Clinical Studies Using Topical Melatonin.

Melatonin is ubiquitously present in all animals and plants, where it exerts a variety of physiological activities thanks to its antioxidant properties and its key role as the first messenger of extracellular signaling functions. Most of the clinical studies on melatonin refer to its widespread oral use as a dietary supplement to improve sleep. A far smaller number of articles describe the clinical applications of topical melatonin to treat or prevent skin disorders by exploiting its antioxidant and anti-inflammatory activities. This review focuses on the clinical studies in which melatonin was applied on the skin as a photoprotective, anti-aging, or hair growth-promoting agent. The methodologies and results of such studies are discussed to provide an overall picture of the state of the art in this intriguing field of research. The clinical studies in which melatonin was applied on the skin before exposure to radiation (UV, sunlight, and high-energy beams) were all characterized by an appropriate design (randomized, double-blind, and placebo-controlled) and strongly support its clinical efficacy in preventing or reducing skin damage such as dermatitis, erythema, and sunburn. Most of the studies examined in this review do not provide a clear demonstration of the efficacy of topical melatonin as a skin anti-aging or as a hair growth-promoting agent owing to limitations in their design and/or to the use of melatonin combined with extra active ingredients, except for one trial that suggests a possible beneficial role of melatonin in treating some forms of alopecia in women. Further research efforts are required to reach definitive conclusions concerning the actual benefits of topical melatonin to counteract skin aging and hair loss.

Annurca Apple Oleolite as Functional Ingredient for the Formulation of Cosmetics with Skin-Antiaging Activity.

The identification of natural remedies for the management of the skin aging process is an increasingly growing issue. In this context, ursolic acid (UA), a ubiquitous molecule, mainly contained in Annurca apple (AA) fruit, has demonstrated valuable cosmetic potential. To this end, in the current study, the AA oleolite (AAO, extract in sunflower oil containing 784.40 ± 7.579 µg/mL of UA) was evaluated to inhibit porcine elastase enzymatic reactions through a validated spectrophotometric method. AAO has shown a valuable capacity to contrast the elastase enzyme with a calculated IC50 of 212.76 mg/mL, in comparison to UA (IC50 of 135.24 µg/mL) pure molecules and quercetin (IC50 of 72.47 µg/mL) which are used as positive controls. In this context and in view of the valuable antioxidant potential of AAO, its topical formulation with 2.5% (w/w) AAO was tested in a placebo-controlled, double-blind, two-arm clinical study on 40 volunteers. Our results indicated that after 28 days of treatment, a significant reduction of the nasolabial fold (-7.2 vs. baseline T0, p < 0.001) and forehead wrinkles (-5.3 vs. baseline T0, p < 0.001) were registered in combination with a valuable improvement of the viscoelastic skin parameters, where skin pliability/firmness (R0) and gross elasticity (R2) were significantly ameliorated (-13% vs. baseline T0, p < 0.001 for R0 and +12% vs. baseline T0, p < 0.001 for R2). Finally, considering the positive correlation between skin elasticity and hydration, the skin moisture was evaluated through the estimation of Trans epidermal water loss (TEWL) and skin conductance.

NAD-Driven Sirtuin Activation by Cordyceps sinensis Extract: Exploring the Adaptogenic Potential to Promote Skin Longevity.

In recent years, there has been increasing interest in utilizing Traditional Chinese Medicine principles and natural bioactive compounds to combat age-related ailments and enhance longevity. A Cordyceps sinensis mycelium hydroethanolic extract (CsEx), which was standardized in cordycepin and adenosine using UHPLC-DAD, was investigated for its adaptogenic properties using in vitro assays and a double-blind, placebo-controlled clinical trial involving 40 subjects. The CsEx demonstrated activity at a concentration of 0.0006%, significantly increasing sirtuin expression (SirT1: +33%, SirT3: +10%, SirT6: +72%, vs. CTR, p < 0.05) and NAD+ synthesis in HaCat cells (+20% vs. CTR, p < 0.001). Moreover, the CsEx boosted ATP production by 68% in skin cells, correlating with higher skin energy values (+52.0% at D28, p < 0.01) in the clinical trial. Additionally, CsEx notably reduced cytosolic reactive oxygen species (ROS) by 30% in HaCaT cells (p < 0.05) and enhanced collagen production both in vitro (+69% vs. CTR, p < 0.01) and in vivo (+10% vs. D0, p < 0.01), confirmed by ultrasound examination. Furthermore, CsEx's stimulation of fibroblasts, coupled with its antioxidant and energizing properties, led to a significant reduction in wrinkles by 28.0% (D28, p < 0.001). This study underscores Cordyceps sinensis hydroethanolic extract's potential in regulating skin cell energy metabolism and positively influencing the mechanisms associated with skin longevity control.

