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Very early onset inflammatory bowel disease (VEO-IBD) represents approximately 25% of cases of IBD-like colitis occurring during childhood and, by definition, it is characterized by an onset prior to 6 years of age. This subgroup of patients presents significant differences from IBD occurring in older children and in adults, including a more severe clinical course, a reduced responsiveness to conventional IBD therapy, and a greater proportion of cases featuring an underlying monogenic disorder. Histological findings from gastro-intestinal (GI) biopsies are characterized by an IBD-like, apoptotic or enterocolitis-like pattern, complicating the differential diagnosis with other pediatric diseases involving GI tract. Moreover, individuals with monogenic disorders may develop significant comorbidities, such as primary immunodeficiency (PID), impacting treatment options. Without an appropriate diagnosis, the clinical course of VEO-IBD has greater potential for escalated treatment regimens involving extensive surgery, more intensive medical therapies and, even more important, inadequate recognition of underlying monogenic defect that may lead to inappropriate (sometimes fatal) therapy. For these reasons, an adequate context leading to an appropriate diagnosis is imperative, calling for a close collaboration between pediatricians, pathologists, geneticists, and immunologists.

The use of dasatinib and nilotinib in the treatment of patients with chronic myeloid leukemia represents a valid therapeutic option for patients resistant or intolerant to imatinib. In this multicentre study, adherence, persistence and efficacy in real life over two years of treatment were evaluated.Adherence to treatment was calculated as the ratio between the dose received and the prescribed dose. The dose received was calculated using pharmacy refill data. The persistence with treatment was calculated as the difference between the end and the beginning of the treatment. Efficacy was assigned as Progression-Free Survival (PFS) and Events-Free Survival (EFS) and represented through the Kaplan-Meier curve.The number of patients analysed was 117, 70 treated with dasatinib and 47 with nilotinib. Adherence to treatment for dasatinib and nilotinib at two years was 0.91 and 0.82 respectively. Persistence at two years was 77% while the PFS was 92% for both drugs in the study.Adherence to the treatment calculated over two years showed a superiority of dasatinib over nilotinib. Nevertheless, the efficacy in terms of PFS and EFS is superimposable between the two drugs in the study.

Introduction Following pivotal trials, real-world evidence is important to assess the impact of new drugs in everyday clinical practice. The RESTORE-1 study aimed to compare effectiveness and safety of the second-generation basal insulins (2BI), i.e., insulin glargine 300 U/ml (Gla-300) vs. degludec 100 U/ml (IDeg-100), in type 1 diabetes (T1D). Methods Retrospective, non-inferiority, multicenter study, based on electronic medical records. All patients switching to Gla-300 or IDeg-100 from first-generation basal insulins (1BI) were 1:1 propensity score matched (PSM). Changes during 6 months in HbA1c (primary endpoint), fasting plasma glucose (FPG), body weight, and insulin doses were assessed using linear mixed models for repeated measures. Incidence rates (IR) of hypoglycemic events were assessed. Results Overall, 19 centers provided data on 585 patients in each PSM cohort. For both groups, statistically significant reductions in HbA1c from baseline to 6 months were documented: − 0.20%; (95% CI − 0.32; − 0.08) in the Gla-300 group and − 0.14%; (95% CI − 0.24; − 0.04) in the IDeg-100 group. The non-inferiority of Gla-300 vs. IDeg-100 was confirmed (non-inferiority margin of 0.30%; upper 95% CI at 6 months, 0.09%). No statistically significant between-group differences emerged in FPG and body weight. Dose changes of basal and short-acting insulin were small in both groups, but higher in the Gla-300 group than in the Deg-100 group (p

Introduction Primary aim was to provide real-world evidence of the outcomes after the switch to glargine 300 U/ml (Gla-300) from other basal insulins (first or second generation) in Italy. Methods Multicenter, observational, retrospective study based on electronic medical records. Results Overall, 953 T2DM insulin ± OAD treated people switched to Gla-300 or Gla-100 from January 2015 to July 2018. Three clinically relevant cohorts were identified: patients switching to Gla-300 from first-generation basal insulin (cohort 1), patients switching to Gla-300 from degludec-100 (Deg-100) (cohort 2), and those switching to Gla-100 from any basal insulin (cohort 3). The three cohorts differed in terms of age, diabetes duration, and metabolic control. HbA1c changes after 6 months from the switch were − 0.27% (95% CI − 0.38; − 0.16), − 0.06% (95% CI − 0.31; 0.19), and − 0.30% (95% CI − 0.51; − 0.09) in the three cohorts, respectively. FPG significantly decreased in cohort 1 (− 14.07 mg/dl, 95% CI − 20.25; − 7.89), while body weight significantly decreased in cohort 2 (− 1.47 kg, 95% CI − 2.55; − 0.39). Doses of insulin marginally changed during the follow-up (+ 0.89 U in basal insulin daily dose in cohort 1 and + 2.07 U in short-acting insulin daily dose in cohort 2). Conclusions Switching to Gla-300 from first-generation basal insulin in the real world is associated with improvements in metabolic control despite a suboptimal titration of both basal and short-acting insulins. Inertia in insulin titration documented in the Gla-100 cohort is also observed with the second-generation basal insulin. The switch to Gla-300 from Deg-100 was associated with a decrease in body weight of − 1.47 kg despite a slight increase in short-acting insulin daily doses of about + 2 U.

Understanding the bacterial behavior in response to sublethal stresses is crucial for the optimization of antimicrobial treatments, particularly in food processing. However, the data regarding the effect of sublethal concentrations of essential oils (EOs) on microbial cells are still scarce. In this study, we evaluated the response of Listeria monocytogenes ATCC 7644 to the sublethal concentration of 1.25 μL/mL Origanum vulgare L. EO at 30 °C for 1 h, by means of Phenotype Microarray, modelling the kinetic data obtained by inoculating the control and treated cells into GEN III microplates (Biolog Inc.) for 96 h after EO removal. The results showed important differences regarding the growth dynamics in the presence of carbohydrates and environmental conditions often encountered in food products and that normally sustain the growth of the pathogen (i.e. pH 6.0, pH 5.0, NaCl 1–8%, presence of lactic acid and sodium lactate). In detail, the lag phase of the treated cells was extended, the growth rate was slowed down and the maximum concentration was often significantly reduced. Interestingly, the susceptibility to antimicrobials such as vancomycin, lincomycin and rifamycin was restored after EO application and removal, suggesting a potential role in combating antibiotic resistance. Confocal laser scanner microscopy showed a diffuse aggregation of the treated cells, as a response to the stress encountered. In conclusion, a single exposure to a sublethal concentration of O. vulgare EO causes a stressing effect that persists after its removal. This outcome should be better investigated for potential applications both in food production, to combine low EO concentrations with other hurdles to guarantee food safety, and in medicine, to restore the sensitivity to antibiotics.

Aims This study aimed to evaluate the effectiveness of selected essential oils (EOs) and hydrolates (Hs) against Listeria monocytogenes biofilms on polystyrene (PS) and stainless steel (SS) surfaces. Methods and Results Among others, Origanum hirtum EO, Corydothymus capitatus EO and Citrus aurantium H were selected to treat L. monocytogenes biofilms during and after biofilm formation. Sub-minimum inhibitory concentrations (MICs) of C. capitatus EO (0.31 µl/ml) showed the highest inhibiting effect against biofilm formation on PS, while on SS no significant differences between the EOs were observed (43.7%–88.7% inhibition). Overall, the tested biosanitizers showed limited activity as biofilm removal agents. Although generally less effective, C. aurantium H exhibited good biofilm inhibition performance at 62.5 µl/ml, particularly on PS. Confocal laser scanning microscopy proved that sub-MICs of the biosanitizers drastically changed L. monocytogenes biofilm architecture, with bacterial cells elongation in the presence of C. capitatus EO. Conclusions Our findings suggest that the tested EOs and H are able to control Listeria biofilms, particularly preventing biofilm formation on both materials. Considering its mild aroma and hydrophilicity, the H exhibited promising perspectives of application. Significance and Impact of Study This study raises the possibility of applying EOs and Hs to control biofilms on different surfaces in the food industry.

