Search

Abstract Atrial fibrillation (AF) is more common in patients with malignancies than in general population. The pathophysiological processes include the pro-inflammatory condition and the exaggerated inflammatory reaction to chemotherapy, radiotherapy, and surgery interventions. Thus, it is pivotal to decrease morbidity and mortality in this group by providing appropriate care and prevention. In this subset, the risk of thromboembolic and bleeding events is high and the common risk score such as CHA2DS2-VASc and HAS-BLED employed in non-oncologic patients have limited evidence in cancer patients. A paucity of evidence in the setting in individuals having both malignancies and atrial fibrillation entangle the clinician when it comes to therapeutic management. Tailored management is recommended of anticoagulation treatment could be difficult, and there is. In this review, we try to explain the mechanism of AF in cancer patients as well as its management in this setting.

Abstract Extracellular vesicles (EVs) are promising natural nanocarriers for the delivery of therapeutic agents. As with any other kind of cell, red blood cells (RBCs) produce a limited number of EVs under physiological and pathological conditions. Thus, RBC-derived extracellular vesicles (RBCEVs) have been recently suggested as next-generation delivery systems for therapeutic purposes. In this paper, we show that thanks to their unique biological and physicochemical features, RBCs can be efficiently pre-loaded with several kinds of molecules and further used to generate RBCEVs. A physical vesiculation method, based on “soft extrusion”, was developed, producing an extremely high yield of cargo-loaded RBCEV mimetics. The RBCEVs population has been deeply characterized according to the new guidelines MISEV2023, showing great homogeneity in terms of size, biological features, membrane architecture and cargo. In vitro preliminary results demonstrated that RBCEVs are abundantly internalized by cells and exert peculiar biological effects. Indeed, efficient loading and delivery of miR-210 by RBCEVs to HUVEC has been proven, as well as the inhibition of a known mRNA target. Of note, the bench-scale process can be scaled-up and translated into clinics. In conclusion, this investigation could open the way to a new biomimetic platform for RNA-based therapies and/or other therapeutic cargoes useful in several diseases.

BackgroundSarcopenia, characterized by muscle mass, strength, and performance decline, significantly impacts outcomes in older adults. This study aims to assess the predictive value of calf circumference (CC), in conjunction with SARC-F and hand grip, concerning in-hospital complications and post-discharge mortality among hospitalized frail older adults.MethodsA cohort of 158 hospitalized patients aged over 65 years underwent Comprehensive Geriatric Assessment and sarcopenia screening, including CC measurement. Multivariable regression analyses, adjusted for confounders, were conducted to assess predictive associations.ResultsThe study cohort, comprising 53% males with a median age of 86 years, exhibited significant sarcopenia prevalence based on SARC-F (85% indicating sarcopenia), hand grip strength (probable sarcopenia in 77% of males and 72% of females), and CC (sarcopenia in 83%). Multivariate analysis, adjusting for age, sex, Clinical Frailty Scale (CFS), and Mini Nutritional Assessment-Short Form (MNA-SF), demonstrated associations of CC and SARC-F with in-hospital complications, while CC also showed a significant association with reduced risks of in-hospital mortality (OR 0.441, 95% CI 0.257 to 0.754, p = 0.003) and 90-day mortality (OR 0.714, 95% CI 0.516 to 0.988, p = 0.043).ConclusionThis study provides insights into the predictive accuracy of sarcopenia screening tools on mortality in real-world hospitalized older adults with frailty. Notably, CC emerges as a robust predictor of mortality outcomes. Further research is warranted to validate and elucidate the respective contributions of CC and frailty to mortality in vulnerable populations.

