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Objectives: Mitral regurgitation due to anterior mitral leaflet lesions is associated with an increased risk of MR recurrence after mitral valve repair compared with posterior leaflet-related lesions. Both edge-to-edge and neochordal repair, associated with ring annuloplasty, have been used in our Institution to address isolated anterior mitral leaflet lesions. The aim of this study was to compare the clinical and echocardiographic long-term results of those two approaches for isolated anterior mitral leaflet lesions by means of a propensity match analysis., Materials and Methods: An institutional database retrospective review within the time-frame 2000 to 2021 was carried out. Kaplan-Meier method and cumulative incidence function were employed. Cox regression was employed to identify the risk factor for mortality during the follow-up., Results: The estimated freedom from reoperative mitral valve surgery at 20 years was 78% in the E-to-E group and 64% in the neochordae group (p = 0.032). The longitudinal analysis performed to analyze the MR recurrence rate showed a higher rate of mitral regurgitation ≥ 3+ recurrence in the neochordae group at 5 (5.1% vs 8.7%) -10 (8.2% vs 13.2%) and 15 years (8.8% vs 16.5%) (p < 0.001)., Conclusions: Isolated anterior leaflet pathology can be effectively treated with edge-to-edge or neochordal repair and ring annuloplasty. In our series, clinical and echocardiographic results were better in edge-to-edge group. The excellent durability of this technique up to 20 years of follow-up, together with its simplicity and reproducibility, confirms the role the edge-to-edge techniques as an excellent treatment option for severe mitral regurgitation due anterior mitral leaflets lesions., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery.)

