University Foundation

Abstract Introduction Minimally invasive techniques have transformed early rectal cancer treatment; yet the optimal approach is unclear. ESD, EMR, and TAMIS are increasingly being used, however, most studies only compare two of these techniques. This meta-analysis directly compares all three in efficacy, safety, and oncological performance. Methods PubMed, Scopus, and Medline were searched to identify relevant studies as of September 2024. Criteria included studies in adults with early rectal cancer treated by ESD, EMR, or TAMIS, reporting at least one outcome and specifying treatment type and cancer stage. Comprehensive Meta-Analysis v4 was used for analysis with heterogeneity assessed via I². Results A total of 127 studies encompassing 8915 patients were included (EMR = 3979, ESD = 4470, and TAMIS = 466). Mean procedural times were: overall 8.3 min (7.7–8.8), I² = 99%; EMR 7.5 (6.9–8.1), I² = 98%; ESD 32.6 (29.3–36), I² = 99%; TAMIS 101.6 (83.9–119.9), I² = 95%. En bloc resection: overall 87.1% (85.6–88.5), I² = 81%; EMR 86.5% (84.4–88.4), I² = 82%; ESD 87.2% (84.4–89.5), I² = 80%; TAMIS 94.1% (88.9–97), I² = 0%. R0 resection: overall 79.7% (78.6–80.8), I² = 80%—EMR 79.9% (78.3–81.5), I² = 85%; ESD 78.7% (77.1–80.3), I² = 76%; TAMIS 87.1% (82.8–90.4), I² = 42%. Conclusions Although EMR appears efficient, it demonstrated less favourable outcomes regarding en bloc resection. ESD showed favourable oncological outcomes while maintaining moderate procedural time. TAMIS is most time-intensive but yields the highest resection quality.

Doxorubicin (DOX) is a highly effective chemotherapeutic agent whose clinical use is limited by dose-dependent cardiotoxicity associated with oxidative stress, inflammation, and cellular stress responses. Here, we investigated whether preventive aerobic training could protect against DOX-induced cardiac injury in Wistar rats. Animals were assigned to sedentary control (C), sedentary DOX (D), trained control (CT), and trained DOX (DT) groups. The moderate-intensity (~50-80% maximal exercise test) treadmill protocol (40 min/day, 4 days/week for 4 weeks) was performed before intraperitoneal administration of DOX (4 mg/kg, weekly for 4 weeks) or saline. Preventive training markedly improved exercise capacity (p < 0.001) and attenuated oxidative damage, maintaining antioxidant enzyme activity (GR, SOD) at control levels (p > 0.05). DOX significantly upregulated cardiac IL-6 and IL-1β expression (p < 0.01), while trained animals preserved IL-1β expression similar to controls (p > 0.99). In parallel, DOX increased cardiac HIF-1 expression (p < 0.05), indicating activation of hypoxia- and stress-related signaling pathways, an effect that was attenuated by preventive training (p > 0.99). DOX-induced cardiac atrophy was evidenced by reduced left ventricular mass (p < 0.001), which was partially prevented by training (p < 0.05). Although hematological toxicity persisted, preventive aerobic exercise effectively counteracted DOX cardiotoxicity by restoring redox homeostasis, dampening inflammation, and limiting apoptotic signaling. Collectively, these findings highlight exercise preconditioning as a promising non-pharmacological strategy in cardio-oncology to mitigate chemotherapy-associated cardiac injury.

Abstract Isolated atrial amyloidosis (IAA) is a localized cardiac disorder characterized by atrial natriuretic peptide (ANP) amyloids deposition in the atria, linked to aging and atrial fibrillation (AF). While monomeric ANP regulates blood pressure, its dimeric form is associated with cardiovascular conditions, including AF. The mechanistic link between ANP aggregation, IAA, and AF remains unclear. Here, we present the first high-resolution structural characterization of ANP fibrils extracted from AF patients, revealing two distinct fibril polymorphs. Both present covalent ANP dimers as building blocks but diverge in their structural architecture: one features antiparallel dimers stabilized by a single disulfide bond, while the other consists of parallel dimers bridged by two interchain disulfide bonds. These fibril morphologies were conserved across patients, suggesting a common aggregation mechanism in IAA. Overall, our findings ascribe to dimeric ANP a critical role in amyloid formation, offering promising directions for earlier detection and treatment of IAA.

