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Purpose: To assess reproducibility of Real time 3D echocardiography (RT3D) and ECG-gated 3D echocardiography (EG3D) when measuring the mitral valve area (MVA) in rheumatic mitral stenosis (MS)., Methods: MVA was assessed by three operators in 68 MS patients using RT3D and EG3D. Reproducibility of each technique was determined by calculating the standard error of measurements (SEM)., Results: SEM was similar between RT3D and EG3D. MVA variability was of 0.4 cm² or 30% of any RT3D or EG3D measured MVA. The minimal change in MVA above which two measurements should be considered to differ significantly for the same operator was of 0.4 cm² for RT3D and 0.5 cm² for EG3D. For two different operators making successive measurements, the minimum significant change was of 0.5 cm² for RT3D and 0.6 cm² for EG3D. The minimum significant difference when switching from RT3D to EG3D or vice versa is of 0.6 cm². Low temporal resolution of 6 Hz has the least variability when using RT3D (0.19 cm² vs. 0.26 cm², p = 0.009) but significantly underestimated MVA (1.3 ± 0.4 cm² vs. 1.4 ± 0.4 cm², p < 10 - 3 ) when compared to EG3D. MVA variability was significantly higher in mild MS when compared to severe MS whether it is RT3D (0.23 cm² vs. 0.18 cm², p = 0.02) or EG3D (0.27 cm² vs. 0.16 cm², p < 0.001)., Conclusion: RT3D and EG3D are equally reproducible in the assessment of MVA in patients with MS. Further measurements standardization is required to have a clinically acceptable estimations of the true 3D MVA and minimal detectable differences., (© 2023. The Author(s), under exclusive licence to Springer Nature B.V.)

Introduction: Type 1 diabetes (T1D) is defined by immune cell infiltration of the pancreas, in particular the islets of Langerhans, referred to as insulitis, which is especially prominent during the early disease stages in association with decreased beta cell mass. An in-depth understanding of the dynamics and phenotype of the immune cells infiltrating the pancreas and the accompanying changes in their profiles in peripheral blood during T1D development is critical to generate novel preventive and therapeutic approaches, as well as to find biomarkers for the disease process., Methods: Using multi-parameter flow cytometry, we explored the dynamic changes of immune cells infiltrating the pancreas and the pancreatic draining lymph nodes (PLN), compared to those in peripheral blood in female and male non-obese diabetic (NOD) mice during T1D progression., Results: The early stages of T1D development were characterized by an influx of innate dendritic cells and neutrophils in the pancreas. While dendritic cells seemed to move in and out (to the PLN), neutrophils accumulated during the pre-symptomatic phase and reached a maximum at 8 weeks of age, after which their numbers declined. During disease progression, CD4 + and CD8 + T cells appeared to continuously migrate from the PLN to the pancreas, which coincided with an increase in beta cell autoimmunity and insulitis severity, and a decline in insulin content. At 12 weeks of age, CD4 + and especially CD8 + T cells in the pancreas showed a dramatic shift from naïve to effector memory phenotype, in contrast to the PLN, where most of these cells remained naïve. A large proportion of pancreas infiltrating CD4 + T cells were naïve, indicating that antigenic stimulation was not necessary to traffic and invade the pancreas. Interestingly, a pre-effector-like T cell dominated the peripheral blood. These cells were intermediates between naïve and effector memory cells as identified by single cell RNA sequencing and might be a potential novel therapeutic target., Conclusion: These time- and tissue-dependent changes in the dynamics and functional states of CD4 + and CD8 + T cells are essential steps in our understanding of the disease process in NOD mice and need to be considered for the interpretation and design of disease-modifying therapies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Bruggeman, Martens, Sassi, Viaene, Wasserfall, Mathieu and Gysemans.)

