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Abstract Epilepsy affects 1% of the general population and 30% of patients are resistant to antiepileptic drugs. Although optogenetics is an efficient antiepileptic strategy, the difficulty of illuminating deep brain areas poses translational challenges. Thus, the search of alternative light sources is strongly needed. Here, we develop pH-sensitive inhibitory luminopsin (pHIL), a closed-loop chemo-optogenetic nanomachine composed of a luciferase-based light generator, a fluorescent sensor of intracellular pH (E2GFP), and an optogenetic actuator (halorhodopsin) for silencing neuronal activity. Stimulated by coelenterazine, pHIL experiences bioluminescence resonance energy transfer between luciferase and E2GFP which, under conditions of acidic pH, activates halorhodopsin. In primary neurons, pHIL senses the intracellular pH drop associated with hyperactivity and optogenetically aborts paroxysmal activity elicited by the administration of convulsants. The expression of pHIL in hippocampal pyramidal neurons is effective in decreasing duration and increasing latency of pilocarpine-induced tonic-clonic seizures upon in vivo coelenterazine administration, without affecting higher brain functions. The same treatment is effective in markedly decreasing seizure manifestations in a murine model of genetic epilepsy. The results indicate that pHIL represents a potentially promising closed-loop chemo-optogenetic strategy to treat drug-refractory epilepsy.

Abstract Hepatocellular carcinoma (HCC) incidence is continuously increasing worldwide, due to the rise of metabolic dysfunction-associated steatohepatitis (MASH) cases. Cholesterol is an essential driver of the metabolic dysregulations that promote HCC progression. Liver X Receptor (LXR) is a nuclear receptor best known for the regulation of lipid and cholesterol homeostasis, with a prominent function in the liver and in the intestine. Here, we aimed to explore whether modifications in intestinal lipid metabolism may contribute to the onset of HCC, particularly taking into account cholesterol metabolism and LXRs. To study the progression of MASH to HCC, we induced metabolic HCC in wild-type male mice and mice carrying an intestinal chronic activation of LXRα. Also, we analysed human hepatic transcriptome datasets. The increased consumption of fat and carbohydrates drives the intestinal activation of LXRα and accelerates the onset of the hepatic tumours. Chronic intestinal-specific activation of LXRα enhances HCC progression only in the presence of a high cholesterol intake. In HCC, despite the increased hepatic cholesterol content, LXR is not active, thus driving liver cancer development. Intriguingly, in line with these results in the mouse model, LXR transcriptome is also downregulated in human hepatocarcinoma and its expression level in liver tumours directly correlates with a decreased survival rate in patients. Overall, our findings establish the relevance of the intestine in influencing the susceptibility to MASH-HCC and point to intestinal LXRα activation as a driver of metabolic liver cancer in the presence of dietary cholesterol.

Abstract Background Metabolic dysfunction-associated steatotic liver disease (MASLD) is defined by the presence of hepatic steatosis, detected on ultrasonography (US) imaging or histology, and at least one of criteria for Metabolic Syndrome diagnosis. Simple non-invasive tests (NITs) have been proposed as an acceptable alternative when US and biopsy are not available or feasible but have not been validated for MASLD. In this observational study, we investigated the reliability of NITs for MASLD detection and whether sex-differences in screening methods should be considered. Methods We included 1069 individuals (48% males and 52% females) who underwent their first clinical examination for Metabolic Syndrome in the period between January 2015 and December 2022. Liver steatosis was detected through US and anthropometric and clinical parameters were recorded. Results Liver steatosis was detected in 648 patients and MASLD was diagnosed in 630 subjects (355 males; 275 females). Women with MASLD showed better metabolic profile and lower prevalence of Metabolic Syndrome criteria than men. Among NITs, Fatty Liver Index (FLI) showed the best ability for detection of MASLD, with a cut-off value of 44 (AUC = 0.82). When considering the two sexes for MASLD detection via FLI, despite no substantial differences regarding FLI correlations with metabolic biomarkers except for age, women showed marked lower FLI cut-off value (32; AUC = 0.80) than men (60; AUC = 0.80). Conclusions In this study, we found that FLI is the best non-invasive predictor of both liver steatosis and MASLD. The finding that in women FLI cut-off value for MASLD detection is 50% lower than in men suggests the need of a sex-specific personalized program of screening and prevention of dysmetabolism-related liver diseases, despite outwardly healthy biomarkers profile.

