^{\mathrm{trans}} $$ was minimally influenced by plasma flow under the tested conditions. However, fitting the ETM often introduced outliers in Ktrans$$ {K}^{\mathrm{trans}} $$ estimates in regions with closed BBB. The 2CXM outperformed the ETM at high signal-to-noise ratios, but its higher complexity led to lower precision at low signal-to-noise ratios. Both these issues were successfully compensated by spatially-regularized model fitting. CONCLUSION: Both Ktrans$$ {K}^{\mathrm{trans}} $$ and PS seem to be eligible options for the quantification of BBB opening, and the correct choice depends on the specifics of the acquired DCE-MRI data. Additionally, spatial regularization has demonstrated its importance in enhancing the accuracy and reproducibility of results for both models.

• MeSH
• Blood-Brain Barrier * diagnostic imaging   metabolism   radiation effects   MeSH
• Contrast Media MeSH
• Humans MeSH
• Magnetic Resonance Imaging * methods   MeSH
• Brain diagnostic imaging   MeSH
• Permeability MeSH
• Computer Simulation MeSH
• Image Processing, Computer-Assisted methods   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Comparative Study MeSH