Background: The aim of this study was to report the long-term results of the clover and edge-to-edge repair techniques for complex tricuspid regurgitation (TR)., Methods: This was a single-center observational study. A competing risks proportional-hazards regression model, using the Fine and Gray model, was performed to analyze the time to TR ≥2+, considering death as a competing risk., Results: A total of 145 consecutive patients (57% female) with severe or moderately severe TR secondary to leaflet prolapse or flail (115 patients), tethering (27 patients), or mixed (3 patients) lesions underwent clover (110 patients) or edge-to-edge repair(35 patients). The TR origin was degenerative in 75% of cases, posttraumatic in 8%, and secondary to dilated cardiomyopathy in 17%. Ring (64%) or suture (31%) annuloplasty was performed in 95% of patients. Concomitant procedures (mainly mitral surgery) were performed in 80% of cases. Hospital death was 5.5%. Follow-up was 98% complete, and median was 15 years (interquartile range, 14-17 years). The 16-year overall survival was 56% ± 5%. Previous cardiac surgery (hazard ratio [HR], 2.83; 95% CI, 1.15-6.93; P = .023) and right ventricular dysfunction (HR, 2.24; 95% CI, 1.01-4.95; P = .046) were identified as predictors of death. The 16-year cumulative incidence function (CIF) of cardiac death with noncardiac death as a competing risk was 19.6%, and previous cardiac surgery (HR, 3.44; 95% CI, 1.23-9.65; P = .019) was detected as the only predictor of the event. At 16 years, the CIF of TR ≥2+ with death as a competing risk was 23.8%. In particular, TR ≥3+ was detected in 4 patients (3%)., Conclusions: When TR could not be treated by annuloplasty alone, concomitant leaflet repair with the clover or edge-to-edge technique effectively restored valve competence with very satisfactory long-term results and a low rate of moderate or greater TR recurrence., Competing Interests: Disclosures The authors have no conflicts of interest to disclose., (Copyright © 2024 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Objective: Cost-effectiveness of surveillance for branch-duct intraductal papillary mucinous neoplasms (BD-IPMNs) is debated. We combined different categories of risks of IPMN progression and of IPMN-unrelated mortality to improve surveillance strategies., Design: Retrospective analysis of 926 presumed BD-IPMNs lacking worrisome features (WFs)/high-risk stigmata (HRS) under surveillance. Charlson Comorbidity Index (CACI) defined the severity of comorbidities. IPMN relevant changes included development of WF/HRS, pancreatectomy or death for IPMN or pancreatic cancer. Pancreatic malignancy-unrelated death was recorded. Cumulative incidence of IPMN relevant changes were estimated using the competing risk approach., Results: 5-year cumulative incidence of relevant changes was 17.83% and 1.6% developed pancreatic malignancy. 5-year cumulative incidences for IPMN relevant changes were 13.73%, 19.93% and 25.04% in low-risk, intermediate-risk and high-risk groups, respectively. Age ≥75 (HR: 4.15) and CACI >3 (HR: 3.61) were independent predictors of pancreatic malignancy-unrelated death. 5-year cumulative incidence for death for other causes was 15.93% for age ≥75+CACI >3 group and 1.49% for age <75+CACI ≤3. 5-year cumulative incidence of IPMN relevant changes were 13.94% in patients with age <75+CACI ≤3 compared with 29.60% in those with age ≥75+CACI >3. In this group 5-year rate of malignancy-free patients was 95.56% with a 5-year survival of 79.51%., Conclusion: Although it is not uncommon the occurrence of changes considered by current guidelines as relevant during surveillance of low risk BD-IPMNs, malignancy rate is low and survival is significantly affected by competing patients' age and comorbidities. IPMN surveillance strategy should be tailored based on these features and modulated over time., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: Uncorrected severe mitral regurgitation (MR) due to posterior prolapse leads to left ventricular dilatation. At this stage, mitral valve repair becomes mandatory to avoid permanent myocardial injury. However, which technique among neochoardae implantation and leaflet resection provides the best results in this scenario remains unknown., Methods: We selected 332 patients with left ventricular dilatation and severe degenerative MR due to posterior leaflet (PL) prolapse who underwent neochoardae implantation (85 patients) or PL resection (247 patients) at our institution between 2008 and 2020. A propensity score matching analysis was carried on to decrease the differences at baseline., Results: Matching yielded 85 neochordae implantations and 85 PL resections. At 10 years, freedom from cardiac death and freedom from mitral valve reoperation were 92.6 ± 6.1% vs 97.8 ± 2.1% and 97.7 ± 2.2% vs 95 ± 3% in the neochordae group and in the PL resection group, respectively. The MR ≥2+ recurrence rate was 23.9 ± 10% in the neochordae group and 20.8 ± 5.8% in the PL resection group (P = 0.834) at 10 years. At the last follow-up, the neochordae group showed a higher reduction of left ventricular end-diastolic diameter (44 vs 48 mm; P = 0.001) and a better ejection fraction (60% vs 55%; P < 0.001) compared to PL resection group., Conclusions: In this subgroup of patients, both neochordae implantation and leaflet resection provide excellent durability of the repair in the long term. Neochordae implantation might have a better effect on dilated left ventricle., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Introduction: Low glomerular filtration rate (GFR) is a leading cause of reduced lifespan in type 2 diabetes. Unravelling biomarkers capable to identify high-risk patients can help tackle this burden. We investigated the association between 188 serum metabolites and kidney function in type 2 diabetes and then whether the associated metabolites improve two established clinical models for predicting GFR decline in these patients., Research Design and Methods: Two cohorts comprising 849 individuals with type 2 diabetes (discovery and validation samples) and a follow-up study of 575 patients with estimated GFR (eGFR) decline were analyzed., Results: Ten metabolites were independently associated with low eGFR in the discovery sample, with nine of them being confirmed also in the validation sample (ORs range 1.3-2.4 per 1SD, p values range 1.9×10 -2 -2.5×10 -9 ). Of these, five metabolites were also associated with eGFR decline (ie, tiglylcarnitine, decadienylcarnitine, total dimethylarginine, decenoylcarnitine and kynurenine) (β range -0.11 to -0.19, p values range 4.8×10 -2 to 3.0×10 -3 ). Indeed, tiglylcarnitine and kynurenine, which captured all the information of the other three markers, improved discrimination and reclassification (all p<0.01) of two clinical prediction models of GFR decline in people with diabetes., Conclusions: Further studies are needed to validate our findings in larger cohorts of different clinical, environmental and genetic background., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: The TRI-SCORE is a recently published risk score for predicting in-hospital mortality in patients undergoing isolated tricuspid valve surgery (ITVS). The aim of this study is to externally validate the ability of the TRI-SCORE in predicting in-hospital and long-term mortality following ITVS., Methods: A retrospective review of our institutional database was carried out to identify all patients undergoing isolated tricuspid valve repair or replacement from March 1997 to March 2021. The TRI-SCORE was calculated for all patients. Discrimination of the TRI-SCORE was assessed using receiver operating characteristic curves. Accuracy of the models was tested calculating the Brier score. Finally, a COX regression was employed to evaluate the relationship between the TRI-SCORE value and long-term mortality., Results: A total of 176 patients were identified and the median TRI-SCORE was 3 (1-5). The cut-off value identified for increased risk of isolated ITVS was 5. Regarding in-hospital outcomes, the TRI-SCORE showed high discrimination (area under the curve 0.82), and high accuracy (Brier score 0.054). This score showed also very good performance in predicting long-term mortality (at 10 years, hazard ratio: 1.47, 95% confidence interval [1.31-1.66], P < 0.001), with high discrimination (area under the curve >0.80 at 1-5 and 10 years) and high accuracy values (Brier score 0.179)., Conclusions: This external validation confirms the good performance of the TRI-SCORE in predicting in-hospital mortality. Moreover, the score showed also very good performance in predicting the long-term mortality., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery.)

