Author Correction: Erythropoietin (EPO) haplotype associated with all-cause mortality in a cohort of Italian patients with Type-2 Diabetes.

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Erythropoietin (EPO) haplotype associated with all-cause mortality in a cohort of Italian patients with Type-2 Diabetes.

Type-2 Diabetes (T2D), diabetic complications, and their clinical risk factors harbor a substantial genetic component but the genetic factors contributing to overall diabetes mortality remain unknown. Here, we examined the association between genetic variants at 21 T2D-susceptibility loci and all-cause mortality in an elderly cohort of 542 Italian diabetic patients who were followed for an average of 12.08 years. Univariate Cox regression analyses detected age, waist-to-hip ratio (WHR), glycosylated haemoglobin (HbA1c), diabetes duration, retinopathy, nephropathy, chronic kidney disease (CKD), and anaemia as predictors of all-cause mortality. When Cox proportional hazards multivariate models adjusted for these factors were run, three erythropoietin (EPO) genetic variants in linkage disequilibrium (LD) with each other (rs1617640-T/G, rs507392-T/C and rs551238-A/C) were significantly (False Discovery Rate < 0.1) associated with mortality. Haplotype multivariate analysis revealed that patients carrying the G-C-C haplotype have an increased probability of survival, while an opposite effect was observed among subjects carrying the T-T-A haplotype. Our findings provide evidence that the EPO gene is an independent predictor of mortality in patients with T2D. Thus, understanding the mechanisms by which the genetic variability of EPO affects the mortality of T2D patients may provide potential targets for therapeutic interventions to improve the survival of these patients.

Circulating miR-146a in healthy aging and type 2 diabetes: Age- and gender-specific trajectories.

To evaluate the combined effect of age and glycemic state on circulating levels of the inflamma-miR-146a levels, 188 healthy subjects (CTR) aged 20-104 years and 144 type-2 diabetic patients (T2DM), aged 40-80 years, were analyzed. In CTR subjects, miR-146a levels showed a significant age-related decline. When a gender-stratified analysis was ran, the miR-146a age-related trajectory was confirmed only in men and a negative correlation with PAI-1, uric acid, and creatinine was also observed. In women, miR-146a circulating levels showed negative correlations with azotemia, uric acid, waist/hip ratio and ferritin. A significant miR-146a decline with aging was also observed in T2DM patients. Significant positive correlations were found between miR-146a in diabetic patients and total cholesterol, LDL-C, ApoA1, ApoB, and platelets, and negative correlations with serum iron and ferritin. Notably, miR-146a was significantly overexpressed in T2DM patients treated with metformin. MiR-146a levels were significantly lower in diabetic patients than in age-matched CTR and negatively correlated to both fasting glucose and HbA1c in males. Finally, age-related trajectories for circulating miR-146a levels showed an inverted U-shaped relationship; however, in T2DM patients the trajectory was significantly shifted towards lower levels. Our findings support the hypothesis that miR-146a could be a functional biomarker of healthy/unhealthy aging.

Discontinuously supervised aerobic training vs. physical activity promotion in the self-management of type 2 diabetes in older Italian patients: design and methods of the 'TRIPL-A' randomized controlled trial.

BACKGROUND: Physical activity (PA) has health benefits for people with type 2 diabetes (T2D). Indeed, regular PA is considered an important part of any T2D management plan, yet most patients adopt a sedentary lifestyle. Exercise referral schemes (ERS) have the potential to effectively promote physical activity among T2D patients, and their effectiveness may be enhanced when they are supported by computer-based technologies. The 'TRIPL-A' study (i.e., a TRIal to promote PhysicaL Activity among patients in the young-old age affected by T2D) aims to assess if realizing an innovative ERS, based on a strong partnership among general practitioners, specialist physicians, exercise specialists, and patients, and supported by a web-based application (WBA), can effectively lead sedentary older T2D patients to adopt an active lifestyle. METHODS: A randomized controlled design will be used, and an ERS, supported by a WBA, will be implemented. 300 physically inactive T2D patients (aged 65-74 years) will be assigned to either an intervention or control arm. Control arm patients will only receive behavioral counseling on physical activity and diet, while intervention arm patients will also undergo an 18-month (3 day/week), discontinuously supervised aerobic exercise training program. The trial will be divided into six three-month periods: during first, third and fifth period, an exercise specialist will supervise the training sessions and, using the WBA, prescribe exercise progression and monitor exercise adherence. Patients will exercise on their own in the other periods. Patients' sedentary behaviors (primary outcome), PA level, fitness status, metabolic profile, psychological well-being, quality of life, and use of health care services (secondary outcomes) will be assessed at baseline and at 6, 12, and 18 months from baseline. Repeated measure ANCOVAs will be used to compare the intervention and control arm with respect to each study outcome measure. DISCUSSION: Primary and secondary outcome results will allow us to evaluate the effectiveness of an ERS, specifically designed for the management of T2D clinical conditions and supported by a WBA, in promoting PA within Italian primary care settings. TRIAL REGISTRATION: This trial is retrospectively registered under the Australian New Zealand Clinical Trials Registry (reference number: ACTRN12618001164280 ; registered 13 July 2018).