PurposeNo approved targeted therapy for the treatment of patients with neuroblastoma RAS viral (v-ras) oncogene homolog (NRAS)-mutant melanoma is currently available.Patients and methodsIn this phase Ib escalation/expansion study (ClinicalTrials.gov identifier: NCT02974725), the safety, tolerability, and preliminary antitumor activity of naporafenib (LXH254), a BRAF/CRAF protein kinases inhibitor, were explored in combination with trametinib in patients with advanced/metastatic KRAS- or BRAF-mutant non-small-cell lung cancer (escalation arm) or NRAS-mutant melanoma (escalation and expansion arms).ResultsThirty-six and 30 patients were enrolled in escalation and expansion, respectively. During escalation, six patients reported grade ≥3 dose-limiting toxicities, including dermatitis acneiform (n = 2), maculopapular rash (n = 2), increased lipase (n = 1), and Stevens-Johnson syndrome (n = 1). The recommended doses for expansion were naporafenib 200 mg twice a day plus trametinib 1 mg once daily and naporafenib 400 mg twice a day plus trametinib 0.5 mg once daily. During expansion, all 30 patients experienced a treatment-related adverse event, the most common being rash (80%, n = 24), blood creatine phosphokinase increased, diarrhea, and nausea (30%, n = 9 each). In expansion, the objective response rate, median duration of response, and median progression-free survival were 46.7% (95% CI, 21.3 to 73.4; 7 of 15 patients), 3.75 (95% CI, 1.97 to not estimable [NE]) months, and 5.52 months, respectively, in patients treated with naporafenib 200 mg twice a day plus trametinib 1 mg once daily, and 13.3% (95% CI, 1.7 to 40.5; 2 of 15 patients), 3.75 (95% CI, 2.04 to NE) months, and 4.21 months, respectively, in patients treated with naporafenib 400 mg twice a day plus trametinib 0.5 mg once daily.ConclusionNaporafenib plus trametinib showed promising preliminary antitumor activity in patients with NRAS-mutant melanoma. Prophylactic strategies aimed to lower the incidence of skin-related events are under investigation.

AimsThoracic aortic aneurysm (TAA) that progress to acute aortic dissection is often fatal and there is no pharmacological treatment that can reduce TAA progression. We aim to evaluate statins’ effects on TAA growth rate and outcomes using a meta-analysis approach.Methods and resultsA detailed search related to the effects of statins on TAA was conducted according to PRISMA guidelines. The analyses of statins’ effects on TAA growth rate were performed on 4 studies (n = 1850), while the impact on outcomes was evaluated on 3 studies (n = 2,867). Patients under statin treatment showed a reduced TAA growth rate (difference in means = −0.36 cm/year; 95%CI: −0.64, −0.08; p = 0.013) when compared to controls, patients not taking statins. Regarding the outcomes (death, dissection, or rupture of the aorta, and the need for operative repair), statins exhibited a protective effect reducing the number of events (log odds ratio = −0.56; 95%CI: −1.06, −0.05; p = 0.030). In vitro, the anti-fibrotic effect of atorvastatin was tested on vascular smooth muscle cells (VMSC) isolated from patients with TAA. Our results highlighted that, in transforming growth factor beta 1 (TGF-β1) pro-fibrotic condition, VSMC expressed a significant lower amount of collagen type I alpha 1 chain (COL1A1) when treated with atorvastatin (untreated = +2.66 ± 0.23 fold-change vs. treated = +1.63 ± 0.09 fold-change; p = 0.014).ConclusionStatins show a protective effect on TAA growth rate and adverse outcomes in patients with TAA, possibly via their anti-fibrotic properties on VSMC. Given the current lack of effective drug treatments for TAA, we believe our findings highlight the need for more in-depth research to explore the potential benefits of statins in this context.

Abstract Background Contrast-enhanced mammography (CEM) is a promising technique. We evaluated the diagnostic potential of CEM performed immediately after contrast-enhanced computed tomography (CE-CT). Methods Fifty patients with breast cancer underwent first CE-CT and then CEM without additional contrast material injection. Two independent radiologists evaluated CEM images. The sensitivity of CEM for detecting index and additional malignant lesions was compared with that of mammography/ultrasonography by the McNemar test, using histopathology as a reference standard. Interobserver agreement for detection of malignant lesions, for classifying index tumors, and for evaluating index tumor size and extent was assessed using Cohen κ. Pearson correlation was used for correlating index tumor size/extent at CEM or mammography/ultrasonography with histopathology. Results Of the 50 patients, 30 (60%) had unifocal disease while 20 (40%) had multicentric or multifocal disease; 5 of 20 patients with multicentric disease (25%) had bilateral involvement, for a total of 78 malignant lesions, including 72 (92%) invasive ductal and 6 (8%) invasive lobular carcinomas. Sensitivity was 63/78 (81%, 95% confidence interval 70.27–88.82) for unenhanced breast imaging and 78/78 (100%, 95.38–100) for CEM (p