A full understanding of the characteristics of Covid-19 patients with a better chance of experiencing poor vital outcomes is critical for implementing accurate and precise treatments. In this paper, two different advanced data-driven statistical approaches along with standard statistical methods have been implemented to identify groups of patients most at-risk for death or severity of respiratory distress. First, the tree-based analysis allowed to identify profiles of patients with different risk of in-hospital death (by Survival Tree-ST analysis) and severity of respiratory distress (by Classification and Regression Tree-CART analysis), and to unravel the role on risk stratification of highly dependent covariates (i.e., demographic characteristics, admission values and comorbidities). The ST analysis identified as the most at-risk group for in-hospital death the patients with age > 65 years, creatinine [Formula: see text] 1.2 mg/dL, CRP [Formula: see text] 25 mg/L and anti-hypertensive treatment. Based on the CART analysis, the subgroups most at-risk of severity of respiratory distress were defined by patients with creatinine level [Formula: see text] 1.2 mg/dL. Furthermore, to investigate the multivariate dependence structure among the demographic characteristics, the admission values, the comorbidities and the severity of respiratory distress, the Bayesian Network analysis was applied. This analysis confirmed the influence of creatinine and CRP on the severity of respiratory distress., (© 2023. The Author(s).)

Aim: This study investigated whether rare, deleterious variants in monogenic diabetes-genes are associated with early-onset type 2 diabetes (T2D)., Methods: A nested case-control study was designed from 9712 Italian patients with T2D. Individuals with age at diabetes onset ≤35 yrs (n = 300; cases) or ≥65 yrs (n = 300; controls) were selected and screened for variants in 27 monogenic diabetes-genes by targeted resequencing. Rare (minor allele frequency-MAF <1%) and possibly deleterious variants were collectively tested for association with early-onset T2D. The association of a genetic risk score (GRS) based on 17 GWAS-SNPs for T2D was also tested., Results: When all rare variants were considered together, each increased the risk of early-onset T2D by 65% (allelic OR =1.64, 95% CI: 1.08-2.48, p = 0.02). Effects were similar when the 600 study participants were stratified according to their place of recruitment (Central-Southern Italy, 182 cases vs. 142 controls, or Rome urban area, 118 vs. 158, p for heterogeneity=0.53). Progressively less frequent variants showed increasingly stronger effects in the risk of early-onset T2D for those with MAF <0.001% (OR=6.34, 95% CI: 1.87-22.43, p = 0.003). One unit of T2D-GRS significantly increased the risk of early-onset T2D (OR 1.09, 95% CI: 1.01-1.18; p = 0.02). This association was stronger among rare variants carriers as compared to non-carriers (p = 0.02)., Conclusion: Rare variants in monogenic-diabetes genes are associated with an increased risk of early-onset T2D, and interact with common T2D susceptibility variants in shaping it. These findings might help develop prediction tools to identify individuals at high risk of developing T2D in early adulthood., Competing Interests: Declaration of Competing Interest No potential conflicts of interest relevant to this article were reported., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

Death rate is increased in type 2 diabetes. Unraveling biomarkers of novel pathogenic pathways capable to identify high-risk patients is instrumental to tackle this burden. We investigated the association between serum metabolites and all-cause mortality in type 2 diabetes and then whether the associated metabolites mediate the effect of inflammation on mortality risk and improve ENFORCE (EstimatioN oF mORtality risk in type2 diabetic patiEnts) and RECODe (Risk Equation for Complications Of type 2 Diabetes), two well-established all-cause mortality prediction models in diabetes. Two cohorts comprising 856 individuals (279 all-cause deaths) were analyzed. Serum metabolites (n = 188) and pro- and anti-inflammatory cytokines (n = 7) were measured. In the pooled analysis, hexanoylcarnitine, kynurenine, and tryptophan were significantly and independently associated with mortality (hazard ratio [HR] 1.60 [95% CI 1.43-1.80]; 1.53 [1.37-1.71]; and 0.71 [0.62-0.80] per 1 SD). The kynurenine-to-tryptophan ratio (KTR), a proxy of indoleamine-2,3-dioxygenase, which degrades tryptophan to kynurenine and contributes to a proinflammatory status, mediated 42% of the significant association between the antiatherogenic interleukin (IL) 13 and mortality. Adding the three metabolites improved discrimination and reclassification (all P < 0.01) of both mortality prediction models. In type 2 diabetes, hexanoylcarnitine, tryptophan, and kynurenine are associated to and improve the prediction of all-cause mortality. Further studies are needed to investigate whether interventions aimed at reducing KTR also reduce the risk of death, especially in patients with low IL-13., (© 2022 by the American Diabetes Association.)

