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Background: Despite advances in asthma treatments, severe asthma exacerbation (SAE) remains a life-threatening condition in adults, and there is a lack of data derived from adult patients admitted to intensive care units (ICUs) for SAE. The current study investigated changes in adult patient characteristics, management, and outcomes of SAE over a 20-year period in 40 ICUs in the greater Paris area. Methods: In this retrospective observational study, admissions to 40 ICUs in the greater Paris area for SAE from January 1, 1997, to December 31, 2016 were analyzed. The primary outcome was the proportion of ICU admissions for SAE during 5-year periods. Secondary outcomes were ICU and hospital mortality, and the use of mechanical ventilation and catecholamine. Multivariate analysis was performed to assess factors associated with ICU mortality. Results: A total of 7049 admissions for SAE were recorded. For each 5-year period, the proportion decreased over time, with SAE accounting for 2.84% of total ICU admissions (n=2841) between 1997 and 2001, 1.76% (n=1717) between 2002 and 2006, 1.05% (n=965) between 2007 and 2011, and 1.05% (n=1526) between 2012 and 2016. The median age was 46 years (interquartile range [IQR]: 32–59 years), 55.41% were female, the median Simplified Acute Physiology Score II was 20 (IQR: 13–28), and 19.76% had mechanical ventilation. The use of mechanical ventilation remained infrequent throughout the 20-year period, whereas the use of catecholamine decreased. ICU and hospital mortality rates decreased. Factors associated with ICU mortality were renal replacement therapy, catecholamine, cardiac arrest, pneumothorax, acute respiratory distress syndrome, sepsis, and invasive mechanical ventilation (IMV). Non-survivors were older, had more severe symptoms, and were more likely to have received IMV. Conclusion: ICU admission for SAE remains uncommon, and the proportion of cases decreased over time. Despite a slight increase in symptom severity during a 20-year period, ICU and hospital mortality decreased. Patients requiring IMV had a higher mortality rate.

Abstract Background Patients infected with the severe acute respiratory syndrome coronavirus 2 (SARS-COV 2) and requiring intensive care unit (ICU) have a high incidence of hospital-acquired infections; however, data regarding hospital acquired bloodstream infections (BSI) are scarce. We aimed to investigate risk factors and outcome of BSI in critically ill coronavirus infectious disease-19 (COVID-19) patients. Patients and methods We performed an ancillary analysis of a multicenter prospective international cohort study (COVID-ICU study) that included 4010 COVID-19 ICU patients. For the present analysis, only those with data regarding primary outcome (death within 90 days from admission) or BSI status were included. Risk factors for BSI were analyzed using Fine and Gray competing risk model. Then, for outcome comparison, 537 BSI-patients were matched with 537 controls using propensity score matching. Results Among 4010 included patients, 780 (19.5%) acquired a total of 1066 BSI (10.3 BSI per 1000 patients days at risk) of whom 92% were acquired in the ICU. Higher SAPS II, male gender, longer time from hospital to ICU admission and antiviral drug before admission were independently associated with an increased risk of BSI, and interestingly, this risk decreased over time. BSI was independently associated with a shorter time to death in the overall population (adjusted hazard ratio (aHR) 1.28, 95% CI 1.05–1.56) and, in the propensity score matched data set, patients with BSI had a higher mortality rate (39% vs 33% p = 0.036). BSI accounted for 3.6% of the death of the overall population. Conclusion COVID-19 ICU patients have a high risk of BSI, especially early after ICU admission, risk that increases with severity but not with corticosteroids use. BSI is associated with an increased mortality rate.

Objective We aimed at identifying baseline predictive factors for emergency department (ED) readmission, with hospitalisation/death, in patients with COVID-19 previously discharged from the ED. We also developed a disease progression velocity index.Design and setting Retrospective cohort study of prospectively collected data. The charts of consecutive patients with COVID-19 discharged from the Reggio Emilia (Italy) ED (2 March 2 to 31 March 2020) were retrospectively examined. Clinical, laboratory and CT findings at first ED admission were tested as predictive factors using multivariable logistic models. We divided CT extension by days from symptom onset to build a synthetic velocity index.Participants 450 patients discharged from the ED with diagnosis of COVID-19.Main outcome measure ED readmission within 14 days, followed by hospitalisation/death.Results Of the discharged patients, 84 (18.7%) were readmitted to the ED, 61 (13.6%) were hospitalised and 10 (2.2%) died. Age (OR=1.05; 95% CI 1.03 to 1.08), Charlson Comorbidity Index 3 versus 0 (OR=11.61; 95% CI 1.76 to 76.58), days from symptom onset (OR for 1-day increase=0.81; 95% CI 0.73 to 0.90) and CT extension (OR for 1% increase=1.03; 95% CI 1.01 to 1.06) were associated in a multivariable model for readmission with hospitalisation/death. A 2-day lag velocity index was a strong predictor (OR for unit increase=1.21, 95% CI 1.08 to 1.36); the model including this index resulted in less information loss.Conclusions A velocity index combining CT extension and days from symptom onset predicts disease progression in patients with COVID-19. For example, a 20% CT extension 3 days after symptom onset has the same risk as does 50% after 10 days.

Background: Prolonged university closures and social distancing-imposed measures due to the COVID-19 pandemic obliged students to at-home learning with online lectures and educational programs promoting potential social isolation, loneliness, hopelessness, and episodes of clinical decompensation.Methods: A web-based cross-sectional survey was carried out in a university institute in Milan, Northern Italy, to assess the COVID-19 lockdown impact on the mental health of the undergraduate students. We estimated the odds ratios (OR) and the corresponding 95% confidence intervals (CI) using adjusted logistic regression models.Results: Of the 8,177 students, 12.8% reported depressive symptoms, 25.6% anxiety, 8.7% insomnia, and 10.6% reported impulsive tracts, with higher proportions among females than males. Mental health symptoms were positively associated with caring for a person at home, a poor housing quality, and a worsening in working performance. Among males compared with females, a poor housing quality showed a stronger positive association with depressive symptoms and impulsivity, and a worsening in the working performance was positively associated with depressive and anxiety symptoms. In addition, the absence of private space was positively associated with depression and anxiety, stronger among males than females.Conclusions: To our knowledge, this is the first multidisciplinary consortium study, involving public mental health, environmental health, and architectural design. Further studies are needed to confirm or refute our findings and consequent recommendations to implement well-being interventions in pandemic conditions.

