BACKGROUND: Various explicit screening tools, developed mostly in central Europe and the USA, assist clinicians in optimizing medication use for older adults. The Turkish Inappropriate Medication use in oldEr adults (TIME) criteria set, primarily based on the STOPP/START criteria set, is a current explicit tool originally developed for Eastern Europe and subsequently validated for broader use in Central European settings. Reviewed every three months to align with the latest scientific literature, it is one of the most up-to-date tools available. The tool is accessible via a free mobile app and website platforms, ensuring convenience for clinicians and timely integration of updates as needed. Healthcare providers often prefer to use their native language in medical practice, highlighting the need for prescribing tools to be translated and adapted into multiple languages to promote optimal medication practices. OBJECTIVE: To describe the protocol for cross-cultural and language validation of the TIME criteria in various commonly used languages and to outline its protocol for clinical validation across different healthcare settings. METHODS: The TIME International Study Group comprised 24 geriatric pharmacotherapy experts from 12 countries. In selecting the framework for the study, we reviewed the steps and outcomes from previous research on cross-cultural adaptations and clinical validations of explicit tools. Assessment tools were selected based on both their validity in accurately addressing the relevant issues and their feasibility for practical implementation. The drafted methodology paper was circulated among the study group members for feedback and revisions leading to a final consensus. RESULTS: The research methodology consists of two phases. Cross-cultural adaptation/language validation phase follows the 8-step approach recommended by World Health Organization. This phase allows regions or countries to make modifications to existing criteria or introduce new adjustments based on local prescribing practices and available medications, as long as these adjustments are supported by current scientific evidence. The second phase involves the clinical validation, where participants will be randomized into two groups. The control group will receive standard care, while the intervention group will have their treatment evaluated by clinicians who will review the TIME criteria and consider its recommendations. A variety of patient outcomes (i.e., number of hospital admissions, quality of life, number of regular medications [including over the counter medications], geriatric syndromes and mortality) in different healthcare settings will be investigated. CONCLUSION: The outputs of this methodological report are expected to promote broader adoption of the TIME criteria. Studies building on this work are anticipated to enhance the identification and management of inappropriate medication use and contribute to improved patient outcomes.
The establishment of the first JBI Affiliated group in Poland at Wroclaw Medical University marks a significant advancement in evidence-based healthcare (EBHC) nationally. This editorial explores the evolution of EBHC and the critical role of JBI in driving its progress. Founded in 1996 as a research institute at the Royal Adelaide Hospital in South Australia and now based at the University of Adelaide, JBI has emerged as an international leader in evidence synthesis, transfer and implementation. Its Feasibility, Appropriateness, Meaningfulness, and Effectiveness (FAME) framework highlights the feasibility, appropriateness, meaningfulness, and effectiveness of healthcare practices, ensuring that decisions are patient-centered and contextually relevant. JBI's global collaboration network encompasses over 85 entities, with 23 located in Europe, emphasizing the importance of cultural inclusivity and international partnerships. Recent initiatives include translating the JBI Model of into Polish, German and Czech, linking global knowledge to local contexts, and enhancing understanding for professionals and students alike. This editorial also underscores the collaborative achievements of JBI entities in Wroclaw, Brandenburg an der Havel, Prague, and Olomouc. These partnerships have propelled regional implementation, research and education, fostering a shared vision for elevating healthcare quality. Launching a new EBHC section in the Advances in Clinical and Experimental Medicine journal is a significant step forward, inviting global contributions and stimulating innovation and knowledge sharing in EBHC. The presence of a JBI Affiliated group at Wroclaw Medical University symbolizes a transformative commitment to excellence and collaboration. It sets new benchmarks for healthcare in Poland and beyond while reinforcing the global mission of evidence-based practice.
