Propiconazole is a triazole fungicide previously shown to induce triglyceride accumulation in human liver HepaRG cells, potentially via activation of the Pregnane X Receptor (PXR). However, whether propiconazole can disrupt hepatic and whole-body metabolism in vivo is currently unknown. Therefore, we aimed to examine the metabolic effects of propiconazole in the context of metabolic dysfunction-associated steatotic liver disease (MASLD), obesity, and insulin resistance. To this end, male C57BL/6J mice were fed a high-fat diet for 20 weeks. During the last 10 weeks, mice additionally received vehicle, 0.04, 30, or 100 mg/kg body weight (bw)/day propiconazole via oral gavage. High-dose propiconazole, but not low or intermediate dose, reduced body weight gain and adipose tissue weight in obese mice. Mice receiving high-dose propiconazole displayed improved glucose tolerance and reduced levels of plasma triglycerides and cholesterol. Propiconazole dose-dependently increased liver weight and triglyceride levels and at high dose caused signs of hepatic inflammation. RNA sequencing on the liver revealed that propiconazole mainly induced PXR target genes. At intermediate and high dose, propiconazole induced pathways related to cell-cell interactions and inflammation, while oxidative phosphorylation was repressed by propiconazole. Comparison of gene regulation in wildtype and PXR knockout primary hepatocytes as well as gene reporter assays confirmed the activation of PXR by propiconazole. All in all, our data underscore the capacity of propiconazole to activate PXR in the liver and thereby promote the development of hepatic steatosis in vivo.
- MeSH
- Diet, High-Fat * MeSH
- Insulin Resistance MeSH
- Liver drug effects metabolism pathology MeSH
- Disease Models, Animal MeSH
- Mice, Inbred C57BL * MeSH
- Mice MeSH
- Obesity * chemically induced MeSH
- Pregnane X Receptor * metabolism genetics MeSH
- Fungicides, Industrial * toxicity MeSH
- Triazoles * toxicity MeSH
- Triglycerides blood metabolism MeSH
- Dose-Response Relationship, Drug MeSH
- Fatty Liver * chemically induced MeSH
- Animals MeSH
- Check Tag
- Male MeSH
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
The treatment of relapsed/refractory acute myeloid leukemia (AML) is associated with a dismal prognosis. The allogeneic hematopoietic cell transplantation (allo-HCT) is frequently performed as salvage therapy. Reduced intensity conditioning protocols have been developed with the aim of reducing the leukemia burden without increasing their toxicity. We compared the reduced intensity conditioning FM140 (fludarabine, 150 mg/m2; melphalan 140 mg/m2) with FBM110 (fludarabine 150 mg/m2; BCNU, also known as carmustine, 300-400 mg/m2; and melphalan 110 mg/m2). From the European Bone Marrow Transplantation (EBMT) Acute Leukemia Working Party registry, we identified 293 adult patients (FM140, n = 118 and FBM110, n = 175) with AML with relapsed/refractory disease prior to allo-HCT. There were some differences such as age (FM140 = 59.5 years vs. FBM110 = 65.1 years, p < 0.001) and graft-versus-host disease (GvHD) prophylaxis based on in vivo T-cell depletion (TCD, FM140 = 39% vs. FBM110 = 75%, p < 0.001). No differences were observed between FM140- and FBM110-treated patients regarding overall survival (OS) (2-year OS: 39.3% vs. 45.7%, p = 0.58), progression-free survival (PFS) (2-year PFS: 36.1% vs. 37.3%, p = 0.69), non-relapse mortality (NRM) (2-year NRM: 15.3% vs. 25.7%, p = 0.10) and relapse incidence (RI) (2-year RI: 48.6% vs. 37.0%, p = 0.7). In conclusion, despite differences in age and GvHD prophylaxis, AML patients with active disease undergoing allo-HCT after FBM110 conditioning showed similar outcomes compared to FM140.