Abstract Background Early prognostication in trauma patients is challenging, but particularly important. We wanted to explore the ability of copeptin, the C-terminal fragment of arginine vasopressin, to identify major trauma, defined as Injury Severity Score (ISS) > 15, in a heterogeneous cohort of trauma patients and to compare its performances with lactate. We also evaluated copeptin performance in predicting other clinical outcomes: mortality, hospital admission, blood transfusion, emergency surgery, and Intensive Care Unit (ICU) admission. Methods This single center, pragmatic, prospective observational study was conducted at Arcispedale Santa Maria Nuova, a level II trauma center in Reggio Emilia, Italy. Copeptin determination was obtained on Emergency Department (ED) arrival, together with venous lactate. Different outcomes were measured including ISS, Revised Trauma Score (RTS), hospital and ICU admission, blood transfusion, emergency surgery, and mortality. Results One hundred and twenty five adult trauma patients admitted to the ED between June 2017 and March 2018. Copeptin showed a good ability to identify patients with ISS > 15 (AUC 0.819). Similar good performances were recorded also in predicting other outcomes. Copeptin was significantly superior to lactate in identifying patients with ISS > 15 (P 0.0015), and in predicting hospital admission (P 0.0002) and blood transfusion (P 0.016). Comparable results were observed in a subgroup of patients with RTS 7.84. Conclusions In a heterogeneous group of trauma patients, a single copeptin determination at the time of ED admission proved to be an accurate biomarker, statistically superior to lactate for the identification of major trauma, hospital admission, and blood transfusion, while no statistical difference was observed for ICU admission and emergency surgery. These results, if confirmed, may support a role for copeptin during early management of trauma patients.

Abstract Background The GLP-1 receptor agonist liraglutide is used to treat hyperglycemia in type 2 diabetes but is also known to induce weight loss, preserve the beta cell and reduce cardiovascular risk. The mechanisms underlying these effects are however still not completely known. Herein we explore the effect of liraglutide on markers of immune cell activity in a population of obese individuals with prediabetes or newly diagnosed type 2 diabetes mellitus. Method Plasma levels of the monocyte/macrophage markers, soluble (s)CD163 and sCD14, the neutrophil markers myeloperoxidase (MPO) and neutrophil gelatinase‐associated lipocalin (NGAL),the T-cell markers sCD25 and T-cell immunoglobulin mucin domain-3 (sTIM-3) and the inflammatory marker TNF superfamily (TNFSF) member 14 (LIGHT/TNFSF14) were measured by enzyme-linked immunosorbent assays in obese individuals with prediabetes or diabetes diagnosed within the last 12 months, prior to and after comparable weight loss achieved with lifestyle changes (n = 20) or liraglutide treatment (n = 20), and in healthy subjects (n = 13). Results At baseline, plasma levels of the macrophage marker sCD163, and the inflammatory marker LIGHT were higher in cases as compared to controls. Plasma levels of sCD14, NGAL, sTIM-3 and sCD25 did not differ at baseline between patients and controls. After weight reduction following lifestyle intervention or liraglutide treatment, sCD163 decreased significantly in the liraglutide group vs. lifestyle (between-group difference p = 0.023, adjusted for visceral adipose tissue and triglycerides basal values). MPO and LIGHT decreased significantly only in the liraglutide group (between group difference not significant). Plasma levels of MPO and in particular sCD163 correlated with markers of metabolic dysfunction and inflammation. After weight loss, only sCD163 showed a trend for decreased levels during OGTT, both in the whole cohort as in those of liraglutide vs lifestyle group. Conclusion Weight loss following treatment with liraglutide was associated with reduced circulating levels of sCD163 when compared to the same extent of weight loss after lifestyle changes. This might contribute to reduced cardiometabolic risk in individuals receiving treatment with liraglutide.

Abstract Purpose Several studies have investigated the association between anorexia nervosa and polymorphisms of genes regulating serotonin neurotransmission, with a focus on the rs6311 polymorphism of 5-HTR2A. However, inconsistent results of these studies and conflicting conclusions of existing meta-analyses complicate the understanding of a possible association. We have updated these results and evaluated the involvement of other serotonin receptor gene polymorphisms in anorexia nervosa. Methods Adhering to PRISMA guidelines, we have searched studies on anorexia nervosa and serotonin-regulating genes published from 1997 to 2022, selected those concerning receptor genes and meta-analyzed the results from twenty candidate gene studies on the 5-HTR2A rs6311 polymorphism and the 5-HTR2C rs6318 polymorphism. Results Present analyses reveal an association for the 5-HTR2A rs6311 polymorphism, with G and A alleles, across eighteen studies (2049 patients, 2877 controls; A vs. G allele, Odds Ratio = 1.24; 95% Confidence Interval = 1.06–1.47; p = 0.009). However, after geographic subgrouping, an association emerged only in a Southern European area, involving five studies (722 patients, 773 controls; A vs. G allele, Odds Ratio = 1.82; 95% Confidence Interval = 1.41–2.37; p

Cardiovascular disease (CVD) remains the leading cause of death worldwide. The risk of a cardiovascular (CV) event is not static and increases along a continuum, making identification and management complex.Aspirin has been the cornerstone of antiplatelet therapy in CV risk reduction and remains the only antiplatelet agent with current guideline recommendations throughout the CV risk continuum. In light of recent trials, the role of aspirin in CVD prevention in asymptomatic patients has been downgraded in clinical guidelines. However, a substantial proportion of asymptomatic patients have underlying conditions, such as advanced subclinical atherosclerosis that are associated with high CV risk. Advanced subclinical atherosclerosis has not been extensively investigated in patients in clinical trials but in the absence of significant bleeding risks, patients with subclinical atherosclerosis may particularly benefit from preventive aspirin therapy.Recent studies and clinical guidelines support the need for a personalized treatment approach for these patients, balancing their risk of future CV events against their relative bleeding risk. In this commentary, we first discussed various tools and strategies currently available for assessing CV and bleeding risks; we then provided two hypothetical cases to outline how these tools can be implemented for optimal management of patients with no prior CV events who, nonetheless, are susceptible to CVD.The first case details a young and apparently healthy patient with underlying advanced subclinical atherosclerosis; whereas the second case describes a patient with recently diagnosed type 2 diabetes mellitus who is at higher risk of CVD than their non-diabetic counterparts. For both cases, we considered patient clinical characteristics, CV and bleeding risks, as well as other risk factors to evaluate the appropriate treatment strategy and determine whether patients would obtain a net clinical benefit from low-dose aspirin therapy. These cases can serve as examples to guide clinical decision-making on the use of low-dose aspirin for primary CVD prevention and improve CVD management via a personalized approach.