Context: Type 2 diabetes (T2D) shows a high mortality rate, partly mediated by atherosclerotic plaque instability. Discovering novel biomarkers may help identify high-risk patients who would benefit from more aggressive and specific managements. We recently described a serum resistin and multicytokine inflammatory pathway (REMAP), including resistin, interleukin (IL)-1β, IL-6, IL-8, and TNF-α, that is associated with cardiovascular disease., Objective: We investigated whether REMAP is associated with and improves the prediction of mortality in T2D., Methods: A REMAP score was investigated in 3 cohorts comprising 1528 patients with T2D (409 incident deaths) and in 59 patients who underwent carotid endarterectomy (CEA; 24 deaths). Plaques were classified as unstable/stable according to the modified American Heart Association atherosclerosis classification., Results: REMAP was associated with all-cause mortality in each cohort and in all 1528 individuals (fully adjusted hazard ratio [HR] for 1 SD increase = 1.34, P < .001). In CEA patients, REMAP was associated with mortality (HR = 1.64, P = .04) and a modest change was observed when plaque stability was taken into account (HR = 1.58; P = .07). REMAP improved discrimination and reclassification measures of both Estimation of Mortality Risk in Type 2 Diabetic Patients and Risk Equations for Complications of Type 2 Diabetes, well-established prediction models of mortality in T2D (P < .05-< .001)., Conclusion: REMAP is independently associated with and improves predict all-cause mortality in T2D; it can therefore be used to identify high-risk individuals to be targeted with more aggressive management. Whether REMAP can also identify patients who are more responsive to IL-6 and IL-1β monoclonal antibodies that reduce cardiovascular burden and total mortality is an intriguing possibility to be tested., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

3T3L1 mouse pre-adipocytes develop into adipocytes differently in response to GALNT2 overexpression or to stimulation with rosiglitazone, a reference inducer of adipogenesis. To investigate the biology of alternative pathways of adipogenesis, we studied lipid droplets (LD) morphology, chromatin organization, and gene expression in GALNT2- versus rosiglitazone-induced 3T3L1 adipogenesis. 3T3L1 overexpressing either GALNT2 (GALNT2) or GFP and treated with rosiglitazone (GFPR) were differentiated into adipocytes. LD and nuclei were profiled measuring their morphological features. The expression of adipogenesis-related genes was measured by RT-PCR. As compared to GFPR, GALNT2 showed smaller and more clustered LD, more nuclei with condensed chromatin and several gene expression changes (P < 0.001 for all). As compared to those stimulated by rosiglitazone, GALNT2 overexpressing cells show differences in the most established readouts of adipogenesis. Characterizing alternative pathways of adipogenesis may help tackle those diseases which are secondary to increased dysfunctional mass of adipose tissue.

Objective: Type 2 diabetes is characterized by increased death rate. In order to tackle this dramatic event, it becomes essential to discover novel biomarkers capable of identifying high-risk patients to be exposed to more aggressive preventive and treatment strategies. hs-CRP and serum amyloid P component (SAP) are two acute-phase inflammation proteins, which interact physically and share structural and functional features. We investigated their combined role in associating with and improving prediction of mortality in type 2 diabetes., Research Design and Methods: Four cohorts comprising 2,499 patients with diabetes (643 all-cause deaths) were analyzed. The improvement of mortality prediction was addressed using two well-established prediction models, namely, EstimatioN oF mORtality risk in type 2 diabetiC patiEnts (ENFORCE) and Risk Equations for Complications of Type 2 Diabetes (RECODe)., Results: Both hs-CRP and SAP were independently associated with all-cause mortality (hazard ratios [HRs] [95% CIs]: 1.46 [1.34-1.58] [ P < 0.001] and 0.82 [0.76-0.89] [ P < 0.001], respectively). Patients with SAP ≤33 mg/L were at increased risk of death versus those with SAP >33 mg/L only if hs-CRP was relatively high (>2 mg/L) (HR 1.96 [95% CI 1.52-2.54] [ P < 0.001] and 1.20 [0.91-1.57] [ P = 0.20] in hs-CRP >2 and ≤2 mg/L subgroups, respectively; hs-CRP-by-SAP strata interaction P < 0.001). The addition of hs-CRP and SAP significantly (all P < 0.05) improved several discrimination and reclassification measures of both ENFORCE and RECODe all-cause mortality prediction models., Conclusions: In type 2 diabetes, hs-CRP and SAP show opposite and synergic associations with all-cause mortality. The use of both markers, possibly in combination with others yet to be unraveled, might improve the ability to predict the risk of death in the real-life setting., (© 2020 by the American Diabetes Association.)

