INTRODUCTION: This study was performed to compare the efficacy and safety of PreserFlo MicroShunt (PMS) implantation with mitomycin C (MMC) applied by sub-tenon injection versus conventional application by MMC-soaked sponges. METHODS: This retrospective, 1-year cohort study included 100 eyes of 100 patients with glaucoma who underwent PMS implantation with MMC (0.4 mg/ml) delivered either by sub-tenon injection (50 eyes) or via soaked sponges (50 eyes). The primary outcome measure at 1 year was intraocular pressure (IOP) reduction, with complete success defined as an IOP reduction of ≥ 20% and achieving a target IOP of ≤ 21 or 18 mmHg without the use of medication. Secondary outcomes, including corneal endothelial cell density (CECD) loss, the number of medications, and complications, were assessed and compared between the groups. RESULTS: Sustained reductions in mean IOP were observed in both groups over the 1-year follow-up, with no significant differences between the groups. The complete success rate, with a target IOP of ≤ 21 mmHg after 1 year, was 19.3% in the sponge group and 26.4% in the injection group. The qualified success rate was 59.0% and 87.4% in the sponge and injection groups, respectively. A longer survival rate was observed in the injection group than in the sponge group when IOP was below 21 mmHg. The mean CECD significantly decreased (P < 0.01) from baseline to each postoperative follow-up time point in both groups. At 1 year postoperatively, the percentage of total CECD loss was 8.1% in the sponge group and 8.0% in the injection group. However, no significant differences in mean CECD values, the number of medications, or adverse events were found between the groups. CONCLUSIONS: PMS implantation with sub-tenon injection of MMC was comparable in terms of efficacy and safety to traditional MMC delivery via soaked sponges. However, the injection group demonstrated a significantly higher success rate than the sponge group.

• Publication type
• Journal Article MeSH

OBJECTIVES: Decision-analytic models assessing the value of emerging Alzheimer's disease (AD) treatments are challenged by limited evidence on short-term trial outcomes and uncertainty in extrapolating long-term patient-relevant outcomes. To improve understanding and foster transparency and credibility in modeling methods, we cross-compared AD decision models in a hypothetical context of disease-modifying treatment for mild cognitive impairment (MCI) due to AD. METHODS: A benchmark scenario (US setting) was used with target population MCI due to AD and a set of synthetically generated hypothetical trial efficacy estimates. Treatment costs were excluded. Model predictions (10-year horizon) were assessed and discussed during a 2-day workshop. RESULTS: Nine modeling groups provided model predictions. Implementation of treatment effectiveness varied across models based on trial efficacy outcome selection (clinical dementia rating - sum of boxes, clinical dementia rating - global, mini-mental state examination, functional activities questionnaire) and analysis method (observed severity transitions, change from baseline, progression hazard ratio, or calibration to these). Predicted mean time in MCI ranged from 2.6 to 5.2 years for control strategy and from 0.1 to 1.0 years for difference between intervention and control strategies. Predicted quality-adjusted life-year gains ranged from 0.0 to 0.6 and incremental costs (excluding treatment costs) from -US$66 897 to US$11 896. CONCLUSIONS: Trial data can be implemented in different ways across health-economic models leading to large variation in model predictions. We recommend (1) addressing the choice of outcome measure and treatment effectiveness assumptions in sensitivity analysis, (2) a standardized reporting table for model predictions, and (3) exploring the use of registries for future AD treatments measuring long-term disease progression to reduce uncertainty of extrapolating short-term trial results by health-economic models.