The exon junction complex (EJC) is a key player in metazoan mRNA quality control and is placed upstream of the exon-exon junction after splicing. Its inner core is composed of Magoh, Y14, eIF4AIII and BTZ and the outer core of proteins involved in mRNA splicing (CWC22), export (Yra1), translation (PYM) and nonsense mediated decay (NMD, UPF1/2/3). Trypanosoma brucei encodes only two genes with introns, but all mRNAs are processed by trans-splicing. The presence of three core EJC proteins and a potential BTZ homologue (Rbp25) in trypanosomes has been suggested to adapt of the EJC function to mark trans-spliced mRNAs. We analysed trypanosome EJC components and noticed major differences between eIF4AIII and Magoh/Y14: (i) whilst eIF4AIII is essential, knocking out both Magoh and Y14 elicits only a mild growth phenotype (ii) eIF4AIII localization is mostly nucleolar, while Magoh and Y14 are nucleolar and nucleoplasmic but excluded from the cytoplasm (iii) eIF4AIII associates with nucleolar proteins and the splicing factor CWC22, but not with Y14 or Magoh, while Magoh and Y14 associate with each other, but not with eIF4AIII, CWC22 or nucleolar proteins. Our data argue against the presence of a functional EJC in trypanosomes, but indicate that eIF4AIII adopted non-EJC related, essential functions, while Magoh and Y14 became redundant. Trypanosomes also possess homologues to the NMD proteins UPF1 and UPF2. Depletion of UPF1 causes only a minor reduction in growth and phylogenetic analyses show several independent losses of UPF1 and UPF2, as well as complete loss of UPF3 in the Kinetoplastida group, indicating that UPF1-dependent NMD is not essential. Regardless, we demonstrate that UPF1 depletion restores the mRNA levels of a PTC reporter. Altogether, we show that the almost intron-less trypanosomes are in the process of losing the canonical EJC/NMD pathways: Y14 and Magoh have become redundant and the still-functional UPF1-dependent NMD pathway is not essential.
- MeSH
- Eukaryotic Initiation Factor-4A metabolism genetics MeSH
- Exons genetics MeSH
- RNA, Messenger genetics metabolism MeSH
- Nonsense Mediated mRNA Decay * MeSH
- Protozoan Proteins * metabolism genetics MeSH
- RNA Splicing MeSH
- Trypanosoma brucei brucei * metabolism genetics MeSH
- Publication type
- Journal Article MeSH
Orthotopic tumor models in pre-clinical translational research are becoming increasingly popular, raising the demands on accurate tumor localization prior to irradiation. This task remains challenging both in x-ray and proton computed tomography (xCT and pCT, respectively), due to the limited contrast of tumor tissue compared to the surrounding tissue. We investigate the feasibility of gadolinium oxide nanoparticles as a multimodal contrast enhancement agent for both imaging modalities. We performed proton radiographies at the experimental room of the Trento Proton Therapy Center using a MiniPIX-Timepix detector and dispersions of gadolinium oxide nanoparticles in sunflower oil with mass fractions up to 8wt%. To determine the minimum nanoparticle concentration required for the detectability of small structures, pCT images of a cylindrical water phantom with cavities of varying gadolinium oxide concentration were simulated using a dedicated FLUKA Monte Carlo framework. These findings are complemented by simulating pCT at dose levels from 80 mGy to 320 mGy of artificially modified murine xCT data, mimicking different levels of gadolinium oxide accumulation inside a fictitious tumor volume. To compare the results obtained for proton imaging to x-ray imaging, cone-beam CT images of a cylindrical PMMA phantom with cavities of dispersions of oil and gadolinium oxide nanoparticles with mass fractions up to 8wt% were acquired at a commercial pre-clinical irradiation setup. For proton radiography, considerable contrast enhancement was found for a mass fraction of 4wt%. Slightly lower values were found for the simulated pCT images at imaging doses below 200 mGy. In contrast, full detectability of small gadolinium oxide loaded structures in xCT at comparable imaging dose is already achieved for 0.5wt%. Achieving such concentrations required for pCT imaging inside a tumor volume inin-vivoexperiments may be challenging, yet it might be feasible using different targeting and/or injection strategies.
