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Background: Carotid artery stenting (CAS) using first-generation single-layer stents is widely accepted as a good alternative to standard carotid endarterectomy (CEA) but it is associated with worse outcomes in terms of both plaque prolapse and cerebral embolization. Aim: To evaluate the perioperative and midterm outcomes of CAS using the new-generation RoadsaverTM dual-layer micromesh-covered carotid stent. Methods: Herein, we present the results of an observational, retrospective, multicentric study on non-consecutive patients who underwent the CAS procedure between January 2017 and December 2022 at three Italian, high-volume vascular surgery centers. The inclusion criteria were the patients’ eligibility for the CAS procedure in accordance with the current Italian guidelines, and the implantation of a Roadsaver stent. Both symptomatic and asymptomatic patients were included in the study. The patients requiring reintervention for carotid restenosis following CEA were also included. Perioperative data regarding procedural success was defined as the successful implantation of the device in the desired position, less than 30% residual stenosis, and the absence of intraoperative neurological complications. The primary outcome was any adverse cerebrovascular event such as stroke or transient ischemic attack (TIA) during the procedure and/or after discharge. The secondary outcomes were the need for further intervention, and all-cause death following procedure. Results: Three-hundred-fifty-three (353) patients were included in our study; the mean age was 74.3 years. A total of 5.9% of the patients were symptomatic on their operated side, while 7.3% had contralateral carotid occlusion. A cerebral embolic protection device (CPD) was employed in all patients. A total of 13.3% of the patients were operated on for restenosis after CEA Technical success was achieved in 96.9% of the cases with an intraoperative report of six TIAs (1.7%) and six ipsilateral strokes (1.7%). The mean hospital stay was 1.8 days. The thirty-day follow up showed one TIA and one more stroke. At the mean 35-month follow-up time, the primary outcome was present in six patients (1.7%), where four TIAs (1.1%) and two strokes (0.5%) were reported. Restenosis occurred in five patients (1.4%). Death for any cause was reported in 11 patients (3.1%). Conclusions: As most recent, high-quality studies show, the CAS procedure with second-generation devices such as the Roadsaver stent is safe and effective in preventing carotid-related cerebrovascular events in both symptomatic and asymptomatic patients. The intraoperative and postoperative cerebrovascular complication rate in high volume centers is very low, ensuring confidence in its employment for the CAS procedure along with a CPD as a valid alternative to CEA.

Since December 2019, the novel coronavirus disease (COVID-19) has had a considerable impact on the health and socio-economic fabric of Italy. The effective reproduction number Rt is one of the most representative indicators of the contagion status as it reports the number of new infections caused by an infected subject in a partially immunized population. The task of predicting Rt values forward in time is challenging and, historically, it has been addressed by exploiting compartmental models or statistical frameworks. The present study proposes an Artificial Neural Networks-based approach to predict the Rt temporal trend at a daily resolution. For each Italian region and autonomous province, 21 daily COVID-19 indicators were exploited for the 7-day ahead prediction of the Rt trend by means of different neural network architectures, i.e., Feed Forward, Mono-Dimensional Convolutional, and Long Short-Term Memory. Focusing on Lombardy, which is one of the most affected regions, the predictions proved to be very accurate, with a minimum Root Mean Squared Error (RMSE) ranging from 0.035 at day t + 1 to 0.106 at day t + 7. Overall, the results show that it is possible to obtain accurate forecasts in Italy at a daily temporal resolution instead of the weekly resolution characterizing the official Rt data.

One of the most important open challenges in climate science is downscaling. It is a procedure that allows making predictions at local scales, starting from climatic field information available at large scale. Recent advances in deep learning provide new insights and modeling solutions to tackle downscaling-related tasks by automatically learning the coarse-to-fine grained resolution mapping. In particular, deep learning models designed for super-resolution problems in computer vision can be exploited because of the similarity between images and climatic fields maps. For this reason, a new architecture tailored for statistical downscaling (SD), named MSG-GAN-SD, has been developed, allowing interpretability and good stability during training, due to multi-scale gradient information. The proposed architecture, based on a Generative Adversarial Network (GAN), was applied to downscale ERA-Interim 2-m temperature fields, from 83.25 to 13.87 km resolution, covering the EURO-CORDEX domain within the 1979–2018 period. The training process involves seasonal and monthly dataset arrangements, in addition to different training strategies, leading to several models. Furthermore, a model selection framework is introduced in order to mathematically select the best models during the training. The selected models were then tested on the 2015–2018 period using several metrics to identify the best training strategy and dataset arrangement, which finally produced several evaluation maps. This work is the first attempt to use the MSG-GAN architecture for statistical downscaling. The achieved results demonstrate that the models trained on seasonal datasets performed better than those trained on monthly datasets. This study presents an accurate and cost-effective solution that is able to perform downscaling of 2 m temperature climatic maps.