On the thermal behavior of protein isolated from different legumes investigated by DSC and TGA.

BACKGROUND: Pea, lentil, faba bean, chickpea and bean proteins are potentially renewable raw materials for bioplastic production that can be obtained from agricultural waste. Plastics are usually processed under heating, and thus thermal stability is a mandatory requirement for the application. In this study, the thermal behavior of several legume protein isolates at different purity degrees was investigated. RESULTS: The thermal stability of proteins extracted from legumes was maximum for chickpeas and minimum for beans and decreased with decreasing protein purity in the range 30-88%. A similar dependence on purity was observed for the glass transition temperature. On the contrary, the denaturation temperature was found not to depend on sample purity and origin and was lower than the degradation temperature only in the case of protein samples with purity higher than 60%. CONCLUSION: Proteins from legumes are suitable to produce thermoplastic biopolymeric materials if isolated at purity higher than 60%. In fact, under this circumstance, they can be denaturized without degrading and thus are suitable for extrusion processing. © 2018 Society of Chemical Industry.

Paclitaxel-Eluting Balloon vs Standard Angioplasty to Reduce Restenosis in Diabetic Patients With In-Stent Restenosis of the Superficial Femoral and Proximal Popliteal Arteries: Three-Year Results of the DEBATE-ISR Study.

PURPOSE: To report the 3-year safety and effectiveness outcomes from the prospective all-comers DEBATE-ISR study (ClinicalTrials.gov identifier NCT01558531) of symptomatic diabetic patients with femoropopliteal in-stent restenosis (ISR) undergoing treatment with paclitaxel-eluting balloons compared with historical diabetic controls. METHODS: From January 2010 to December 2011, 44 consecutive diabetic patients (mean age 74±11 years; 32 men) were treated with drug-eluting balloons (DEBs) and enrolled in the study. The control group comprised 42 consecutive diabetic patients (age 76±7 years; 23 men) treated with conventional balloon angioplasty (BA) from 2008 to 2009. RESULTS: No significant differences in terms of clinical, angiographic, or procedural characteristics were observed between the study groups. Critical limb ischemia was present in the majority of patients. Tosaka class III ISR was observed in more than half of the patients. Mean lesion length was 132±86 and 137±82 mm in the DEB and BA groups, respectively (p=0.7). At 3-year follow-up, the rate of target lesion revascularization (TLR) was 40% in the DEB group vs 43% in the BA group (p=0.8); Kaplan-Meier analysis showed no significant differences in terms of freedom from TLR. The presence of a Tosaka class III occlusion was associated with a worse outcome in both study groups (odds ratio 3.96, 95% confidence interval 1.55 to 10.1, p=0.004). CONCLUSION: Using DEBs for femoropopliteal ISR yielded similar results to BA in terms of TLR at 3-year follow-up. The treatment of more complex ISR lesions was associated with an increased rate of TLR, irrespective of the technology used.

Drug-eluting balloon in peripheral intervention for below the knee angioplasty evaluation (DEBATE-BTK): a randomized trial in diabetic patients with critical limb ischemia.