- MeSH
- Phantoms, Imaging * MeSH
- Gadolinium * chemistry MeSH
- Contrast Media * chemistry MeSH
- Mice MeSH
- Nanoparticles * chemistry MeSH
- Tomography, X-Ray Computed MeSH
- Protons * MeSH
- Animals MeSH
- Check Tag
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
Accelerated partial breast irradiation (APBI) represents a valid option for adjuvant therapy of selected early breast cancer (BC). This single-institution prospective randomized study compares the health-related quality of life (HRQoL) between women treated with the highly conformal-external beam APBI technique and those with the more commonly used moderately hypofractionated whole breast irradiation (hypo-WBI). Eligible patients were women over 50 years with early BC (G1/2 DCIS ≤ 25 mm or G1/2 invasive non-lobular luminal-like HER2 negative carcinoma ≤ 20 mm) after breast-conserving surgery with negative margins. APBI arm consisted of 30 Gy in 5 consecutive daily fractions and WBI arm of 40 Gy in 15 fractions plus 10 Gy in 5 fractions boost to the tumor bed. Patients were requested to complete the official Czech translation of the EORTC QoL questionnaires, including QLQ-C30 and QLQ-BR45, before radiation (baseline), at the end of radiation (M0) and 1 (M1), 3 (M3), 6 (M6), 12 (M12), and 24 (M24) months after radiation. Linear regression models were used to analyze differences in HRQoL between the arms. The 85 enrolled patients exhibited no differences in HRQoL scores between the two arms at baseline. Patients in the APBI arm reported more favorable global health status at M6 (p = 0.055). Other functional scales showed a decrease in the WBI arm at M0 (p = 0.027 for physical functioning). During radiation, symptoms scores increased. Significant between-group differences were observed for the pain (p = 0.002), systemic therapy side effects (p = 0.004), and breast symptoms (p < 0.001) scales at M0, with higher scores in the WBI arm. During follow-up, scores on symptoms scales returned to at least the baseline values. Early BC patients treated with APBI showed non-inferior short-term and late HRQoL outcomes compared to hypo-WBI. In addition to previous findings regarding toxicity, promising pain and breast symptoms results, suggest that APBI should be strongly considered as a treatment option for selected low-risk patients.Trial registration NCT06007118, August 23, 2023 (retrospectively registered).
- MeSH
- Radiotherapy, Adjuvant adverse effects methods MeSH
- Quality of Life * MeSH
- Middle Aged MeSH
- Humans MeSH
- Breast Neoplasms * radiotherapy surgery psychology MeSH
- Prospective Studies MeSH
- Surveys and Questionnaires MeSH
- Mastectomy, Segmental MeSH
- Aged MeSH
- Treatment Outcome MeSH
- Check Tag
- Middle Aged MeSH
- Humans MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Randomized Controlled Trial MeSH
PURPOSE: The AIEOP-BFM ALL 2009 protocol included, at the end of the induction phase, a randomized study of patients with high-risk (HR) ALL to investigate if an intensive exposure to pegylated L-asparaginase (PEG-ASNASE, 2,500 IU/sqm once a week × 4) on top of BFM consolidation phase IB allowed us to decrease minimal residual disease (MRD) and improve outcome. PATIENTS AND METHODS: A total of 1,097 patients presented, from June 2010 to February 2017, with one or more of the following HR criteria: KMT2A::AFF1 rearrangement, hypodiploidy, prednisone poor response, poor bone marrow response at day 15 (Flow MRD ≥10%), or no complete remission (CR) at the end of induction. Of them, 809 (85.1%) were randomly assigned to receive (404) or not receive (405) four weekly doses of PEG-ASNASE. RESULTS: By intention to treat (ITT) analysis, there was no significant difference in the proportion of patients with polimerase chain reaction MRD ≥5 × 10-4 at the end of phase IB in the experimental versus control arm (13.9% v 17.0%, P = .25). The 5-year event-free survival (median follow-up 6.3 years) by ITT in the experimental and control arms was 70.4% (2.3) versus 75.0% (2.2; P = .18), and the 5-year overall survival was 81.5% (2.0) versus 84.0% (1.9; P = .25), respectively. The corresponding 5-year cumulative incidence of death in CR was 9.5% (1.5) versus 5.7% (1.2; P = .08), and that of relapse was 17.7% (1.9) versus 17.2% (1.9), respectively (P = .94). Adverse reactions in phase IB occurred in 22.2% and 8.9% of patients in the experimental and control arm, respectively (P < .001). CONCLUSION: Additional PEG-ASNASE in phase IB did not translate into a benefit for decreasing relapse incidence but was associated with higher toxicity. Further improvements with conventional chemotherapy might be difficult in the context of intensive treatment protocols.