Background Coronary artery calcium testing using noncontrast cardiac computed tomography is a guideline‐indicated test to help refine eligibility for aspirin in primary prevention. However, access to cardiac computed tomography remains limited, with carotid ultrasound used much more often internationally. We sought to update the role of aspirin allocation in primary prevention as a function of subclinical carotid atherosclerosis. Methods and Results The study included 11 379 participants from the MESA (Multi‐Ethnic Study of Atherosclerosis) and ARIC (Atherosclerosis Risk in Communities) studies. A harmonized carotid plaque score (range, 0–6) was derived using the number of anatomic sites with plaque from the left and right common, bifurcation, and internal carotid artery on ultrasound. The 5‐year number needed to treat and number needed to harm as a function of the carotid plaque score were calculated by applying a 12% relative risk reduction in atherosclerotic cardiovascular disease (ASCVD) events and 42% relative increase in major bleeding events related to aspirin use, respectively. The mean age was 57 years, 57% were women, 23% were Black, and the median 10‐year ASCVD risk was 12.8%. The 5‐year incidence rates (per 1000 person‐years) were 5.5 (4.9–6.2) for ASCVD and 1.8 (1.5–2.2) for major bleeding events. The overall 5‐year number needed to treat with aspirin was 306 but was 2‐fold lower for individuals with carotid plaque versus those without carotid plaque (212 versus 448). The 5‐year number needed to treat was less than the 5‐year number needed to harm when the carotid plaque score was ≥2 for individuals with ASCVD risk 5% to 20%, whereas the presence of any carotid plaque demarcated a favorable risk–benefit for individuals with ASCVD risk >20%. Conclusions Quantification of subclinical carotid atherosclerosis can help improve the allocation of aspirin therapy.

Introduzione e obiettivo L’osteoartrosi (OA) è caratterizzata dalla degenerazione della cartilagine che provoca il cedimento strutturale e funzionale delle articolazioni sinoviali, principalmente attraverso un’alterazione regressiva e non infiammatoria della cartilagine. Questa patologia è una delle principali cause di disabilità in tutto il mondo, in gran parte a causa del dolore. L’obiettivo di questo studio è eseguire una revisione sistematica confrontando l’efficacia delle varie terapie riabilitative proposte per questa patologia, studiare l’importanza della prevenzione in soggetti maggiormente esposti ed evidenziare gli interventi di trattamento che apportano maggiori risultati al paziente. Materiali e metodi La ricerca della letteratura, condotta seguendo le linee guida internazionali PRISMA mediante la strategia PICO, è stata effettuata attraverso le banche dati Medline (via PubMed), Scopus, PEDro, LILACS e Trip Databse tra i mesi di Maggio e Giugno 2023. La letteratura presente è stata vagliata mediante la formulazione di diverse stringhe di ricerca: PubMed ((“Osteoarthrosis” [MeSH]) AND (“physiotherapy” [MeSH] OR (“rehabilitation” [MeSH] OR (“exercise” [MeSH])), Scopus, LILACS e Trip Database (“Osteoarthrosis” AND (“physiotherapy” OR “rehabilitation” OR “ exercise”)) e su PEDro è stata utilizzata la stringa “Osteoarthrosis AND Rehabilitation”. Sono stati inclusi solo studi RCT in lingua inglese, pubblicati dal 2013 al 2023 che andassero a prendere in esame l’arto inferiore con un range di età da 55 a 70 anni non operati. Gli articoli duplicati sono stati eliminati mediante il software EndNote. Inizialmente sono stati selezionati gli articoli pertinenti in base al titolo, poi in base alla lettura dell’abstract e infine in base alla lettura del full text. Risultati Dopo l’inclusione sono stati selezionati 6 RCT con una popolazione affetta da osteoartrosi degli arti inferiori. E’ stata valutata la qualità metodologica mediante la scala PEDro. Gli studi inclusi presentano mediamente un punteggio di 7.3. Sono emerse multiple strategie di trattamento: allenamento aerobico, esercizi di stretching dei muscoli dell’anca, esercizi di equilibrio statico e dinamico, esercizi di stabilità e resistenza, elettroterapia, ma è emerso che la maggior parte degli studi inclusi predilige l’esercizio di rinforzo muscolare. Discussione e conclusioni Alla luce dei risultati ottenuti da questa Revisione Sistematica, si ritiene necessario riconoscere gli interventi riabilitativi, attraverso la loro dimensione multidisciplinare, parte fondamentale del trattamento, importanti tanto quanto l’intervento farmacologico, per determinare un rallentamento nella progressione della patologia e un efficace controllo di quest’ultima. L’analisi di questi ultimi ci porta ad affermare che sarebbe necessario ampliare la ricerca tramite follow-up a lungo termine e aumentare la grandezza del campione.

Background: Low-dose aspirin lowers cardiovascular event risk; dual-pathway inhibition (DPI) using low-dose aspirin with low-dose rivaroxaban may reduce this risk further. A systematic literature review and meta-analysis compared the efficacy, safety and net clinical benefit (NCB) of DPI with aspirin. Methods: PubMed and Embase were searched for randomised controlled trials reporting clinical efficacy, safety and NCB of DPI compared with aspirin alone in patients with coronary artery disease (CAD) and/or peripheral artery disease. Six articles representing four trials were included. Results: DPI versus aspirin alone significantly reduced major adverse cardiovascular events (HR 0.77; 95% CI [0.69–0.87]; p

Metabolic dysfunction-associated steatotic liver disease (MASLD) is not only related to traditional cardiovascular risk factors like type 2 diabetes mellitus and obesity, but it is also an independent risk factor for the development of cardiovascular disease. MASLD has been shown to be independently related to endothelial dysfunction and atherosclerosis. MASLD is characterized by a chronic proinflammatory response that, in turn, may induce a prothrombotic state. Several mechanisms such as endothelial and platelet dysfunction, changes in the coagulative factors, lower fibrinolytic activity can contribute to induce the prothrombotic state. Platelets are players and addresses of metabolic dysregulation; obesity and insulin resistance are related to platelet hyperactivation. Furthermore, platelets can exert a direct effect on liver cells, particularly through the release of mediators from granules. Growing data in literature support the use of antiplatelet agent as a treatment for MASLD. The use of antiplatelets drugs seems to exert beneficial effects on hepatocellular carcinoma prevention in patients with MASLD, since platelets contribute to fibrosis progression and cancer development. This review aims to summarize the main data on the role of platelets in the pathogenesis of MASLD and its main complications such as cardiovascular events and the development of liver fibrosis. Furthermore, we will examine the role of antiplatelet therapy not only in the prevention and treatment of cardiovascular events but also as a possible anti-fibrotic and anti-tumor agent.