Gastrointestinal patients, especially those diagnosed with functional digestive disorders (FGIDs), usually present a complex clinical picture that poses a challenge for their management in primary care. The main objective of the current research was to examine the relationship of the congruence of the perception of severity and quality of life between gastroenterologists and their patients with psychological distress and the helping attitude experienced by the latter attended in primary care centres. Additionally, we wanted to explore patients’ and practitioners’ perceptions. We performed a cross-sectional study with a total of 2261 patients (1562 analysed) that attended three primary care centres. Patients completed questionnaires that measured physical functioning, distress, and perception of helping attitude. Gastroenterologists registered the functional status of each participating patient. Patients were then invited to take part in the qualitative part of the study if they were considered to have incongruent views on their functioning with their gastroenterologist. In total, 52 patients took part in one of eight focus groups. Additionally, four individual interviews were carried out with three gastroenterologists and one consultation-liaison psychiatrist specialised in FGIDs. Both incongruence and functional diagnosis correlated with distress. However, incongruent views between patients and gastroenterologists explained more variance. Statistically significant differences in patients’ helping attitude perception were detected between diagnostic but no incongruence groups. In the second stage of the study, a total of five themes were identified from the patient focus groups and the gastroenterologist interviews: illness-emotional and personal problems, disease-health system interaction, health system, intervention, and patients. The current research allowed us to confirm that incongruence in the perception of severity and quality of life between gastroenterologists and patients is related to psychological distress and that this occurs in a multifactorial context where the characteristics of the disorder interact with those of the health system.

mitochondrial neuro-gastrointestinal encephalomyopathy (MNGIE) is a rare genetic disorder characterized by thymidine phosphorylase (TP) enzyme defect. The absence of TP activity induces the imbalance of mitochondrial nucleotide pool, leading to impaired mitochondrial DNA (mtDNA) replication and depletion. Since mtDNA is required to ensure oxidative phosphorylation, metabolically active tissues may not achieve sufficient energy production. The only effective life-saving approach in MNGIE has been the permanent replacement of TP via allogeneic hematopoietic stem cell or liver transplantation. However, the follow-up of transplanted patients showed that gut tissue changes do not revert and fatal complications, such as massive gastrointestinal bleeding, can occur. The purpose of this study was to clarify whether the reintroduction of TP after transplant can recover mtDNA copy number in a normal range. Using laser capture microdissection and droplet-digital-PCR, we assessed the mtDNA copy number in each layer of full-thickness ileal samples of a naive MNGIE cohort vs. controls and in a patient pre- and post-TP replacement. The treatment led to a significant recovery of gut tissue mtDNA amount, thus showing its efficacy. Our results indicate that a timely TP replacement is needed to maximize therapeutic success before irreversible degenerative tissue changes occur in MNGIE.

Compartmental models have long been used in epidemiological studies for predicting disease spread. However, a major issue when using compartmental mathematical models concerns the time-invariant formulation of hyper-parameters that prevent the model from following the evolution over time of the epidemiological phenomenon under investigation. In order to cope with this problem, the present work suggests an alternative hybrid approach based on Machine Learning that avoids recalculation of hyper-parameters and only uses an initial set. This study shows that the proposed hybrid approach makes it possible to correct the expected loss of accuracy observed in the compartmental model when the considered time horizon increases. As a case study, a basic compartmental model has been designed and tested to forecast COVID-19 hospitalizations during the first and the second pandemic waves in Lombardy, Italy. The model is based on an extended formulation of the contact function that allows modelling of the trend of personal contacts throughout the reference period. Moreover, the scenario analysis proposed in this work can help policy-makers select the most appropriate containment measures to reduce hospitalizations and relieve pressure on the health system, but also to limit any negative impact on the economic and social systems.

Background: The presence of mitochondrial alterations in Down syndrome suggests that it might affect neuronal differentiation. We established a model of trisomic iPSCs, differentiating into neural precursor cells (NPCs) to monitor the occurrence of differentiation defects and mitochondrial dysfunction. Methods: Isogenic trisomic and euploid iPSCs were differentiated into NPCs in monolayer cultures using the dual-SMAD inhibition protocol. Expression of pluripotency and neural differentiation genes was assessed by qRT-PCR and immunofluorescence. Meta-analysis of expression data was performed on iPSCs. Mitochondrial Ca2+, reactive oxygen species (ROS) and ATP production were investigated using fluorescent probes. Oxygen consumption rate (OCR) was determined by Seahorse Analyzer. Results: NPCs at day 7 of induction uniformly expressed the differentiation markers PAX6, SOX2 and NESTIN but not the stemness marker OCT4. At day 21, trisomic NPCs expressed higher levels of typical glial differentiation genes. Expression profiles indicated that mitochondrial genes were dysregulated in trisomic iPSCs. Trisomic NPCs showed altered mitochondrial Ca2+, reduced OCR and ATP synthesis, and elevated ROS production. Conclusions: Human trisomic iPSCs can be rapidly and efficiently differentiated into NPC monolayers. The trisomic NPCs obtained exhibit greater glial-like differentiation potential than their euploid counterparts and manifest mitochondrial dysfunction as early as day 7 of neuronal differentiation.

