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The arrow of time in Parkinson's disease
No full textBackground: Parkinson's disease (PD) is a system-level disorder that implicates brain network dynamics across multiple scales. Detecting the ‘arrow of time’, or temporal reversibility of the brain's information processing flow enables quantification of equilibrium in the brain and inferences on the hierarchical organization. Therefore we aimed to explore disturbances in resting-state equilibrium levels as well as changes in the hierarchical organization due to PD. Methods: Structural and functional MRI of 29 PD patients and 19 healthy controls were acquired and analyzed. Empirical non-reversibility was computed as the distance between time-shifted forward- and artificially-reversed time series. Levels of equilibrium were subsequently assessed globally and within two cortico-subcortical motor networks implicated in PD. Moreover, whole-brain generative computational models consisting of 1051 Hopf oscillators were constructed to evaluate effective connectivities and alterations of the functional hierarchical organization. Results: We found that PD is characterized by disrupted equilibrium regimes, marked by distinct effective connectivity patterns, particularly within the motor networks. Additionally, we observed a flatter hierarchical organization in PD, with the cerebellum and thalamus exerting increased influence. Conclusion: The arrow of time methodology effectively identifies distinct and informative characteristics of PD. Our analyses suggest that PD shifts the brain towards less efficient, non-equilibrium dynamics that impair intrinsic flexibility and disrupt motor coordination. Thus, these findings not only provide insight into widespread system alterations in PD that could serve as potential biomarkers, but also lay the groundwork for next-generation stimulation techniques aimed at restoring balance in the Parkinsonian brain
PARP9-PARP13-PARP14 axis tunes colorectal cancer response to radiotherapy
No full textBACKGROUND: Colorectal cancer (CRC) is the third most prevalent cancer worldwide. Despite substantial advancements in CRC therapy in recent years, ionizing radiation (IR) continues to be the predominant treatment for colon malignances. However, it still lacks the precision required for excellent therapeutic outcomes, ultimately resulting in tumor radioresistance. This study seeks to explore the potential of atypical PARPs including PARP9, PARP12, PARP13 and PARP14 as innovative radiosensitizing targets for CRC. METHODS: We utilized CRISPR/Cas9-mediated gene editing to knockout the PARP9, PARP12, PARP13 and PARP14 in HT29 and DLD1 cells. The cells were exposed to either a single dose of 6-10 Gy or to fractionated dose of 5 × 2 Gy X-ray radiation cultivating cells in 2D, laminin-rich ECM 3D and multicellular spheroid models. The transcriptomes of nonirradiated and irradiated cells were analyzed using microarrays. Gene set enrichment analysis was conducted to determine the pathways in which PARP13 is engaged. Cell viability was assessed using a clonogenic assay. Gene expression levels in cells and patient samples were quantified using RT-qPCR. RESULTS: The expression of PARP9, PARP12, PARP13 and PARP14 was particularly elevated in irradiated colorectal cancer HT29 cells in a microenvironment-dependent manner. PARP13 deficiency significantly enhanced the sensitivity of HT29 cells to both single-dose and multifractionated irradiation regimens, resulting in reduced colony formation and spheroidal integrity. Microarray analysis indicated that PARP13 may modulate the expression genes associated with immune response signaling pathways, including members of PARP family. Furthermore, PARP13 loss in HT29 cells markedly impaired the expression of immune response related genes following multifractionated ionizing irradiation. Finally, chemoradiotherapy significantly elevated the expression of PARP9, PARP12, PARP13 and PARP14 in rectal tumors, while having no effect on adjacent normal colon tissues. Elevated pre-treatment PARP9 expression levels and a blunted post-treatment increase in PARP9 and PARP14 expression predicted poor overall survival in rectal cancer patients, while PARP13 emerged as the most significant discriminator between tumor and healthy tissue. CONCLUSIONS: Collectively, the PARP9/13/14 axis is implicated in the response of CRC to radiation treatment in both preclinical and clinical settings, demonstrating the atypical members of the PARP family as attractive targets for neoadjuvant radiotherapy
Immuno-haemostatic dysregulation in heart failure with preserved ejection fraction