MG53 is a myokine modulating insulin signaling in several tissues; its relationship to glucose tolerance or risk of developing type 2 diabetes mellitus (T2DM) is unknown. This observational, prospective study aimed at evaluating the relationship between MG53 and glucose tolerance, testing whether its circulating levels may be associated with disease progression in a cohort at high risk of T2DM.Five hundred and fifteen subjects who underwent a deep characterization of their glucose tolerance in the years 2003-2005 participated in this study. MG53 levels were measured at baseline. Glucose tolerance status was available over a follow-up of 15 ± 2 years for 283 of them; their vital status as of December 2020 was also retrieved.MG53 levels were significantly lower in subjects with normal glucose tolerance than in subjects with impaired glucose regulation (IGR) or T2DM. Individuals in the highest MG53 levels quartile had more frequently 1h-post load glucose ≥ 155 mg/dL (54% vs 39%; p = 0.015), worse proportional control of β-cell function (p 0.05-0.01), as determined by mathematical modeling, and worse Disposition Index (DI) (0.0155 ± 0.0081 vs 0.0277 ± 0.0030; p 0.0001). At follow-up, baseline MG53 levels were higher in progressors than in non-progressors (120.1 ± 76.7 vs 72.7 ± 63.2 pg/ml; p = 0.001; ROC curve area for incident diabetes of 0.704). In a multivariable regression with classic risk factors for T2DM and DI, MG53 remained independently associated with progression with T2DM.MG53 may be a novel biomarker of glucose dysregulation associated with β-cell dysfunction, likely improving our ability to identify, among high-risk subjects, those more likely to develop T2DM.

The process in which locally confined epithelial malignancies progressively evolve into invasive cancers is often promoted by unjamming, a phase transition from a solid-like to a liquid-like state that occurs in various tissues. Whether this tissue-level mechanical transition impact phenotypes during carcinoma progression remains unclear. We show, here that the large fluctuations in cell density that accompany unjamming result in repeated mechanical deformations of cells and nuclei. Cells react to these protracted mechanical stresses by mounting a mechano-protective response that includes enlarged nuclear size and rigidity, altered heterochromatin distribution, and the remodeling of the perinuclear actin architecture into actin rings. The chronic strains and stresses associated with unjamming together with reduction of Lamin B1 levels eventually result in DNA damage and nuclear envelope ruptures, with the release of cytosolic DNA that activates a cGAS/STING-dependent cytosolic DNA response gene program. This mechanically-driven transcriptional rewiring ultimately results in a change in cell state, with the emergence of malignant traits, including epithelial-to-mesenchymal plasticity phenotypes and chemo-resistance in invasive breast carcinoma. One-Sentence Summary: A solid-to-fluid phase transition promotes a pro-inflammatory transcriptional response in invasive breast carcinoma

Aims The European Society of Cardiology (ESC) recently defined cardiovascular risk classes for subjects with diabetes. Aim of this study was to explore the distribution of subjects with type 1 diabetes (T1D) by cardiovascular risk groups according to the ESC classification and to describe the quality indicators of care. Methods The study is based on data extracted from electronic medical records of patients treated at the 258 Italian diabetes centers participating in the AMD (Associazione Medici Diabetologi) Annals initiative. Patients with T1D were stratified by cardiovascular risk. Measures of intermediate outcomes, intensity/appropriateness of pharmacological treatment, and overall quality of care were evaluated. Results Overall, 29.368 subjects with type 1 diabetes (64.7% at very high cardiovascular risk, 28.5% at high risk and 6.8% at moderate risk) were evaluated. A lack of use of drugs in case of high values and an inadequate control despite the antihypertensive and lipid-lowering treatment was recognized. The overall quality of care tended to be lower as the level of cardiovascular risk increased. Conclusion A large proportion of subjects with T1D is at high or very high risk. Antihypertensive and lipid-lowering treatment seem not adequately used. Several actions are necessary to improve the quality of care.

Introduction. Gdue is a nutraceutical obtained from the association of two marine algae, Ascophyllum nodosum and Fucus vesiculosus, in addition to chromium picolinate, which could be useful for the treatment of dysglycemia, overweight, and the other components of the metabolic syndrome. The aim of the study was to assess the real-world effectiveness and safety of Gdue when administered to subjects with one or more components of the metabolic syndrome. Methods. A longitudinal, retrospective, observational study, conducted among primary care physicians, nutritionists, and specialists from various disciplines. The impact of 180 days of administration of Gdue was assessed on body weight, waist circumference, fasting blood glucose, HbA1c, lipid profile, and blood pressure levels. The likelihood of experiencing a first major cardiovascular event over ten years was estimated using Italian risk charts. General linear models for repeated measures were applied to assess changes in the parameters of interest during the follow-up. Results are expressed as estimated marginal means with their 95% confidence interval. Results. Overall, 505 patients were enrolled by 282 physicians. After 6 months of treatment with Gdue, body weight was reduced on average by 7.3 kg (-8.0; -6.6), waist circumference by 7.5 cm (-8.2; -6.8), fasting blood glucose by 16.3 mg/dL (-17.8; -14.7), HbA1c by 0.55% (-0.62; -0.49), systolic and diastolic blood pressure by 7.1 mmHg (-8.3; -6.0) and 4.2 mmHg (-5.0; -3.5), respectively, LDL cholesterol by 18.2 mg/dL (-21.2; -15.3), and triglycerides by 39 mg/dL (-45; -32). HDL cholesterol was significantly increased by 2.9 mg/dL (0.7; 5.0). The 10-year risk of cardiovascular events significantly decreased by 1.8%, corresponding to a relative risk reduction of 27.7%. Conclusion. Our real-world study shows that 6 months of treatment with Gdue have an impact on all the components of the metabolic syndrome, thus offering the potential for decreasing the cardiovascular risk associated with metabolic syndrome.

Randomized clinical trials (RCT) showed benefits of FRC of basal insulin (BI) and GLP1-RAs in terms of glycemic target, no weight gain, low risk of hypoglycemia, and gastrointestinal side effects. Real-world evidence (RWE) complements RCT to assess effectiveness and safety of drugs in clinical practice. The study evaluated the impact of iGlarLixi [once-daily FRC of basal insulin glargine 100 U/mL and GLP1-RA lixisenatide] in T2D. This was a retrospective, multicenter study, based on electronic medical records. All subjects initiating iGlarLixi in May 2018-July 2020 were analyzed. Overall, 25 centers provided data on 675 subjects with the following baseline characteristics (mean and standard deviation or proportion): age: 66.4±10.1 years, 54.2% men, T2DM duration 15.5±11.5 years, HbA1c 8.6±1.4%, and BMI 30.8±5.3 Kg/m2. Before starting iGlarLixi, 67.3% of subjects were treated with BI and 9.9% with GLP1-RA (5.5% as free combinations). Drugs associated with iGlarLixi were not only metformin and SGLT2 inhibitors, as by summary of product characteristics (SmPC); off-label combinations were found in 32.4% of patients (21.4% sulphonylureas). Effectiveness data (N=184) showed that HbA1c decreased by -0.77% [95%CI -1.00;-0.54] after 6 months and by -0.92% [95%CI -1.22;-0.62] in patients treated as by SmPC. Weight significantly decreased by 1.21 Kg. iGlarLixi dose increased by 5.14 U. Rates of blood glucose ≤70 and Disclosure R. Candido: None. M. Modugno: None. E. Gabellieri: None. A. Nicolucci: Advisory Panel; Self; AstraZeneca, Research Support; Self; Novo Nordisk, Pikdare, Sanofi, Shionogi & Co., Ltd., SOBI. M. Rossi: Research Support; Self; Novo Nordisk, Sanofi, Shionogi & Co., Ltd., Swedish Orphan Biovitrum AB. M. Larosa: Employee; Self; Sanofi. On behalf of ensure study group: n/a. Funding Sanofi