- MeSH
- Leukemia, Myeloid, Acute * therapy mortality MeSH
- Adult MeSH
- Transplantation, Homologous methods MeSH
- Carmustine therapeutic use administration & dosage MeSH
- Middle Aged MeSH
- Humans MeSH
- Melphalan * therapeutic use administration & dosage MeSH
- Transplantation Conditioning methods MeSH
- Antineoplastic Combined Chemotherapy Protocols therapeutic use MeSH
- Recurrence MeSH
- Registries * MeSH
- Aged MeSH
- Hematopoietic Stem Cell Transplantation * methods MeSH
- Vidarabine * analogs & derivatives therapeutic use administration & dosage MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Multicenter Study MeSH
- Comparative Study MeSH
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 European Renal Association (ERA) Registry collects data on kidney replacement therapy (KRT) in patients with end-stage kidney disease (ESKD). This paper summarizes the ERA Registry Annual Report 2022, with a special focus on comparisons by sex. The supplement of this paper contains the complete ERA Registry Annual Report 2022. Data was collected from 53 national and regional KRT registries from 35 countries. Using this data, incidence, and prevalence of KRT, kidney transplantation rates, survival probabilities, and expected remaining lifetimes were calculated. In 2022, 530 million people of the European general population were covered by the ERA Registry. The incidence of KRT was 152 per million population (pmp). In incident patients, 54% were 65 years or older, 64% were male, and the most common primary renal disease (PRD) was diabetes mellitus (22%). At KRT initiation, 83% of patients received haemodialysis, 12% received peritoneal dialysis, and 5% underwent pre-emptive kidney transplantation. On 31 December 2022, the prevalence of KRT was 1074 pmp. In prevalent patients, 48% were 65 years or older, 62% were male, the most common PRD was of miscellaneous origin (18%), 56% of patients received haemodialysis, 5% received peritoneal dialysis, and 39% were living with a functioning graft. In 2022, the kidney transplantation rate was 40 pmp, with most kidneys coming from deceased donors (66%). For patients starting KRT between 2013 to 2017, 5-year survival probability was 52%. Compared with the general population, the expected remaining lifetime was 66% and 68% shorter for males and females, respectively, receiving dialysis, and 46% and 49% shorter for males and females, respectively, living with a functioning graft.
- Publication type
- Journal Article MeSH
- Review MeSH
INTRODUCTION: This study aimed to assess the impact of midline lumbar fusion with cortical bone trajectory screws (MIDLF/CBT) on the multifidus muscles, focusing on the evaluation of their postoperative atrophy. CLINICAL RATIONALE FOR THE STUDY: MIDLF/CBT is a relatively new technique increasingly used to treat spinal instability. Despite its reduced invasiveness compared to traditional posterior lumbar interbody fusion with traditional pedicle screws (PLIF/TP), concerns remain about potential damage to the multifidus muscles that are crucial for spinal stability. Understanding the extent of muscular atrophy post-MIDLF/CBT is vital for improving surgical outcomes, and potentially patient rehabilitation strategies. MATERIAL AND METHODS: This study retrospectively analysed preoperative and postoperative MRI scans of patients who underwent MIDLF/CBT for degenerative segmental spondylolisthesis. The bilateral width of the multifidus muscles at the operated segment and adjacent segments was measured using axial T2-weighted MRI scans. Statistical comparisons were made using a paired t test, with significance set at p < 0.05. RESULTS: The study included 16 patients with an average age of 57 ± 10 years, 10 of whom (62.5%) were women, and featured a mean follow-up period of 37 ± 25 months. Postoperative measurements showed a significant reduction in the width of the multifidus muscles at the operated segment (mean difference -3.3mm, p = 0.02) and the inferior adjacent segment (-7.4 mm, p < 0.01). A decrease in muscle width at the superior adjacent segment was also observed, although this was not statistically significant. CONCLUSIONS AND CLINICAL IMPLICATIONS: Our study concluded that MIDLF/CBT results in significant multifidus muscle atrophy at and below the operated segment, potentially impacting postoperative rehabilitation and recovery. These findings highlight the need for further research comparing MIDLF/CBT to other spinal stabilisation techniques. Additionally, incorporating functional electromyographic assessments of paraspinal muscles could provide deeper insights into the long-term consequences of spinal surgeries and helpdevelop new approaches and strategies to mitigate paravertebral muscles atrophy, thus enhancing patient outcomes.
- MeSH
- Lumbar Vertebrae * surgery diagnostic imaging MeSH
- Spinal Fusion * methods MeSH
- Paraspinal Muscles * diagnostic imaging pathology MeSH
- Cortical Bone surgery diagnostic imaging MeSH
- Middle Aged MeSH
- Humans MeSH
- Magnetic Resonance Imaging MeSH
- Pedicle Screws MeSH
- Postoperative Complications diagnostic imaging MeSH
- Retrospective Studies MeSH
- Aged MeSH
- Spondylolisthesis * surgery diagnostic imaging MeSH
- Muscular Atrophy * etiology diagnostic imaging MeSH
- Check Tag
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
Due to methodological reasons, the X-chromosome has not been featured in the major genome-wide association studies on Alzheimer's Disease (AD). To address this and better characterize the genetic landscape of AD, we performed an in-depth X-Chromosome-Wide Association Study (XWAS) in 115,841 AD cases or AD proxy cases, including 52,214 clinically-diagnosed AD cases, and 613,671 controls. We considered three approaches to account for the different X-chromosome inactivation (XCI) states in females, i.e. random XCI, skewed XCI, and escape XCI. We did not detect any genome-wide significant signals (P ≤ 5 × 10-8) but identified seven X-chromosome-wide significant loci (P ≤ 1.6 × 10-6). The index variants were common for the Xp22.32, FRMPD4, DMD and Xq25 loci, and rare for the WNK3, PJA1, and DACH2 loci. Overall, this well-powered XWAS found no genetic risk factors for AD on the non-pseudoautosomal region of the X-chromosome, but it identified suggestive signals warranting further investigations.