No full textAims: Heart failure with preserved ejection fraction (HFpEF) is a complex condition with partially unclear pathophysiology, in which systemic inflammation is a central contributor to changes in cardiac structure and function. The contribution of non-traditional immune effectors—such as platelets and coagulation—remains underexplored in HFpEF. We characterized platelet function, as well as coagulation and neutrophil activation, in patients with HFpEF. Methods: The in vivo activation of platelets, neutrophils, endothelial cells and coagulation was measured in plasma from patients with HFpEF (n = 103), age- and sex-matched controls (n = 40) and pooled plasma from a healthy reference cohort. Flow cytometric and microfluidic assays were performed to investigate platelet function ex vivo. Results: Compared with matched controls, patients with HFpEF exhibited reduced platelet reactivity, characterized by alterations in platelet integrin activation and granule release, and an overall decrease in thrombus activation, contraction and fibrin formation. In vivo platelet activation markers β-TG and CXCL4 were increased in plasma from patients with HFpEF and matched controls compared with the healthy reference cohort (β-TG: 923.01 and 822.25 vs. 335.06 ng/mL; CXCL4: 660.16 and 603.63 vs. 458.34 ng/mL). Linear regression analyses showed an association between platelet aberrant activation and function and the presence of HFpEF, independent of comorbidities or medications [e.g., thrombus characteristics (size, contraction, height): P values Fully adjusted model = <0.001; <0.001; <0.001]. Patients with HFpEF showed higher levels of the neutrophil activation markers MPO and S100A8/A9 compared with matched controls (MPO: P value = 0.0152; S100A8/A9: P value = 0.0041). Levels of endothelial markers ICAM-1 and VCAM-1 were unaltered between groups. Coagulation was found elevated in patients with HFpEF, particularly in patients not on anticoagulant (AC) medications, showing increased plasma levels of plasma kallikrein, factor XI, factor IX, thrombin and D-dimer (kallikrein: P value = 0.0415; AC excluded: FXIa:C1inh: P value = 0.0110; FIXa:AT: P value = 0.0095; T:AT: 4.46 vs. reference 4 μg/L; D-dimer: 0.65 vs. reference 0.5 mg/L). Conclusions: Patients with HFpEF present with dysfunctional platelets, a procoagulant state and neutrophil activation. The association of immuno-haemostatic processes including aberrant platelet function with the presence of HFpEF, independent of comorbidities or medications, suggests that platelet dysfunction is an intrinsic feature of HFpEF.</p
The GENIFEM Pilot Randomized Trial:Genicular Nerve Block vs Femoral Triangle Block vs Local Infiltration Analgesia for Total Knee Arthroplasty
No full textInternational consensus on the content of prehabilitation in spine surgery:results of a nominal group technique
No full textBACKGROUND CONTEXT: Spine surgery, like all major surgeries, carries the risk of adverse events and delayed recovery. Prehabilitation programs may mitigate negative prognostic factors to reduce complications and promote faster recovery postoperatively following spine surgery. There is no international consensus or recommendations regarding prehabilitation components in spine surgery. PURPOSE: This study aims to establish international consensus on important modalities of prehabilitation before spine surgery for patients appropriate for prehabilitation using a modified nominal group technique (NGT). STUDY DESIGN/SETTING: A modified NGT. PATIENT SAMPLE: This study used a modified NGT to establish consensus among 50 participants during the International Forum for Back and Neck Pain (ILBP Forum) 2023 and International Society for the Study of the Lumbar Spine (ISSLS) 2024 conference. OUTCOME MEASURES: The rank for each theme and component was computed as the mean of the ranking. We expressed the dispersion in ranking as a measure of consensus. METHODS: During the workshops participants consisting of clinicians and researchers ranked themes and components of a prehabilitation intervention for patients scheduled for spine surgery. The rank for each theme and component was calculated as the mean rank, the dispersion in rankings was used as a measure of consensus. RESULTS: Five main prehabilitation themes were identified and ranked from most to least important by the participants: education (consensus=0.65), psychological prehabilitation (consensus=0.56), physical prehabilitation (consensus=0.37), multidisciplinary prehabilitation (consensus=0.54) and lifestyle factors (consensus=0.53). Within themes, different prehabilitation components were identified and ranked by priority. CONCLUSIONS: The 5 themes identified by this NGT consensus process (education, psychological prehabilitation, physical prehabilitation, multidisciplinary prehabilitation and lifestyle factors) can help inform the design of innovative prehabilitation interventions for optimizing recovery from spine surgery.</p
User-Driven Development of a Digital Behavioral Intervention for Chronic Pain:Multimethod Multiphase Study
No full textBACKGROUND: Recent research shows that chronic pain affects 27% of the adult population. For many, pain significantly impairs quality of life and everyday functioning. Behavioral interventions have shown utility, but access remains limited. Digital health solutions can increase reach, but there is a need for user-friendly, feasible, and evidence-based digital interventions. OBJECTIVE: This study aimed to clarify how a digital behavioral intervention for people with chronic pain can be developed through a user-centered approach to address the needs and preferences of the target population. METHODS: This study used a multimethod approach involving end users, namely, patients with chronic pain and therapists, to develop prototypes for a digital behavioral intervention across 3 phases. In the preparation phase (phase 0), fictional patient personas (n=3) were created to represent the diversity of the target population while emphasizing transdiagnostic features across people with chronic pain. In the design phase (phase 1), qualitative data from focus groups with patients (n=5; aged 37-51 years; 4/5, 80% women; 2/5, 40% diagnosed with Ehlers-Danlos syndrome; 3/5, 60% either undiagnosed or uncertain about their diagnosis) and therapists (n=12 licensed psychologists; aged 29-64 years; 9/12, 75% women) were collected to explore end-user preferences for the intervention design and content. In the testing phase (phase 2), the initial full prototype of the digital intervention was piloted with patients (n=11; aged 36-58 years; 9/11, 82% women; with diverse diagnoses, including migraine, arthritis, fibromyalgia, complex regional pain syndrome, hypermobile Ehlers-Danlos syndrome, herniated disc, chronic fatigue syndrome, and 1/11, 9% cases of undiagnosed pain) and therapists (n=3 licensed psychologists; aged 36-58 y; 3/3, 100% women). The Consolidated Framework for Implementation Research was used to structure analyses of end-user feedback. RESULTS: On the basis of end-user input, a 6-week digital behavioral intervention for chronic pain was created. Focus groups highlighted the importance of accessibility and adaptability of the digital intervention, emphasizing the need for tailored content, flexibility (eg, contact with the therapist via asynchronous messaging, telephone, or video calls), and user-friendly design (eg, easy navigation between modules, short microsessions, and visualizations). Average weekly ratings (scale from 1=not at all to 7=very much) by patients during pilot-testing indicated that the intervention was helpful (mean range 4.27-5.45, SD range 1.20-2.20), enjoyable (mean range 3.81-4.81, SD range 1.12-2.08), and understandable (mean range 4.45-6, SD range 1.30-1.86), suggesting initial acceptability and usability of the intervention. CONCLUSIONS: The results illustrated the utility of the patient personas when preparing, of the focus groups when designing, and of the end-user feedback when testing this new digital intervention for people with chronic pain. The findings indicated that the intervention is promising while also providing relevant end-user suggestions (eg, video content, text-to-speech function, and add-on modules) to guide further improvements
Correction: Protein carbamylation in atherosclerotic plaques correlates with uremia and disease progression, localizing predominantly to foam cells
No full textIn the published article, there was an error in the Funding statement. The funding mentioned “This project has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 764474 (CaReSyAn).” was incomplete. The correct Funding statement appears below. “This project has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 764474 (CaReSyAn). VJankowski and JJankowski are funded by the German Research Foundation (DFG) through the Transregional Collaborative Research Center (TRR 219; Project ID 322900939), (subproject S-03), (INST 948/4S-1); CRU 5011 project number 445703531, Cost-Action CA 21165, IZKF Multiorgan complexity in Friedreich Ataxia, and Phase Transition in Disease 1-1), ERA-PerMed (ERA-PERMED2022-202-KidneySign).” The original article has been updated.</p
E171-induced toxicity in human iPSC-derived colon organoids:Effects on cell viability, ROS generation, DNA damage, and gene expression changes
No full textFood-grade titanium dioxide (E171) is a widely used food additive with debated safety, particularly regarding its genotoxic effects. This study assessed the dose-dependent toxicity of E171 in human induced pluripotent stem cell (iPSC)-derived colon organoids. Organoids were exposed to E171 (0.1-1000 µg/mL) for 24 h, and effects on cell viability, reactive oxygen species (ROS) generation, DNA damage, and gene expression were evaluated. Results showed no impact on cell viability but a dose-dependent increase in ROS formation, peaking at 1000 µg/mL. Electrospin Resonance Spectroscopy (ESR) showed a dose-dependent increase in ROS, with increased E171 concentrations. The alkaline comet assay revealed significant DNA damage from 100 µg/mL, with oxidative DNA damage detected at 10 µg/mL using formamidopyrimidine DNA glycosylase (FPG). RNA sequencing identified differentially expressed genes (DEGs) at 100 and 250 µg/mL, linked to translational activity, signal transduction, and DNA damage repair. Gene set enrichment analysis (GSEA) indicated activation of ribosome, chemical carcinogenesis-ROS, and metabolic pathways (carbon metabolism, glycolysis), while key regulatory pathways (Wnt, MAPK, PI3K-Akt) were suppressed. These findings suggest that E171 induces oxidative stress and DNA damage, modulating transcriptomic pathways associated with metabolism, proliferation, and cancer. Further research is necessary to determine its long-term effects on human gastrointestinal health
Optimizing Preclinical Models for Oral Cancer:The Influence of 4NQO Administration Routes on Tumor Development
No full textBACKGROUND/OBJECTIVES: Oral squamous cell carcinoma (OSCC) is the most common oral cancer, progressing from hyperplasia to dysplasia, carcinoma in situ (CIS), and finally invasive squamous cell carcinoma (ISCC). Developing an animal model that mimics both early and advanced OSCC stages has been challenging. The 4-Nitroquinoline 1-oxide (4NQO) model is considered one of the most suitable, as it represents all stages of OSCC. Nevertheless, thoroughly understanding the properties of the 4NQO model is essential for preclinical testing of novel therapeutics. METHODS: We aimed to characterize the 4NQO rat model using two application methods-drinking water and topical application-over eight months. Monthly sacrifices allowed histopathological analysis and ex vivo magnetic resonance imaging (MRI) to track tumor progression. RESULTS: CIS was observed at three months in the drinking water group, evolving into ISCC by six months, while topical application induced CIS at eight months without ISCC formation. The tongue was divided into three regions and histological properties, lesion size, and invasion depth were analyzed. In the drinking water group, particularly in the body of the tongue, we saw earlier CIS development, larger lesions, and deeper invasion. Additionally, assessment of proliferative properties showed an increased cell division in dysplastic lesions that reduced upon invasion. MRI was able to show macroscopic tumoral lesions, in concordance with histology. CONCLUSIONS: Overall, the drinking water method closely mimics human OSCC, validating the 4NQO model for translational OSCC research
Efficacy and Safety of Low-Dose Rivaroxaban in High-Ischemic-Risk Patients with Chronic Coronary Syndrome:Rationale and Design of the DUTCH CCS Registry
No full textBackground/Objectives: Despite progress in secondary prevention, people with chronic coronary syndrome (CCS) still face a residual risk of ischemic events. Antithrombotic therapy reduces this risk and helps stabilize chronic cardiovascular disease. Studies have shown that combining low-dose rivaroxaban with aspirin—an approach called dual-pathway inhibition (DPI)—can lower this risk and reduce major adverse cardiovascular events (MACEs). However, researchers have not yet gathered enough real-world data to confirm the efficacy and safety of this strategy. The DUTCH CCS registry aims to collect real-world data on how effective and safe low-dose rivaroxaban combined with aspirin is for patients with CCS in The Netherlands. The study aims to provide insights into the outcomes, benefits, and risks of DPI in a real-world setting, beyond the scope of controlled clinical trials. Methods: The DUTCH CCS registry operates as a national, multicenter, prospective observational study. It enrolls 1000 patients with CCS who receive rivaroxaban (2.5 mg twice daily) and aspirin (80 mg or 100 mg once daily). The study targets individuals at high ischemic risk due to coronary artery disease (CAD) and follows a single-arm design. Researchers will measure the primary efficacy endpoint by tracking MACEs, clinically driven coronary, peripheral, or carotid revascularization, and stent thrombosis over one year. They will assess the primary safety endpoint by recording major bleeding events at one year. The team will collect data at both 3-month and 1-year follow-ups. Conclusions: As an observational study, this registry is not designed to establish causality. However, it seeks to improve our understanding of how DPI performs in real-world secondary prevention for CCS patients. The results may help update treatment guidelines and inform clinical decisions in everyday practice.</p