Second generation basal insulin (2BI) provide similar/improved efficacy with better safety compared to first generation BI. Real-world data on 2BI in patients with type 2 diabetes (T2D) are still limited. The study aimed at comparing effectiveness of 2BI (Gla-300 vs. iDeg-100) in insulin-naïve T2D. This was a retrospective, non-inferiority, multicenter study, from electronic medical records. All patients initiating Gla-300 or iDeg-100 in January 2017-2020 were 1:1 propensity score matched. Linear mixed models for repeated measures were applied to assess changes during 6 months in HbA1c, fasting blood glucose (FBG), body weight, and insulin doses. Incidence rates (IR) of hypoglycemic events were compared using Poisson regression models. Overall, 19 centers provided data on 357 patients in each PSM cohort. Estimated mean baseline levels of HbA1c were 9.2%. Marked reductions in HbA1c after 6 months were documented: -1.70%; (95%CI -1.90; -1.50) in Gla-300 group and -1.69%; (95%CI -1.89; -1.49) in IDeg-100 group (between group mean difference: 0.01; 95%CI -0.29; 0.27), confirming non-inferiority of Gla-300 vs. IDeg-100. FBG was reduced by about 60 mg/dl in both groups; minor changes in body weight were documented. In both groups, the mean prescribed dose was about 12 U (0.15 U/Kg) and was slightly titrated during 6 months up to +4U (0.20 U/Kg). IR (episodes per patient-months) of BG≤70 mg/dl was 0.13 (95%CI 0.07;0.26) in Gla-300 group and 0.14 (95%CI 0.07;0.27) in IDeg-100 group (p=0.87). IR of BG Disclosure G. Fadini: Board Member; Self; Novo Nordisk, Sanofi, Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Lilly Diabetes, Novo Nordisk, Sanofi. R. Buzzetti: None. A. Nicolucci: Advisory Panel; Self; AstraZeneca, Research Support; Self; Novo Nordisk, Pikdare, Sanofi, Shionogi & Co., Ltd., SOBI. M. Rossi: Research Support; Self; Novo Nordisk, Sanofi, Shionogi & Co., Ltd., Swedish Orphan Biovitrum AB. M. Larosa: Employee; Self; Sanofi. D. Cucinotta: None. On behalf of restore-2 study group: n/a. Funding Sanofi

Introduction Real-world evidence on the effectiveness and safety of insulin degludec (IDeg) in patients with diabetes is a priority. We have therefore evaluated the effectiveness and safety of IDeg, including impact on metabolic control, glycemic variability, weight gain and hypoglycemia, in patients with type 1 diabetes under routine clinical practice conditions. Methods This was an observational longitudinal multicenter study. A retrospective chart review of all patients with type 1 diabetes who were switched from basal insulin to IDeg was performed, and temporal trends in clinical outcomes were assessed. Results Data obtained from 195 patients, with a median age of 42.8 [interquartile range (IQR) 24.6–56.4] years and a median diabetes duration of 16 (IQR 10.0–28) years, were analyzed. Median follow-up was 9.5 (IQR 7.7–11.3) months. Improvements were found in glycated hemoglobin (− 0.34%; p

AIM: In this paper, inspiring Darwin’s theory, we propose a model which connects evolutions of neural circuits with evolutions of cosmos. In this model, in the beginning, there are some closed strings which decay into two groups of open strings. METHODS: First group couple to our universe from one side and produce matters like some genes of DNAs and couple to an anti-universe from another side with opposite sign and create anti-matters like some anti-genes of anti-DNAs. Second group couple to the star and planet’s cores like the earth’s core from one side and produce anti-matters like stringy black anti-DNA and couple to outer layers of stars and planets like the earth from other side and produce matters like some genes of DNAs on the earth. Each DNA or anti-DNA contains some genetic circuits which act like the circuits of receiver or sender of radio waves. To transfer waves of these circuits, some neurons emerge which some of them are related to genetic circuits of anti-DNAs in anti-universe, and some are related to genetic circuits of stringy black anti-DNA within the earth’s core. A collection of these neural circuits forms the little brain on the heart at first and main brain after some time. RESULTS: To examine the model, we remove effects of matters in outer layers of earth in the conditions of microgravity and consider radiated signals of neural circuits in a chick embryo. We observe that in microgravity, more signals are emitted by neural circuits respect to normal conditions. This is a signature of exchanged waves between neural circuits and structures within the earth’s core. CONCLUSION: These communications help some animals to predict the time and place of an earthquake.

Following the US Food and Drug Administration (FDA) guidance on the evaluation of novel agents for the treatment of type 2 diabetes mellitus (T2DM), a number of cardiovascular outcomes safety trials (CVOTs) on sodium-glucose cotransporter-2 inhibitors (SGLT2i) have been conducted. These trials show similarities in study design and definition of primary endpoints, but differ in their eligibility criteria. The aim of the present study was to investigate the generalizability of CVOTs on SGLT2i to Italian adults with T2DM; we estimated the proportions of this patient population who would be eligible for enrollment in EMPA-REG OUTCOME (empagliflozin), CANVAS (canagliflozin), DECLARE-TIMI 58 (dapagliflozin), and VERTIS-CV (ertugliflozin) studies. This observational, cross-sectional study was conducted in 222 Italian diabetes clinics. Data on 455,662 adult patients with T2DM seen during 2016 were analyzed against the published patient eligibility criteria for the four CVOTs. The current use of SGLT2i in potentially eligible patients was assessed. Among the population identified, the proportion of patients meeting major eligibility criteria was 11.7% for EMPA-REG OUTCOME, 29.4% for CANVAS, 55.9% for DECLARE-TIMI 58, and 12.8% for VERTIS-CV. Of the patients eligible for these CVOTs, only a minority (range 4.4–6.8%) was actually prescribed an SGLT2i. Compared with patients in the CVOTs, eligible patients in the real world showed older age and longer diabetes duration, lower BMI and HbA1c levels, lower prevalence of established cardiovascular and cerebrovascular disease, and higher rates of microvascular complications and peripheral arterial disease. The percentage of patients potentially eligible for treatment with SGLT2i varies as a reflection of different eligibility criteria applied in the trials. A large number of patients that could benefit from SGLT2i in terms of not only cardiovascular protection but also renal protection do not receive the treatment. AstraZeneca.

To recover chick embryos damaged the brain, two methods are presented. In both of them, somatic cells of an embryo introduced into an egg cell and an embryo have emerged. In one method, injured a part of the brain in the head of an embryo is replaced with a healthy part of the brain. In the second method, the heart of brain embryo dead is transplanted with the embryo heart. In this mechanism, new blood cells are emerged in the bone marrow and transmit information of transplantation to subventricular zone (SVZ) of the brain through the circulatory system. Then, SVZ produces new neural stem cells by a subsequent dividing into neurons. These neurons produce new neural circuits within the brain and recover the injured brain. To examine the model, two hearts of two embryos are connected, and their effects on neural circuits are observed.

Salmonella is a foodborne pathogen able to adhere and persist on biotic and abiotic surfaces, including vegetables, which are even more linked to foodborne outbreaks. In this work, first we investigated the capability of Salmonella to adhere on different surfaces (stainless steel, polypropylene and lettuce), then we evaluated the potential effect of essential oils in reducing the adhesion and persistence of the pathogen on lettuce. Eight essential oils (EO) were tested on five Salmonella enterica strains (serovars Derby, Thompson, Napoli, Kasenyi and Veneziana). Cinnamomum zeylanicum EO (CEO) was the most effective, according to Minimal Inhibitory Concentration (MIC 1.25–1.87 μL/mL) and to growth/inhibition dynamics. To simulate real conditions, a cocktail of Salmonella Kasenyi, S. Veneziana and S. Napoli was applied on the three surfaces, but it adhered only on lettuce, starting from 1 h of contact (4.59 ± 0.34 Log UFC/cm2). Five μL/mL CEO, applied on lettuce, immediately reduced the loosely and strongly attached cells (reduction of 0.78 Log and 0.63 Log CFU/cm2, respectively), with significant effect up to 120 h. CEO also inhibited the Polyphenol Oxidase activity, thus preserving lettuce colour during storage. Cinnamon EO could therefore help to improve safety and appearance of fresh-cut lettuce during storage.