The aim of this study was to outline the role of genetic abnormalities, including chromosomal anomalies, single-gene mutations, epigenetic changes, and mitochondrial DNA (mtDNA) defects, in male factor infertility. Recent advances in genetic research have brought incredible new perspectives to understanding male infertility, thanks in large part to next-generation sequencing. Chromosomal abnormalities like Klinefelter syndrome and Y chromosome microdeletions remain key contributors, with new insights into their variable presentations and impact on sperm retrieval. Advanced discoveries in genes such as CFTR and ADGRG2 have reframed our approach to conditions like CBAVD, while epigenetic disruptions and mitochondrial DNA mutations are revealing previously unrecognized mechanisms behind impaired spermatogenesis and sperm motility. Rare copy number variations and genetic syndromes like Kallmann and Noonan further underscore the complex interplay between systemic disorders and male fertility. The field of genetic infertility is rapidly evolving, offering new insights into the molecular mechanisms behind impaired spermatogenesis and fertility. These findings highlight the importance of integrating genetic testing into infertility evaluations to guide personalized management strategies.

IntroductionMajor depressive disorder (MDD) is a severe psychiatric condition with a high risk of suicide. Research on MDD and suicidality has identified structural and functional abnormalities in the cortico-limbic network as candidate biomarkers, but little is known about the temporal dynamics of these brain regions. Recently, abnormal amygdala habituation to emotional stimuli has been highlighted as a reliable fMRI phenotype linked to emotional dysregulation and increased suicide risk.ObjectivesOur study aimed to assess amygdala habituation to emotional stimuli in MDD and explore differences between suicide attempters (SA) and non-attempters (nSA). Additionally, we examined the relationship between amygdala habituation and depressive symptoms.Methods414 MDD patients (239 SA, 175 nSA) selected from the UK Biobank underwent fMRI during a block-designed emotion processing task, including faces and shapes conditions. We obtained bilateral amygdala activation for each block using FSL. Habituation was quantified using two methods: the regression approach (REG) and First minus Last block (FmL). One sample T-tests were used to investigate whether habituation rates significantly differed from zero. Group differences were analysed using Mann-Whitney U-tests. Generalized linear models (GLM) were applied to examine relationships between habituation and depression severity, controlling for age, sex, group (SA vs. nSA), and handedness.ResultsIn both MDD and SA groups, no significant habituation was observed for either emotional or non-emotional stimuli (pFDR&gt;.05). However, the nSA group showed significantly positive habituation rates for left amygdala in both conditions and for right amygdala in faces condition using REG (pFDR&lt;.05), suggesting a possible sensitization process. Moreover, nSA showed significantly higher habituation rates than SA in all conditions with REG (pFDR&lt;.01). GLM analyses revealed no significant associations with depression severity.ConclusionsOur results suggest that MDD is characterized by a lack of amygdala habituation to emotional stimuli, potentially offering new insights into its pathophysiology. This biomarker may help in developing novel therapeutic strategies targeting the amygdala and its regulation within the cortico-limbic system.FundingsThe current study was supported by the Italian Ministry of Health, GR-2019-12370616.Disclosure of InterestNone Declared