Conventional T1- and T2-weighted magnetic resonance imaging (MRI) of the pancreas can vary significantly due to factors such as scanner differences and pulse sequence variations. This review explores T1 and T2 mapping techniques, modern MRI methods providing quantitative information about tissue relaxation times. Various T1 and T2 mapping pulse sequences are currently under investigation. Clinical and research applications of T1 and T2 mapping in the pancreas include their correlation with fibrosis, inflammation, and neoplasms. In chronic pancreatitis, T1 mapping and extracellular volume (ECV) quantification demonstrate potential as biomarkers, aiding in early diagnosis and classification. T1 mapping also shows promise in evaluating pancreatic exocrine function and detecting glucose metabolism disorders. T2* mapping is valuable in quantifying pancreatic iron, offering insights into conditions like thalassemia major. However, challenges persist, such as the lack of consensus on optimal sequences and normal values for healthy pancreas relaxometry. Large-scale studies are needed for validation, and improvements in mapping sequences are essential for widespread clinical integration. The future holds potential for mixed qualitative and quantitative models, extending the applications of relaxometry techniques to various pancreatic lesions and enhancing routine MRI protocols for pancreatic pathology diagnosis and prognosis.

Mammalian sperm motility is getting more relevant due to rising infertility rates worldwide, generating the need to improve conventional analysis and diagnostic approaches. Nowadays, computer assisted sperm analysis (CASA) technologies represent a popular alternative to manual examination which is generally performed by observing sperm motility in very confined geometries. However, under physiological conditions, sperm describe three-dimensional motility patterns which are not well reconstructed by the limited depth of standard acquisition chambers. Therefore, affordable and more versatile alternatives are needed. Here, a motility analysis in unconfined conditions is proposed. In details, the analysis is characterized by a significant longer duration -with respect to conventional systems- with the aim to observe eventually altered motility patterns. Brightfield acquisition in rectangular glass capillaries captured frozen–thawed bovine spermatozoa which were analyzed by means of a self-written tracking routine and classified in sub-populations, based on their curvilinear velocity. To test the versatility of our approach, cypermethrin -a commonly used pesticides- known to be responsible for changes in sperm motility was employed, assessing its effect at three different time-steps. Experimental results showed that such drug induces an increase in sperm velocity and progressiveness as well as circular pattern formation, likely independent of wall interactions. Moreover, this resulted in a redistribution of sperm with the rapid class declining in number with time, but still showing an overall velocity increase. The flexibility of the approach permits parameter modifications with the experimental needs, allowing us to conduct a comprehensive examination of sperm motility. This adaptability facilitated data acquisition which can be computed at different frame rates, extended time periods, and within deeper observation chambers. The suggested approach for sperm analysis exhibits potential as a valuable augmentation to current diagnostic instruments.

Background. Lower extremity peripheral artery disease (LEPAD) frequently coexists with coronary artery disease (CAD) in patients with multisite vascular disease (MVD). While percutaneous revascularization is well-established for both LEPAD and CAD, limited evidence exists for patients eligible for both procedures. Specifically, the feasibility of concomitant LEPAD and CAD percutaneous revascularization remains unknown. Objectives. To compare the efficacy and safety of concomitant coronary and lower extremity elective percutaneous revascularization. Methods. Between 2012 and 2021, we included 135 patients in an observational, retrospective single-center registry. The population was stratified into two groups: 45 patients (concomitant group) underwent simultaneous coronary and peripheral percutaneous interventions, and 90 patients (deferred group) underwent two separate procedures within one year. The primary efficacy endpoint was major adverse cardiovascular events (MACE) at one year, while the primary safety endpoint was in-hospital contrast-induced nephropathy (CIN). Results. Study groups were well-balanced in baseline characteristics. In terms of coronary features, the concomitant revascularization group more often underwent single-vessel percutaneous coronary intervention (PCI), while the deferred group had multivessel PCI with diffuse coronary disease. No differences were detected in the number of LEPAD lesions between groups. For the primary efficacy endpoint, the incidence of MACE at one year was 37.8% in the concomitant group vs. 34.4% in the deferred group (HR 1.20, 95% CI 0.64–2.10; p = 0.61). No significant differences were found in CIN occurrence between the concomitant and deferred groups (11.1% vs. 8.9%; OR 1.30; 95% CI 0.36–4.21; p = 0.68). Conclusions. Multisite vascular disease patients eligible for CAD and LEPAD percutaneous revascularization exhibited a high cardiovascular risk profile with diffuse multivessel coronary and lower extremity disease. Our study suggests the efficacy and safety of concomitant coronary and lower extremity percutaneous revascularization based on one-year MACE incidence and in-hospital CIN. However, dedicated studies are warranted to confirm the short- and long-term outcomes of the concomitant revascularization strategy.