There is an unmet need for simplified in vitro models of malignancy and metastasis that facilitate fast, affordable and scalable gene and compound analysis. “Adherent” cancer cell lines frequently release “free-floating” cells into suspension that are viable and can reattach. This, in a simplistic way, mimics the metastatic process. We compared the gene expression profiles of naturally co-existing populations of floating and adherent cells in SW620 (colon), C33a (cervix) and HeLa (cervix) cancer cells. We found that 1227, 1367 and 1333 genes were at least 2-fold differentially expressed in the respective cell lines, of which 122 were shared among the three cell lines. As proof of principle, we focused on the anti-metastatic gene NM23-H1, which was downregulated both at the RNA and protein level in the floating cell populations of all three cell lines. Knockdown of NM23-H1 significantly increased the number of floating (and viable) cells, whereas overexpression of NM23-H1 significantly reduced the proportion of floating cells. Other potential regulators of these cellular states were identified through pathway analysis, including hypoxia, mTOR (mechanistic target of rapamycin), cell adhesion and cell polarity signal transduction pathways. Hypoxia, a condition linked to malignancy and metastasis, reduced NM23-H1 expression and significantly increased the number of free-floating cells. Inhibition of mTOR or Rho-associated protein kinase (ROCK) significantly increased cell death specifically in the floating and not the adherent cell population. In conclusion, our study suggests that dynamic subpopulations of free-floating and adherent cells is a useful model to screen and identify genes, drugs and pathways that regulate the process of cancer metastasis, such as cell detachment and anoikis.

Postprandial objective abdominal distention is frequently associated with a subjective sensation of abdominal bloating, but the relation between both complaints is unknown. While the bloating sensation has a visceral origin, abdominal distention is a behavioral somatic response, involving contraction and descent of the diaphragm with protrusion of the anterior abdominal wall. Our aim was to determine whether abdominal distention influences digestive sensations. In 16 healthy women we investigated the effect of intentional abdominal distention on experimentally induced bloating sensation (by a meal overload). Participants were first taught to produce diaphragmatic contraction and visible abdominal distention. After a meal overload, sensations of bloating (0 to 10) and digestive well-being (−5 to + 5) were measured during 30-s. maneuvers alternating diaphragmatic contraction and diaphragmatic relaxation. Compared to diaphragmatic relaxation, diaphragmatic contraction was associated with diaphragmatic descent (by 21 + 3 mm; p < 0.001), objective abdominal distension (32 + 5 mm girth increase; p = 0.001), more intense sensation of bloating (7.3 + 0.4 vs. 8.0 + 0.4 score; p = 0.010) and lower digestive well-being (−0.9 + 0.5 vs. −1.9 + 0.5 score; p = 0.028). These results indicate that somatic postural tone underlying abdominal distention worsens the perception of visceral sensations (ClinicalTrials.gov ID: NCT04691882).

The neural mechanisms underlying subjective responses to meal ingestion remain incompletely understood. We previously showed in healthy men an increase in thalamocortical, and a decrease in insular-cortical connectivity in response to a palatable meal. As sex is increasingly recognized as an important biological variable, we aimed to evaluate sex differences and commonalities in the impact of a well-liked meal on thalamic and anterior insular connectivity in healthy individuals. Participants (20 women and 20 age-matched men) underwent resting-state magnetic resonance imaging (rsMRI) before and after ingesting a palatable meal. In general, the insula showed extensive postprandial reductions in connectivity with sensorimotor and prefrontal cortices, while the thalamus showed increases in connectivity with insular, frontal, and occipital cortices, in both women and men. However, reductions in insular connectivity were more prominent in men, and were related to changes in meal-related sensations (satiety and digestive well-being) in men only. In contrast, increases in thalamic connectivity were more prominent in women, and were related to changes in satiety and digestive well-being in women only. These results suggest that brain imaging may provide objective and sex-specific biomarkers of the subjective feelings associated with meal ingestion.