BACKGROUND: The 1-year restenosis rate after balloon angioplasty of long lesions in below-the-knee arteries may be as high as 70%. Our aim was to investigate the efficacy of a paclitaxel drug-eluting balloons versus conventional percutaneous transluminal angioplasty (PTA) for the reduction of restenosis in diabetic patients with critical limb ischemia undergoing endovascular intervention of below-the-knee arteries. METHODS AND RESULTS: The Drug-Eluting Balloon in Peripheral Intervention for below the knee angioplasty evaluation (DEBATE-BTK) is a randomized, open-label, single-center study comparing drug-eluting balloons and PTA. Inclusion criteria were diabetes mellitus, critical limb ischemia (Rutherford class 4 or higher), significant stenosis or occlusion >40 mm of at least 1 below-the-knee vessel with distal runoff, and life expectancy >1 year. Binary in-segment restenosis at a 1-year angiographic or ultrasonographic follow-up was the primary end point. Clinically driven target lesion revascularization, major amputation, and target vessel occlusion were the secondary end points. One hundred thirty-two patients with 158 infrapopliteal atherosclerotic lesions were enrolled. Mean length of the treated segments was 129±83 mm in the drug-eluting balloon group compared with 131±79 mm in the PTA group (P=0.7). Binary restenosis, assessed by angiography in >90% of patients, occurred in 20 of 74 lesions (27%) in the drug-eluting balloon group compared with 55 of 74 lesions (74%) in the PTA group (P<0.001); target lesion revascularization, in 12 (18%) versus 29 (43%; P=0.002); and target vessel occlusion, in 12 (17%) versus 41 (55%; P<0.001). Only 1 major amputation occurred, in the PTA group (P=0.9). CONCLUSIONS: Drug-eluting balloons compared with PTA strikingly reduce 1-year restenosis, target lesion revascularization, and target vessel occlusion in the treatment of below-the-knee lesions in diabetic patients with critical limb ischemia.

Paclitaxel-eluting balloon vs. standard angioplasty to reduce recurrent restenosis in diabetic patients with in-stent restenosis of the superficial femoral and proximal popliteal arteries: the DEBATE-ISR study.

PURPOSE: To test the ability of a drug-eluting balloon (DEB) to reduce recurrent in-stent restenosis (ISR) in diabetic patients with femoropopliteal stents. METHODS: A prospective all-comers study [Drug-Eluting Balloon in Peripheral Intervention for In-Stent Restenosis (DEBATE-ISR); ClinicalTrials.gov identifier NCT01558531] of symptomatic diabetic patients with femoropopliteal ISR undergoing treatment with paclitaxel-eluting balloons was designed to compare their 12-month recurrent restenosis rate with that of historical diabetic controls. From January 2010 to December 2011, 44 consecutive diabetic patients (32 men; mean age 74±11 years) were treated with DEBs and enrolled in the study. The control group comprised 42 diabetic patients (23 men; mean age 76±7 years) treated with a conventional balloon for femoropopliteal ISR from 2008 to 2009. RESULTS: No significant differences in terms of clinical, angiographic, or procedural characteristics were observed between the study groups. Lesion length was 132±86 mm in the DEB group vs. 137±82 mm in the BA group. Procedural success, defined as a residual stenosis <30% in the restenotic segment (stent +5 mm at proximal and distal edges), was obtained in all treated lesions. At 1-year follow-up, 6 patients died (3 in each group), and 1 patient in the BA group underwent major amputation. Recurrent restenosis, assessed by angiography (66%) or ultrasound (34%), occurred in 8/41 (19.5%) patients in the DEB group vs. 28/39 (71.8%) in the BA group (p<0.001). Target lesion revascularization for symptomatic recurrent restenosis was performed in 6/44 (13.6%) patients in the DEB vs.13/42 (31.0%) in the BA group (p=0.045). CONCLUSION: Using DEB for treating femoropopliteal ISR led to a significant reduction in recurrent restenosis and repeat angioplasty at 1-year follow-up as compared to historical controls.

Synthesis, characterization, and solid-state NMR investigation of organically modified bentonites and their composites with LDPE.