AbstractVitamin D (VD) has been shown to exert immunomodulatory activities, especially in promoting immune tolerance. For these properties VD has been proposed in the therapy of immunological conditions in which the loss of tolerance is the key pathogenetic aspect of the disease, such as allergies. Despite these properties available literature suggests VD is not useful in treating or preventing allergic diseases and whether low serum VD levels favor allergic sensitization and severity is debated. The level of VD is one of the many conditions that can influence allergic sensitization and therefore only a multivariate analysis on a numerically adequate cohort of patients, that considers all the factors that can favor allergy, would be able to assign the weight of each variable and determine the extent to which VD inhibits allergic sensitization and march. On the contrary, VD is able to potentiate the antigen-specific tolerogenic response induced by Allergen Immunotherapy (AIT) as demonstrated by the large majority of studies. In our experience, the association of VD and Sublingual AIT (LAIS, Lofarma, Italy) gave an excellent clinical and immune response in particular enhancing the differentiation of memory T regulatory cells. While waiting for a more extensive literature, VD/AIT combination should be always performed in treating allergies. In any case, the assessment of the level of VD should become a routine in allergic patients with an indication to AIT as, in case of VD deficiency or insufficiency, VD seems a particularly active adjuvant to the immune treatment.

Cell outer membranes contain glycosphingolipids and protein receptors, which are integrated into glycoprotein domains, known as lipid rafts, which are involved in a variety of cellular processes, including receptor-mediated signal transduction and cellular differentiation process. In this study, we analyzed the lipidic composition of human Dental Pulp-Derived Stem Cells (DPSCs), and the role of lipid rafts during the multilineage differentiation process. The relative quantification of lipid metabolites in the organic fraction of DPSCs, performed by Nuclear Magnetic Resonance (NMR) spectroscopy, showed that mono-unsaturated fatty acids (MUFAs) were the most representative species in the total pool of acyl chains, compared to polyunsatured fatty acids (PUFAs). In addition, the stimulation of DPSCs with different culture media induces a multilineage differentiation process, determining changes in the gangliosides pattern. To understand the functional role of lipid rafts during multilineage differentiation, DPSCs were pretreated with a typical lipid raft affecting agent (MβCD). Subsequently, DPSCs were inducted to differentiate into osteoblast, chondroblast and adipoblast cells with specific media. We observed that raft-affecting agent MβCD prevented AKT activation and the expression of lineage-specific mRNA such as OSX, PPARγ2, and SOX9 during multilineage differentiation. Moreover, this compound significantly prevented the tri-lineage differentiation induced by specific stimuli, indicating that lipid raft integrity is essential for DPSCs differentiation. These results suggest that lipid rafts alteration may affect the signaling pathway activated, preventing multilineage differentiation.

Gastrointestinal bleedings are relevant side effects in patients during anticoagulant therapy for atrial fibrillation. Direct oral anticoagulants (DOACs) are less correlated with major bleeding events than vitamin K antagonists (VKAs), but concerns are present about the relative risk of gastrointestinal bleeding. Here we report the case of a patient with atrial fibrillation and dementia on DOAC treatment who developed a SSRI-associated thrombocytopenia with subsequent life-threatening bleeding. Physicians should be aware of the possible correlation between SSRI-induced thrombocytopenia and concomitant use of anticoagulant and/or antiplatelet drugs, thus preventing life-threatening bleedings.

Type 2 diabetes is a key player in atherothrombosis. Inflammation participates in metabolic homeostasis interacting with adipose tissue-specific macrophages. Platelets appear as addresses and players carrying and transducing metabolic derangement into vascular injury. AGE-RAGE pathway is recognized as the driver of metabolic memory. Human platelets have insulin receptors that participate in the regulation of platelet function and platelets are potential sites of insulin resistance. The present mini-review addresses key pathophysiological aspects including i) the role of inflammation in the pathogenesis of diabetes; ii) platelets as inflammatory cells; iii) the involvement on inflammation in the interindividual variability in aspirin response. Taken together, these aspects may contribute to expand knowledge about the link between the extent of inflammation, platelet activation and turnover, and interindividual variability in the development of atherothrombosis and its prevention, in a view of precision medicine.

Abstract The 7th Cardiovascular Outcome Trial (CVOT) Summit on Cardiovascular, Renal, and Glycemic Outcomes, was held virtually on November 18–19, 2021. Pursuing the tradition of the previous summits, this reference congress served as a platform for in-depth discussion and exchange on recently completed CVOTs. This year’s focus was placed on the outcomes of EMPEROR-Preserved, FIGARO-DKD, AMPLITUDE-O, SURPASS 1–5, and STEP 1–5. Trial implications for diabetes and obesity management and the impact on new treatment algorithms were highlighted for endocrinologists, diabetologists, cardiologists, nephrologists, and general practitioners. Discussions evolved from outcome trials using SGLT2 inhibitors as therapy for heart failure, to CVOTs with nonsteroidal mineralocorticoid receptor antagonists and GLP-1 receptor agonists. Furthermore, trials for glycemic and overweight/obesity management, challenges in diabetes management in COVID-19, and novel guidelines and treatment strategies were discussed. Trial registration The 8th Cardiovascular Outcome Trial Summit will be held virtually on November 10–11, 2022 ( http://www.cvot.org )