Background/objectives: A better understanding of adipose tissue biology is crucial to tackle insulin resistance and eventually coronary heart disease and diabetes, leading causes of morbidity and mortality worldwide. GALNT2, a GalNAc-transferase, positively modulates insulin signaling in human liver cells by down-regulating ENPP1, an insulin signaling inhibitor. GALNT2 expression is increased in adipose tissue of obese as compared to that of non-obese individuals. Whether this association is secondary to a GALNT2-insulin sensitizing effect exerted also in adipocytes is unknown. We then investigated in mouse 3T3-L1 adipocytes the GALNT2 effect on adipogenesis, insulin signaling and expression levels of both Enpp1 and 72 adipogenesis-related genes., Methods: Stable over-expressing GALNT2 and GFP preadipocytes (T 0 ) were generated. Adipogenesis was induced with (R+) or without (R-) rosiglitazone and investigated after 15 days (T 15 ). Lipid accumulation (by Oil Red-O staining) and intracellular triglycerides (by fluorimetric assay) were measured. Lipid droplets (LD) measures were analyzed at confocal microscope. Gene expression was assessed by RT-PCR and insulin-induced insulin receptor (IR), IRS1, JNK and AKT phosphorylation by Western blot., Results: Lipid accumulation, triglycerides and LD measures progressively increased from T 0 to T 15 R- and furthermore to T 15 R+. Such increases were significantly higher in GALNT2 than in GFP cells so that, as compared to T 15 R+GFP, T 15 R- GALNT2 cells showed similar (intracellular lipid and triglycerides accumulation) or even higher (LD measures, p < 0.01) values. In GALNT2 preadipocytes, insulin-induced IR, IRS1 and AKT activation was higher than that in GFP cells. GALNT2 effect was totally abolished during adipocyte maturation and completely reversed at late stage maturation. Such GALNT2 effect trajectory was paralleled by coordinated changes in the expression of Enpp1 and adipocyte-maturation key genes., Conclusions: GALNT2 is a novel modulator of adipogenesis and related cellular phenotypes, thus becoming a potential target for tackling the obesity epidemics and its devastating sequelae.

Context: We previously developed and validated an inexpensive and parsimonious prediction model of 2-year all-cause mortality in real-life patients with type 2 diabetes., Objective: This model, now named ENFORCE (EstimatioN oF mORtality risk in type 2 diabetiC patiEnts), was investigated in terms of (i) prediction performance at 6 years, a more clinically useful time-horizon; (ii) further validation in an independent sample; and (iii) performance comparison in a real-life vs a clinical trial setting., Design: Observational prospective randomized clinical trial., Setting: White patients with type 2 diabetes., Patients: Gargano Mortality Study (GMS; n = 1019), Foggia Mortality Study (FMS; n = 1045), and Pisa Mortality Study (PMS; n = 972) as real-life samples and the standard glycemic arm of the ACCORD (Action to Control Cardiovascular Risk in Diabetes) clinical trial (n = 3150)., Main Outcome Measure: The endpoint was all-cause mortality. Prediction accuracy and calibration were estimated to assess the model's performances., Results: ENFORCE yielded 6-year mortality C-statistics of 0.79, 0.78, and 0.75 in GMS, FMS, and PMS, respectively (P heterogeneity = 0.71). Pooling the three cohorts showed a 6-year mortality C-statistic of 0.80. In the ACCORD trial, ENFORCE achieved a C-statistic of 0.68, a value significantly lower than that obtained in the pooled real-life samples (P < 0.0001). This difference resembles that observed with other models comparing real-life vs clinical trial settings, thus suggesting it is a true, replicable phenomenon., Conclusions: The time horizon of ENFORCE has been extended to 6 years and validated in three independent samples. ENFORCE is a free and user-friendly risk calculator of all-cause mortality in white patients with type 2 diabetes from a real-life setting., (Copyright © 2019 Endocrine Society.)