• MeSH
• Alzheimer Disease * economics   drug therapy   MeSH
• Cost-Benefit Analysis * MeSH
• Models, Economic MeSH
• Cognitive Dysfunction * economics   MeSH
• Quality-Adjusted Life Years MeSH
• Humans MeSH
• Decision Support Techniques MeSH
• Disease Progression MeSH
• Treatment Outcome MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Comparative Study MeSH

Human migration is an increasingly common phenomenon and migrants are at risk of disadvantageous treatment. We reasoned that migrants may receive differential treatment by locals based on the closeness of their facial features to the host average. Residents of Türkiye, the country with the largest number of refugees currently, served as participants. Because many of these refugees are of Arabic origin, we created target facial stimuli varying along the axis connecting Turkish and Arabic morphological prototypes (excluding skin colour) computed using geometric morphometrics and available databases. Participants made judgements of two universal dimensions of social perception-warmth and competence-on these faces. We predicted that participants judging faces manipulated towards the Turkish average would provide higher warmth and competence ratings compared to judging the same faces manipulated towards the Arabic average. Bayesian statistical tools were employed to estimate parameter values in multilevel models with intercorrelated varying effects. The findings did not support the prediction and revealed raters (as well as target faces) to be an important source of variation in social judgements. In the absence of simple cues (e.g. skin colour, group labels), the effect of facial morphology on social judgements may be much more complex than previously assumed.

• MeSH
• Bayes Theorem MeSH
• Adult MeSH
• Humans MeSH
• Judgment * MeSH
• Adolescent MeSH
• Young Adult MeSH
• Face anatomy & histology   MeSH
• Facial Recognition physiology   MeSH
• Social Perception * MeSH
• Stereotyping * MeSH
• Refugees psychology   MeSH
• Check Tag
• Adult MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Geographicals
• Turkey MeSH

Class A G protein-coupled receptors (GPCRs) continue to garner interest for their essential roles in cell signalling and their importance as drug targets. Although numerous drugs in the clinic target these receptors, over 60% GPCRs remain unexploited. Moreover, the adverse effects triggered by the available unbiased GPCR modulators, limit their use and therapeutic value. In this context, the elucidation of biased signalling has opened up new pharmacological avenues holding promise for safer therapeutics. Functionally selective ligands favour receptor conformations facilitating the recruitment of specific effectors and the modulation of the associated pathways. This review surveys the current drug discovery landscape of GPCR-biased modulators with a focus on recent advances. Understanding the biological effects of this preferential coupling is at different stages depending on the Class A GPCR family. Therefore, with a focus on individual GPCR families, we present a compilation of the functionally selective modulators reported over the past few years. In doing so, we dissect their therapeutic relevance, molecular determinants and potential clinical applications. LINKED ARTICLES: This article is part of a themed issue Complexity of GPCR Modulation and Signaling (ERNST). To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v182.14/issuetoc.

• MeSH
• Humans MeSH
• Ligands MeSH
• Drug Discovery * MeSH
• Receptors, G-Protein-Coupled * metabolism   agonists   MeSH
• Signal Transduction drug effects   MeSH
• Drug Development MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Review MeSH

Using immunohistochemistry, we examined a large cohort of 135 ovarian tumors, made up of 96 low-grade serous carcinomas (LGSCs) and 39 serous borderline tumors (micropapillary variant, mSBT), with the aim of exploring their HER2 status (overexpression). We followed with comprehensive genomic analyses on this sample set from our previous study, which revealed HER2 mutation in 5% (4/75) of LGSC and 10% (3/29) of mSBT. No cases were evaluated as HER2-positive, but 6 LGSCs and 1 mSBT were scored as HER2 1+, and 2 LGSCs and 1 mSBT showed the so-called HER2 "ultra-low" phenotype. This could be of clinical value as a potential therapeutical target concerning emerging therapeutic treatments (antibody conjugates). However, the clinical significance of this expression still needs to be established.

• MeSH
• Adult MeSH
• Immunohistochemistry MeSH
• Middle Aged MeSH
• Humans MeSH
• Mutation MeSH
• Biomarkers, Tumor genetics   metabolism   MeSH
• Ovarian Neoplasms * pathology   genetics   metabolism   MeSH
• Receptor, ErbB-2 * genetics   metabolism   MeSH
• Aged MeSH
• Cystadenocarcinoma, Serous * pathology   genetics   metabolism   MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

