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Aims/hypothesisThe strict rules applied in Italy during the recent COVID-19 pandemic, with the prohibition to attend any regular outdoor activity, are likely to influence the degree of metabolic control in patients with type 2 diabetes. We explored such putative effect immediately after the resolution of lockdown rules, in the absence of any variation of pharmacologic treatment.MethodsOne-hundred and fourteen patients with adequate metabolic control took part in this single-centre, prospective, observational study. The metabolic profile tested 1 week after the end of the lockdown was compared with the last value and the mean of the last three determinations performed before the pandemic emergency (from 6 months to 2 years before).ResultsAfter 8 weeks of lockdown, an increase of HbA1c > 0.3% (mean +0.7%) was observed in 26% of the participants; these were also characterized by a persistent elevation in serum triglycerides able to predict the worsening of glucose control.ConclusionsLockdown determined a relevant short-term metabolic worsening in approximately one-fourth of previously well-controlled type 2 diabetic individuals; pre-lockdown triglycerides were the only parameter able to predict such derangement of glucose control.

Background: Inflammatory hyperreflective retinal foci (I-HRF) have been recognized as an optical coherence tomography (OCT) biomarker of aggregates of activated microglial cells. Microglia, the principal resident immune cells, are key players in geographic atrophy (GA) development and progression. Objective: To quantify I-HRF distribution across inner (IR) and outer (OR) retinal layers in GA compared with healthy controls. Methods: Retrospective observational study including patients aged ≥50 years with GA lesion area >1.25 mm2 and age-matched healthy subjects. GA eyes were classified as bilateral GA (B-GA) or unilateral GA (U-GA; fellow eye with macular neovascularization). Using Spectralis OCT, I-HRF (≤30 μm; RNFL-like reflectivity; no posterior shadowing) were identified and counted across IR and OR. Results: Sixty-eight eyes from 46 patients with GA (B-GA: 49 eyes; U-GA: 19 eyes) and 19 control eyes were studied. I-HRF were higher in IR than in OR in all groups (p < 0.001). I-HRF were higher in GA eyes in both layers compared with controls (p < 0.05). U-GA exhibited higher I-HRF than B-GA in IR (44.32 ± 8.47 vs. 30.10 ± 7.62; p < 0.001), while I-HRF were not significantly different in OR (9.58 ± 3.04 vs. 8.02 ± 3.33; p = 0.081). Conclusions: I-HRF are increased in GA. They are more numerous in IR, consistent with their proposed inflammatory origin. These findings further support the role microglia may play in GA pathology. I-HRF may become an OCT biomarker to track GA-associated neuroinflammation in different GA phenotypes. Longitudinal studies are needed to clarify I-HRF significance in GA progression.

Background Type 2 diabetes (T2D) shows a high mortality rate, dependent on disease duration, comorbidities and glucose control over time. Data on patients with short disease duration are scanty. Methods We prospectively followed a cohort of newly-diagnosed T2D patients referring to a single diabetes centre, treated according to the international guidelines and checked every 6–12 months. All-cause mortality and major cardiovascular (CV) events were registered. Results 289 patients out of 3019 consecutive first attendances matched inclusion criteria and were included in the observation. Mean follow-up was 51.2 months. At 31 December 2018, 253 patients were alive and 36 deceased. At baseline, deceased individuals were older, with lower eGFR and lower uric acid, higher prevalence of atrial fibrillation. During the follow-up, 18 non-fatal CV events were adjudicated; patients with incident CV disease (CVD) differed at baseline for sex, previous history of CVD and retinopathy, higher use of secretagogues and lower use of metformin. At multivariate analysis, age and previous CVD were the only independent determinants of all-cause mortality and incident CVD, respectively. In deceased individuals, eGFR slope was markedly unstable and ΔeGFR at the end of the follow-up was higher (p < 0.001), and predicted mortality. Conclusion Newly-diagnosed T2D patients followed according to the best clinical practice show a mortality rate similar to that reported in more complicated patients with longer disease duration; none of the clinical and biochemical variables commonly measured at baseline can predict mortality or incident CVD; early metformin use seems to be associated with no risk of prevalent or incident retinopathy.