The yeast Saccharomyces cerevisiae ensures successful fermentation in winemaking, although the persistent use of commercial strains lead to the loss of aroma complexity of wines. Hence, the research of indigenous S. cerevisiae with proper oenological features and well adapted to specific wine-growing areas become of great interest for winemakers. Here, 206 pure cultures of S. cerevisiae were isolated from two wineries during a two-year sampling campaign and bio-typed through interdelta sequences analyses with the aim to evaluate the occurrence and persistence of the S. cerevisiae wild population linked to each winery. Both wineries belong to the same Verdicchio DOC wine area (Castelli di Jesi), and never used commercial yeasts during fermentation. Results showed 19 different biotypes with a specific population of S. cerevisiae in each winery, without cross-contamination with each other and with commercial starter strains. Moreover, inside each winery a persistence of some dominant biotypes was observed over time (three biotypes in winery 1; 95% of isolates in the two years and one biotype in winery 2; 20% of isolates in the two years), indicating a sort of “winery-effect”. The evaluation of S. cerevisiae populations for the oenological characters by microfermentations showed a proper and well distinct aromatic imprinting on the resulted wines supporting the concept of “winery effect”.

Plastic pollution and the reduction in synthetic food additives are demands that emerge from consumers, leading to the development of biodegradable plastic materials. The use of essential oils—EOs—has been researched because it is a natural product with antioxidant properties. Due to its nature, EO is composed of volatile compounds that can be lost during extrusion. The aim of this work was to produce active biodegradable starch/PBAT films with the incorporation of neat Eucalyptus citriodora EO (0.5, 1.0, and 1.5%) or EO microencapsulated by spray drying (2.5, 5.0, and 7.5%), aiming at the protection of the EO. The produced films showed adequate mechanical properties (tensile strength ranged from 5.72 to 7.54 MPa and the elongation at break ranged from 319 to 563%). Testing in food simulants showed that the films retained antioxidant activity, being more suitable for use in fatty or non-acid foods, with the microencapsulation process offering protection to the EO during the process.

Summary: Background: Major depressive disorder (MDD) is prevalent and disabling among older adults. Standing on its tolerability profile, vortioxetine might be a promising alternative to selective serotonin reuptake inhibitors (SSRIs) in such a vulnerable population. Methods: We conducted a randomised, assessor- and statistician-blinded, superiority trial including older adults with MDD. The study was conducted between 02/02/2019 and 02/22/2023 in 11 Italian Psychiatric Services. Participants were randomised to vortioxetine or one of the SSRIs, selected according to common practice. Treatment discontinuation due to adverse events after six months was the primary outcome, for which we aimed to detect a 12% difference in favour of vortioxetine. The study was registered in the online repository clinicaltrials.gov (NCT03779789). Findings: The intention-to-treat population included 179 individuals randomised to vortioxetine and 178 to SSRIs. Mean age was 73.7 years (standard deviation 6.1), and 264 participants (69%) were female. Of those on vortioxetine, 78 (44%) discontinued the treatment due to adverse events at six months, compared to 59 (33%) of those on SSRIs (odds ratio 1.56; 95% confidence interval 1.01–2.39). Adjusted and per-protocol analyses confirmed point estimates in favour of SSRIs, but without a significant difference. With the exception of the unadjusted survival analysis showing SSRIs to outperform vortioxetine, secondary outcomes provided results consistent with a lack of substantial safety and tolerability differences between the two arms. Overall, no significant differences emerged in terms of response rates, depressive symptoms and quality of life, while SSRIs outperformed vortioxetine in terms of cognitive performance. Interpretation: As opposed to what was previously hypothesised, vortioxetine did not show a better tolerability profile compared to SSRIs in older adults with MDD in this study. Additionally, hypothetical advantages of vortioxetine on depression-related cognitive symptoms might be questioned. The study's statistical power and highly pragmatic design allow for generalisability to real-world practice. Funding: The study was funded by the Italian Medicines Agency within the “2016 Call for Independent Drug Research”.

Abstract Gut microbiota is an emerging editable cardiovascular risk factor. We aim to investigate gut and coronary plaque microbiota, using fecal samples and angioplasty balloons from patients with acute coronary syndrome (ACS), chronic coronary syndrome (CCS) and control subjects. We examined bacterial communities in gut and coronary plaques by 16S rRNA sequencing and we performed droplet digital PCR analysis to investigate the gut relative abundance of the bacterial genes CutC/CntA involved in trimethylamine N-oxide synthesis. Linear discriminant analysis effect size (LEfSe) at the genus and species levels displayed gut enrichment in Streptococcus, Granulicatella and P. distasonis in ACS compared with CCS and controls; Roseburia, C. aerofaciens and F. prausnitzii were more abundant in controls than in patients. Principal component analysis (PCA) of 41 differentially abundant gut taxa showed a clustering of the three groups. In coronary plaque, LEfSe at the genus level revealed an enrichment of Staphylococcus and Streptococcus in ACS, and Paracoccus in CCS, whereas PCA of 15 differentially abundant plaque taxa exhibited clustering of ACS and CCS patients. CutC and CntA genes were more abundant in ACS and CCS than in controls while no significant difference emerged between ACS and CCS. Our results indicate that ACS and CCS exhibit a different gut and plaque microbial signature, suggesting a possible role of these microbiotas in coronary plaque instability.

Abstract Background Recombinant MVAs (rMVAs) are widely used both in basic and clinical research. Our previously developed Red-to-Green Gene Swapping Method (RGGSM), a cytometry-based Cell-Sorting protocol, revolves around the transient expression of a green fluorescent cytoplasmic marker, to subsequently obtain purified untagged rMVA upon loss of that marker by site-specific recombination. The standard RGSSM is quite costly in terms of bench work, reagents, and Sorting Facility fees. Although faster than other methods to obtain recombinant MVAs, the standard RGSSM still is time-consuming, taking at least 25 days to yield the final product. Methods The direct sorting of fluorescent virions is made amenable by the marker HAG, a flu hemagglutinin/EGFP fusion protein, integrated into the external envelope of extracellular enveloped virions (EEVs). Fluorescent EEVs-containing supernatants of infected cultures are used instead of purified virus. Direct Virus-Sorting was performed on BD FACSAria Fusion cell sorter equipped with 4 lasers and a 100-mm nozzle, with 20 psi pressure and a minimal flow rate, validated using Megamix beads. Results Upon infection of cells with recombinant EEVs, at the first sorting step virions that contain HAG are harvested and cloned, while the second sorting step yields EEVs that have lost HAG, allowing to clone untagged rMVA. Because only virion-containing supernatants are used, no virus purification steps and fewer sortings are necessary. Therefore, the final untagged rMVA product can be obtained in a mere 8 days. Conclusions Altogether, we report that the original RGSSM has been markedly improved in terms of time- and cost efficiency by substituting Cell-Sorting with direct Virus-Sorting from the supernatants of infected cells. The improved virometry-based RGGSM may find wide applicability, considering that rMVAs hold great promise to serve as personalized vaccines for therapeutic intervention against cancer and various types of infectious diseases. Graphical Abstract

Long-term treatment of schizophrenia with clozapine (CLZ), an atypical antipsychotic drug, is associated with an increased incidence of metabolic disorders mediated by poorly understood mechanisms. We herein report that CLZ, while slowing down the morphological changes and lipid accumulation occurring during SW872 cell adipogenesis, also causes an early (day 3) inhibition of the expression/nuclear translocation of CAAT/enhancer-binding protein β and peroxisome proliferator-activated receptor γ. Under the same conditions, CLZ blunts NADPH oxidase-derived reactive oxygen species (ROS) by a dual mechanism involving enzyme inhibition and ROS scavenging. These effects were accompanied by hampered activation of the nuclear factor (erythroid-derived2)-like 2 (Nrf2)-dependent antioxidant responses compared to controls, and by an aggravated formation of mitochondrial superoxide. CLZ failed to exert ROS scavenging activities in the mitochondrial compartment but appeared to actively scavenge cytosolic H2O2 derived from mitochondrial superoxide. The early formation of mitochondrial ROS promoted by CLZ was also associated with signs of mitochondrial dysfunction. Some of the above findings were recapitulated using mouse embryonic fibroblasts.We conclude that the NADPH oxidase inhibitory and cytosolic ROS scavenging activities of CLZ slow down SW872 cell adipogenesis and suppress their Nrf2 activation, an event apparently connected with increased mitochondrial ROS formation, which is associated with insulin resistance and metabolic syndrome. Thus, the cellular events characterised herein may help to shed light on the more detailed molecular mechanisms explaining some of the adverse metabolic effects of CLZ.

Objective: This paper aims to investigate the duration of the pricing & reimbursement (P&R) procedures submitted in Italy by pharmaceutical marketing authorization holders (MAH) for drugs indicated for rare diseases. Methods: All the data used in this analysis were publicly available on different sources of the Italian Ministry of Health, the Italian Medicines Agency (AIFA) and other official websites. The information was systematically collected to investigate the timeline (days) needed to complete the P&R process. The process was divided into 6 simplified steps and the median and range of days needed for each phase were estimated based on data reported in official/published documents. The analysis was stratified considering every single step of the assessment phase and included segmentation of drugs into indications for rare diseases, Orphan designation, Innovation assessment and Managed entry agreements (MEAs). Results: Overall, 181 first indication procedures were submitted to AIFA in the period considered and, of these, 167 (92.3%) were completed and 129 procedures were considered for the final analysis and the median duration of the entire process (MAH submission to final Gazette publication) was 434 days (range 176.0-918.0). The duration of procedures for rare diseases (n = 53) was longer than those for non-rare-disease procedures (n = 76) (463.0 days vs 407.5 days respectively). Among rare disease procedures, orphan designation and MEAs represent predictors for time prolongation while innovation is associated with a shorter assessment time. Conclusion: The study describes the time spent in each phase of the assessment and the appraisal process and demonstrates that uncertainty represents the main driver for the increment in the overall time.

Currently, an increasing number of intolerant and vegan consumers are driving the market towards plant-based milk alternatives. Here, selected probiotic yeasts, belonging to the Candida zeylanoides, Kluyveromyces lactis and Debaryomyces hansenii species, previously characterized for their aptitude to ferment animal milk, were tested in soy milk. Trials at different fermentation times with the developed yeast consortium (Yc) coinoculated with a lactic bacterium commercial strain were carried out.Yc showed good fermentation performance, conferring distinctive analytical and aromatic properties to the resulted soy fermented beverage, a product similar to an industrial kefir. Analytical determinations did not show significant variations between the end of fermentation and cold storage (4 weeks at 4 °C), indicating full stability. Phenol amounts and antioxidant activity were significantly increased in soy fermented beverage fermented by Yc. All yeasts remained viable until the end of storage with a final concentration of approximately 8 Log CFU/ml, a value suitable for a probiotic commercial claim. Overall, the results suggest that Yc is a promising multistarter candidate for functional soy products.

Hyper-/hypoglycemic states are rare but well-established causes of hyperkinetic movements, including chorea and ballismus, usually associated with brain lesions in the basal ganglia. We report a case of hemichorea-hemiballismus (HCHB) syndrome that developed after a severe hypoglycemic episode in a 71-year-old man with poorly controlled type 2 diabetes mellitus. Uncommonly, brain MRI showed contralateral cortical-subcortical T2 and T2-FLAIR-hyperintense frontoparietal lesions, with cingulate gyrus involved, while the basal ganglia were unaffected. In patients with hypoglycemic encephalopathy associated with cortical lesions, the long-term prognosis is usually poor. Nevertheless, in our patient, the dyskinesias and the cerebral lesions progressively regressed by achieving good glycemic control. After four and 12 months, the patient’s neurological examination was normal. To our knowledge, this is the first evidence of hypoglycemic etiology of cortical HCHB syndrome, supporting recent theories that cortical circuitries may independently contribute to the pathogenesis of chorea and ballismus. This is also the first report of cingulate gyrus involvement in hypoglycemic encephalopathy. Finally, this case may indicate that a subset of patients with cortical lesions due to hypoglycemia could present a good clinical outcome, likely depending on the size of the lesions and the duration and severity of the hypoglycemic episode.

Zooplankton are a critical link to higher trophic levels and play an important role in global biogeochemical cycles. This Review examines key responses of zooplankton to ocean warming, highlights key knowledge and geographic gaps that need to be addressed, and discusses how better use of observations and long-term zooplankton monitoring programmes can help fill these gaps.

Non-alcoholic beer (NAB) and low-alcoholic beer (LAB) are taking over the market with growing sales. Sustainable recycling and valorization of exhausted brewer’s spent grain (BSG) coming from craft beer is a relevant issue in the brewing process. In this work, recycled BSG and BSG + GJ (supplemented with 10% grape juice) were used as a wort substrate to inoculate Lachancea thermotolerans, Wickeramhomyces anomalus, Torulaspora delbruecki and Pichia kluyveri non-conventional yeasts to produce NABLAB craft beer. Results showed that wort composed of only recycled BSG produced appreciated NAB beers (ethanol concentration from 0.12% to 0.54% v/v), while the addition of 10% grape juice produced LAB beers (ethanol concentration from 0.82 to 1.66% v/v). As expected, volatile compound production was highest with the addition of grape juice. L. thermotolerans showed lactic acid production, characterizing both worts with the production of ethyl butyrate and isoamyl acetate. T. delbrueckii exhibited relevant amounts of hexanol, phenyl ethyl acetate and β-phenyl ethanol (BSG + GJ). W. anomalus and P. kluyveri showed consistent volatile production, but only in BSG + GJ where fermentation activity was exhibited. The overall results indicated that reused BSGs, non-conventional yeasts and grape juice are suitable bioprocesses for specialty NABLAB beer.

Telemedicine has emerged as a vital component of contemporary healthcare, revolutionizing the way medical services are delivered and accessed (e.g., it enables patients living in underserved or rural areas to receive medical consultation and treatment remotely). Moreover, telemedicine plays a pivotal role in improving healthcare efficiency by reducing wait times, minimizing unnecessary hospital visits, and optimizing resource allocation. In this paper, we present HealthTracker, a monitoring infrastructure for patients comprising two Internet of Things (IoT) devices (one of which was designed and created by us) and a mobile app that sends data collected by the IoT devices to a cloud service. All these components work together to provide an innovative system able to monitor patient health condition, provide alerts in emergency cases, and elaborate upon data to improve the quality of medical care. Preliminary tests show that the system works well, and real experimentation will start soon in collaboration with the local health authority.