Background: Healthy plant-based diets rich in fermentable residues may induce gas-related symptoms. Our aim was to determine the potential of a fermented milk product with probiotics in improving digestive comfort with such diets. Methods: In an open design, a 3-day high-residue diet was administered to healthy subjects (n = 74 included, n = 63 completed) before and following 28 days consumption of a fermented milk product (FMP) containing Bifidobacterium animalis subsp. lactis CNCM I-2494 and lactic acid bacteria. Main outcomes: digestive sensations, number of daytime anal gas evacuations, and gas volume evacuated during 4 h after a probe meal. Results: As compared to the habitual diet, the high-residue diet induced gas-related symptoms (flatulence score 4.9 vs. 1.2; p ≤ 0.0001), increased the daily number of anal gas evacuations (20.7 vs. 8.7; p < 0.0001), and impaired digestive well-being (1.0 vs. 3.4; p < 0.05). FMP consumption reduced flatulence sensation (by −1.7 [−1.9; −1.6]; p < 0.0001), reduced the number of daily evacuations (by −5.8 [−6.5; −5.1]; p < 0.0001), and improved digestive well-being (by +0.6 [+0.4; +0.7]; p < 0.05). FMP consumption did not affect the gas volume evacuated after a probe meal. Conclusion: In healthy subjects, consumption of a FMP containing B. lactis CNCM I-2494 and lactic acid bacteria improves the tolerance of a flatulogenic diet by subjective and objective criteria (sensations and number of anal gas evacuations, respectively).

In a previous study, we demonstrated that women enjoyed and tolerated lower meal loads than men. Hence, we hypothesized that with the same meal load, their postprandial response is more pronounced than in men. We performed a randomized parallel trial in 12 women and 12 men comparing the postprandial responses to a palatable comfort meal. We measured homeostatic sensations (hunger/satiety, fullness) and hedonic sensations (digestive well-being, mood) on 10 cm scales, vagal tone by heart ratio variability and the metabolomic profile before and after meal ingestion. Gender differences were analyzed by repeated measures ANCOVA. Overall (n = 24), ingestion of the probe meal induced satiation, fullness, digestive well-being and improved mood (main time-effect p ≤ 0.005 for all). Women exhibited a more intense sensory experience, specially more postprandial fullness, than men [main gender-effect F (1, 21) = 7.14; p = 0.014]; hedonic responses in women also tended to be stronger than in men. Women exhibited more pronounced effects on vagal tone [main gender-effect F (1, 21) = 5.5; p = 0.029] and a different lipoprotein response than men. In conclusion, our data indicate that gender influences the responses to meal ingestion, and these differences may explain the predisposition and higher incidence in women of meal-related functional disorders.

Ingestion of a meal induces conscious sensations depending of the characteristics of the meal and the predisposition of the eater. We hypothesized that the eating schedule plays a conditioning role, specifically, that an extemporaneous meal is less rewarding than when eaten at the habitual schedule. We conducted a randomized parallel trial in 10 women and 10 men comparing the responses to a consistent savoury lunch-type meal (stewed beans) eaten at the habitual afternoon schedule or at an unconventional time in the morning. Schedule and gender differences were analyzed by repeated measures analysis of covariance. In women, the sensory experience induced by the probe meal, particularly postprandial satisfaction, was weaker when eaten at an unconventional time for breakfast. Men were resilient to the schedule effect and experienced the same sensations regardless of the timing of ingestion; the effect of the eating schedule was significantly more pronounced in women for fullness (F(1,55) = 14.9; p < 0.001), digestive well-being (F(1,36.8) = 22.3; p < 0.001), mood (F(1,12.4) = 13.8; p < 0.001), and anxiety (F(1,11.9) = 10.9; p = 0.001). No differences in the physiological responses induced by the afternoon and morning meals were detected either in women or men. Our data indicate that women are more susceptible to changes in meal schedule than men.

Various conditioning factors influence the sensory response to a meal (inducible factors). We hypothesized that inherent characteristics of the eater (constitutive factors) also play a role. The aim of this proof-of-concept study was to determine the role of gender, as an individual constitutive factor, on the meal-related experience. Randomized parallel trial in 10 women and 10 men, comparing the sensations before, during, and after stepwise ingestion of a comfort meal up to full satiation. Comparisons were performed by repeated Analysis of Covariance (ANCOVA) measures. During stepwise ingestion, satisfaction initially increased up to a peak, and later decreased down to a nadir at the point of full satiation. Interestingly, the amount of food consumed at the well-being peak was lower, and induced significantly less fullness in women than in men. Hence, men required a larger meal load and stronger homeostatic sensations to achieve satisfaction. The same pattern was observed at the level of full satiation: men ate more and still experienced positive well-being, whereas in women, well-being scores dropped below pre-meal level. The effect of gender on the ingestion experience suggests that other constitutive factors of the eater may also influence responses to meals.