The eastern gray squirrel (Sciurus carolinensis) has been labeled as one of the 100 worst invasive alien species by the IUCN. In Europe, the species has been introduced to Britain, Ireland and Italy, and its subsequent spread has resulted in wide-scale extinction of native Eurasian red squirrels (Sciurus vulgaris) from the areas colonized by the gray squirrel. This replacement of a native by an alien competitor is one of the best documented cases of the devastating effects of biological invasions on native fauna. To understand how this replacement occurs, we present a systematic review of the literature on competition and interactions between red and gray squirrels. We describe the patterns of red and gray squirrel distribution in those parts of Europe where gray squirrels occur and summarize the evidence on the different processes and mechanisms determining the outcome of competition between the native and alien species including the influence of predators and pathogens. Some of the drivers behind the demise of the red squirrel have been intensively studied and documented in the past 30 years, but recent field studies and mathematical models revealed that the mechanisms underlying the red-gray paradigm are more complex than previously thought and affected by landscape-level processes. Therefore, we consider habitat type and multi-species interactions, including host-parasite and predator-prey relationships, to determine the outcome of the interaction between the two species and to better address gray squirrel control efforts.

The neurohormone oxytocin (OXT) has been implicated in the regulation of social behavior and is intensively investigated as a potential therapeutic treatment in neurodevelopmental disorders characterized by social deficits. In the Magel2-knockout (KO) mouse, a model of Schaaf-Yang Syndrome, an early postnatal administration of OXT rescued autistic-like behavior and cognition at adulthood, making this model relevant for understanding the actions of OXT in (re)programming postnatal brain development. The oxytocin receptor (OXTR), the main brain target of OXT, was dysregulated in the hippocampus of Magel2-KO adult males, and normalized upon OXT treatment at birth. Here we have analyzed male and female Magel2-KO brains at postnatal day 8 (P8) and at postnatal day 90 (P90), investigating age, genotype and OXT treatment effects on OXTR levels in several regions of the brain. We found that, at P8, male and female Magel2-KOs displayed a widespread, substantial, down-regulation of OXTR levels compared to wild type (WT) animals. Most intriguingly, the postnatal OXT treatment did not affect Magel2-KO OXTR levels at P8 and, consistently, did not rescue the ultrasonic vocalization deficits observed at this age. On the contrary, the postnatal OXT treatment reduced OXTR levels at P90 in male Magel2-KO in a region-specific way, restoring normal OXTR levels in regions where the Magel2-KO OXTR was upregulated (central amygdala, hippocampus and piriform cortex). Interestingly, Magel2-KO females, previously shown to lack the social deficits observed in Magel2-KO males, were characterized by a different trend in receptor expression compared to males; as a result, the dimorphic expression of OXTR observed in WT animals, with higher OXTR expression observed in females, was abolished in Magel2-KO mice. In conclusion, our data indicate that in Magel2-KO mice, OXTRs undergo region-specific modifications related to age, sex and postnatal OXT treatment. These results are instrumental to design precisely-timed OXT-based therapeutic strategies that, by acting at specific brain regions, could modify the outcome of social deficits in Schaaf-Yang Syndrome patients.

Traditionally, guidelines divide patients into primary and secondary prevention for atherosclerotic cardiovascular disease (ASCVD) risk management. However, the modern understanding of the biological progression of atherosclerosis is inconsistent with this binary approach. Therefore, a new approach demonstrating both atherosclerosis and ASCVD risk as a continuum is needed to give clinicians a framework for better matching risk and intensity of therapy. Advances in coronary imaging have most clearly brought this problem into view, as for example coronary artery calcium (CAC) scoring has shown that some individuals in the primary prevention have equal or higher ASCVD risk as certain subgroups in secondary prevention. This article introduces “advanced subclinical atherosclerosis” as a new and distinct clinical group that sits between the traditional groups of primary and secondary prevention. Importantly, this article also introduces a new graphic to visualize this intermediate population that is explicitly based on plaque burden. The aim of the graphic is both to educate and to allow for better identification of a patient's cardiovascular risk and guide more effective risk-based management.

Abstract Background Soluble suppression of tumorigenesis-2 (sST2) and galectin (Gal)-3 are two biomarkers related to inflammation, metabolic disturbances and to myocardial fibrosis that characterize several cardiac pathological conditions. Increased circulating levels of these molecules have been associated with risk of cardiovascular death. Treatment with liraglutide, a glucagon-like peptide 1 analog, is associated with weight loss, improved glycemic control, and reduced cardiovascular risk. We wanted to assess (I) potential differences between subjects with prediabetes or type 2 diabetes mellitus (T2DM) and healthy controls in sST2 and Gal-3 circulating levels, and their relationship with glycemic control and markers of beta cell function and myocardial injury; (II) whether liraglutide treatment modulates these markers in subjects with prediabetes or early T2DM independently of weight loss; (III) whether baseline levels of any of these two molecules may predict the response to liraglutide treatment. Methods Forty metformin-treated obese subjects (BMI ≥ 30) with prediabetes [impaired fasting glucose (IFG) or impaired glucose tolerance (IGT) or both (n = 23)] or newly diagnosed T2DM (n = 17), were randomized to liraglutide or lifestyle counseling until achieving a comparable weight loss (7% of initial body weight). Thirteen subjects were enrolled as healthy controls for baseline sST2 and Gal-3 levels. Results Baseline sST2 levels were comparable between controls and obese patients (p = 0.79) whereas Gal-3 levels were significantly higher in patients as compared to controls (p

Celiac disease (CD) is an intestinal disease that develops in genetically predisposed individuals and is triggered by the ingestion of gluten. CD was considered a Th1-disease. Today, the role of Th17, IL-21, and IL-17A lymphocytes is well known. Inflammation is regulated by the activity of gluten-specific CD4+ T lymphocytes that produce pro-inflammatory cytokines, including IFN-γ, TNF-α, and IL-21, perpetuating the Th1 response. These cytokines determine an inflammatory state of the small intestine, with consequent epithelial infiltration of lymphocytes and an alteration of the architecture of the duodenal mucosa. B cells produce antibodies against tissue transglutaminase and against deamidated gliadin. Although the role of the adaptive immune response is currently known, the evidence about the role of innate immunity cells is still poorly understood. Epithelial damage determines the release of damage-associated molecular patterns (DAMPs), also known as alarmins. Together with the intestinal epithelial cells and the type 1 innate lymphoid cells (ILC1s), alarmins like TSLP, IL-33, and HMGB1 could have a fundamental role in the genesis and maintenance of inflammation. Our study aims to evaluate the evidence in the literature about the role of ILCs and alarmins in celiac disease, evaluating the possible future diagnostic and therapeutic implications.