Endovascular treatment of diabetic peripheral arterial disease in older and oldest old patients: a retrospective study.

BACKGROUND: Peripheral arterial disease (PAD) is frequent among older diabetic patients, but the evidence about endovascular revascularization is very limited. METHOD: We retrospectively analyzed data collected from 120 diabetic patients consecutively admitted to a Diabetic Foot Clinic, including 64 patients aged 65-79 years and 56 patients aged 80 or more. RESULTS: Percutaneous transluminal angioplasty (PTA) was followed by technical success in 82.5% of older patients and 62.5% of oldest old ones (p = 0.05). No significant difference was observed in regards to complete re-epithelization (76.6 vs 76.8%, p = 0.820), recurrent stenosis (26.6 vs 19.6%, p = 0.371), intra- or post-procedure complications (21.9 vs 10.7%, p = 0.102), and amputations (12.5 vs 5.4%, p = 0.176). DISCUSSION: Our findings suggest that older and oldest old patients with diabetic foot and critical ischemia could be effectively and safely treated with PTA.

Comparison of Removable and Irremovable Walking Boot to Total Contact Casting in Offloading the Neuropathic Diabetic Foot Ulceration.

BACKGROUND: Despite its efficacy in healing neuropathic diabetic foot ulcers (DFUs), total contact cast (TCC) is often underused because of technical limitations and poor patient acceptance. We compared TCC to irremovable and removable commercially available walking boots for DFU offloading. METHODS: We prospectively studied 60 patients with DFUs, randomly assigned to 3 different offloading modalities: TCC (group A), walking boot rendered irremovable (i-RWD; group B), and removable walking boot (RWD; group C). Patients were followed up weekly for 90 days or up to complete re-epithelization; ulcer survival, healing time, and ulcer size reduction (USR) were considered for efficacy, whereas number of adverse events was considered for safety. Patients' acceptance and costs were also evaluated. RESULTS: Mean healing time in the 3 groups did not differ (P = .5579), and survival analysis showed no difference between the groups (logrank test P = .8270). USR from baseline to the end of follow-up was significant (P < .01) in all groups without differences between the groups. Seven patients in group A (35%), 2 in group B (10%), and 1 in group C (5%) (Fisher exact test P = .0436 group A vs group C) reported nonsevere adverse events. Patients' acceptance and costs were significantly better in group C (P < .05). CONCLUSIONS: Our results suggest that a walking boot was as effective and safe as TCC in offloading the neuropathic DFUs, irrespective of removability. The better acceptability and lesser costs of a removable device may actually extend the possibilities of providing adequate offloading. LEVEL OF EVIDENCE: Level II, prospective comparative study.

Photodynamic topical antimicrobial therapy for infected foot ulcers in patients with diabetes: a randomized, double-blind, placebo-controlled study--the D.A.N.T.E (Diabetic ulcer Antimicrobial New Topical treatment Evaluation) study.

This study was designed to assess the antimicrobial effect and tolerability of a single dose of a photo-activated gel containing RLP068 in the treatment for infected foot ulcers in subjects with diabetes. A randomized, double-blind, parallel series, placebo-controlled phase IIa trial was performed with three concentrations of RLP068 (0.10, 0.30, and 0.50 %), measuring total and pathogen microbial load on Day 1 (before and 1 h after topical gel application and photoactivation with 689 nm red light), on Days 3, 8, and 15, as add-on to systemic treatment with amoxicillin and clavulanic acid. Blood samples were also drawn 1, 2, and 48 h after administration for the assessment of systemic drug absorption. The trial was performed on 62 patients aged ≥18 years, with type 1 or type 2 diabetes and infected foot ulcer, with an area of 2-15 cm(2) and a maximum diameter ≤4.6 cm. A dose-dependent reduction in total microbial load was observed (-1.92 ± 1.21, -2.94 ± 1.60, and -3.00 ± 1.82 LogCFU/ml for 0.10, 0.30, and 0.50 % RPL068 vs. -1.00 ± 1.02 LogCFU/ml with placebo) immediately after illumination, with a progressive fading of the effect during follow-up. No safety issues emerged from the analysis of adverse events. Systemic absorption of RLP068 was negligible. Photodynamic antimicrobial treatment with RLP068 of infected diabetic foot ulcers is well tolerated and produces a significant reduction in germ load. Further clinical trials are needed to verify the efficacy of this approach as add-on to systemic antibiotic treatment.