Polymer/clay nanocomposites show remarkably improved properties (mechanical properties, as well as decreased gas permeability and flammability, etc.) with respect to their microscale counterparts and pristine polymers. Due to the substantially apolar character of most of the organic polymers, natural occurring hydrophilic clays are modified into organophilic clays with consequent increase of the polymer/clay compatibility. Different strategies have been developed for the preparation of nanocomposites with improved properties, especially aimed at achieving the best dispersion of clay platelets in the polymer matrix. In this paper we present the preparation and characterization of polymer/clay nanocomposites composed of low-density polyethylene (LDPE) and natural clay, montmorillonite-containing bentonite. Two different forms of the clay have been considered: the first, a commercial organophilic bentonite (Nanofil 15), obtained by exchanging the natural cations with dimethyldioctadecylammonium (2C18) cations, and the second, obtained by performing a grafting reaction of an alkoxysilane containing a polymerizable group, 3-(trimethoxysilyl)propyl methacrylate (TSPM), onto Nanofil 15. Both the clays and LDPE/clay nanocomposites were characterized by thermal, FT-IR, and X-ray diffraction techniques. The samples were also investigated by means of (29)Si, (13)C, and (1)H solid-state NMR, obtaining information on the structural properties of the modified clays. Moreover, by exploiting the effect of bentonite paramagnetic (Fe(3+)) ions on proton spin-lattice relaxation times (T1's), useful information about the extent of the polymer-clay dispersion and their interfacial interactions could be obtained.

Brief Report: Long-Term Clinical, Immunologic, and Virologic Outcomes Among Early-Treated Children With HIV in Botswana: A Nonrandomized Controlled Clinical Trial.

BACKGROUND: Early antiretroviral treatment (ART) improves outcomes in children, but few studies have comprehensively evaluated the impact of ART started from the first week of life. METHODS: Children diagnosed with HIV within 96 hours of life were enrolled into the Early Infant Treatment Study in Botswana and followed on ART for 96 weeks. Nevirapine, zidovudine, and lamivudine were initiated; nevirapine was switched to lopinavir/ritonavir between weeks 2-5 in accordance with gestational age. Clinical and laboratory evaluations occurred at weeks 1, 2, 4, 8, 12, 24, 36, 48, 60, 72, 84, and 96. FINDINGS: Forty children initiated ART at a median of 2 (IQR 2, 3) days of life; 38 (95%) completed follow-up through 96 weeks, and 2 (5%) died between 12 and 24 weeks. ART was well tolerated; 9 children (24%) experienced a grade 3 or 4 hematologic event, and 2 (5%) required treatment modification for anemia. The median 96-week CD4 count was 1625 (IQR 1179, 2493) cells/mm 3 with only 5/38 (13%) having absolute counts <1000 cells/mm 3 . Although 23 (61%) had at least one visit with HIV-1 RNA ≥40 copies/mL at or after 24 weeks, 28 (74%) had HIV-1 RNA <40 copies/mL at the 96-week visit. Median cell-associated HIV-1 DNA at 84/96-week PBMCs was 1.9 (IQR 1.0, 2.6) log 10 copies/10 6 cells. Pre-ART reservoir size at birth was predictive of the viral reservoir at 84/96 weeks. INTERPRETATION: Initiation of ART in the first week of life led to favorable clinical outcomes, preserved CD4 cell counts, and low viral reservoir through 96 weeks of life.

An In Situ Experiment to Evaluate the Aging and Degradation Phenomena Induced by Marine Environment Conditions on Commercial Plastic Granules.

In this paper, we present two novel experimental setups specifically designed to perform in situ long-term monitoring of the aging behaviour of commercial plastic granules (HDPE, PP, PLA and PBAT). The results of the first six months of a three year monitoring campaign are presented. The two experimental setups consist of: (i) special cages positioned close to the sea floor at a depth of about 10 m, and (ii) a box containing sand exposed to atmospheric agents to simulate the surface of a beach. Starting from March 2020, plastic granules were put into the cages and plunged in seawater and in a sandboxe. Chemical spectroscopic and thermal analyses (GPC, SEM, FTIR-ATR, DSC, TGA) were performed on the granules before and after exposure to natural elements for six months, in order to identify the physical-chemical modifications occurring in marine environmental conditions (both in seawater and in sandy coastal conditions). Changes in colour, surface morphology, chemical composition, thermal properties, molecular weight and polydispersity, showed the different influences of the environmental conditions. Photooxidative reaction pathways were prevalent in the sandbox. Abrasive phenomena acted specially in the sea environment. PLA and PBAT did not show significant degradation after six months, making the possible reduction of marine pollution due to this process negligible.