OBJECTIVES: Dignity of patients with early-stage dementia (PwESD) is a core value of person-centered care. To evaluate the effectiveness of the intervention programs targeted at this population, a reliable tool that would measure dignity in PwESD is needed. Based on a qualitative analysis of how PwESD perceive and experience dignity, this study aims to determine the adequacy of the Czech version of the Patient Dignity Inventory (PDI-CZ) for this patient population. METHOD: The sample from two outpatient clinics in Czechia included home-dwelling individuals aged 60 years or older with mild dementia. In the first interview (T1), there were 21 respondents; 10 of whom participated in the second interview (T2) that was conducted after 12 months. The qualitative material was analyzed using a deductive approach based on the PDI-CZ domains. RESULTS: Thematic analysis shows that the PwESD thematized all domains of the PDI-CZ in their interviews and their views of dignity were stable over time. Some experiences were not considered in the PDI-CZ (such as lowered support of the society, lowered ability to advocate for oneself, or feeling of not suitable living conditions). CONCLUSION: When developing a revised version of the tool, items that reflect missing views of dignity should be included.

• MeSH
• Dementia * psychology   MeSH
• Personhood * MeSH
• Qualitative Research MeSH
• Middle Aged MeSH
• Humans MeSH
• Longitudinal Studies MeSH
• Independent Living * MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Respect * MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Geographicals
• Czech Republic MeSH

Úvod: Obstrukce žlučových cest je závažným stavem spojeným s vysokou morbiditou a mortalitou, vyžadující přesnou diagnostiku a vhodně indikovanou terapii. Cílem prospektivní studie bylo zhodnotit proveditelnost a senzitivitu perkutánní endobiliární kryobiopsie ve srovnání s klešťovou biopsií u pacientů se stenózou žlučových cest podstupujících perkutánní drenáž žlučových cest. Metodika: Klešťová biopsie i kryobiopsie byly provedeny během jednoho zákroku a jejich pořadí bylo randomizováno. Byl hodnocen technický úspěch, velikost vzorků, jejich kvalita a diagnostická přesnost. Výsledky: Celkem bylo získáno 90 vzorků (n = 47 biopsie kleštěmi, n = 43 kryobiopsie) od sedmi pacientů. Kryobiopsie poskytla signifikantně větší celkovou plochu mikroskopických vzorků (medián: 2,67 mm2 pro kryobiopsii vs. 0,44 mm2 pro kleště; p < 0,01) a signifikantně větší plochu vzorků bez artefaktů (medián: 1,47 mm2 vs. 0 mm2; p < 0,01). Počet nehodnotitelných vzorků kvůli artefaktům byl u kryobiopsie významně nižší (11,63 % vs. 53,19 %; p < 0,01). Medián hmotnosti vzorků z kryobiopsie byl rovněž signifikantně vyšší než u vzorků z biopsie kleštěmi (7,6 mg vs. 3,5 mg; p = 0,015). Při hodnocení histopatologické kvality na Likertově škále dosáhly vzorky z kryobiopsie významně lepších výsledků než vzorky z biopsie kleštěmi (medián 4 vs. 1; p < 0,01), a to i v podílu vzorků hodnocených jako kvalitní (Likert > 2) (74,42 % vs. 29,79 %; p < 0,01). Adenokarcinom byl prokázán u pěti pacientů, benigní etiologie stenózy u dvou pacientů. Kryobiopsie úspěšně diagnostikovala všech pět případů adenokarcinomu (5/5), zatímco biopsie kleštěmi odhalila pouze dva z těchto pěti případů. Závěr: Získané výsledky naznačují, že kryobiopsie představuje efektivní a přesnou metodu pro diagnostiku malignit žlučových cest, s potenciálním přínosem pro včasnou diagnostiku a cílenou terapii.