Abstract Context Mechanisms mediating the cardiovascular and renal protection exerted by SGLT2 inhibitors are still partially unknown. We investigated whether dapagliflozin modulates systemic and renal vascular function and structure, and induces epigenetic modifications. Subjects and Methods Forty hypertensive patients with type 2 diabetes were randomly assigned to 4-week treatment with dapagliflozin 10 mg or hydrochlorothiazide (HCT) 12.5 mg. Routine analyses; plasma renin activity; aldosterone, catecholamine, and 24-hour urinary electrolyte levels; flow-mediated dilation (FMD) of the brachial artery; carotid-femoral pulse-wave velocity (PWV); augmentation index; and resistive index and dynamic renal resistive index (DRIN) were measured at baseline and after treatment. Circulating miRNAs (miRs) related to heart failure (miR30e-5p, miR199a-3p), endothelial dysfunction (miR27b and miR200b), and renal function (miR130b-3p, miR21-5p) were assessed and related to the effects of treatments. Results Dapagliflozin and HCT marginally lowered blood pressure. Fasting glucose was lowered, whereas 24-hour diuresis, glycosuria, and osmolar clearance were increased by dapagliflozin (P < 0.001 for all), without affecting sodium excretion and glomerular filtration rate. Magnesium levels significantly increased after dapagliflozin treatment (P = 0.02). Neither dapagliflozin nor HCT modified FMD or PWV. DRIN did not vary in the dapagliflozin group, whereas it increased in the HCT group (P = 0.047 for time by treatment interaction). Both treatments induced variations in the expression of some miRs; dapagliflozin, but not HCT, significantly up-regulated miR30e-5p and downregulated miR199a-3p. Conclusion A putative epigenetic regulation of the protecting cardiovascular effect exerted by SGLT2 inhibitors was found. Dapagliflozin might exert nephroprotection by preserving renal vasodilating capacity. Hemodynamic and systemic vascular effects of dapagliflozin undergo epigenetic regulation that favorably affects two miRs involved in heart failure.

Objectives: Achromatopsia (ACHM) is a rare autosomal, recessively inherited disease that is characterized by cone dysfunction, for which several gene therapies are currently on trial. The aim of this study was to find correlations between the morphological macular changes identified using optical coherence tomography (OCT) and some visual functional parameters. Visual acuity (VA), contrast sensitivity (CS), and macular sensitivity obtained by means of microperimetry were assessed. Methods: Adolescents with ACHM underwent macular microperimetry (S-MAIA device) in mesopic condition, macular OCT, best corrected visual acuity (BCVA), low luminance visual acuity (LLVA), near vision acuity (NVA), and CS measurement. Results: Eight patients (15 eyes) with ACHM were analyzed. The mean age was 17 ± 2.7 years, and genetic variants involved the CNGA3 gene (37.5%) and CNGB3 gene (62.5%). OCT staging significantly correlated with microperimetry sensitivity parameters, namely the sensitivity of the central foveal point (p = 0.0286) and of the first and second perifoveal rings (p = 0.0008 and p = 0.0014, respectively). No correlations were found between OCT staging and VA measurements, nor with CS value. Conclusions: Among the extensive evaluated visual function tests, only microperimetry sensitivity showed a correlation with morphological macular changes identified at OCT. Microperimetry sensitivity may thus represent a useful visual function tool in natural ACHM history studies considering the upcoming research on gene therapies for the treatment of ACHM.

Edentulism, extreme consequence of severe periodontitis, carries a high cardiovascular and all-cause death risk. The prevailing phenotype of edentulous patients with type 2 diabetes (T2D) has never been defined, neither it is known whether an epigenetic signature of such condition exists. We collected clinical and biochemical data and administered a questionnaire on oral health in 248 consecutive T2D individuals. Vital status was checked after 17 ± 7 months. miRNAs involved in periodontal inflammation were measured. Forty-seven patients (19%) were edentulous (ED), a higher prevalence than in the Italian general population (10.9% from ISTAT data). ED were older, with low level of instruction and higher fasting glucose vs not edentulous (noED). Participants displayed a scarce awareness of the association periodontitis-T2D. ED showed a specific epigenetic signature (lower miR214-5p and higher miR126-5p urinary levels). At the follow-up, metabolic profile similarly improved in ED and noED; death occurrence was similar. In this cohort of T2D, age is the only variable associated with edentulism; such condition displays an epigenetic signature, independent of the clinical phenotype; awareness of the clinical relevance and implications of periodontitis and edentulism are scarce. However, edentulism does not mark an increased rate of micro-macrovascular complications or mortality. •Edentulism is characterized by a high prevalence of CV morbidity and death.•In our cohort of T2D subjects, prevalence of edentulism is two-fold higher than in the general population.•Edentulism shows a peculiar epigenetic signature independent of the clinical phenotype.•Edentulism does not mark an increased rate of micro-macrovascular complications or mortality over a 2-year follow up.

AimsThe rate of all-cause mortality is twofold higher in type 2 diabetes than in the general population. Being able to identify patients with the highest risk from the very beginning of the disease would help tackle this burden.MethodsWe tested whether ENFORCE, an established prediction model of all-cause mortality in type 2 diabetes, performs well also in two independent samples of patients with early-stage disease prospectively followed up.ResultsENFORCE’s survival C-statistic was 0.81 (95%CI: 0.72–0.89) and 0.78 (95%CI: 0.68–0.87) in both samples. Calibration was also good. Very similar results were obtained with RECODe, an alternative prediction model of all-cause mortality in type 2 diabetes.ConclusionsIn conclusion, our data show that two well-established prediction models of all-cause mortality in type 2 diabetes can also be successfully applied in the early stage of the disease, thus becoming powerful tools for educated and timely prevention strategies for high-risk patients.