Information on the common carotid artery and cerebral microcirculation can be obtained by micro-ultrasound (µUS). The aim of the study described here was to investigate high-fat diet-induced alterations in vascular parameters in ApoE–/– mice. Twenty-two ApoE–/– male mice were examined by µUS and divided into the standard diet (ApoE–/–SD) and high-fat diet (ApoE–/–HF) groups. The µUS examination was repeated after 4 mo (T1). Carotid stiffness, reflection magnitude and reflection index were measured; the amplitudes of the first (W1) and second (W2) local maxima, the local minimum (Wb) and the reflection index (RIWIA = Wb/W1) were assessed with wave intensity analysis. At T1, ApoE–/–HF mice had increased carotid stiffness (1.48 [0.36] vs. 1.88 [0.51]) and reflection magnitude (0.89 [0.07] vs. 0.94 [0.07]) values. Longitudinal comparisons highlighted increases in carotid stiffness for ApoE–/–HF mice (from 1.37 [0.25] to 1.88 [0.51] m/s) but not for ApoE–/–SD mice (from 1.40 [0.62] to 1.48 [0.36] m/s). ApoE–/–HF mice exhibited carotid artery stiffening and increased wave reflections.

BACKGROUND AND PURPOSE Neuroinflammation and probably systemic inflammation, with abnormal α-synuclein deposition, participate in the development of Parkinson's disease (PD). The P2X7 receptor/NLRP3 inflammasome complex is upregulated in the brain of PD patients. By a prospective approach, the degree of systemic activation of such complex, and its regulatory mechanisms, were explored in treatment-naive PD individuals. METHODS The expression and functional activity of the inflammasome were measured in peripheral blood mononuclear cells of 25 newly diagnosed PD patients and 25 controls at baseline and after 12 months of pharmacological treatment, exploring the intracellular signalling involved and its epigenetic regulation. RESULTS De novo PD patients were characterized by a systemic hyper-expression of the P2X7R/NLRP3 inflammasome platform, probably able to modulate lymphomonocyte α-synuclein, whose brain deposits represent the main pathogenetic factor of PD. A reduced c-Jun N-terminal kinase (JNK) phosphorylation might be the intracellular signalling mediating this effect. miR-7 and miR-30, implied in the pathogenesis of PD and in the post-transcriptional control of α-synuclein and NLRP3 expression, were also increased in PD. After 1 year of usual anti-Parkinson treatments, such inflammatory platform was significantly reduced. CONCLUSIONS Mononuclear cells of newly diagnosed PD subjects display a hyper-expression of the P2X7R/NLRP3 inflammasome platform that seems to modulate cellular α-synuclein content and is reduced after PD treatment; an impaired JNK phosphorylation might be the intracellular signalling mediating this effect, undergoing an epigenetic regulation by miR-7 and miR-30.

Nucleocytosolic transport, a membrane process, is impaired in motor neurons in amyotrophic lateral sclerosis (ALS). This study analyzes the nuclear lipidome in motor neurons in ALS and examines molecular pathways linked to the major lipid alterations. Nuclei were obtained from the frozen anterior horn of the lumbar spinal cord of ALS patients and age-matched controls. Lipidomic profiles of this subcellular fraction were obtained using liquid chromatography and mass spectrometry. We validated the mechanisms behind presumable lipidomic changes by exploring ALS surrogate models including human motor neurons (derived from ALS lines and controls) subjected to oxidative stress, the hSOD-G93A transgenic mice, and samples from an independent cohort of ALS patients. Among the differential lipid species, we noted 41 potential identities, mostly belonging to phospholipids (particularly ether phospholipids, as plasmalogens), as well as diacylglycerols and triacylglycerides. Decreased expression of alkyldihydroxyacetonephosphate synthase (AGPS)-a critical peroxisomal enzyme in plasmalogen synthesis-is found in motor neuron disease models; this occurs in parallel with an increase in the expression of sterol carrier protein 2 (SCP2) mRNA in ALS and Scp2 levels in G93A transgenic mice. Further, we identified diminished expression of diacylglycerol-related enzymes, such as phospholipase C βI (PLCβI) and protein kinase CβII (PKCβII), linked to diacylglycerol metabolism. Finally, lipid droplets were recognized in the nuclei, supporting the identification of triacylglycerides as differential lipids. Our results point to the potentially pathogenic role of altered composition of nuclear membrane lipids and lipids in the nucleoplasm in the anterior horn of the spinal cord in ALS. Overall, these data support the usefulness of subcellular lipidomics applied to neurodegenerative diseases.

Background The European Society of Cardiology (ESC) recently defined cardiovascular risk classes for subjects with diabetes. Aim of this study was to explore the distribution of subjects with type 2 diabetes (T2D) by cardiovascular risk groups according to the ESC classification and to describe the quality indicators of care, with particular regard to cardiovascular risk factors. Methods The study is based on data extracted from electronic medical records of patients treated at the 258 Italian diabetes centers participating in the AMD Annals initiative. Patients with T2D were stratified by cardiovascular risk. General descriptive indicators, measures of intermediate outcomes, intensity/appropriateness of pharmacological treatment for diabetes and cardiovascular risk factors, presence of other complications and overall quality of care were evaluated. Results Overall, 473,740 subjects with type 2 diabetes (78.5% at very high cardiovascular risk, 20.9% at high risk and 0.6% at moderate risk) were evaluated. Among people with T2D at very high risk: 26.4% had retinopathy, 39.5% had albuminuria, 18.7% had a previous major cardiovascular event, 39.0% had organ damage, 89.1% had three or more risk factors. The use of DPP4-i markedly increased as cardiovascular risk increased. The prescription of secretagogues also increased and that of GLP1-RAs tended to increase. The use of SGLT2-i was still limited, and only slightly higher in subjects with very high cardiovascular risk. The overall quality of care, as summarized by the Q score, tended to be lower as the level of cardiovascular risk increased. Conclusions A large proportion of subjects with T2D is at high or very high risk. Glucose-lowering drug therapies seem not to be adequately used with respect to their potential advantages in terms of cardiovascular risk reduction. Several actions are necessary to improve the quality of care.

Background and Objectives: The diagnosis of psychosis is a challenge for the scientific community, both in terms of its definition and treatment. Some recent studies have investigated the relationship between personality and psychosis onset to prevent or intervene early. Materials and Methods: Sixty young adults were recruited during their first access in 2019 near the Community Mental Health Service of Niguarda Hospital, Milan, Italy. The assessment included the Social and Occupational Functioning Assessment Scale (SOFAS), the Global Assessment of Functioning (GAF) (clinician scales), the 16-item Version of the Prodromal Questionnaire (PQ-16), the Personality Inventory for DSM-5 (PID-5) (self-report), and a clinical session. Statistical analysis was performed by SPSS. Results: The results show a negative correlation between the Detachment domain and the GAF scores. Correlational analysis also highlights that all PID-5 domains, except for Antagonism, have positive correlations with high scores in the PQ-16. The multivariate analysis of variance showed that patients diagnosed with versus without a psychotic disorder significantly differed on Detachment, Antagonism and Psychoticism PID-5 domains. Conclusions: The involvement of the personality construct in psychopathological development is displayed. In particular, higher levels of Detachment and Psychoticism can distinguish people who are more vulnerable to psychosis or who already have overt psychosis from those who do not have a psychotic predisposition. The study highlights the fundamental role of personality traits, emerging from PID-5, to distinguish young adults at risk of onset.

Coronavirus disease 19 (COVID-19) has had a strong psychological impact on the Italian population. Italy was heavily affected by the virus before other countries in Europe, experiencing the highest number of deaths. Unknown symptoms in the early stages of the pandemic and the absence of clear transmission links affected people’s wellbeing. Individual personality differences played a key role in perceived psychological wellbeing during the pandemic. The present exploratory study sought to evaluate the impact of COVID-19 on psychological health and identify how psychological wellbeing is influenced by personality traits. A total of 2103 participants (64% female and 36% male) completed an online survey that included the Psychological General Wellbeing Index (PGWBI), the Italian Short Personality Inventory (ITAPI), and a general questionnaire. Descriptive statistics and hierarchical regressions were performed using SPSS 25.0 (IBM Corp., Armonk, NY, USA) (The findings showed poor psychological wellbeing in the Italian population. Young people reported the lowest scores. Vulnerability traits negatively influenced some PGWBI domains, such as the total score (β = −0.62), anxiety (β = −0.55), depression (β = −0.46), positivity and wellbeing (β = −0.51), vitality (β = −0.45), general health (β = −0.12), and self-control (β = −0.52). On the other hand, dynamism traits positively affected vitality (β = 0.12) and positivity and wellbeing (β = 0.14). In other words, personality factors related to vulnerability in particular created risk, whereas dynamism offered protection. The results highlight how COVID-19 helped to trigger anxious and depressive states. People feel helpless and vulnerable when facing new, unexpected conditions caused by the virus. These findings may assist mental healthcare professionals in safeguarding psychological wellbeing during emergencies such as the pandemic.

Despite much progress in improving graft outcome during cardiac transplantation, chronic allograft vasculopathy (CAV) remains an impediment to long‐term graft survival. MicroRNAs (miRNAs) emerged as regulators of the immune response. Here, we aimed to examine the miRNA network involved in CAV. miRNA profiling of heart samples obtained from a murine model of CAV and from cardiac‐transplanted patients with CAV demonstrated that miR‐21 was most significantly expressed and was primarily localized to macrophages. Interestingly, macrophage depletion with clodronate did not significantly prolong allograft survival in mice, while conditional deletion of miR‐21 in macrophages or the use of a specific miR‐21 antagomir resulted in indefinite cardiac allograft survival and abrogated CAV. The immunophenotype, secretome, ability to phagocytose, migration, and antigen presentation of macrophages were unaffected by miR‐21 targeting, while macrophage metabolism was reprogrammed, with a shift toward oxidative phosphorylation in naïve macrophages and with an inhibition of glycolysis in pro‐inflammatory macrophages. The aforementioned effects resulted in an increase in M2‐like macrophages, which could be reverted by the addition of L‐arginine. RNA‐seq analysis confirmed alterations in arginase‐associated pathways associated with miR‐21 antagonism. In conclusion, miR‐21 is overexpressed in murine and human CAV, and its targeting delays CAV onset by reprogramming macrophages metabolism., The authors show that, after heart transplantation, microRNA‐21 is overexpressed in chronic allograft vasculopathy (CAV), that pharmacological and genetic modulation of microRNA‐21 mitigated CAV, and that microRNA‐21 antagonism abrogated CAV by reprogramming macrophage metabolism.

The neonatal and paediatric spectrum of small bowel disorders encompass a wide variety of conditions, ranging from food allergies to life-threatening surgical emergencies or life-long medical conditions and, as such, it comes with a whole set of diagnostic challenges for the non-paediatric pathologist. Histologic examination is a cornerstone of diagnosis in a large number of diseases and may still provide important diagnostic clues in the appropriate clinical context. In this review, divided in two sections, we aim to provide a comprehensive histopathological summary of paediatric small bowel alteration and their differential diagnoses with a reference to the main clinical aspects required for appropriate interpretation. Specifically, in this first part, we describe congenital and metabolic disorders, intestinal lymphangiectasia, immunodeficiencies, GVHD, and necrotising enterocolitis.

Objective To evaluate sodium-glucose cotransporter-2 (SGLT-2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists in patients with type 2 diabetes at varying cardiovascular and renal risk. Design Network meta-analysis. Data sources Medline, Embase, and Cochrane CENTRAL up to 11 August 2020. Eligibility criteria for selecting studies Randomised controlled trials comparing SGLT-2 inhibitors or GLP-1 receptor agonists with placebo, standard care, or other glucose lowering treatment in adults with type 2 diabetes with follow up of 24 weeks or longer. Studies were screened independently by two reviewers for eligibility, extracted data, and assessed risk of bias. Main outcome measures Frequentist random effects network meta-analysis was carried out and GRADE (grading of recommendations assessment, development, and evaluation) used to assess evidence certainty. Results included estimated absolute effects of treatment per 1000 patients treated for five years for patients at very low risk (no cardiovascular risk factors), low risk (three or more cardiovascular risk factors), moderate risk (cardiovascular disease), high risk (chronic kidney disease), and very high risk (cardiovascular disease and kidney disease). A guideline panel provided oversight of the systematic review. Results 764 trials including 421 346 patients proved eligible. All results refer to the addition of SGLT-2 inhibitors and GLP-1 receptor agonists to existing diabetes treatment. Both classes of drugs lowered all cause mortality, cardiovascular mortality, non-fatal myocardial infarction, and kidney failure (high certainty evidence). Notable differences were found between the two agents: SGLT-2 inhibitors reduced admission to hospital for heart failure more than GLP-1 receptor agonists, and GLP-1 receptor agonists reduced non-fatal stroke more than SGLT-2 inhibitors (which appeared to have no effect). SGLT-2 inhibitors caused genital infection (high certainty), whereas GLP-1 receptor agonists might cause severe gastrointestinal events (low certainty). Low certainty evidence suggested that SGLT-2 inhibitors and GLP-1 receptor agonists might lower body weight. Little or no evidence was found for the effect of SGLT-2 inhibitors or GLP-1 receptor agonists on limb amputation, blindness, eye disease, neuropathic pain, or health related quality of life. The absolute benefits of these drugs vary substantially across patients from low to very high risk of cardiovascular and renal outcomes (eg, SGLT-2 inhibitors resulted in 3 to 40 fewer deaths in 1000 patients over five years; see interactive decision support tool ( https://magicevidence.org/match-it/200820dist/#!/ ) for all outcomes. Conclusions In patients with type 2 diabetes, SGLT-2 inhibitors and GLP-1 receptor agonists reduced cardiovascular and renal outcomes, with some differences in benefits and harms. Absolute benefits are determined by individual risk profiles of patients, with clear implications for clinical practice, as reflected in the BMJ Rapid Recommendations directly informed by this systematic review. Systematic review registration PROSPERO CRD42019153180.

Introduction: Colon cancer (CC) and epithelial ovarian cancer (EOC) are common and severe neoplasms frequently sharing a massive inflammatory involvement of peritoneum. A detailed molecular characterization of such carcinomatosis has not been performed, so far. Methods: Omental adipocytes were isolated from thirty-three adult women who underwent primary surgery for CC or EOC. Expression of several pro-inflammatory genes was determined by real-time PCR and immunofluorescence. Data were related to the clinical phenotype of the patients. Results: CD68, FGFR1, and IL-6 were significantly more expressed in adipocytes from CC patients and VEGF in adipocytes from EOC. TNFα, TGFβ, or MCP-1, as well as the pro-inflammatory platform P2X7R-NLRP3, did not differ between the 2 cancers. White blood cell count, mirroring systemic inflammation, was related to adipocyte P2X7R (R = 0.508, p = 0.003), NLRP3 (R = 0.405; p = 0.02), and MCP-1 (R = 0.448; p = 0.009). P2X7R and NLRP3 were the only inflammatory factors significantly more expressed in patients carrying both omental and peritoneal carcinosis, who were also characterized by a higher leukocytosis. None of the tested inflammatory markers was associated with tumor grading for both neoplasms; however, the presence of metastases was associated with a higher adipocyte expression of FGFR1 and TGFβ. Conclusion: We show here that rarely measured molecules seem to specifically characterize omental carcinomatosis of CC or EOC, while more common inflammatory agents like TNFα, TGFβ, or MCP-1 do not; the P2X7R-NLRP3 complex marks omental and peritoneal carcinosis and is related to circulating white blood cells and MCP-1, involved in monocyte-macrophage tissue infiltration; increased TGFβ and FGFR1 characterize the tumoral dissemination.

In dairy processing environments, many bacterial species adhere and form biofilms on surfaces and equipment, leading to foodborne illness and food spoilage. Among them, Listeria monocytogenes and Pseudomonas spp. could be present in mixed-species biofilms. This study aimed to evaluate the interactions between L. monocytogenes and P. fluorescens in biofilms simulating dairy processing conditions, as well as the capability of P. fluorescens in co-culture to produce the blue pigment in a Ricotta-based model system. The biofilm-forming capability of single- and mixed-cultures was evaluated on polystyrene (PS) and stainless steel (SS) surfaces at 12 &deg, C for 168 h. The biofilm biomass was measured, the planktonic and sessile cells and the carbohydrates in biofilms were quantified. The biofilms were also observed through Confocal Laser Scanning Microscopy analysis. Results showed that only P. fluorescens was able to form biofilms on PS. Moreover, in dual-species biofilms at the end of the incubation time (168 h at 12 &deg, C), a lower biomass compared to P. fluorescens mono-species was observed on PS. On SS, the biofilm cell population of L. monocytogenes was higher in the dual-species than in mono-species, particularly after 48 h. Carbohydrates quantity in the dual-species system was higher than in mono-species and was revealed also at 168 h. The production of blue pigment by P. fluorescens was revealed both in single- and co-culture after 72 h of incubation (12 &deg, C). This work highlights the interactions between the two species, under the experimental conditions studied in the present research, which can influence biofilm formation (biomass and sessile cells) but not the capability of P. fluorescens to produce blue pigment.

Background Neuro, and likely systemic inflammation, with abnormal α-synuclein deposition, participate in the development of Parkinson’s disease (PD). The P2 × 7 receptor/NLRP3 inflammasome complex is upregulated in the brain of PD patients. Aim of this study was to explore whether the systemic activation of such complex might participate in the pathogenesis of PD. Methods Systemic expression and functional activity of the inflammasome were measured in 25 newly diagnosed PD patients and 25 controls at baseline and after twelve months of pharmacologic treatment, exploring the involved intracellular signalling and its epigenetic regulation. A putative mechanistic explanation of the results was validated in a murine model of neuroinflammation. Results De-novo PD patients were characterized by a systemic hyper-expression of the P2 × 7R/NLRP3 inflammasome platform, likely modulating circulating and lymphomonocyte α-synuclein, whose deposits represent the main pathogenetic factor of PD. A reduced JNK phosphorylation might be the involved intracellular signalling. miR-7 and miR-30, implied in the pathogenesis of PD and in the post-transcriptional control of α-synuclein and NLRP3 expression, were also increased in PD. After one year of usual anti-Parkinson treatments, such inflammatory platform was significantly reduced. In the substantia nigra of P2 × 7R KO mice, a neuroinflammatory stimulus induced a strong expression of parkin, a protective protein, suggesting that P2 × 7R activation might participate in the inflammatory damage occurring in specific brain areas also by inhibiting parkin expression. Conclusion Newly-diagnosed PD subjects display a systemic hyper-expression of the P2 × 7R/NLRP3 inflammasome platform that seems to modulate circulating and lymphomonocyte α-synuclein; a reduced JNK phosphorylation might be the intracellular signalling mediating this effect, undergoing an epigenetic regulation by miR-7 and miR-30. Trial registration ClinicalTrials.gov (NCT03918616).

The aim of this study was to assess the impact of osteopathic manipulative treatment (OMT) on newborn babies admitted at a neonatal intensive care unit (NICU). This was an observational, longitudinal, retrospective study. All consecutive admitted babies were analyzed by treatment (OMT vs. usual care). Treatment group was randomly assigned. Between-group differences in weekly weight change and length of stay (LOS) were evaluated in the overall and preterm populations. Among 1249 babies (48.9% preterm) recorded, 652 received usual care and 597 received OMT. Weight increase was more marked in the OMT group than in the control group (weekly change: +83 g vs. +35 g, p &lt, 0.001). Similar trends were found in the subgroup of preterm babies. A shorter LOS was found in the OMT group vs. the usual care group both in overall population (average mean difference: &minus, 7.9 days, p = 0.15) and in preterm babies (&minus, 12.3 days, p = 0.04). In severe preterm babies, mean LOS was more than halved as compared to the control group. OMT was associated with a more marked weekly weight increase and, especially in preterm babies, to a relevant LOS reduction: OMT may represent an efficient support to usual care in newborn babies admitted at a NICU.

Breast lesions classified as of “uncertain malignant potential” represent a heterogeneous group of abnormalities with an increased risk of associated malignancy. Clinical management of B3 lesions diagnosed on vacuum-assisted breast biopsy (VABB) is still challenging: surgical excision is no longer the only available treatment and VABB may be sufficient for therapeutic excision. The aim of the present study is to evaluate the positive predictive value (PPV) for malignancy in B3 lesions that underwent surgical excision, identifying possible upgrading predictive factors and characterizing the malignant lesions eventually diagnosed. These results are compared with a subset of patients with B3 lesions who underwent follow-up. A total of 1250 VABBs were performed between January 2006 and December 2017 at our center. In total, 150 B3 cases were diagnosed and 68 of them underwent surgical excision. VABB findings were correlated with excision histology. A PPV for malignancy for each B3 subtype was derived. The overall PPV rate was 28%, with the highest upgrade rate for atypical ductal hyperplasia (41%), followed by classical lobular neoplasia (29%) and flat epithelial atypia (11%). Only two cases of carcinoma were detected in the follow-up cohort, both associated with atypical ductal hyperplasia at VABB. Open surgery is recommended in case of atypical ductal hyperplasia while, for other B3 lesions, excision with VABB only may be an acceptable alternative if radio-pathological correlation is assessed, if all microcalcifications have been removed by VABB, and if the lesion lacks high-risk cytological features. • Surgical treatment is strongly recommended in case of ADH, while the upgrade rate in case of pure FEA, especially following complete microcalcification removal by VABB, may be sufficiently low to advice surveillance as a management strategy. • The use of 11-G- or 8-G-needle VABB, resulting in possible complete diagnostic excision of the lesion, can be an acceptable alternative in case of RS, considering open surgery only for selected high-risk patients. • LN management is more controversial: surgical excision may be recommended following classical LN diagnosis on breast biopsy if an additional B3 lesion is concurrently detected while in the presence of isolated LN with adequate radiological-pathological correlation follow-up alone could be an acceptable option.

Purpose The goal of this study was to evaluate the effectiveness and safety of exenatide once weekly (EOW) and to determine predictors of treatment response and drug discontinuation in patients with type 2 diabetes mellitus (T2DM) followed up for 18 months in a real-world setting. Methods This retrospective cohort study included patients with T2DM who initiated EOW 2 mg between 2014 and 2019 in an outpatient diabetes clinic in Italy. Data were collected at baseline and at follow-up visits (6, 12, and 18 months after EOW). We estimated glycosylated hemoglobin (HbA1c) and body weight mean changes from baseline to follow-up visits and assessed the proportion of patients reaching HbA1c target ≤7% and a 5% weight loss after 12 months of treatment. We then attempted to establish predictors of glycemic and weight response, and compared patient characteristics between subjects who persisted on treatment versus those who discontinued EOW. Findings One-hundred eighty-six patients (46.2% male) were included in the study. The mean (SD) age and diabetes duration were 63.2 (8.9) years and 10.7 years (18.3), respectively. Significant reductions in HbA1c values (−0.9%; 95% CI, −1.1 to −0.8) and body weight (−2.8 kg; 95% CI, −3.4 to −2.2) were observed after 6 months. Sixty-one percent of patients (87 of 143) achieved target HbA1c values ≤ 7% after 12 months, and 34% (45 of 134) exhibited a weight loss of at least 5% of baseline body weight. Blood glucose and weight reductions were maintained after an 18-month follow-up. Predictors of adequate glycemic and weight response were shorter diabetes duration and nonuse of a different GLP-1RA, respectively. Patients on sulfonylureas failed to reach metabolic and body weight targets. The most common adverse events were gastrointestinal side effects (7.5%) and injection site reactions (6.4%), followed by headache (1.1%) and allergic reactions (1.1%). Forty-three percent of patients (79 of 186) discontinued EOW. The main reasons for discontinuation were insufficient HbA1c improvement and/or limited weight reduction (19.9%), side effects (16.1%), or patient decision (6.5%). Predictors of discontinuation were higher HbA1c levels at baseline and use of basal insulin therapy before EOW treatment. Implications EOW treatment, in a real-world setting, offers sustained and effective glycemic control and weight loss over 18 months in patients with T2DM. Diabetes duration and basal insulin therapy, however, may affect the outcome of EOW treatment, suggesting that early initiation of EOW could improve glycemic control and reduce the risk of treatment discontinuation.

Objectives This study aimed to describe the preliminary results of a modified sympathicotomy for cardiac sympathetic denervation (CSD), which may reduce the predictive risk and intraoperative surgical time of the procedure. Background CSD, in patients with refractory ventricular tachycardia (VT), is comprehensively recognized as an important treatment option for patients with structural heart disease as well as congenital inherited arrhythmia syndrome. Methods We consecutively enrolled 5 patients with refractory VT. Baseline demographic, medical, and surgical data as well as arrhythmia outcomes and procedural complications were evaluated. Results A total of 5 patients (mean age: 67.4 years) were enrolled for the treatment of refractory VT with a modified CSD technique. In 3 of 5 patients, an overall reduction in VT burden (ranging from 75% to 100%) and VT number was observed after the CSD despite an in-hospital early recurrence. Conclusions A modified CSD (sympathicotomy T2–T5) with stellate ganglion sparing and the use of unipolar radiofrequency is feasible, effective, and safe in the setting of untreatable VT.

Background No data exist about the changes induced by the transition from first‐generation long‐acting insulins to second‐generation long‐acting analogues in the paediatric population. Objective To assess changes in insulin/carbohydrate ratio (I:CHO) after the first 6 months of degludec therapy in a paediatric population with type 1 diabetes previously treated with glargine U100. Subjects All patients treated with degludec under routine clinical practice conditions were retrospectively analysed. Methods Nonprofit observational retrospective study. Changes during the follow‐up in mean CHO/I ratio were assessed using longitudinal linear models for repeated measures. Rate of hypoglycaemia, ketoacidosis and adverse events was evaluated. Results Overall, 51 children (mean age 13.8 ± 4.6 years; mean diabetes duration 5.8 ± 3.9 years) started therapy with degludec in the period between April 2017 and April 2018. I:CHO ratio before starting degludec therapy significantly differed among the three meals, being the lowest at breakfast and the highest at dinner. After introducing degludec, I:CHO ratio at lunch (−1.29 95% CI −2.02;−0.57) and at dinner (−3.08 95% CI −4.35;−1.8) significantly decreased, while it slightly increased at breakfast (+1.37 95% CI 0.47;2.28). No episodes of severe hypoglycaemia, ketoacidosis and adverse event were recorded during 6 months. Conclusions Our data show that the use of degludec is associated with a significant change in the I:CHO ratio at the different meals compared to the previous glargine therapy. This could derive from the flat and prolonged pharmacokinetic profile of degludec. This has important clinical implications for daily insulin dose adjustments., No data exist about the changes induced by the transition from first‐generation long‐acting insulins to second‐generation long‐acting analogues in the paediatric population. The study assessed changes in insulin/carbohydrate ratio (I:CHO) after the first 6 months of degludec therapy in a paediatric population with type 1 diabetes previously treated with glargine U100. Our data showed that the use of degludec is associated with a flattening in the I:CHO ratio at the different meals compared to the previous glargine therapy.

Lung infections caused by Pseudomonas aeruginosa pose a serious threat to patients suffering from, among others, cystic fibrosis, chronic obstructive pulmonary disease, or bronchiectasis, often leading to life-threatening complications. The establishment of a chronic infection is substantially related to communication between bacteria via quorum-sensing networks. In this study, we aimed to assess the role of quorum-sensing signaling molecules of the Pseudomonas quinolone signal (PQS) and to investigate the viscoelastic properties of lung tissue homogenates of PA-infected mice in a prolonged acute murine infection model. Therefore, a murine infection model was successfully established via intra-tracheal infection with alginate-supplemented Pseudomonas aeruginosa NH57388A. Rheological properties of lung homogenates were analyzed with multiple particle tracking (MPT) and quorum-sensing molecules were quantified with LC–MS/MS. Statistical analysis of bacterial load and quorum-sensing molecules showed a strong correlation between these biomarkers in infected lungs. This was accompanied by noticeable changes in the consistency of lung homogenates with increasing infection severity. Furthermore, viscoelastic properties of the lung homogenates strongly correlated with bacterial load and quorum sensing molecules. Considering the strong correlation between the viscoelasticity of lung homogenates and the aforementioned biomarkers, the viscoelastic properties of infected lungs might serve as reliable new biomarker for the evaluation of the severity of P. aeruginosa infections in murine models.

Elimination of pulmonary Pseudomonas aeruginosa (PA) infections is challenging to accomplish with antibiotic therapies, mainly due to resistance mechanisms. Quorum sensing inhibitors (QSIs) interfering with biofilm formation can thus complement antibiotics. For simultaneous and improved delivery of both active agents to the infection sites, self‐assembling nanoparticles of a newly synthesized squalenyl hydrogen sulfate (SqNPs) were prepared. These nanocarriers allowed for remarkably high loading capacities of hydrophilic antibiotic tobramycin (Tob) and a novel lipophilic QSI at 30 % and circa 10 %, respectively. The drug‐loaded SqNPs showed improved biofilm penetration and enhanced efficacy in relevant biological barriers (mucin/human tracheal mucus, biofilm), leading to complete eradication of PA biofilms at circa 16‐fold lower Tob concentration than Tob alone. This study offers a viable therapy optimization and invigorates the research and development of QSIs for clinical use., Breaking through: Tob and QSI (1) co‐loaded squalenyl hydrogen sulfate nanoparticles (SqNPs) are shown to act on all stages of P. aeruginosa infections to eradicate bacterial infection [(a–c) and (e)] and penetrate biofilm, preventing its formation and recurrence (d).

Chemical disinfectants represent one of the commonly used practice in minimal processed vegetables food-chain. However, the scarce safety and sustainability of these agents force food industry to move toward more sustainable “green washing solutions”. Among the latter, while the application of plant derivates for the control of several pathogens is already well-known, specific information on the potential anti-Salmonella activity of Coriandrum sativum seeds derivates are still limited and were therefore investigated in this study. In detail, Minimal Inhibitory Concentration (MIC) and Minimal Bactericidal Concentration (MBC) of different coriander seed derivates (i.e. essential oil, hydrosol and ethanolic extract) were determined by broth dilution against six Salmonella enterica strains isolated from fresh and minimally processed fruits and vegetables. Only the essential oil (EO) was effective in vitro with strain-dependent results. In addition, when mixed in co-culture, the strains were more sensitive to the essential oil treatment. Chemical investigations allowed to define (s)-(+)-linalool as major compound, and to underline interesting phenolic content with correlated antioxidant capacity. A cocktail of three strains of different serovars was selected and employed for a preliminary in situ trial on stick carrots. The obtained results allowed to establish that the application of coriander seed EO at concentrations of 5 µL mL-1 was able to reduce and contain the growth of the Salmonella cocktail up to 24 hours at 10°C. Good sensory evaluation results were obtained by applying this EO concentration as washing treatment, especially in terms of color parameter. Further studies should be undertaken to emphasize the upstream activity, improving the formulation or exploiting a combined effect with other sanitizers or treatments (e.g. physical treatments). The present study contributes to the knowledge on coriander derivates activity against Salmonella spp. and on the potential application as sustainable washing treatment in removing this pathogen from fresh cut carrots.

Primary myelofibrosis (PMF) is a myeloproliferative neoplasm characterized by an excessive production of pro-inflammatory cytokines resulting in chronic inflammation and genomic instability. Besides the driver mutations in JAK2, MPL, and CALR genes, the deregulation of miRNA expression may also contribute to the pathogenesis of PMF. To this end, we recently reported the upregulation of miR-382-5p in PMF CD34+ cells. In order to unveil the mechanistic details of the role of miR-382-5p in pathogenesis of PMF, we performed gene expression profiling of CD34+ cells overexpressing miR-382-5p. Among the downregulated genes, we identified superoxide dismutase 2 (SOD2), which is a predicted target of miR-382-5p. Subsequently, we confirmed miR-382-5p/SOD2 interaction by luciferase assay and we showed that miR-382-5p overexpression in CD34+ cells causes the decrease in SOD2 activity leading to reactive oxygen species (ROS) accumulation and oxidative DNA damage. In addition, our data indicate that inhibition of miR-382-5p in PMF CD34+ cells restores SOD2 function, induces ROS disposal, and reduces DNA oxidation. Since the pro-inflammatory cytokine transforming growth factor-β1 (TGF-β1) is a key player in PMF pathogenesis, we further investigated the effect of TGF-β1 on ROS and miR-382-5p levels. Our data showed that TGF-β1 treatment enhances miR-382-5p expression and reduces SOD2 activity leading to ROS accumulation. Finally, inhibition of TGF-β1 signaling in PMF CD34+ cells by galunisertib significantly reduced miR-382-5p expression and ROS accumulation and restored SOD2 activity. As a whole, this study reports that TGF-β1/miR-382-5p/SOD2 axis deregulation in PMF cells is linked to ROS overproduction that may contribute to enhanced oxidative stress and inflammation. Our results suggest that galunisertib may represent an effective drug reducing abnormal oxidative stress induced by TGF-β1 in PMF patients. DATABASE LINKING: GEO: https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE103464.

In the last years, due to new regulatory guidelines requiring a stringent documentation of cardiovascular (CV) safety of novel drugs for type 2 diabetes, cardiovascular outcomes safety trials (CVOTs) are requested. CVOTs increase the knowledge about the safety profile of the new drugs, but they have intrinsic limits that make difficult their transferability to clinical practice. For this reason, real world evidence is considered an important complement to experimental data. Among the glucagon-like peptide-1 receptor agonists, liraglutide in the LEADER CVOT demonstrated superiority in reducing the risk of major CV events (MACEs) vs. placebo. We conducted an observational, retrospective, longitudinal study based on 307 patients with T2DM treated with liraglutide under routine clinical practice conditions. Real world impact of liraglutide on metabolic control, CV risk factors, hypoglycemia and CV events was assessed. Improvements during 36 months were found in HbA1c (–1.0%; p Incidence of MACEs in this cohort was lower than in the LEADER study (2.59 vs. 3.4 events per 100 person-years), confirming CV safety of liraglutide even in the real world. On the other hand, a higher incidence of CV event in patients with established CV disease was documented (8.1 events per 100 person-years), in spite of the use of liraglutide. In conclusion, 36-month durability and CV safety of liraglutide were documented in a real world cohort of T2DM patients, with sustained benefits on a large array of CV risk factors.

Introduction Real-world evidence on effectiveness and safety of insulin degludec (IDeg) in patients with diabetes is a priority. The aim of the study was to evaluate patterns of use and the long-term effectiveness and safety of IDeg in routine clinical practice. Methods This was an observational longitudinal study. A retrospective chart review of all patients with type 2 diabetes treated with IDeg was performed and temporal trends in clinical outcomes were assessed. All data was stratified by treatment modality: the switch group consisted of patients already treated with another basal insulin before initiating IDeg; the add-on group consisted of basal insulin-naïve patients. Results Overall, 247 patients were analyzed (55 in the add-on group and 192 in the switch group), mean age 67.0 ± 10.9 years ,and diabetes duration 16.3 ± 8.9 years. Median (interquartile range) follow-up was 9.7 (8.0–11.9) months. In the add-on group, improvements were found in glycated hemoglobin (HbA1c) (– 1.68%; p

The affiliations listed for author Antonio Ceriello have been amended to a single affiliation note, …

Background P esticides have a negative impact on the health of consumers and on the environment, and as a consequence, the use of naturally occurring antimicrobial agents have become more popular to prevent food spoilage. An alternative is the use of chitosan, because of its antimicrobial, antioxidant activities and its capacity to form films having good mechanical properties. Chitosan has been used in the preparation of films and coatings for the preservation of different food products, and the addition of essential oils have been shown to be a good strategy to improve its antimicrobial activity in situ. Scope and approach This review compiles information related to studies and research that employ chitosan as matrix for films, coatings and nanogels with essential oils extracted from plants, as antifungal agent. A special emphasis has been addressed to the effect exerted on the most pathogenic fungi for crops, also highlighting the mechanisms of action that researchers attribute to the composite, together with inhibition data. Key Findings and Conclusion Effective natural treatments, using chitosan-essential oils films or nano-emulsions, improve the preservation of fruit in terms of fungal decay. The effect is particularly dependent on the ability to release the antimicrobial compounds from the polymer matrix, the type of essential oils, the fungal species, and the incubation temperature. Several efforts are still required to understand in detail the mechanism of degradation of perishable food, how the chitosan-essential oils composites control or inhibit food decay, the effects on other pathogenic and non-pathogenic moulds as well as on the production of mycotoxins.

Rodent-borne hanta- and arenaviruses are an emerging public health threat in Europe; however, their circulation in human populations is usually underestimated since most infections are asymptomatic. Compared to other European countries, Italy is considered 'low risk' for these viruses, yet in the Province of Trento, two pathogenic hantaviruses (Puumala and Dobrava-Belgrade virus) and one arenavirus (Lymphocytic Choriomeningitis Virus) are known to circulate in rodent reservoirs. In this paper, we performed a follow-up serological screening in humans to detect variation in the prevalence of these three viruses compared to previous analyses carried out in 2002. We also used a statistical model to link seropositivity to risk factors such as occupational exposure, cutting firewood, hunting, collecting mushrooms, having a garden and owning a woodshed, a dog or a companion rodent. We demonstrate a significant increase in the seroprevalence of all three target viruses between 2002 and 2015, but no risk factors that we considered were significantly correlated with this increase. We conclude that the general exposure of residents in the Alps to these viruses has probably increased during the last decade. These results provide an early warning to public health authorities, and we suggest more detailed diagnostic and clinical investigations on suspected cases.

Calreticulin (CALR) is a chaperone protein that localizes primarily to the endoplasmic reticulum (ER) lumen where it is responsible for the control of proper folding of neo-synthesized glycoproteins and the retention of calcium. Recently, mutations affecting exon 9 of the CALR gene have been described in approximately 40% of patients with myeloproliferative neoplasms (MPNs). Although the role of mutated CALR in the development of MPNs has begun to be clarified, there are still no data available on the function of wild-type (WT) CALR during physiological hematopoiesis. To shed light on the role of WT CALR during normal hematopoiesis, we performed gene silencing and overexpression experiments in hematopoietic stem progenitor cells (HSPCs). Our results showed that CALR overexpression is able to affect physiological hematopoiesis by enhancing both erythroid and megakaryocytic (MK) differentiation. In agreement with overexpression data, CALR silencing caused a significant decrease in both erythroid and MK diff...

Among pathogens, L. monocytogenes has the capability to persist on Food Processing Environment (FPE), first of all posing safety issues, then economic impact on productivity. The aim of this work was to determine the influence of biofilm forming-ability and molecular features on the persistence of 19 Listeria monocytogenes isolates obtained from FPE, raw and processed products of a cold-smoked salmon processing plant. To verify the phenotypic and genomic correlations among the isolates, different analyses were employed: serotyping, Clonal Complex (CC), core genome Multi-Locus Sequence Typing (cgMLST) and Single Nucleotide Polymorphisms (SNPs) clustering, and evaluation of the presence of virulence- and persistence-associated genes. From our results, the biofilm formation was significantly higher (*P 0.05) at 37 °C, compared to 30 and 12 °C, suggesting a temperature-dependent behaviour. Moreover, the biofilm-forming ability showed a strain-specific trend, not correlated with CC or with strains persistence. Instead, the presence of internalin (inL), Stress Survival Islet (SSI) and resistance to erythromycin (ermC) genes was correlated with the ability to produce biofilms. Our data demonstrate that the genetic profile influences the adhesion capacity and persistence of L. monocytogenes in food processing plants and could be the result of environmental adaptation in response to the external selective pressure.