Introduction: Obstruction of the bile ducts is a serious condition associated with high morbidity and mortality, requiring accurate diagnosis and appropriate therapy. The goal of this prospective study is to assess the feasibility and sensitivity of percutaneous endobiliary cryobiopsy in comparison with forceps biopsy in patients with billiary duct stenosis. Methods: Both forceps biopsy and cryobiopsy were performed during a single proce- dure, the order of sampling was randomized. Technical success, sample size, quality, and diagnostic accuracy were evaluated. Results: A total of 90 samples were collected (n = 47 conventional forceps biopsy, n = 43 cryobiopsy). Cryobiopsy provided a significantly larger total sample area of microscopic specimen (median 2,67 vs. 0,44 mm2 ; p < 0,01), artefact-free sample area (median 1,47 vs. 0 mm2 ; p < 0,01), smaller number of samples non-evaluable for artefacts (11,6 % vs. 53,2 %; p < 0,01). Median weight of cryobiopsy samples was significantly greater than that of forceps biopsy (7,6 vs. 3,5 mg; p = 0,015). In quality assessment cryobiopsy samples achieved significantly better results than the forceps biopsy both in terms of the median Likert scale value (4 vs. 1; p < 0.01) and in terms of the frequency of quality samples rated as Likert > 2 (74,42 vs. 29,79%; p < 0.01). Biopsy proved adenocarcinoma in 5 patients, 5/5 of them in set of cryobiopsy samples, while only 2/5 in forceps biopsy samples. Conclusion: The obtained results suggest that cryobiopsy could represent an effective and accurate method for diagnosing bile duct malignancies, with potential benefits for early diagnosis and targeted therapy.

BACKGROUND: Adolescents' movement behaviours (MB) vary between schooldays and weekends, potentially impacting health-related quality of life (HRQoL) and well-being. This study aimed to identify transitions between 24-h MB profiles on schooldays and weekends and examine their associations with HRQoL and well-being. METHODS: This is a cross-sectional study of 1070 Czech adolescents (average age: 13.8 years and standard deviation: 2.2 years; 56% girls). Participants wore accelerometers for 7 consecutive days to assess physical activity (PA) of different intensities, sedentary behaviour (SB) and sleep. A subsample of 451 participants provided data on HRQoL, which was measured using the Paediatric Quality of Life Inventory, and 484 provided valid well-being data measured with the 5-item World Health Organisation Well-Being Index. Latent transition analysis was used on the MB variables to identify transitions across MB profiles, and linear regression was used to examine associations between transitions and HRQoL or well-being. RESULTS: Four MB profiles were identified: Excellent (high PA, low SB and high sleep duration), Good (average MB values), Fair (below-average PA and sleep, above-average SB) and Poor (low PA and sleep, high SB). Most adolescents transitioned to less favourable profiles on weekends. Those remaining in the Excellent profile had higher HRQoL than those transitioning to less favourable profiles. Transitions to the Poor profile were associated with the lowest HRQoL and well-being scores. CONCLUSION: This study underscores the dynamic nature of adolescents' MB and the importance of consistent, healthy routines. Interventions optimizing 24-h MB throughout the week and especially on weekends may enhance adolescent HRQoL and well-being, but further evidence from longitudinal and intervention studies is needed. SUMMARY: We observed a contrast in 24-h MB between schooldays and weekends: 29.7% of adolescents were in the Excellent on schooldays, but only 5.8% did so on weekends, while the prevalence of the Poor profile rose from 1.6% on schooldays to 27.7% on weekends. Adolescents who maintained the Excellent profile across the whole week recorded the highest scores for HRQoL and well-being. Moving into the Poor profile on weekend was associated with about 9 points poorer HRQoL and 14 points lower well-being, compared with peers who remained in the Excellent profile. Behaviour change strategies should target the entire week to preserve PA, reduce SB and protect sleep.

• MeSH
• Accelerometry MeSH
• Time Factors MeSH
• Adolescent Behavior * psychology   physiology   MeSH
• Exercise * psychology   physiology   MeSH
• Quality of Life * psychology   MeSH
• Humans MeSH
• Adolescent MeSH
• Cross-Sectional Studies MeSH
• Sedentary Behavior MeSH
• Sleep physiology   MeSH
• Check Tag
• Humans MeSH
• Adolescent MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Geographicals
• Czech Republic MeSH