Immunomodulation combined with antigen therapy holds great promise to arrest autoimmune type 1 diabetes, but clinical translation is hampered by a lack of prognostic biomarkers. Low-dose anti-CD3 plus Lactococcus lactis bacteria secreting proinsulin and IL-10 reversed new-onset disease in nonobese diabetic (NOD) mice, yet some mice were resistant to the therapy. Using miRNA profiling, six miRNAs (i.e., miR-34a-5p, miR-125a-3p, miR-193b-3p, miR-328, miR-365-3p, and miR-671-3p) were identified as differentially expressed in plasma of responder versus nonresponder mice before study entry. After validation and stratification in an independent cohort, plasma miR-193b-3p and miR-365-3p, combined with age and glycemic status at study entry, had the best power to predict, with high sensitivity and specificity, poor response to the therapy. These miRNAs were highly abundant in pancreas-infiltrating neutrophils and basophils with a proinflammatory and activated phenotype. Here, a set of miRNAs and disease-associated parameters are presented as a predictive signature for the L. lactis-based immunotherapy outcome in new-onset type 1 diabetes, hence allowing targeted recruitment of trial participants and accelerated trial execution., Article Highlights: Low-dose anti-CD3 combined with oral gavage of genetically modified Lactococcus lactis bacteria secreting human proinsulin and IL-10 holds great promise to arrest autoimmune type 1 diabetes, but the absence of biomarkers predicting therapeutic success hampers clinical translation. A set of cell-free circulation miRNAs together with age and glycemia at baseline predicts a poor response after L. lactis-based immunotherapy in nonobese mice with new-onset diabetes. Pancreas-infiltrating neutrophils and basophils are identified as potential cellular sources of discovered miRNAs. The prognostic signature could guide targeted recruitment of patients with newly diagnosed type 1 diabetes in clinical trials with the L. lactis-based immunotherapy., (© 2023 by the American Diabetes Association.)

Objective: This pilot randomized controlled trial evaluates the preliminary efficacy of a 4-month well-being therapy (WBT) and lifestyle intervention among adults with type 2 diabetes and overweight/obesity., Methods: Fifty-eight patients were recruited from two outpatient clinics and randomized to receive the WBT-lifestyle intervention or the lifestyle intervention alone. Data were collected at baseline (T0), immediate postintervention (T1), 6-month follow-up (T2), and 12-month follow-up (T3). Primary efficacy outcomes included changes in weight, psychological distress, and well-being, whereas secondary efficacy outcomes included changes in lifestyle and physiological parameters., Results: Compared with the lifestyle-alone intervention, the WBT-lifestyle intervention showed greater improvements in depression (p = .009, d = -0.6), hostility (p = .018, d = -0.6), and personal growth (p = .026, d = 0.5) at T1, in self-reported physical activity at T2 (p = .013, d = 0.7) and T3 (p = .040, d = 0.5), and in triglycerides (p = .019, d = -1.12) at T3. There were no differences between treatment groups in weight and other physiological parameters., Conclusions: These findings suggest that WBT may be a valuable addition to lifestyle interventions for improving short-term psychological outcomes and promoting long-term healthy changes in physical activity, with a potential impact on physiological outcomes.Trial Registration:ClinicalTrials.gov identifier: NCT03609463., (Copyright © 2022 by the American Psychosomatic Society.)

The antifungal activity of natural antimicrobials such as essential oils (EOs), citrus extracts, and other natural derivatives was evaluated against 10 fungal strains using minimum inhibitory concentration (MIC) analysis. Compounds having the highest inhibitory activity at the lowest concentrations were subsequently selected to evaluate the possible synergistic interactions by checkerboard method (FIC). The results showed that citrus extract A (CEA) and EOs rich in cinnamaldehyde had the highest inhibitory capacity against evaluated strains (Aspergillus niger, Aspergillus versicolor, Aureobasidium pullulans, Eurotium rubrum, Paecilomyces spp., Penicillium chrysogenum, Penicillium citrinum, Penicillium commune, Penicillium crustosum, and Penicillium roqueforti). The stability of the antifungal mixture was then optimized using lecithin and sucrose monopalmitate (SMP) as surfactants. Stability test showed that lecithin:SMP at HLB 10 maintains emulsion stability for 15 days of storage at 4°C. Encapsulation process for the loaded emulsion was optimized using whey protein isolate (WPI) and maltodextrin (MD) blend with ratios WPI:MD (1:2) and WPI:MD (1:3). The results showed that WPI:MD (1:3) led to a higher physicochemical stability (-40.5 mV), encapsulation efficiency (91%), and antifungal activity (315 ppm). Microencapsulation maintained the available active compounds content more prolonged with an average interval of 7 days compared to the nonencapsulated formulations during storage at 4°C., (© 2022 Institute of Food Technologists®.)