Introduction The differential diagnosis between Major Depressive Disorder (MDD) and Bipolar Disorder (BD) heavily relies on clinical observation. However, the two disorders often show similar symptomatologic profiles, leading to high misdiagnosis rates. Reliable biomarkers are therefore crucial to accurately discriminate between MDD and BD and provide better treatments. In this regard, Machine Learning (ML) could represent a turning point in the field precision psychiatry, given its capability of making single-subject level predictions. Objectives In the present work, we aimed at providing a biomarker-based differential diagnosis between MDD and BD. To that end, we implemented: i) a structural MRI-based ML model; ii) a combined ML model, trained on MRI data and Polygenic Risk Scores (PRS) for different psychiatric disorders. Methods 168 depressed patients (73 MDD, 95 BD) were recruited at the IRCCS San Raffaele Scientific Institute. All patients underwent T1-weighted and Diffusion Tensor Imaging scans. Voxel-Based Morphometry (VBM) measures were extracted with Computational Anatomy Toolbox 12 (CAT12). Fractional Anisotropy (FA), Axial Diffusivity (AD), Mean Diffusivity (MD), and Radial Diffusivity (RD) were extracted with Tract-Based Spatial Statistics (TBSS). PRS for MDD, BD, Schizophrenia, Attention Deficit/Hyperactivity Disorder, Anorexia Nervosa and Autism were computed for a subsample of 155 patients (67 MDD; 88 BD) through Infinium PsychArray 24 BeadChip. We trained a Multiple Kernel Learning (MKL) algorithm with voxel-wise VBM and DTI features, subsequently combining them with the extracted PRS. Results The neuroimaging model achieved a Balanced Accuracy (BA) of 71.65% and an Area Under the Curve (AUC) of 0.77 (85.44% sensitivity, 57.86% specificity). All the features contributed to the prediction, with AD (63%) and MD (26%) as the most predictive. Adding PRS to neuroimaging resulted in an improved performance, reaching 74.18% BA and 0.77 AUC (90.97% sensitivity, 57.38% specificity). The most predictive features of the neuroimaging-PRS model were MD (56%) and AD (27%). Conclusions Structural MRI discriminated between MDD and BD, and adding PRS to neuroimaging features improved the performance of the ML model. These results highlight the predictive power of structural neuroimaging for the differential diagnosis between MDD and BD, as well as prompting multimodal classifiers as a promising tool in the context of precision psychiatry. Disclosure of Interest None Declared

Photonic crystal fibers offer a versatile fiber whose parameters, such as dispersion and nonlinearity, can be designed in great detail. As the position, configuration, and geometry of the complex air hole structure determine the fiber parameters, any associated deviations can impact the overall fiber performance. With a white light interferometry setup for a wavelength range from 930-1070 nm, the longitudinal variation in group velocity dispersion is measured for two different photonic crystal fibers with similar zero dispersion wavelengths and core sizes. The nonlinear pulse propagation of femtosecond pulses in the photonic crystal fibers is characterized and from the optical performance, nonlinear coefficients can be extracted based on numerical simulations. Experimental differences between forward and backward propagation directions are correlated to variations in fiber parameters along the draw distance.

Palliative care is underutilised in older people living with frailty, partly due to difficulties in identifying patients likely to be in the last year of their life. Dysphagia is a common problem in older people and a poor prognostic indicator associated with an increased risk of aspiration pneumonia, morbidity and mortality. Management of dysphagia includes modifying diet and fluids or electing to eat and drink with an acknowledgement of risk (EDAR). Patients are faced with making a difficult decision between enhancing their life quality, by eating and drinking as they choose, versus prolonging life but with potentially less enjoyment of their last weeks, months or years. This decision may be made easier if those patients at a higher risk of an aspiration-related death were identified. Currently there are fifteen known risk factors which can confound decision-making and don’t reflect functional wellbeing. The Clinical Frailty Score is an established frailty scale which incorporates these factors and may be a better prognostic guide.This retrospective study reviewed the electronic records of 230 patients eating and drinking at risk, comparing 15 risk factors with the Clinical Frailty Score. Mortality was monitored over eighteen months and an aspiration risk calculation was completed to establish if these risk factors had been relevant in outcome prediction.Although risk of aspiration pneumonia contributes to a poor prognosis, results from this study suggest that a more general assessment of wellbeing is required if we are to identify which patients are most likely to tolerate EDAR. The interim results suggest that the risk factors applied were too numerous to predict the likelihood of an aspiration-related death in older people. Most older people died shortly after commencing EDAR due to other co-morbidities including frailty. Furthermore the Clinical Frailty Score may be a better predictor of outcomes in patients with dysphagia.