Conflict deeply affects human experiences, frequently testing individual resilience to its breaking point and leaving enduring psychological and societal wounds. The current conflict in Ukraine, initiated by Russia's invasion in 2022, illustrates this phenomenon by altering regional relationships and triggering a major humanitarian crisis marked by extensive displacement, loss of life, and emotional turmoil. This study explores the factors influencing hope and distress in Ukraine alongside six nearby European countries during the ongoing conflict. A cross-sectional survey collected data primarily via internet panel samples from the Czech Republic, Georgia, Lithuania, Poland, Romania, Slovakia, and Ukraine in the second year since the war's initiation. The current study utilised validated instruments, collecting data on levels of hope, distress, individual resilience, community resilience, societal resilience, morale, sense of danger, perceived security threats, and demographic characteristics. Hope and distress levels differ across countries, with Ukraine exhibiting the highest levels of both (3.74 ± 1.02 and 2.89 ± 0.87, respectively). Overall, average scores of hope were higher than average distress levels. Across the regression models for the seven countries, hope showed strong associations with individual (between β = 0.089 and β = 0.327) and societal resilience (between β = 0.206 and β = 0.514), while morale (between β = -0.104 and β = -0.479) and individual resilience (between β = -0.077 and β = -0.335) displayed a protective relationship against distress (all β values were significant, p < 0.01). Monitoring hope and distress is crucial during the Russian-Ukrainian war and other adversities, as these factors give insight into the current and future psychological states of affected populations. The results offer valuable information that can guide the development of tailored strategies to enhance hope and buffer distress in war-impacted countries, as well as those experiencing its broader effects. Fostering individual and societal resilience, alongside enhancing morale, may strengthen hope and mitigate distress amid adversity. Developing targeted interventions that address each population's unique needs, as well as their sociocultural and geopolitical contexts can enhance efficacy.

• MeSH
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Young Adult MeSH
• Hope * MeSH
• Armed Conflicts * psychology   MeSH
• Cross-Sectional Studies MeSH
• Resilience, Psychological * MeSH
• Psychological Distress * MeSH
• Stress, Psychological * psychology   MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Young Adult MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Geographicals
• Russia MeSH
• Ukraine MeSH

N-Methyl-d-aspartate receptors (NMDARs) play a crucial role in excitatory neurotransmission, with numerous pathogenic variants identified in the GluN subunits, including their ligand-binding domains (LBDs). The prevailing hypothesis postulates that the endoplasmic reticulum (ER) quality control machinery verifies the agonist occupancy of NMDARs, but this was tested in a limited number of studies. Using microscopy and electrophysiology in the human embryonic kidney 293 (HEK293) cells, we found that surface expression of GluN1/GluN2A receptors containing a set of alanine substitutions within the LBDs correlated with the measured EC50 values for glycine (GluN1 subunit mutations) while not correlating with the measured EC50 values for l-glutamate (GluN2A subunit mutations). The mutant cycle of GluN1-S688 residue, including the pathogenic GluN1-S688Y and GluN1-S688P variants, showed a correlation between relative surface expression of the GluN1/GluN2A receptors and the measured EC50 values for glycine, as well as with the calculated ΔGbinding values for glycine obtained from molecular dynamics simulations. In contrast, the mutant cycle of GluN2A-S511 residue did not show any correlation between the relative surface expression of the GluN1/GluN2A receptors and the measured EC50 values for l-glutamate or calculated ΔGbinding values for l-glutamate. Coexpression of both mutated GluN1 and GluN2A subunits led to additive or synergistic alterations in the surface number of GluN1/GluN2A receptors. The synchronized ER release by ARIAD technology confirmed the altered early trafficking of GluN1/GluN2A receptors containing the mutated LBDs. The microscopical analysis from embryonal rat hippocampal neurons (both sexes) corroborated our conclusions from the HEK293 cells.

• MeSH
• Glycine metabolism   MeSH
• HEK293 Cells MeSH
• Hippocampus cytology   metabolism   MeSH
• Rats MeSH
• Glutamic Acid metabolism   MeSH
• Humans MeSH
• Ligands MeSH
• Mutation genetics   MeSH
• Protein Domains MeSH
• Nerve Tissue Proteins MeSH
• Receptors, N-Methyl-D-Aspartate * metabolism   genetics   chemistry   MeSH
• Protein Transport physiology   genetics   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Humans MeSH
• Male MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH