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Right heart failure and mortality in patients undergoing transcatheter tricuspid valve interventions
No full textAims: To assess the association between right heart failure (RHF) and mortality in patients with severe tricuspid regurgitation (TR) undergoing transcatheter tricuspid valve intervention (TTVI), and to determine whether clinical RHF status reduces the survival benefit of successful versus failed TTVI. Methods and results: The TriValve International Registry (Transcatheter Tricuspid Valve Therapies) is a multicenter registry collecting data of patients with symptomatic, severe or greater TR undergoing TTVI. The population was stratified according to RHF status defined by the following clinical criteria: history of previous hospitalization for RHF (<1 year) OR presence of signs of RHF (jugular venous distension, ascites, peripheral oedema) OR high dose diuretic (≥125 mg/day of furosemide or equivalent). The outcome of interest was 1-year all-cause death. Among 639 patients included in the TriValve registry, 498 had complete data regarding RHF status. Overall, 54 (10.8 %) patients had no criteria for RHF, 133 (26.7 %) patients fulfilled 1 criterion, 240 (48.2 %) 2 criteria and 71 (14.3 %) 3 criteria. At a median follow-up of 216 days (IQR 49–372 days), cumulative incidence of all-cause death was higher in patients with 2 or 3 RHF criteria versus those with no or 1 RHF criterion (adjusted HR 2.91–95 % CI 1.46–5.83, P = 0.002). However, RHF status did not influence the association between procedural success and all-cause death at 1-year follow-up (p for interaction 0.857). Conclusions: In a large real-world population undergoing TTVI for severe TR, the presence of at least 2 RHF clinical criteria was independently associated with an increased risk of 1-year mortality. Procedural success was associated with a lower risk of mortality regardless of RHF status
Unveiling the biological side of PET-derived biomarkers: a simulation-based approach applied to PDAC assessment
No full textPurpose: Radiomics has revolutionized clinical research by enabling objective measurements of imaging-derived biomarkers. However, the true potential of radiomics necessitates a comprehensive understanding of the biological basis of extracted features to serve as a clinical decision support. In this work, we propose an end-to-end framework for the in silico simulation of [18F]FLT PET imaging process in Pancreatic Ductal Adenocarcinoma, accounting for the biological characterization of tissues (including perfusion and fibrosis) on tracer delivery. We thus establish a direct association between radiomics features and the underlying biological properties of tissues. Methods: We considered 4 immunohistochemically stained Whole Slide Images of pancreatic tissue of one healthy control and three patients with PDAC and/or precursor lesions. From marker-specific images, tissue-depending diffusivity properties were estimated and computational domains were built to simulate the [18F]FLT spatial-temporal uptake exploiting Partial Differential Equations and Finite Elements Method. Consequently, we simulated the imaging process obtaining surrogated PET images for the considered patients, and we performed image-derived features extraction from PET images to be mapped with biological properties via correlation estimation. Results: The framework captured the phenotypic differences and generated Time Activity Curves reflecting the underlying tissue composition. Image-derived biomarkers were ranked in view of their association with biological characteristics of the tissue, unveiling their molecular correlative. Moreover, we showed that the proposed pipeline could serve as a digital phantom to optimize the image acquisition for lesion detection. Conclusions: This innovative framework holds the potential to enhance interpretability and reliability of radiomics, fostering the adoption in personalized nuclear medicine and patient care
Exploring the diversity of biological processes regulated by glial cell line-derived neurotrophic factor, a pleiotropic molecule with therapeutic potential
Get PDFGlial cell line–derived neurotrophic factor (GDNF) is a potent trophic factor essential for neuronal survival and function. Encoded by the GDNF gene, its mature protein arises from specific post-translational modifications and is secreted through distinct isoform-dependent pathways. Once released, GDNF binds to its receptors, GFRα1 and RET, activating downstream signaling cascades that regulate cell growth, differentiation, and survival. In the central nervous system, GDNF exerts protective effects on dopaminergic neurons—highlighted in Parkinson’s disease research—and shows promise for modulating schizophrenia, depression, and addiction. Beyond dopaminergic pathways, GDNF influences synaptic plasticity in hippocampal neurons and supports GABAergic function. Glial cells also produce and respond to GDNF: astrocyte-derived GDNF can promote neuroprotection but also modulate microglial state and neuroinflammation. Other cell sources, such as pericytes and endothelial cells, contribute to GDNF levels, impacting blood-brain and blood-nerve barrier permeability. Peripherally, GDNF is critical for sympathetic and parasympathetic neuron development, somatic sensory neuron maintenance, and motor neuron reinnervation at the neuromuscular junction. Finally, GDNF has been recently implicated in tumour biology, underscoring its multifaceted role at the interface between beneficial and detrimental effects. Clinically, its therapeutic potential is being explored in different diseases, including neurodegenerative disorders and epilepsy. In this review, we will explore various aspects of GDNF biology and then focus our attention to the physiological mechanisms of GDNF-regulated processes in the central and peripheral nervous system, concluding with a brief perspective related to its therapeutic potential for central nervous system disorders. A deeper knowledge of the mechanisms regulating GDNF secretion and signaling, particularly the cellular source and the specificity of the GDNF-engaged intracellular signaling pathways, could be helpful to develop more precise therapeutic strategies for different CNS diseases
Unraveling the role of GBA1 genotype in axial signs response to subthalamic deep brain stimulation
No full textGBA1 variants represent the most common genetic risk factor for Parkinson's disease (PD) and are associated with higher risk of developing cognitive decline and axial motor impairment. While cognitive outcomes following subthalamic deep brain stimulation (STN-DBS) have recently received growing attention, axial signs progression remains poorly defined in this population. In this retrospective multicentric study, we analyzed a cohort of 353 PD patients who underwent bilateral STN-DBS surgery (75 GBA+ and 253 GBA-). 5-year follow-up data were available for 233 patients, including 43 mutated subjects. Lower off-medication UPDRS III score and levodopa responsiveness at baseline were identified as independent predictors of axial signs worsening after DBS, while GBA1 genotype was not identified as risk factor. The presence of GBA1 variants did not exert a detrimental effect on axial signs in PD patients up to five years following STN-DBS, supporting its consideration as a valid therapeutic option in this genetic subgroup
Profiling the real-world migraine patient: public health insights from sociodemographic, lifestyle, and clinical data in the Italian National Migraine Registry (I-GRAINE)
Get PDFBackground: Although migraine attacks have been precisely characterized over the years − with significant advances in pathophysiology and treatment − the comprehensive identity of the migraine patient remains poorly defined. Real-world data capturing the full sociodemographic and clinical spectrum of individuals with migraine is still limited. The Italian National Migraine Registry (I-GRAINE) was established to address this gap by systematically collecting data on individuals with migraine across Italy’s public healthcare system. Methods: I-GRAINE is an ongoing, nationwide, multicenter, prospective registry involving 43 publicly funded headache centers. Since 19/04/2021, patients diagnosed with episodic migraine (EM) or chronic migraine (CM) have been systematically enrolled. Data were collected through face-to-face interviews conducted by trained neurologists using a dedicated electronic platform. Information included sociodemographic and lifestyle factors, comorbidities, and detailed clinical characteristics. We aimed to define the patient profile, explore the broad clinical phenotype, and compare EM and CM subgroups. Results: As of 02/05/2025, 1,630 patients had been enrolled (81.7% EM, 18.3% CM), predominantly female (85.4%), mean age 45.7 years, normal BMI (23.2 kg/m2), and high education level. Over 70% were physically inactive, and 32.2% reported sleep disturbances. Headache was typically unilateral (69.1%), pulsating (64.0%), and lasted > 24 h (57.1%). Frequently reported non-ICHD-3 symptoms included osmophobia (41.5%), allodynia (40.5%), dopaminergic symptoms (37.2%), cephalalgiaphobia (34.0%), and dizziness (16.9%). ≥ 1 comorbidity was present in 41.2% of patients. Compared to those with EM, CM patients had higher BMI (24.0 vs. 23.0, p < 0.001), greater sleep disturbances (39.1% vs. 30.6%, p = 0.006), earlier onset (16.5 vs. 17.7 years, p = 0.032), more severe pain (NRS: 8.1 vs. 7.5, p < 0.001), and higher prevalence of medication overuse (58.3% vs. 14.5%, p < 0.001), dopaminergic symptoms (45.1% vs. 35.4%, p = 0.002), allodynia (47.5% vs. 38.9%, p = 0.009), and cephalalgiaphobia (41.4% vs. 32.3%, p = 0.004). Disability was also greater (MIDAS: 76.3 vs. 41.9; HIT-6: 64.3 vs. 61.2; both p < 0.001). Conclusions: The typical patient attending Italian headache centers is a 45-year-old, normal-weight, well-educated, employed woman, often physically inactive, affected by sleep disturbances, and experiencing an average of 9.8 migraine days/month. I-GRAINE identifies migraine symptoms that may represent endophenotypes and distinct patterns associated with CM, offering valuable real-world insights to inform personalized care, research, and health policy
Viral Hepatitis in Western Patients with Advanced Intrahepatic Cholangiocarcinoma: Retrospective Assessment of Prevalence, Prognostic and Predictive Significance
No full textDespite a biologically established causative role of viral hepatitis (VH), i.e. HBV and HCV infections, on intrahepatic cholangiocarcinoma (ICC), only few large Western cohorts exploring the association between VH and ICC development are available. The prognostic significance of VH in ICC is debated, and no data are available regarding a predictive role for standard first-line CT (CT1), consisting of gemcitabine +/− platinoids. VH-positivity definition is often clinically incomplete and inconsistent among studies. Five different VH conditions, based on laboratory and anamnestic data, were investigated in a multicentric retrospective cohort of advanced ICC cases. Depending on the specific VH condition considered, 139–194 of 472 ICC cases could be categorized according to the presence of the mentioned VH conditions. VH prevalence ranged from 9.3 to 25.3%. No VH condition showed an impact on survival, although a non-significant worse outcome was observed for some HBV-related conditions. HCV-related conditions were associated to lower pre-CT1 biomarkers of inflammation, markedly higher disease control, and numerically longer time-to-progression with CT1. No benefit on time-to-progression was demonstrated for the addition of platinoids to gemcitabine in VH-positive patients (HR 0.77, CI95% 0.41–1.45), at least in HBV-related cases. These findings are clinically relevant and deserve further investigation.Despite a biologically established causative role of viral hepatitis (VH), i.e. HBV and HCV infections, on intrahepatic cholangiocarcinoma (ICC), only few large Western cohorts exploring the association between VH and ICC development are available. The prognostic significance of VH in ICC is debated, and no data are available regarding a predictive role for standard first-line CT (CT1), consisting of gemcitabine +/− platinoids. VH-positivity definition is often clinically incomplete and inconsistent among studies. Five different VH conditions, based on laboratory and anamnestic data, were investigated in a multicentric retrospective cohort of advanced ICC cases. Depending on the specific VH condition considered, 139–194 of 472 ICC cases could be categorized according to the presence of the mentioned VH conditions. VH prevalence ranged from 9.3 to 25.3%. No VH condition showed an impact on survival, although a non-significant worse outcome was observed for some HBV-related conditions. HCV-related conditions were associated to lower pre-CT1 biomarkers of inflammation, markedly higher disease control, and numerically longer time-to-progression with CT1. No benefit on time-to-progression was demonstrated for the addition of platinoids to gemcitabine in VH-positive patients (HR 0.77, CI95% 0.41–1.45), at least in HBV-related cases. These findings are clinically relevant and deserve further investigation
A Composite Endpoint of Liver Surgery (CELS): Development and Validation of a Clinically Relevant Endpoint Requiring a Smaller Sample Size
No full textBackground: The feasibility of trials in liver surgery using a single-component clinical endpoint is low because single endpoints require large samples due to their low incidence. The current study sought to develop and validate a novel composite endpoint of liver surgery (CELS) to facilitate the generation of more feasible and robust high-level evidence in the field of liver surgery. Methods: Patients who underwent curative-intent hepatectomy for hepatocellular carcinoma, intrahepatic cholangiocarcinoma, or colorectal liver metastasis were identified using a multi-institutional database. Components of CELS were selected based on perioperative liver surgery-specific complications using univariable logistic regression models. The association of CELS with prolonged length of stay (LOS) and surgery-related death was evaluated and externally validated. Sample sizes were calculated for both individual outcomes and CELS. Results: Among 1958 patients, 377 (19.3%) met CELS criteria based on postoperative bile leak (n = 221, 11.3%), post-hepatectomy liver failure (n = 71, 3.6%), post-hepatectomy hemorrhage (n = 38, 1.9%), or intraoperative blood loss of 2000 ml or greater (n = 101, 5.2%). CELS demonstrated favorable discriminative accuracy of surgery-related death (analytic cohort: area under the curve [AUC], 0.79 vs external validation cohort: AUC, 0.85). In addition LOS was longer among the patients with a positive CELS (analytic cohort: 14 vs. 9 days [p < 0.001] vs. the validation cohort: 10 vs. 6 days [p < 0.001]). Relative to individual endpoints, CELS allowed a 45.8–91.6% reduction in sample size. Conclusion: CELS effectively predicted surgery-related death and can be used as a standardized, clinically relevant endpoint in prospective trials, facilitating smaller sample sizes and enhancing feasibility compared with single quality outcome metrics
Moving toward precision and personalized treatment strategies in psychiatry
No full textPrecision psychiatry aims to improve routine clinical practice by integrating biological, clinical, and environmental data. Many studies have been performed in different areas of research on major depressive disorder, bipolar disorder, and schizophrenia. Neuroimaging and electroencephalography findings have identified potential circuit-level abnormalities predictive of treatment response. Protein biomarkers, including IL-2, S100B, and NfL, and the kynurenine pathway illustrate the role of immune and metabolic dysregulation. Circadian rhythm disturbances and the gut microbiome have also emerged as critical transdiagnostic contributors to psychiatric symptomatology and outcomes. Moreover, advances in genomic research and polygenic scores support the perspective of personalized risk stratification and medication selection.While challenges remain, such as data replication issues, prediction model accuracy, and scalability, the progress so far achieved underscores the potential of precision psychiatry in improving diagnostic accuracy and treatment effectiveness
Gamified Interventions for Obesity and Overweight Prevention and Treatment: A Scoping Review
No full textBackground: Obesity and overweight affect approximately 30% of the world's population. These conditions present a global challenge, as they lead to morbidity and the development of chronic diseases such as type 2 diabetes, cardiovascular disease, and cancer. Various strategies are available to address obesity and overweight. Nonpharmacological strategies include therapeutic patient education, which employs novel approaches to inform and engage patients, including gamification, the integration of gaming elements into nongaming contexts. Purpose: This scoping review aimed to explore, map, and investigate gamified tools for obesity and overweight prevention and treatment, as well as their effectiveness. Methods: The review was conducted in accordance with the JBI guidelines for scoping reviews and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews (PRISMA-ScR) checklist. Searches were conducted in MEDLINE, CINAHL, PsycInfo, Embase, Scopus, and the Cochrane Library. Results: Six articles, primarily from the United States and published within the last eight years, were included in the review. Three main themes emerged: the use of gamification to reduce weight, the use of gamification to encourage physical activity, and the use of gamification to facilitate behavior change (adoption of a healthy diet). Conclusion: Further research should be conducted on the use of gamification to prevent and treat obesity and overweight, because it seems to be effective in certain subpopulations and for reaching specific outcomes
Abnormally slow dynamics in occipital cortex of depression
No full textAim: Major depressive disorder (MDD) is characterized by altered activity in various higher-order regions like the anterior cingulate and prefrontal cortex. While some findings also show changes in lower-order sensory regions like the occipital cortex in MDD, the latter's exact neural and temporal, e.g., dynamic characterization and symptom severity remains yet unclear. Methods: We conducted resting state fMRI in MDD (N = 49) and healthy controls to investigate the global activity representation of the brain's spontaneous activity in occipital cortex including lower-order (V1) and higher-order (hMT+) regions in the hierarchy of the visual cortex. We further explored (i) these regions' functional connectivity to higher-order prefrontal and subcortical regions, (ii) global signal correlation differences between MDD and controls in different frequency bands, and (iii) their power spectrum's correlation (using median frequency/MF) with symptom severity. Results: Our findings in MDD show: (i) abnormally high functional connectivity of the occipital cortex to both subcortical and higher-order cortical regions; (ii) occipital global signal correlation is reduced mainly in the faster infraslow frequency range (slow 3: 0.073 to 0.198 Hz) as distinguished from the slower ones (slow 5 and 4: 0.01 to 0.027 Hz, and 0.027 to 0.073 Hz); (iii) the reduced neural dynamics in occipital cortex (MF) correlate with the severity of both overall depressive symptoms and psychomotor retardation scores. Conclusions: MDD shows reduced global activity with abnormally slow neural dynamics in occipital cortex that is functionally connected with higher-order regions like the anterior cingulate cortex. The slow dynamics in occipital cortex relates to overall symptom severity and psychomotor retardation