Context: Some studies have surprisingly indicated that serum adiponectin is positively related to mortality rate, thus casting doubts on its role as a therapeutic target for cardiovascular disease., Objective: To summarize evidence about direction, strength and modulators of this controversial association., Data Sources: MEDLINE, Web of Science, CINHAL, Cochrane Library and Scopus from inception through June 2018., Study Selection: English-language prospective studies reporting the association between adiponectin and all-cause or cardiovascular mortality., Data Extraction: Two investigators independently extracted data and assessed study quality using standard criteria following the Preferred Reporting Items for Systematic Reviews and Meta-analyses and The Newcastle-Ottawa Scale, respectively. Pooled hazard ratios (HRs) (95% confidence intervals-CIs) were derived using a fixed or random effects models when appropriated and were expressed for one standard deviation (SD) increment of adiponectin., Data Synthesis: We identified fifty-five (n=61,676 subjects) and twenty-eight (n=43,979 subjects) studies for all-cause and cardiovascular mortality, respectively. Pooled HRs, were 1.24 (1.17-1.31) and 1.28 (1.19-1.37) for all-cause and cardiovascular mortality, respectively. Similar results were obtained also for High Molecular Weight adiponectin. When meta-analyses were restricted to studies reporting data on natriuretic peptides a 43% and 28% reduction on a log scale of these associations were observed after natriuretic peptides adjustment., Conclusions: Our results strongly points to a paradoxical association between high adiponectin levels and increased mortality rate, which is partly modulated by natriuretic peptides.

To investigate the role of IRS1 locus on failure to oral antidiabetes drugs (OADs) we genotyped single-nucleotide polymorphisms (SNPs), rs2943641, rs7578326 (tagging all SNPs genome-wide associated with type 2 diabetes (T2D) and related traits at this locus) and rs1801278 (that is, the loss-of-function IRS1 G972R amino acid substitution) in 2662 patients with T2D. Although no association with OAD failure was observed for rs2943641 and rs7578326 SNPs (odds ratio (OR): 1.04, 95% confidence interval (CI): 0.93-1.16 and OR: 0.97, 95% CI: 0.87-1.09 respectively), a significant association was observed for rs1801278 (OR: 1.34, 95% CI: 1.08-1.66). When meta-analyzed with previous published data, an allelic OR of 1.41 (1.15-1.72; P=0.001) was obtained, so that homozygous R972R individuals have >80% higher risk of failing to OADs as compared with their G972G counterparts. In all, though further studies are needed for confirming this finding, our present data point to IRS1 rs1801278 as a potential biomarker for pursuing the goal of stratified medicine in the field of antihyperglycemic treatment in T2D.

Recently, response-adaptive designs have been proposed in randomized clinical trials to achieve ethical and/or cost advantages by using sequential accrual information collected during the trial to dynamically update the probabilities of treatment assignments. In this context, urn models-where the probability to assign patients to treatments is interpreted as the proportion of balls of different colors available in a virtual urn-have been used as response-adaptive randomization rules. We propose the use of Randomly Reinforced Urn (RRU) models in a simulation study based on a published randomized clinical trial on the efficacy of home enteral nutrition in cancer patients after major gastrointestinal surgery. We compare results with the RRU design with those previously published with the non-adaptive approach. We also provide a code written with the R software to implement the RRU design in practice. In detail, we simulate 10,000 trials based on the RRU model in three set-ups of different total sample sizes. We report information on the number of patients allocated to the inferior treatment and on the empirical power of the t-test for the treatment coefficient in the ANOVA model. We carry out a sensitivity analysis to assess the effect of different urn compositions. For each sample size, in approximately 75% of the simulation runs, the number of patients allocated to the inferior treatment by the RRU design is lower, as compared to the non-adaptive design. The empirical power of the t-test for the treatment effect is similar in the two designs.

Multigenerational diabetes of adulthood is a mostly overlooked entity, simplistically lumped into the large pool of type 2 diabetes. The general aim of our research in the past few years is to unravel the genetic causes of this form of diabetes. Identifying among families with multigenerational diabetes those who carry mutations in known monogenic diabetes genes is the first step to then allow us to concentrate on remaining pedigrees in which to unravel new diabetes genes. Targeted next-generation sequencing of 27 monogenic diabetes genes was carried out in 55 family probands and identified mutations verified among their relatives by Sanger sequencing. Nine variants (in eight probands) survived our filtering/prioritization strategy. After likelihood of causality assessment by established guidelines, six variants were classified as "pathogenetic/likely pathogenetic" and two as "of uncertain significance." Combining present results with our previous data on the six genes causing the most common forms of maturity-onset diabetes of the young allows us to infer that 23.6% of families with multigenerational diabetes of adulthood carry mutations in known monogenic diabetes genes. Our findings indicate that the genetic background of hyperglycemia is unrecognized in the vast majority of families with multigenerational diabetes of adulthood. These families now become the object of further research aimed at unraveling new diabetes genes., (© 2017 by the American Diabetes Association.)