- MeSH
- Precursor Cell Lymphoblastic Leukemia-Lymphoma * MeSH
- Asparaginase * MeSH
- Infant MeSH
- Humans MeSH
- Neoplasm Recurrence, Local drug therapy MeSH
- Polyethylene Glycols MeSH
- Prednisone adverse effects MeSH
- Disease-Free Survival MeSH
- Antineoplastic Combined Chemotherapy Protocols adverse effects MeSH
- Randomized Controlled Trials as Topic MeSH
- Recurrence MeSH
- Treatment Outcome MeSH
- Check Tag
- Infant MeSH
- Humans MeSH
- Publication type
- Journal Article MeSH
- Clinical Trial Protocol MeSH
Obstructive sleep apnea increases morbidity and mortality risks. The most common treatment is continuous positive airway pressure, with nasal mask usage being important, but not always optimal. While most research on treatment adherence focuses on the patient, the bed partner's involvement may be detrimental. Our study aim is to obtain a European-wide picture of the bed partner's attitude and support towards continuous positive airway pressure therapy, including effects on relationship satisfaction and intimacy. The English translation of a German bed partner questionnaire, assessing relationship satisfaction and three major components (general attitude, perceived mask looks, intimacy effects) was distributed within the European Sleep Apnea Database Network and translated in participating countries' local language. Data were collected for 2 years. In total, 10 European countries (13 sleep centres) participated with 1546 questionnaires. Overall, 91% of bed partners had a positive attitude towards continuous positive airway pressure therapy, 86% perceived mask looks not negative, 64% stated no negative intimacy effects. More specifically, 71% mentioned improved sleep quality, 68% supported nightly device usage. For 41% of bed partners, relationship satisfaction increased (no change for 47%). These results were significantly more pronounced in Eastern/Southern Europe compared with Middle Europe, especially regarding intimacy effects. However, increased continuous positive airway pressure therapy length affected attitude negatively. These results provide necessary information to improve treatment strategies by including educational couple-focused approaches. Among others, we revealed that negative intimacy effects are not considered a barrier to continuous positive airway pressure adherence. These results may inspire more research identifying regional gaps with need for treatment adjustments.
- MeSH
- Adult MeSH
- Interpersonal Relations MeSH
- Middle Aged MeSH
- Humans MeSH
- Sleep Apnea, Obstructive * therapy psychology MeSH
- Personal Satisfaction * MeSH
- Perception MeSH
- Surveys and Questionnaires MeSH
- Aged MeSH
- Sexual Partners psychology MeSH
- Continuous Positive Airway Pressure * MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Geographicals
- Europe MeSH
BACKGROUND: Regenerative medicine and transplantation science continuously seek methods to circumvent immune-mediated rejection and promote tissue regeneration. Sertoli cells, with their inherent immunoprotective properties, emerge as pivotal players in this quest. However, whether Sertoli cells can play immunomodulatory role in tadpole tail regeneration and can thus benefit the regeneration process are needed to be discovered. METHODS: Immature Sertoli cells from Xenopus tropicalis (XtiSCs) were transplanted into X. tropicalis tadpoles, followed by the amputation of the final third of their tails. We assessed the migration of XtiSCs, tail regeneration length, muscle degradation and growth, and macrophage counts across various regions including the entire tail, tail trunk, injection site, and regeneration site. The interactions between XtiSCs and macrophages were examined using a confocal microscope. To deplete macrophages, clodronate liposomes were administered prior to the transplantation of XtiSCs, while the administration of control liposomes acted as a negative control. Student's t-test was used to compare the effects of XtiSCs injection to those of a 2/3PBS injection across groups with no liposomes, control liposomes, and clodronate liposomes. RESULTS: XtiSCs have excellent viability after transplantation to tadpole tail and remarkable homing capabilities to the regeneration site after tail amputation. XtiSCs injection increased macrophage numbers at 3 days post-amputation and 5 days post-amputation in the tail trunk, specifically at the injection site and at the regenerated tail, in a macrophage depleted environment (clodronate-liposome injection). What's more, XtiSCs injection decreased muscle fibers degradation significantly at 1 day post-amputation and facilitated new muscle growth significantly at 3 days post-amputation. In addition, whole-mount immunostaining showed that some XtiSCs co-localized with macrophages. And we observed potential mitochondria transport from XtiSCs to macrophages using MitoTracker staining in tadpole tail. CONCLUSIONS: Our study delineates the novel role of XtiSCs in facilitating muscle regeneration post tadpole tail amputation, underscoring a unique interaction with macrophages that is crucial for regenerative success. This study not only highlights the therapeutic potential of Sertoli cells in regenerative medicine but also opens avenues for clinical translation, offering insights into immunoregulatory strategies that could enhance tissue regeneration and transplant acceptance.