Purpose: Report a case where the patient desired spectacle independence after phacoemulsification and Descemet membrane endothelial keratoplasty (DMEK) due to Fuchs’ endothelial dystrophy. Observations: A 52-year-old female presented with corrected distance visual acuity (CDVA) of 20/40 in both eyes with low ametropia. Slit lamp examination revealed corneal edema 1+/4+, guttae, and nuclear cataract 2+/4+ in both eyes. First, given the diagnostic suspicion of Fuchs’ endothelial corneal dystrophy and cataracts, phacoemulsification with monofocal toric intraocular lens (IOL) implantation combined with DMEK was performed in both eyes. Postoperatively, the patient was not satisfied with her near vision. Therefore, a supplementary trifocal sulcus IOL was implanted into the right eye. At 30 days postoperatively, the uncorrected distance visual acuity (UDVA) was 20/20 and the uncorrected near visual acuity (UCNVA) was J1, with clear cornea, centered IOL. Conclusions and importance: This is the first report of supplementary trifocal IOL implantation in a pseudophakic patient with a history of DMEK. This afforded spectacle-independence at all distances with high patient satisfaction. This procedure is safe, predictable, and reversible.

IntroductionBody image concerns related to breast cancer surgery may challenge patients’ quality of life and their treatment outcomes, thus representing a key aspect to be assessed in the psycho-oncological settings. The present longitudinal study is aimed to (1) investigate the association between preoperative body image and postoperative psychological symptoms in breast cancer patients; (2) explore the impact of pre−/post-surgery variation in body image on psychological symptomatology.MethodsN = 72 women undergoing breast cancer surgery were preoperatively screened (T1) using the Body Uneasiness Test (BUT) and were assessed postoperatively (T2) using the Symptom Checklist-90 Revised (SCL-90-R) and re-administered the BUT. Spearman’s correlation was used to investigate the relationship between age, preoperative body image and postoperative psychological symptoms, and variation in body image. To predict post-surgical psychological symptomatology, two separated multiple regression models were used to evaluate preoperative body image and its variation after surgery controlling for covariates (i.e., education; intervention type). P significance was set as 0.05 for all analyses and adjusted for multiple comparisons.ResultsAt T1, anxiety in relation to body image scores emerged as the most frequently experienced psychological symptomatology after surgery (all adjusted p 0.05). Pre-surgery body avoidance was significantly associated with post-intervention psychological symptoms (SOMβ = 0.453, p = 0.0001; DEPβ = 0.507, p = 0.0001; AXβ = 0.459, p = 0.0001; HOSβ = 0.410, p=. 0001). However, increased weight phobia between pre- and post-surgery was statistically associated with increased somatization, anxiety, depression and hostility at T2 (βSOM = 0.439, p = 0.0001; βDEP = 0.454, p = 0.0001; βANX = 0.471, p = 0.0001).DiscussionOverall, pre−/post-intervention body concerns were significantly associated with primary psychological symptoms in breast cancer patients undergoing surgery. Higher levels of body avoidance and weight phobia were significantly associated with the primary psychological dimensions assessed. As body concerns might act as quality-of-life predictors, their evaluation is crucial in fostering patients’ well-being and treatment adherence.

Abstract Neuropathic pain (NP) is a chronic pain disorder arising from somatosensory nervous system impairment. Extensive evidence supports the notion that the gut microbiota (GM) is crucial in maintaining human health by performing vital tasks. At the same time, its disruption has been linked to the emergence and advancement of an expanding range of disorders, including NP, in which GM could play a role in its pathophysiology. The crosstalk between the nervous system and GM happens through immune mediators, metabolites, and nervous structures and involves both central and peripheral nervous systems. This literature review aims to thoroughly investigate the function of modulating GM in the treatment of NP. It will achieve this by integrating existing knowledge, identifying underlying mechanisms, and evaluating the possible clinical consequences of exploiting the gut–brain axis. We will cover the main therapeutic applications of the described GM-modulators, such as probiotics, faecal microbiota transplantation, dietary supplements and emotional support, to the main kinds of NP in which any evidence, even if only pre-clinical, has been unravelled in recent years. The explored NP areas include chemotherapy-induced peripheral neuropathy, diabetic neuropathy, trauma-induced neuropathic pain, trigeminal neuralgia, postherpetic neuralgia and low back pain.

Abstract Optical stimulation and control of muscle cell contraction opens up a number of interesting applications in hybrid robotic and medicine. Here we show that recently designed molecular phototransducer can be used to stimulate C2C12 skeletal muscle cells, properly grown to exhibit collective behaviour. C2C12 is a skeletal muscle cell line that does not require animal sacrifice Furthermore, it is an ideal cell model for evaluating the phototransducer pacing ability due to its negligible spontaneous activity. We study the stimulation process and analyse the distribution of responses in multinuclear cells, in particular looking at the consistency between stimulus and contraction. Contractions are detected by using an imaging software for object recognition. We find a deterministic response to light stimuli, yet with a certain distribution of erratic behaviour that is quantified and correlated to light intensity or stimulation frequency. Finally, we compare our optical stimulation with electrical stimulation showing advantages of the optical approach, like the reduced cell stress.

Background: Fibro-calcific aortic valve disease (FCAVD) is a progressive disorder characterized by the thickening and calcification of the aortic valve, eventually leading to aortic stenosis. Adiponectin and leptin, known for their anti-inflammatory and proinflammatory properties, respectively, have been implicated in cardiovascular diseases, but their associations with FCAVD are controversial. This meta-analysis aims to evaluate the relationships between adiponectin and leptin levels and FCAVD, particularly in patients with severe aortic stenosis (AS). Methods: A systematic search was conducted across the PubMed, Scopus, and Web of Science databases to identify studies on adiponectin and leptin levels in FCAVD. The methodological quality of each study was assessed using the Newcastle–Ottawa Scale. Standardized mean differences (SMDs) and 95% confidence intervals (CIs) were calculated, and publication bias was evaluated using Egger’s test and funnel plots. Results: Out of 191 articles identified, 10 studies involving 2360 patients (989 with FCAVD and 1371 controls) were included. The analysis suggested trends in the associations of lower adiponectin levels (SMD = −0.143, 95% CI: −0.344, 0.057, p = 0.161) and higher leptin levels (SMD = 0.175, 95% CI: −0.045, 0.395, p = 0.119) with FCAVD. The association remained a trend for low adiponectin but showed a significant correlation with high leptin in severe AS patients (SMD = 0.29, 95% CI: 0.036, 0.543, p = 0.025). Conclusion: This meta-analysis indicates a potential association between elevated leptin levels and severe aortic stenosis, while the relationship with adiponectin levels remains inconclusive. These findings highlight the need for further and dedicated research to clarify the roles of these adipokines in the pathogenesis of FCAVD and their potential roles as biomarkers for disease progression.

Neurodegenerative disorders are the main cause of cognitive and physical disabilities, affect millions of people worldwide, and their incidence is on the rise. Emerging evidence pinpoints a disturbance of the communication of the gut–brain axis, and in particular to gut microbial dysbiosis, as one of the contributors to the pathogenesis of these diseases. In fact, dysbiosis has been associated with neuro-inflammatory processes, hyperactivation of the neuronal immune system, impaired cognitive functions, aging, depression, sleeping disorders, and anxiety. With the rapid advance in metagenomics, metabolomics, and big data analysis, together with a multidisciplinary approach, a new horizon has just emerged in the fields of translational neurodegenerative disease. In fact, recent studies focusing on taxonomic profiling and leaky gut in the pathogenesis of neurodegenerative disorders are not only shedding light on an overlooked field but are also creating opportunities for biomarker discovery and development of new therapeutic and adjuvant strategies to treat these disorders. Lactiplantibacillus plantarum (LBP) strains are emerging as promising psychobiotics for the treatment of these diseases. In fact, LBP strains are able to promote eubiosis, increase the enrichment of bacteria producing beneficial metabolites such as short-chain fatty acids, boost the production of neurotransmitters, and support the homeostasis of the gut–brain axis. In this review, we summarize the current knowledge on the role of the gut microbiota in the pathogenesis of neurodegenerative disorders with a particular focus on the benefits of LBP strains in Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, autism, anxiety, and depression.

Ovarian cancer (OC) is the most lethal gynaecologic malignancy, attributed to its insidious growth, non-specific symptoms and late presentation. Unfortunately, current screening modalities are inadequate at detecting OC and many lack the appropriate specificity and sensitivity that is desired from a screening test. Nearly 70% of cases are diagnosed at stage III or IV with poor 5-year overall survival. Therefore, the development of a sensitive and specific biomarker for early diagnosis and screening for OC is of utmost importance. Currently, diagnosis is guided by CA125, the patient’s menopausal status and imaging features on ultrasound scan. However, emerging evidence suggests that a combination of CA125 and HE4 (another serum biomarker) and patient characteristics in a multivariate index assay may provide a higher specificity and sensitivity than either CA125 and HE4 alone in the early detection of OC. Other attempts at combining various serum biomarkers into one multivariate index assay such as OVA1, ROMA and Overa have all shown promise. However, significant barriers exist before these biomarkers can be implemented in clinical practice. This article aims to provide an up-to-date review of potential biomarkers for screening and early diagnosis of OC which may have the potential to transform its diagnostic landscape.

Abstract Non-alcoholic fatty liver disease (NAFLD), specifically liver steatosis and fibrosis with steatohepatitis (NASH), is often associated with visceral adiposopathy, whose pathogenetic features have been proposed as tumorigenic triggers. We performed a prospective analysis in 653 metabolic women to reveal any conditions that may predict and concur to cancer development during a 8-years period of follow-up. Among clinical and biochemical variables, only AST and non-invasive liver fibrosis scores (AARPRI, APRI, FIB-4, mFIB4) significantly distinguished cancer-developer women (n = 62, 9.5%) from those who did not develop cancer (p

Abstract Dietary lipids can affect metabolic health through gut microbiota-mediated mechanisms, but the influence of lipid-microbiota interaction on liver steatosis is largely unknown. We investigate the impact of dietary lipids on human gut microbiota composition and the effects of microbiota-lipid interactions on steatosis in male mice. In humans, low intake of saturated fatty acids (SFA) is associated with increased microbial diversity independent of fiber intake. In mice, poorly absorbed dietary long-chain SFA, particularly stearic acid, induce a shift in bile acid profile and improved metabolism and steatosis. These benefits are dependent on the gut microbiota, as they are transmitted by microbial transfer. Diets enriched in polyunsaturated fatty acids are protective against steatosis but have minor influence on the microbiota. In summary, we find that diets enriched in poorly absorbed long-chain SFA modulate gut microbiota profiles independent of fiber intake, and this interaction is relevant to improve metabolism and decrease liver steatosis.

Recent years have ushered in a transformative era in in vitro modeling with the advent of organoids, three-dimensional structures derived from stem cells or patient tumor cells. Still, fully harnessing the potential of organoids requires advanced imaging technologies and analytical tools to quantitatively monitor organoid growth. Optical coherence tomography (OCT) is a promising imaging modality for organoid analysis due to its high-resolution, label-free, non-destructive, and real-time 3D imaging capabilities, but accurately identifying and quantifying organoids in OCT images remain challenging due to various factors. Here, we propose an automatic deep learning-based pipeline with convolutional neural networks that synergistically includes optimized preprocessing steps, the implementation of a state-of-the-art deep learning model, and ad-hoc postprocessing methods, showcasing good generalizability and tracking capabilities over an extended period of 13 days. The proposed tracking algorithm thoroughly documents organoid evolution, utilizing reference volumes, a dual branch analysis, key attribute evaluation, and probability scoring for match identification. The proposed comprehensive approach enables the accurate tracking of organoid growth and morphological changes over time, advancing organoid analysis and serving as a solid foundation for future studies for drug screening and tumor drug sensitivity detection based on organoids.

Despite the availability of vaccines and antivirals and the biological evolution of SARS-CoV-2, the rate of hospitalizations and deaths from COVID-19 remains high in Italy. It is crucial to understand whether and how the clinical characteristics of patients hospitalized for COVID-19 have changed over 2021–2022 and which risk factors are currently associated with adverse outcomes to develop targeted interventions. In this study, we present and compare the characteristics and outcomes of 310 patients with COVID-19 who were hospitalized between 1 August and 9 December 2021, when the Delta SARS-CoV-2 variant was prevalent (Group A), and between 3 January and 30 June 2022, when the Omicron variant was predominant (Group B). Using Survival Analysis, we estimated the cumulative 28-day hazard ratio (H.R.) of Intensive Care Unit (ICU) admission/death of patients in Group B vs. A. We built uni- and multivariate Cox regression models for the overall population and each group to identify risk factors for ICU admission/death among patient features. We found that Group B had a comparable risk of ICU admission/death (HR 1.60, 95% Confidence Interval, C.I. 1.00–2.58, p = 0.05) but a higher prevalence of elderly and co-morbid subjects than Group A. Non-invasive ventilation requirement was associated with adverse outcomes in both Group A (HR 21.03, 95% C.I. 5.34–82.80, p < 0.001) and Group B (HR 4.53, 95% C.I. 2.39–8.59, p < 0.001), as well as in the overall population (HR 3.88, 95% C.I. 2.49–6.06, p < 0.001). During the Omicron wave, elderly and co-morbid subjects had the highest risk of hospitalization and poor outcomes.

Background & Aims: The gut–liver axis modulates the progression of metabolic dysfunction-associated steatotic liver disease (MASLD), a spectrum of conditions characterised by hepatic steatosis and a progressive increase of inflammation and fibrosis, culminating in metabolic dysfunction-associated steatohepatitis. Peroxisome proliferator-activated receptor-gamma coactivator 1α (Pgc1α) is a transcriptional co-regulator of mitochondrial activity and lipid metabolism. Here, the intestinal-specific role of Pgc1α was analysed in liver steatosis and fibrosis. Methods: We used a mouse model in which Pgc1α was selectively deleted from the intestinal epithelium. We fed these mice and their wild-type littermates a Western diet to recapitulate the major features of liver steatosis (after 2 months of diet) and metabolic dysfunction-associated steatohepatitis (after 4 months of diet). The chow diet was administered as a control diet. Results: In humans and mice, low expression of intestinal Pgc1α is inversely associated with liver steatosis, inflammation, and fibrosis. Intestinal disruption of Pgc1α impairs the transcription of a wide number of genes, including the cholesterol transporter Niemann–Pick C1-like 1 (Npc1l1), thus limiting the uptake of cholesterol from the gut. This results in a lower cholesterol accretion in the liver and a decreased production of new fatty acids, which protect the liver from lipotoxic lipid species accumulation, inflammation, and related fibrotic processes. Conclusions: In humans and mice, intestinal Pgc1α induction during Western diet may be another culprit driving hepatic steatosis and fibrosis. Here, we show that enterocyte-specific Pgc1α ablation protects the liver from steatosis and fibrosis by reducing intestinal cholesterol absorption, with subsequent decrease of cholesterol and de novo fatty acid accumulation in the liver. Impact and implications: Liver diseases result from several insults, including signals from the gut. Although the incidence of liver diseases is continuously increasing worldwide, effective drug therapy is still lacking. Here, we showed that the modulation of an intestinal coactivator regulates the liver response to a Western diet, by limiting the uptake of dietary cholesterol. This results in a lower accumulation of hepatic lipids together with decreased inflammation and fibrosis, thus limiting the progression of liver steatosis and fibrosis towards severe end-stage diseases.

Two (consecutive) reductions of the complete Gatenby–Gawlinski model for cancer invasion are proposed in order to investigate the mathematical framework, mainly from a computational perspective. After a brief overview of the full model, we proceed by examining the case of a two-equations-based and one-equation-based reduction, both obtained by means of a quasi-steady-state assumption. We focus on invasion fronts, exploiting a numerical strategy based on a finite volume approximation, and perform corresponding computational simulations to study the sharpness/smoothness of the traveling waves. Then, we employ a space-averaged wave speed estimate—referred to as the LeVeque–Yee formula—to quantitatively approach the propagation phenomenon. Concerning the one-equation-based model, we propose a scalar degenerate reaction-diffusion equation, which proves to be effective in order to qualitatively recover the typical trends arising from the Gatenby–Gawlinski model. Finally, we carry out some numerical tests in a specific case where the analytical solution is available.

The rapid growth of drone use in urban areas has prompted authorities to review airspace regulations, forcing drone manufacturers to anticipate and reduce the noise emissions during the design stage. Additionally, micro air vehicles (MAVs) are designed to be aerodynamically efficient, allowing them to fly farther, longer and safer. In this study, a steady aerodynamic code and an acoustic propagator based on the non-linear vortex lattice method (NVLM) and Farassat’s formulation-1A of the Ffowcs Williams and Hawkings (FW-H) acoustic analogy, respectively, are coupled with pymoo, a python-based optimization framework. This tool is used to perform a multi-objective (noise and aerodynamic efficiency) optimization of a 20 cm diameter two-bladed rotor under hovering conditions. From the set of optimized results, (i.e., the Pareto front), three different rotors are 3D-printed using a stereolithography (SLA) technique and tested in an anechoic room. Here, an array of far-field microphones captures the acoustic radiation and directivity of the rotor, while a balance measures the aerodynamic performance. Both the aerodynamic and aeroacoustic performance of the three different rotors, in line with what has been predicted by the numerical codes, are compared and guidelines for the design of aerodynamically and aeroacoustically efficient MAV rotors are extracted.

Background. Gastrointestinal (GI) cancers are one of the most relevant causes of death globally, frequently associated with poor dietary patterns. The Mediterranean Diet (MedDiet) contributes to cancer prevention. To assess adherence to MedDiet, our research group validated a new score, the Chrono Med Diet Score (CMDS), that captures increased visceral adiposity. Methods. We enrolled 401 subjects who underwent an evaluation for metabolic diseases and specific screening procedures according to current guidelines and were asked to answer CMDS. A total of 71 new cancer cases were recorded, including 40 GI and 31 non-gastrointestinal (NON-GI) cancers. Results. We found that CMDS was reduced in subjects who were diagnosed with cancers. Patients who reported a CMDS score of 12 or less had an over three times increased risk of being diagnosed with GI cancers and presented increased waist circumference and triglycerides and reduced HDL cholesterol compared to adherent subjects. Conclusions. Low CMDS values capture the risk for cancer diagnosis, especially for GI cancers. Thus, CMDS, along with waist circumference, can be considered as a bona fide marker for increased risk of cancer, requiring anticipated screening procedures for the detection of premalignant and early stage GI cancers in patients with low adherence to MedDiet.

IntroductionThyroid cancer incidence is increasing, and adiposity-related conditions are gaining space in its pathogenesis. In this study, we aimed to detect any anthropometric, biohumoral, and clinical features that might be associated with thyroid nodule malignancy, potentially representing novel non-invasive markers of thyroid cancer.Materials and methodsThe study was conducted in a group of 142 consecutive outpatients (47 men and 95 women) who underwent fine-needle aspiration biopsy/cytology (FNAB/C) due to suspicion of malignancy from January 2018 to September 2022. We compared lipid and glycemic blood profiles as well as non-invasive liver fibrosis indexes such as aspartate aminotransferase (AST) to alanine aminotransferase (ALT) ratio (AAR), AST to platelet ratio index (APRI), and fibrosis index based on four factors (FIB-4) between patients with benign and malignant newly diagnosed nodules. Then, we performed receiver operating characteristic (ROC) analysis to assess their best cutoff values for discrimination of malignant nodules and chi-squared test to evaluate the association of specific dysmetabolic conditions with malignancy. To understand whether and to what degree dysmetabolic conditions increased the risk of thyroid nodule malignancy, we also calculated the odds ratio (OR) of the main biomarkers.ResultsAfter FNAB/C, 121 (85%) patients were diagnosed with benign thyroid nodules, while 21 (15%) individuals were diagnosed with thyroid cancer. Comparing patients with benign and malignant nodules, we found that individuals with thyroid cancer exhibited increased body mass index (BMI) (p = 0.048) and fasting plasma glucose (p = 0.046). Intriguingly, considering non-invasive scores for liver fibrosis, subjects with thyroid cancer presented increased AAR (p < 0.001) and APRI (p = 0.007), and these scores were associated with malignancy (p < 0.005) with OR = 7.1 and OR = 5, respectively. Moreover, we showed that only in the cancer group, low levels of vitamin D correlated with stigmata of impaired metabolism.DiscussionIn our study, AAR and APRI scores were associated with thyroid nodule malignancy and could be used to predict it and to speed up the diagnostic process. From a pathogenic point of view, we speculated that metabolic-associated fatty liver disease (MAFLD) along with hyperglycemia and vitamin D deficiency may represent putative drivers of thyroid carcinogenesis.

It is known that inflammation worsen the course of schizophrenia and induce high clozapine serum levels. However, no study evaluated this change in function of clozapine daily dose in schizophrenia. We assessed the correlation between inflammation and severity symptoms in patients with schizophrenia that take and do not take clozapine. We also assessed the correlation between clozapine daily dose and inflammatory markers to patients who take this drug. Patients were recruited from Schizophrenia Ambulatory and Psychosocial Care Center of Clinical Hospital of Porto Alegre and from an association of relatives of patients with schizophrenia. Exam results, and other important clinical exam were assessed in patients record or patients were asked to show their exam in the case of outpatients. We included 104 patients, 90 clozapine users and 14 non-clozapine users. We calculate the systemic inflammatory markers [neutrophil-lymphocyte ratio (NLR), systemic immune inflammation index (SII), and the psychopathology severity by the Brief Psychiatric Rating Scaled anchored (BPRS-a)]. These variables were compared between clozapine users and non-clozapine users. It was used mean/median test according to data distributing, with study factor (SII, MLR, and PLR), the clinical outcome: severity of symptomatology (BPRS score), and clozapine daily dose as adjustment factor. Clozapine users exhibited a significantly higher neutrophil count (mean ± SD: 5.03 ± 2.07) compared to non-clozapine users (mean ± SD: 3.48 ± 1.27; p = 0.031). After controlling for comorbidity, other parameters also showed significant differences. These findings are consistent with previous studies that have demonstrated an inflammatory response following the administration of clozapine.

Abstract Background Epicardial adipose tissue (EAT) plays an important role in cardiometabolic risk. EAT is a modifiable risk factor and could be a potential therapeutic target for drugs that already show cardiovascular benefits. The aim of this study is to evaluate the effect of cardiometabolic drugs on EAT reduction. Methods A detailed search related to the effect on EAT reduction due to cardiometabolic drugs, such as glucagon-like peptide-1 receptor agonist (GLP-1 RA), sodium-glucose cotransporter-2 inhibitors (SGLT2-i), and statins was conducted according to PRISMA guidelines. Eighteen studies enrolling 1064 patients were included in the qualitative and quantitative analyses. Results All three analyzed drug classes, in particular GLP-1 RA, show a significant effect on EAT reduction (GLP-1 RA standardize mean difference (SMD) = − 1.005; p

Abstract Critically ill patients undergo early impairment of their gut microbiota (GM) due to routine antibiotic therapies and other environmental factors leading to intestinal dysbiosis. The GM establishes connections with the rest of the human body along several axes representing critical inter-organ crosstalks that, once disrupted, play a major role in the pathophysiology of numerous diseases and their complications. Key players in this communication are GM metabolites such as short-chain fatty acids and bile acids, neurotransmitters, hormones, interleukins, and toxins. Intensivists juggle at the crossroad of multiple connections between the intestine and the rest of the body. Harnessing the GM in ICU could improve the management of several challenges, such as infections, traumatic brain injury, heart failure, kidney injury, and liver dysfunction. The study of molecular pathways affected by the GM in different clinical conditions is still at an early stage, and evidence in critically ill patients is lacking. This review aims to describe dysbiosis in critical illness and provide intensivists with a perspective on the potential as adjuvant strategies (e.g., nutrition, probiotics, prebiotics and synbiotics supplementation, adsorbent charcoal, beta-lactamase, and fecal microbiota transplantation) to modulate the GM in ICU patients and attempt to restore eubiosis.

Abstract Nonalcoholic fatty liver disease (NAFLD) is defined by a set of hepatic conditions ranging from steatosis to steatohepatitis (NASH), characterized by inflammation and fibrosis, eventually predisposing to hepatocellular carcinoma (HCC). Together with fatty acids (FAs) originated from adipose lipolysis and hepatic lipogenesis, intestinal‐derived FAs are major contributors of steatosis. However, the role of mono‐unsaturated FAs (MUFAs) in NAFLD development is still debated. We previously established the intestinal capacity to produce MUFAs, but its consequences in hepatic functions are still unknown. Here, we aimed to determine the role of the intestinal MUFA‐synthetizing enzyme stearoyl‐CoA desaturase 1 (SCD1) in NAFLD. We used intestinal‐specific Scd1‐KO (iScd1−/−) mice and studied hepatic dysfunction in different models of steatosis, NASH, and HCC. Intestinal‐specific Scd1 deletion decreased hepatic MUFA proportion. Compared with controls, iScd1−/− mice displayed increased hepatic triglyceride accumulation and derangement in cholesterol homeostasis when fed a MUFA‐deprived diet. Then, on Western diet feeding, iScd1−/− mice triggered inflammation and fibrosis compared with their wild‐type littermates. Finally, intestinal‐Scd1 deletion predisposed mice to liver cancer. Conclusions: Collectively, these results highlight the major importance of intestinal MUFA metabolism in maintaining hepatic functions and show that gut‐derived MUFAs are protective from NASH and HCC.

ObjectiveIncreased Fibroblast Growth Factor-21 (FGF-21) circulating levels have been described in obesity. In this observational study, we analysed a group of subjects with metabolic disorders to unravel the putative link between visceral adiposity and FGF-21 serum levels.MethodsTotal and intact serum FGF-21 concentration was measured with an ELISA assay respectively in 51 and 46 subjects, comparing FGF-21 levels in dysmetabolic conditions. We also tested Spearman’s correlations between FGF-21 serum levels and biochemical and clinical metabolic parameters.ResultsFGF-21 was not significantly increased in high-risk conditions such as visceral obesity, Metabolic Syndrome, diabetes, smoking, and atherosclerosis. Waist Circumference (WC), but not BMI, positively correlated with total FGF-21 levels (r=0.31, p