Cardiovascular (CV) disease prevention with low-dose aspirin can be less effective in patients with a faster recovery of platelet (PLT) cyclooxygenase (COX)-1 activity during the 24-hour dosing interval. We previously showed that incomplete suppression of TXA2 over 24 hours can be rescued by a twice daily aspirin regimen. Here we show that reduced PLT glycoprotein (GP)Ibα shedding characterizes patients with accelerated COX-1 recovery and may contribute to higher thrombopoietin (TPO) production and higher rates of newly formed PLT, escaping aspirin inhibition over 24 hours. Two hundred aspirin-treated patients with high CV risk (100 with type 2 diabetes mellitus) were stratified according to the kinetics of PLT COX-1 activity recovery during the 10- to 24-hour dosing interval. Whole proteome analysis showed that PLT from patients with accelerated COX-1 recovery were enriched in proteins involved in cell survival, inhibition of apoptosis and cellular protrusion formation. In agreement, we documented increased plasma TPO, megakaryocyte maturation and proplatelet formation, and conversely increased PLT galactose and reduced caspase 3, phosphatidylserine exposure and ADAM17 activation, translating into diminished GPIbα cleavage and glycocalicin (GC) release. Treatment of HepG2 cells with recombinant GC led to a dose-dependent reduction of TPO mRNA in the liver, suggesting that reduced GPIbα ectodomain shedding may unleash thrombopoiesis. A cluster of clinical markers, including younger age, non-alcoholic fatty liver disease, visceral obesity and higher TPO/GC ratio, predicted with significant accuracy the likelihood of faster COX-1 recovery and suboptimal aspirin response. Circulating TPO/GC ratio, reflecting a dysregulation of PLT lifespan and production, may provide a simple tool to identify patients amenable to more frequent aspirin daily dosing.

The most recent primary cardiovascular disease (CVD) prevention clinical guidelines used in Europe, Italy, the USA, China, and South Korea differ in aspects of their approach to CVD risk assessment and reduction. Low dose aspirin use is recommended in certain high-risk patients by most but not all the countries. Assessment of traditional risk factors and which prediction models are commonly used differ between countries. The assessments and tools may not, however, identify all patients at high risk but without manifest CVD. The use of coronary artery calcium (CAC) score to guide decisions regarding primary prevention aspirin therapy is recommended only by the US primary prevention guidelines and the 2021 European Society of Cardiology guidelines. A more consistent and comprehensive global approach to CVD risk estimation in individual patients could help to personalize primary CVD prevention. Wider detection of subclinical atherosclerosis, together with structured assessment and effective mitigation of bleeding risk, may appropriately target patients likely to gain net benefit from low dose aspirin therapy.

Despite decades of research, no therapies are available to halt or slow down the course of neuro-degenerative disorders. Most of the drugs developed to fight neurodegeneration are aimed to alleviate symptoms, but none has proven adequate in altering the course of the pathologies. Cell therapy has emerged as an intriguing alternative to the classical pharmacological approach. Cell therapy consists of the transplantation of stem cells that can be obtained from various embryonal and adult tissues. Whereas the former holds notable ethical issue, adult somatic stem cells can be obtained without major concerns. However, most adult stem cells, such as those derived from the bone marrow, are committed toward the mesodermal lineage, and hence need to be reprogrammed to induce the differentiation into the neurons. The discovery of neural crest stem cells in the dental pulp, both in adults’ molar and in baby teeth (dental pulp stem cells and stem cells from human exfoliated deciduous teeth, respectively) prompted researchers to investigate their utility as therapy in nervous system disorders. In this review, we recapitulate the advancements on the application of these stem cells in preclinical models of neurodegenerative diseases, highlighting differences and analogies in their maintenance, differentiation, and potential clinical application.

Abstract Protease proprotein convertase subtilisin/kexin type 9 (PCSK9) is a regulator of LDL cholesterol clearance and has been associated with cardiovascular risk. PCSK9 inhibitors increase in vivo circulating endothelial progenitor cells (EPCs), a subtype of immature cells involved in ongoing endothelial repair. We hypothesized that the effect of PCSK9 on vascular homeostasis may be mediated by EPCs in patients with or without type 2 diabetes mellitus (T2DM). Eighty-two patients (45 with, 37 without T2DM) at high cardiovascular risk were enrolled in this observational study. Statin treatment was associated with higher circulating levels of PCSK9 in patients with and without T2DM (p

Gangliosides (GGs) are a glycolipid class present on Mesenchymal Stem Cells (MSCs) surfaces with a critical appearance role in stem cell differentiation, even though their mechanistic role in signaling and differentiation remains largely unknown. This review aims to carry out a critical analysis of the predictive role of gangliosides as specific markers of the cellular state of undifferentiated and differentiated MSCs, towards the osteogenic, chondrogenic, neurogenic, and adipogenic lineage. For this reason, we analyzed the role of GGs during multilineage differentiation processes of several types of MSCs such as Umbilical Cord-derived MSCs (UC-MSCs), Bone Marrow-derived MSCs (BM-MSCs), Dental Pulp derived MSCs (DPSCs), and Adipose derived MSCs (ADSCs). Moreover, we examined the possible role of GGs as specific cell surface markers to identify or isolate specific stem cell isotypes and their potential use as additional markers for quality control of cell-based therapies.

Background: real-life studies are encouraged to evaluate the effectiveness and safety of allergen immunotherapy (AIT). In this context, a retrospective cohort study was conducted to assess the effectiveness and safety of carbamylated monomeric allergoid subcutaneous immunotherapy (MA-SCIT), along with patient satisfaction. Methods: a total of 291 patients with rhinoconjunctivitis with or without asthma with inhalant (house dust mite, grass, and pellitory) allergies were enrolled in this study. Perceived efficacy and perceived satisfaction with MA-SCIT, symptom score by VAS, ARIA classification of rhinitis, drug consumption, number of asthma worsening episodes, and asthma symptom control were evaluated by questionnaires before, after one year, at the end of treatment, and after one or two years of MA-SCIT. Results: the overall symptom score significantly decreased over the years of MA-SCIT, irrespective of specific sensitization (p < 0.01). There was a substantial amelioration of rhinitis severity, with a significant reduction (p < 0.01) in drug use. A significant reduction was observed in the asthma symptom VAS score and asthma-worsening episodes requiring systemic steroids. None of the patients reported any severe adverse reactions. Finally, 90% of the patients reported full satisfaction with the treatment. Conclusions: the study showed that AIT with carbamylated monomeric allergoids of grass, pellitory, and mites was effective and well tolerated by patients.

Allergic reactions to COVID-19 vaccine components are rare but should be considered. Polyethylene glycol (PEG) is responsible for anaphylaxis in mRNA vaccines. Skin tests have been used in the allergological work-up programs for COVID-19 vaccine evaluation. However, the reproducibility of the skin prick test is time-dependent and the reactivity declines over time. Therefore, we combined the administration of the skin tests with the basophil activation test (BAT) using PEG2000, PEG4000 and DMG-PEG2000, where the BAT was considered positive when the percentage of activated basophils was higher than 6%, 5% and 6.5%, for PEG 4000, PEG2000 and DMG-PEG2000, respectively. To this end, among the subjects that underwent allergy counseling at the Allergy Unit of our Institution during the 2020/2021 vaccination campaign, 13 patients had a suggested medical history of PEG/drug hypersensitivity and were enrolled together with 10 healthy donors. Among the enrolled patients 2 out of 13 tested patients were positive to the skin test. The BAT was negative in terms of the percentages of activated basophils in all analyzed samples, but the stimulation index (SI) was higher than 2.5 in 4 out of 13 patients. These data evidenced that, when the SI is higher than 2.5, even in the absence of positivity to BAT, the BAT to PEG may be a useful tool to be coupled to skin tests to evidence even low-grade reactions.

Sodium–glucose co-transporter-2 inhibitors or gliflozins, the newest anti-hyperglycemic class, induce cardioprotective benefits in patients with type 2 diabetes (T2D). As platelet activation and oxidative stress play a key role in atherothrombotic-related complications, we hypothesized that gliflozins might modulate oxidative stress, platelet activation and thrombus formation. We performed an interventional open-label single-arm before-after study in 32 T2D patients on top of their ongoing metformin therapy. The population was divided into two groups: treatment with GLP-1 receptor agonists (GLP-1RA, Group A) and gliflozins (Group B). Oxidative stress, platelet activation and thrombus growth were assessed before and after 15 days of treatment. Compared to the baseline, gliflozins treatment significantly decreased sNOX2-dp (−45.2%, p < 0.001), H2O2 production (−53.4%, p < 0.001), TxB2 (−33.1%, p < 0.001), sP-selectin (−49.3%, p < 0.001) and sCD40L levels (−62.3%, p < 0.001) as well as thrombus formation (−32%, p < 0.001), whereas it potentiated anti-oxidant power (HBA, +30.8%, p < 0.001). Moreover, a significant difference in oxidative stress, platelet activation and thrombus formation across groups A and B was found. In addition, an in vitro study on stimulated platelets treated with gliflozins (10–30 μM) showed a reduction in oxidative stress, platelet activation and thrombus growth. Our results showed that gliflozins have antiplatelet and antithrombic activity related to an NOX2 down-regulation, suggesting a new mechanism responsible for cardiovascular protection.

Background: Protease inhibitors have been considered as possible therapeutic agents for COVID-19 patients.Objectives: To describe the association between lopinavir/ritonavir (LPV/r) or darunavir/cobicistat (DRV/c) use and in-hospital mortality in COVID-19 patients.Study Design: Multicenter observational study of COVID-19 patients admitted in 33 Italian hospitals. Medications, preexisting conditions, clinical measures, and outcomes were extracted from medical records. Patients were retrospectively divided in three groups, according to use of LPV/r, DRV/c or none of them. Primary outcome in a time-to event analysis was death. We used Cox proportional-hazards models with inverse probability of treatment weighting by multinomial propensity scores.Results: Out of 3,451 patients, 33.3% LPV/r and 13.9% received DRV/c. Patients receiving LPV/r or DRV/c were more likely younger, men, had higher C-reactive protein levels while less likely had hypertension, cardiovascular, pulmonary or kidney disease. After adjustment for propensity scores, LPV/r use was not associated with mortality (HR = 0.94, 95% CI 0.78 to 1.13), whereas treatment with DRV/c was associated with a higher death risk (HR = 1.89, 1.53 to 2.34, E-value = 2.43). This increased risk was more marked in women, in elderly, in patients with higher severity of COVID-19 and in patients receiving other COVID-19 drugs.Conclusions: In a large cohort of Italian patients hospitalized for COVID-19 in a real-life setting, the use of LPV/r treatment did not change death rate, while DRV/c was associated with increased mortality. Within the limits of an observational study, these data do not support the use of LPV/r or DRV/c in COVID-19 patients.

Abstract Background With aging of the population, screening and prevention health programs for blood donors will increasingly be a priority. We aimed at: assessing the 10 year-cardiovascular disease (CVD) risk in blood donors, according to Italian CUORE risk score (CRS); determining the association of homocysteine (Hcy), lipoprotein (Lp)(a) and socio-demographic or lifestyle variables with estimated 10-year CVD risk. Methods Between June 2015 and July 2017, 1,447 (61.2% men) unselected blood donors (aged 18–69 years) were enrolled at the Blood Transfusion Service of the Pescara General Hospital, Italy. The project entailed evaluation of unalterable (age and gender) and modifiable CV risk factors (total cholesterol, HDL, LDL, triglycerides, fasting glucose, smoking, hypertension). The educational attainment, socio-demographic and lifestyle behavior information were obtained through a structured self-report questionnaire, and Health-related quality of life (HRQoL) through the Short Form Survey (SF-12). Plasma Hcy and Lp(a) were determined in the fasting state. Results A CRS within the moderate-high risk range was reported in 21.7% donors. Multivariate logistic regression, after adjustment for clinical and demographic variables, showed that Hcy [OR (95% CI): 1.09 (1.04–1.13); p 30 mg/dL in 22.4% of the examined population, but without any significant correlation with CRS. Conclusions Our study highlights a previously unappreciated need for CV risk assessment in blood donors, which may include evaluation of educational attainment as a non-traditional risk marker.

As previously described by several authors, dental pulp stem cells (DPSCs), when adequately stimulated, may acquire a neuronal-like phenotype acting as a favorable source of stem cells in the generation of nerves. Besides, it is known that hypoxia conditioning is capable of stimulating cell differentiation as well as survival and self-renewal, and that multiple growth factors, including Epidermal Growth factor (EGF) and basic fibroblast growth factor (bFGF), are often involved in the induction of the neuronal differentiation of progenitor cells. In this work, we investigated the role of hypoxia in the commitment of DPSCs into a neuronal phenotype. These cells were conditioned with hypoxia (O2 1%) for 5 and 16 days; subsequently, we analyzed the proliferation rate and morphology, and tested the cells for neural and stem markers. Moreover, we verified the possible autocrine/paracrine role of DPSCs in the induction of neural differentiation by comparing the secretome profile of the hypoxic and normoxic conditioned media (CM). Our results showed that the hypoxia-mediated DPSC differentiation was time dependent. Moreover, conditioned media (CM derived from DPSCs stimulated by hypoxia were able, in turn, to induce the neural differentiation of SH-SY5Y neuroblastoma cells and undifferentiated DPSCs. In conclusion, under the herein-mentioned conditions, hypoxia seems to favor the differentiation of DPSCs into neuron-like cells. In this way, we confirm the potential clinical utility of differentiated neuronal DPSCs, and we also suggest the even greater potential of CM-derived-hypoxic DPSCs that could more readily be used in regenerative therapies.

Non-alcoholic fatty liver disease (NAFLD) is the most widespread liver disease, characterized by fatty acids liver accumulation and subsequent fibrosis. NAFLD prevalence ranges from 80% to 90% in obese subjects and is estimated to be around 50% in patients with metabolic syndrome. In this clinical scenario, diet and lifestyle modifications can play an important role. There are several imaging techniques that can accurately diagnose fatty liver. Recently, ultrasound has acquired a leading role in the diagnosis and follow-up of fatty liver disease. Furthermore, elastosonography represents a valid alternative to liver biopsy. Shear wave elastosonography evaluates the elastic and mechanical properties of liver tissue. The aim is to evaluate the effects of lifestyle and nutritional interventions and a loss of body weight during hepatic steatosis through ultrasonographic and elastosonographic techniques. Thirty-two female subjects with metabolic syndrome were subjected to clinical, anthropometric, and laboratory assessments, as well as abdominal ultrasonographic/elastosonographic measurements taken from enrollment time (T0) and after 3 months (T1) of lifestyle modifications. After 3 months of lifestyle changes, significant weight loss was observed, with a marked improvement in all adiposity indices. The laboratory parameters at T1 showed significant decreases in total and LDL cholesterol, triglycerides, basal blood glucose, 120 min glycaemia, basal insulin and HOMA Index (p < 0.001). A similar improvement was observed at T1 for steatosis degree (p < 0.01) and elastosonographic measurements (Kpa p < 0.001). The linear regression analysis of the baseline conditions documented that the size of the liver positively correlated with body weight, BMI, neck and waist circumferences, waist to height ratio (WhtR), insulin and HOMA Index, fat mass and visceral fat, and steatosis grade. After 3 months, the liver size showed improvement with positive correlations to all previous variables. Hepatic stiffness (Kpa) positively correlated with neck circumference, visceral fat, and ALT, with basal insulin, gamma-GT, and AST, and with waist circumference, WhtR, and fat mass. The degree of steatosis was positively correlated with more variables and with greater statistical significance at T1 with respect to T0. Particularly, the positive correlations between the degree of steatosis and neck circumference (p < 0.001), HOMA Index, and triglycerides (p < 0.001) appeared to be very significant. NAFLD management in women with metabolic syndrome should be focused on lifestyle modifications. Moreover, liver involvement and improvement at follow-up could be evaluated in a non-invasive manner through ultrasonographic and elastosonographic techniques.

Background: Growing evidence indicates that cognitive decline and cardiovascular diseases (CVDs) share common vascular risk factors. Protease proprotein convertase subtilisin/kexin type 9 (PCSK9) is associated with CV disease risk and has been also involved in neuronal differentiation.Aim: Evaluate whether in patients at high CV risk cognitive function is related to PCSK9 levels.Methods. One hundred sixty-six patients (67 female) were enrolled. A detailed neuropsychological (NP) assessment was performed. PCSK9 levels were measured with ELISA.Results: Men had significantly higher short-term memory, executive function, and praxic and mental representation skills, as reflected by Forward Digit Span (FDS) (p = 0.005), Trail Making Test-A (TMT-A) (p = 0.047), Clock Drawing Test (CDT) (0.016). Endogenous PCSK9 levels were higher in female (p = 0.005). On linear regression analysis PCSK9 predicts short term memory only in females (Beta = 0.408, p = 0.001), with an interaction between PCSK9 and gender (p = 0.004 for interaction PCSK9 by sex). The association of PCSK9 with FDS in female was partially mediated by waist circumference (mediation effect 8.5%).Conclusions: In patients at high CV risk short term memory was directly related to PCSK9 levels only in women, revealing the relevance of sex in this relationship. The association of PCSK9 with memory function may be mediated, at least in part, by waist circumference.

Proprotein convertase subtilisin/kexin type 9 (PCSK9), mainly secreted in the liver, is a key regulator of cholesterol homeostasis inducing LDL receptors’ degradation. Beyond lipid metabolism, PCSK9 is involved in the development of atherosclerosis, promoting plaque formation in mice and human, impairing the integrity of endothelial monolayer and promoting the events that induce atherosclerosis disease progression. In addition, the PCSK9 ancillary role in the atherothrombosis process is widely debated. Indeed, recent evidence showed a regulatory effect of PCSK9 on redox system and platelet activation. In particular, the role of PCSK9 in the activation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (Nox2) system, of MAP-kinase cascades and of CD36 and LOX-1 downstream pathways, suggests that PCSK9 may be a significant cofactor in atherothrombosis development. This evidence suggests that the serum levels of PCSK9 could represent a new biomarker for the occurrence of cardiovascular events. Finally, other evidence showed that PCSK9 inhibitors, a novel pharmacological tool introduced in clinical practice in recent years, counteracted these phenomena. In this review, we summarize the evidence concerning the role of PCSK9 in promoting oxidative-stress-related atherothrombotic process.