The hormonally-active form of vitamin D, 1,25-dihydroxyvitamin D 3 , can modulate both innate and adaptive immunity, through binding to the nuclear vitamin D receptor expressed in most immune cells. A high dose of regular vitamin D protected non-obese diabetic (NOD) mice against type 1 diabetes (T1D), when initiated at birth and given lifelong. However, considerable controversy exists on the level of circulating vitamin D (25-hydroxyvitamin D 3 , 25(OH)D 3 ) needed to modulate the immune system in autoimmune-prone subjects and protect against T1D onset. Here, we evaluated the impact of two doses of dietary vitamin D supplementation (400 and 800 IU/day), given to female NOD mice from 3 until 25 weeks of age, on disease development, peripheral and gut immune system, gut epithelial barrier function, and gut bacterial taxonomy. Whereas serum 25(OH)D 3 concentrations were 2.6- (400 IU/day) and 3.9-fold (800 IU/day) higher with dietary vitamin D supplementation compared to normal chow (NC), only the 800 IU/day vitamin D-supplemented diet delayed and reduced T1D incidence compared to NC. Flow cytometry analyses revealed an increased frequency of FoxP3 + Treg cells in the spleen of mice receiving the 800 IU/day vitamin D-supplemented diet. This vitamin D-induced increase in FoxP3 + Treg cells, also expressing the ecto-5'-nucleotidase CD73, only persisted in the spleen of mice at 25 weeks of age. At this time point, the frequency of IL-10-secreting CD4 + T cells was also increased in all studied immune organs. High-dose vitamin D supplementation was unable to correct gut leakiness nor did it significantly modify the increased gut microbial diversity and richness over time observed in NOD mice receiving NC. Intriguingly, the rise in alpha-diversity during maturation occurred especially in mice not progressing to hyperglycaemia. Principal coordinates analysis identified that both diet and disease status significantly influenced the inter-individual microbiota variation at the genus level. The abundance of the genera Ruminoclostridium&#95;9 and Marvinbryantia gradually increased or decreased, respectively in faecal samples of mice on the 800 IU/day vitamin D-supplemented diet compared to mice on the 400 IU/day vitamin D-supplemented diet or NC, irrespective of disease outcome. In summary, dietary vitamin D reduced T1D incidence in female NOD mice at a dose of 800, but not of 400, IU/day, and was accompanied by an expansion of Treg cells in various lymphoid organs and an altered intestinal microbiota signature., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Martens, Centelles-Lodeiro, Ellis, Cook, Sassi, Verlinden, Verstuyf, Raes, Mathieu and Gysemans.)

We investigated the relationship between Left Atrium strain reservoir function and symptoms and its impact on modulating Left Ventricular mechanics, diastolic filling, stroke volume, mean trans-mitral gradient and pulmonary pressure in mitral stenosis (MS) patients. We examined 195 full spectrum MS patients which were divided into two groups: Group 1 (n = 109) included patients with NYHA I & II functional class and group 2 (n = 86) included patients with NYHA III & IV functional class. LA strain reservoir function and classical echocardiographic parameters were calculated. LASr was significantly higher in group 1 versus group 2 in patients with MVA ≤ 1cm 2 [8.8(6.0-12.6) vs 6.8(4.1-8.9), p = 0.03) and when 1cm 2  < MVA ≤ 1.5 cm 2 [10.0 (5.4-13.8) vs 6.7(4.5-9.0), p = 0.02). In patients with Pulmonary Hypertension, group 1 had significantly higher LASr than group 2 [11.1(6.6-14.8) vs 5.9(4.3-9.0), p = 0.002) By multivariate analysis, diabetes (OR = 4.11, 95%CI: 1.6-10.4), stroke (OR = 2.9, 95%CI: 1.1-7.9), LASr (OR = 0.9, 95%CI: 0.80-0.99) and LV ejection fraction (LVEF)(OR = 0.9, 95%CI: 0.91-0.99) were independently associated with NYHA functional class. LASr was significantly and positively correlated to MVA (r = 0.3, p < 10 -3 ), stroke volume (r = 0.25, p = 10 -3 ), mitral inflow (r = 0.4, p < 10 -3 ) and LVEF(r = 0.14, p = 0.05). It was significantly and negatively correlated to left ventricular strain (r = -0.65, p < 10 -3 ), LA indexed volume (r = -0.40, p < 10 -3 ), maximum tricuspid regurgitation velocity (r = -0.25, p = 0.003), MTMG (r = -0.25, p = 10 -3 ), and heart rate (r = -0.4, p < 10 -3 ). We demonstrated a large range of interaction between LASr and mitral valve echocardiographic parameters. This may explain the reasons we identified LASr as an independent factor for MS functional tolerance., (© 2021. The Author(s), under exclusive licence to Springer Nature B.V.)