- MeSH
- Alzheimer Disease * genetics MeSH
- Genome-Wide Association Study methods MeSH
- Genetic Predisposition to Disease genetics MeSH
- X Chromosome Inactivation genetics MeSH
- Polymorphism, Single Nucleotide genetics MeSH
- Humans MeSH
- Chromosomes, Human, X * genetics MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Case-Control Studies MeSH
- Check Tag
- Humans MeSH
- Male MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
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
BACKGROUND: Limited licensed medications are available for multiple sclerosis (MS) in pediatric patients. OBJECTIVE: To evaluate the efficacy, safety, and tolerability of alemtuzumab in pediatric patients with relapsing-remitting multiple sclerosis (RRMS) and disease activity on prior disease-modifying therapies (DMTs). METHODS: LemKids was a multicenter, multinational, single-arm, open-label, switch (from ongoing DMT to alemtuzumab treatment) study in pediatric RRMS patients (aged 10-<18 years), with disease activity on DMT. The primary endpoint was a comparison of the number of new/enlarging T2 lesions on the magnetic resonance imaging of the brain between the prior-DMT period and alemtuzumab treatment. RESULTS: This study was prematurely terminated due to low enrollment and an European Medicines Agency Article-20 pharmacovigilance review of alemtuzumab in adult RRMS. Of 46 screened patients, 16 were enrolled; 12 completed prior-DMT treatment period; 11 received alemtuzumab of whom 7 completed treatment. Patients on alemtuzumab developed fewer new/enlarging T2 lesions compared with prior-DMT (7 vs 178, relative risk (95% confidence interval): 0.04 (0.01-0.14)). No significant pharmacodynamic changes or safety concerns were noted in this limited dataset. CONCLUSION: Alemtuzumab treatment was associated with a low number of new/enlarging T2 lesions in pediatric patients with RRMS and was safe and well tolerated in seven patients during infusion and the initial 4 months.
- MeSH
- Alemtuzumab * adverse effects MeSH
- Child MeSH
- Immunologic Factors * adverse effects administration & dosage MeSH
- Humans MeSH
- Magnetic Resonance Imaging MeSH
- Adolescent MeSH
- Multiple Sclerosis, Relapsing-Remitting * drug therapy diagnostic imaging MeSH
- Treatment Outcome MeSH
- Check Tag
- Child MeSH
- Humans MeSH
- Adolescent MeSH
- Male MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Multicenter Study MeSH
OBJECTIVES: In axial spondyloarthritis (axSpA) and psoriatic arthritis (PsA) patients initiating secukinumab, we aimed to assess retention rates and proportions of patients achieving remission and low disease activity (LDA), according to disease activity measures and patient-reported outcomes at 24 and 48 months. PATIENTS AND METHODS: Data on patients with axSpA and PsA who initiated secukinumab treatment were pooled from 13 European registries. Analyses were performed overall and stratified according to the number of previous biologic/targeted synthetic Disease-Modifying Antirheumatic Drugs (b/tsDMARDs, 0/1/≥2). Kaplan-Meier plots and Cox regression analyses were performed to assess and compare secukinumab retention rates. Comparisons of remission and LDA rates were performed by logistic regression analyses. RESULTS: The overall 24-/48-month secukinumab retention rates were 61%/51% in 767 axSpA patients, and 64%/49% in 975 PsA patients, respectively. Compared to b/tsDMARD naïve patients, a higher risk of withdrawal from secukinumab was found for those with≥2 prior b/tsDMARDs in axSpA and PsA, and 1 prior b/tsDMARD in axSpA. Generally, remission and LDA rates were numerically higher in b/tsDMARD naïve patients. After adjustment for confounders, statistically significantly higher remission and LDA rates were found for b/tsDMARD naïve patients compared to patients with≥ 2 prior b/tsDMARDs at 24 months in axSpA and PsA. CONCLUSION: This large European real-world study demonstrates that 4-year secukinumab retention rates were approximately 50% in both axSpA and PsA. b/tsDMARD naïve patients had higher retention, remission and LDA rates than patients with prior b/tsDMARD exposure.
- MeSH
- Antirheumatic Agents * therapeutic use MeSH
- Axial Spondyloarthritis * drug therapy diagnosis MeSH
- Time Factors MeSH
- Adult MeSH
- Patient Reported Outcome Measures MeSH
- Antibodies, Monoclonal, Humanized * therapeutic use MeSH
- Remission Induction MeSH
- Middle Aged MeSH
- Humans MeSH
- Follow-Up Studies MeSH
- Arthritis, Psoriatic * drug therapy diagnosis MeSH
- Registries MeSH
- Severity of Illness Index MeSH
- Treatment Outcome MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Multicenter Study MeSH
- Observational Study MeSH
- Geographicals
- Europe MeSH
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