Nutritional science is gaining increasing attention due to the implicit potential to prevent cardio-metabolic diseases. It is also becoming clear that food-making process might influence the metabolic response to the meal. We have conducted a proof-of-concept study to investigate whether slowly processed pasta might positively impact glucose homeostasis. A total of 14 healthy male volunteers underwent two different mixed-meal tests in a randomized order. One meal was composed of 100 g of normally processed pasta and the other 100 g of slowly processed pasta. Each meal was completed with 10 g of olive oil and 10 g of parmesan cheese. Glucose, insulin, and incretin post-prandial responses were assessed at 15, 30, 60, 90, 120, 150, and 180 min. Glucose tolerance, insulin, and incretin response were unaffected by the two different pasta types. However, a slight difference was evident in the shape of the curve of post-prandial insulin (i.e., mildly delayed with the slowly processed pasta). Despite the common belief of a different impact of normally processed and slowly processed pasta on glucose metabolism, they show a superimposable post-prandial metabolic response after a single meal in male healthy individuals. Further studies are required to confirm these results also in chronic, real-life settings and then to translate them to metabolically impaired individuals.

Lumpy skin disease (LSD) is caused by a . Live attenuated vaccines, which are commercially available, could be not safe because of the side effects. The aim of this study was the evaluation of the safety, immunogenicity, and effects on the qualitative and quantitative parameters of milk. The feasibility of identifying vaccinated animals using our inactivated vaccine in dairy cows was analysed. The vaccine was tested in guinea pigs as an immunogenicity predictive model. LSD virus was propagated on Madin-Darby Bovine Kidney (MDBK) cells, then inactivated and supplemented with keyhole limpet hemocyanin (KLH) protein, obtaining a positive marker vaccine. This was inoculated in guinea pigs and in dairy cows, and animal sera were analysed using enzyme-linked immunosorbent assay (ELISA) and a serum neutralisation (SN) test. Quantitative and qualitative analyses were performed on milk. The vaccine was previously tested for efficacy in vaccinated calves, showing a pronounced reduction in clinical symptoms after challenge. The safety and immunogenicity obtained in calves were also confirmed in dairy cows in this study. In fact, high values of the SN test (1:20 to 1:80) and ELISA (90 and 240 S/P%) were obtained after vaccination. Moreover, high immunogenicity of the vaccine was also assessed in guinea pigs. In addition, the results of the milk analyses did not show any differences between vaccinated and control groups. The KLH was able to elicit an immune response detectable using an ELISA (3.0 and 3.5 optical density values). Finally, our vaccine could be used to reduce LSD symptoms and identify vaccinated animals.

Pre‐eclampsia (PE) is one of the most severe syndromes in human pregnancy, and the underlying mechanisms of PE have yet to be determined. Pre‐eclampsia is characterized by the alteration of the immune system's activation status, an increase in inflammatory Th1/Th17/APC cells, and a decrease in Th2/Treg subsets/cytokines. Moreover, inflammatory infiltrates have been detected in the amniotic membranes of pre‐eclamptic placentae, and to this date limited data are available regarding the role of amniotic membrane cells in PE. Interestingly, we and others have previously shown that human amniotic mesenchymal stromal cells (hAMSC) possess anti‐inflammatory properties towards almost all immune cells described to be altered in PE. In this study we investigated whether the immunomodulatory properties of hAMSC were altered in PE. We performed a comprehensive study of cell phenotype and investigated the in vitro immunomodulatory properties of hAMSC isolated from pre‐eclamptic pregnancies (PE‐hAMSC), comparing them to hAMSC from normal pregnancies (N‐hAMSC). We demonstrate that PE‐hAMSC inhibit CD4/CD8 T‐cell proliferation, suppress Th1/Th2/Th17 polarization, induce Treg and block dendritic cells and M1 differentiation switching them to M2 cells. Notably, PE‐hAMSC generated a more prominent induction of Treg and higher suppression of interferon‐γ when compared to N‐hAMSC, and this was associated with higher transforming growth factor‐β1 secretion and PD‐L2/PD‐L1 expression in PE‐hAMSC. In conclusion, for the first time we demonstrate that there is no intrinsic impairment of the immunomodulatory features of PE‐hAMSC. Our results suggest that amniotic mesenchymal stromal cells do not contribute to the disease, but conversely, could participate in offsetting the inflammatory environment which characterizes PE.