The activities of corticotropin-releasing factor (CRF) and related peptides are mediated a number of receptors with seven transmembrane domains that are coupled to the Gs and Gq proteins. These receptors are known as CRF-Rs. In vitro studies have evidenced that urocortin (UCN) and CRF provoke an increase in the contractility of the uterus which is induced by endometrial prostaglandin F2a. Furthermore, through trophoblasts, it stimulates the secretion of adrenocorticotropic hormone (ACTH) and prostaglandin PGE2 and has a vasodilatory effect on the placenta. While it is well known that the placenta produces considerable quantities of CRF, several studies have, however, excluded that the placenta can generate significant quantities of UCN. In the short term, the human fetal adrenal gland produces more cortisol and dehydroepiandrosterone sulfate. The gestational tissues express UCN3 and UCN2 mRNA in cytotrophoblast and syncytiotrophoblast cells, while UCN2 is only to be found in the maternal and fetal vessels and amniotic cells. Nevertheless, gestational tissues express UCN2 and UCN3 differentially and do not stimulate placental ACTH secretion. In term pregnancies, maternal plasma levels of CRF and UCN are lower than at the beginning of pregnancy and are correlated to labor onset. Conversely, they do not decrease in post-term pregnancies. This evidence would seem to indicate that the fine-regulated expression of these neuropeptides is important in determining the duration of human gestation. In this scenario, low concentrations of UCN in the amniotic fluid at mid-term may be considered a sign of predisposition to preterm birth.

By color-Doppler ultrasound it's possible to visualize urine flow jet from ureter into the bladder. Aim of the study was to evaluate of ureteral jet in patients with benign prostatic hyperplasia before, during and after with one or two drugs medical therapy. Thirteen patients, aged 51-63 years, were studied; they were not affected by metabolic, hepatic, renal diseases and by prostate inflammation. Eco color Doppler p.w. (Toshiba SSA 270A) with a convex probe of 3.5 MHz was used. A transabdominal ultrasound study was performed, prostate volume measured and ureteral jet visualized before and along treatment (at six months interval) with Finasteride and at the end of treatment. Successively, in four patients, with relapse of prostatic synptomatology, a transabdominal ultrasound study was performed, before and along a treatment with Finasteride, 5 mg/die (Finastid, Neopharmed) and Terazosin hydrochloride, 5 mg/die (Teraprost, Malesci), and at the end of treatment.

Purposes: To investigate the capabilities of fast spin echo (FSE) sequences in diagnosing spinal metastases and to compare two fat-suppression techniques: CHESS (chemical shift selective saturation) and STIR (short T1 inversion recovery). Fat suppression is recommended with FSE sequences because on them, different from conventional spin echo (SE) sequences, fat has high signal intensity in both T1 and T2 weighting, masking such high-signal bone lesions as metastases., Methods: Ninety metastatic lesions in 32 patients were studied with T1-weighted SE and T2-weighted FSE sequences with and without fat suppression (FSE-CHESS and STIR-FSE). Quantitative analyses (metastasis size, signal intensity, margins and conspicuity) and qualitative analyses (artifacts and fat saturation homogeneity) were carried out of both fat-suppression sequences. Signal-to-noise (S/N) and contrast-to-noise (C/N) ratios were calculated in 20 metastatic lesions. The results were analyzed with the chi 2 method and the paired t-test., Results: Both fat-suppression FSE sequences were more sensitive to focal lesions (100%) than T1-weighted SE sequences (96.6%). Lesion signal was higher than that of surrounding bone in 95.5% of fat-suppressed images, which facilitated the recognition of spinal metastases. On the contrary, conspicuity was higher (73.3%) and the margins more definite (68.8%) on T1-weighted SE than on T2-weighted FSE sequences. Fat suppression was more apparent on STIR-FSE than on FSE-CHESS sequences, even with no significant difference in C/N ratio., Conclusion: Both STIR-FSE and FSE-CHESS sequences are rapid and useful techniques to obtain fat saturation in FSE images. CHESS saturation is selective on fat signal, while STIR suppresses the signal of all the substances with the same short T1 as fat.