- MeSH
- Immunomodulation MeSH
- Larva * MeSH
- Macrophages * metabolism immunology MeSH
- Tail MeSH
- Regeneration * MeSH
- Sertoli Cells * cytology metabolism MeSH
- Xenopus * MeSH
- Animals MeSH
- Check Tag
- Male MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
Spermatogenesis starts with the onset of puberty within the seminiferous epithelium of the testes. It is a complex process under intricate control of the endocrine system. Physiological regulations by steroid hormones in general and by estrogens in particular are due to their chemical nature prone to be disrupted by exogenous factors acting as endocrine disruptors (EDs). 17α-Ethynylestradiol (EE2) is an environmental pollutant with a confirmed ED activity and a well-known effect on spermatogenesis and chromatin remodeling in haploid germ cells. The aim of our study was to assess possible effects of two doses (2.5ng/ml; 2.5 μg/ml) of EE2 on both histone-to-protamine exchange and epigenetic profiles during spermatogenesis performing a multi/transgenerational study in mice. Our results demonstrated an impaired histone-to-protamine exchange with a significantly higher histone retention in sperm nuclei of exposed animals, when this process was accompanied by the changes of histone post-translational modifications (PTMs) abundancies with a prominent effect on H3K9Ac and partial changes in protamine 1 promoter methylation status. Furthermore, individual changes in molecular phenotypes were partially transmitted to subsequent generations, when no direct trans-generational effect was observed. Finally, the uncovered specific localization of the histone retention in sperm nuclei and their specific PTMs profile after EE2 exposure may indicate an estrogenic effect on sperm motility and early embryonic development via epigenetic mechanisms.
- MeSH
- Endocrine Disruptors pharmacology toxicity MeSH
- Epigenesis, Genetic * drug effects MeSH
- Ethinyl Estradiol * pharmacology MeSH
- Histones * metabolism MeSH
- Mice MeSH
- Protein Processing, Post-Translational drug effects MeSH
- Protamines * metabolism genetics MeSH
- Spermatogenesis * drug effects genetics MeSH
- Spermatozoa drug effects metabolism MeSH
- Testis * drug effects metabolism MeSH
- Animals MeSH
- Check Tag
- Male MeSH
- Mice MeSH
- Female MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
Článek obsahuje kritiku Doporučeného postupu pro léčbu endokarditidy, který vydala Evropská kardiologická společnost na podzim 2023 a který byl přeložen do češtiny a vydán v časopise Cor et Vasa na jaře 2024. Doporučený postup obsahuje řadu formálních i věcných závad v oblasti antibiotické profylaxe i léčby. Autor kritického komentáře radí českým lékařům nepřijímat doporučované režimy antibiotické profylaxe a terapie bez předchozí konzultace s pracovníky místních antibiotických středisek nebo antibiotickými konzultanty.
The article contains criticism of the 2023 ESC Guidelines for the management of endocarditis, which was published by the European Society of Cardiology in autumn 2023 and which was translated into Czech and published in the Cor et Vasa journal in spring 2024. The Guidelines contain a number of formal and factual mistakes in the field of antibiotic prophylaxis and treatment. The author of the critical comments advises Czech doctors not to accept the recommended regimens of antibiotic prophylaxis and therapy without prior consultation with the local antibiotic center or antibiotic consultant.