Objective: To establish the precision of sonographic measurement of the thickness of the articular cartilage of the hip and knee in children., Design: The precision was assessed by evaluating the intra- and interobserver variations in sonographic measurements., Patients: A total of 65 healthy children were in the study. The articular cartilage of the right hip and knee of 40 subjects (mean age 10.3 years, range 4-16.9 years) was evaluated in masked fashion by two observers to assess the interobserver variability. The articular cartilage of the right hip and knee of 25 children (mean age 10.4 years, range 6.2-15.5 years) was examined twice by the same observer to assess the intraobserver variability., Results and Conclusions: Discrepancies between repeated measurements were expressed as data differences. The "limits of agreement" of data differences, i.e. the mean +2 SD and the mean -2 SD, ranged from -0.26 to +0.22 mm and from -0.56 to +0.48 mm for the interobserver analysis of the femoral head cartilage (FHC) and femoral condylar cartilage (FCC), respectively. The "limits of agreement" for the intraobserver analysis ranged from -0.16 to +0.15 mm and from -0.51 to +0.41 mm for the FHC and the FCC, respectively. The overall precision of the sonographic measurements was satisfactory. When used for determination of skeletal age, sonographic assessment of FHC thickness resulted in under/overestimation of skeletal age by about 7.5 months. In conclusion, sonographic measurement of articular cartilage is precise enough to be used in clinical practice.

Despite its frequency, pneumonia is often surprisingly difficult to diagnose in children and young adults. In particular, the etiologic agent of pneumonia is difficult to recognize in an early stage, which obviously implies an empirical or delayed treatment. Chest radiography is one of the most common procedures required when pneumonia is suspected. This retrospective study was carried out to investigate the capabilities of chest radiography to identify the specific patterns of mycoplasma pneumonia in children. The chest radiographs of 76 children and adolescents (aged 4.2 to 16.4 years) with a radiographic diagnosis of pneumonia were reviewed. All patients were tested twice for serum antimycoplasma antibodies. Thirty-eight subjects (50%) with markedly increased antimycoplasma antibody levels were diagnosed as having mycoplasma infection. In the remaining 38 patients, viral (22 patients, 29%), bacterial (13 patients, 17%) and mixed (3 patients, 4%) infections were diagnosed on the grounds of clinical and laboratory data. Parahilar peribronchial infiltrates were found to be associated with both viral and mycoplasma infections, whereas segmental or lobar consolidation was associated with bacterial, viral and mycoplasma infections. Reticulonodular infiltrates were a specific pattern of mycoplasma pneumonia. The authors conclude that, in the presence of a reticulonodular infiltrate in a lobe, mycoplasma pneumonia can be confidently diagnosed.

The comparative efficacy of transcatheter arterial chemoembolization and percutaneous ethanol injection (PEI) in the treatment of hepatocellular carcinoma (HCC) was investigated in a series of 243 consecutive patients: 146 of them were submitted to 1-6 chemoembolization sessions at 1 and 3 months' intervals and 30 to PEI; the remaining 67 patients refused any treatment. The follow-up ranged 3 to 36 months. Survival rates were statistically analyzed with the life table analysis. Patients' survival was affected by the number of nodules and by Child's and Okuda's classes; no relationship was found between survival rates and histologic grade or nodule vascular feeding. In case of single lesions, chemoembolization was more effective than PEI in Okuda's class I. In case of multifocal HCC, chemoembolization was better than no treatment in Okuda's class I and Child's class A. In conclusion, we suggest chemoembolization as the treatment of choice in Child A or Okuda I patients with multifocal HCCs, while its use seems of little help in Child B-C or Okuda II-III patients. In case of unifocal HCC, PEI or surgical resection should be combined with chemoembolization.

Couple's study infertility sometimes need repeated hysterosalpingographical evaluations. In three cases the A.A. value echohysterosalpingography's utility. The echohysterosalpingography gives morphological and functional dates, is easy repeatable and the patients aren't exposed to ionizing radiations.

Since in the early years of 1980, the diagnostic for images about male's urethral injury was exclusively assigned to urethrocystography. Sially in repeated check the gonads too often are exposed to ionizing radiations. Our results show urethrocystography/ultrasonography good correlation (13/15) cases) with 86% sensibility. Even if the urethrocystography is a methodic of first instance, the urethral ultrasonography is efficacious in follow up of urethral injury, particularly in the study of anterior urethra.