Unravelling Main- and Side-Chain Motions in Polymers with NMR Spectroscopy and Relaxometry: The Case of Polyvinyl Butyral.

Polyvinyl butyral (PVB) is an amorphous polymer employed in many technological applications. In order to highlight the relationships between macroscopic properties and dynamics at a microscopic level, motions of the main-chain and of the propyl side-chains were investigated between Tg - 288 °C and Tg + 55 °C, with Tg indicating the glass transition temperature. To this aim, a combination of solid state Nuclear Magnetic Resonance (NMR) methods was applied to two purposely synthesized PVB isotopomers: one fully protonated and the other perdeuterated on the side-chains. 1H time domain NMR and 1H field cycling NMR relaxometry experiments, performed across and above Tg, revealed that the dynamics of the main-chain corresponds to the α-relaxation associated to the glass transition, which was previously characterized by dielectric spectroscopy. A faster secondary relaxation was observed for the first time and ascribed to side-chains. The geometry and rate of motions of the different groups in the side-chains were characterized below Tg by 2H NMR spectroscopy.

Preparations of Poly(lactic acid) Dispersions in Water for Coating Applications.

A green, effective methodology for the preparation of water-based dispersions of poly(lactic acid) (PLA) for coating purposes is herein presented. The procedure consists of two steps: in the first one, an oil-in-water emulsion is obtained by mixing a solution of PLA in ethyl acetate with a water phase containing surfactant and stabilizer. Different homogenization methods as well as oil/water phase ratio, surfactant and stabilizer combinations were screened. In the second step, the quantitative evaporation of the organic provides water dispersions of PLA that are stable, at least, over several weeks at room temperature or at 4 °C. Particle size was in the 200-500 nm range, depending on the preparation conditions, as confirmed by scanning electron microscope (SEM) analysis. PLA was found not to suffer significant molecular weight degradation by gel permeation chromatography (GPC) analysis. Furthermore, two selected formulations with glass transition temperature (Tg) of 51 °C and 34 °C were tested for the preparation of PLA films by drying in PTFE capsules. In both cases, continuous films that are homogeneous by Fourier-transform infrared spectroscopy (FT-IR) and SEM observation were obtained only when drying was performed above 60 °C. The formulation with lower Tg results in films which are more flexible and transparent.

Antimicrobial Photodynamic Therapy in Infected Diabetic Foot Ulcers: A Multicenter Preliminary Experience.

BACKGROUND: The increasing resistance of bacteria to antibiotics and the frequency of comorbid conditions of patients make the treatment of diabetic foot infections problematic. In this context, photodynamic therapy could be a useful tool to treat infected wounds. The aim of this study was to evaluate the effect of repeated applications of a phthalocyanine derivative (RLP068) on the bacterial load and on the healing process. METHODS: The present analysis was performed on patients with clinically infected ulcers who had been treated with RLP068. A sample for microbiological culture was collected at the first visit before and immediately after the application of RLP068 on the ulcer surface, and the area was illuminated for 8 minutes with a red light. The whole procedure was repeated three times per week at two centers (Florence and Arezzo, Italy) (sample A), and two times per week at the third center (Stuttgart, Germany) (sample B) for 2 weeks. RESULTS: Sample A and sample B were composed of 55 and nine patients, respectively. In sample A, bacterial load decreased significantly after a single treatment, and the benefit persisted for 2 weeks. Similar effects of the first treatment were observed in sample B. In both samples, the ulcer area showed a significant reduction during follow-up, even in patients with ulcers infected with gram-negative germs or with exposed bone. CONCLUSIONS: RLP068 seems to be a promising topical wound management procedure for the treatment of infected diabetic foot ulcers.

Randomized Controlled Trial of Acotec Drug-Eluting Balloon Versus Plain Balloon for Below-the-Knee Angioplasty.

OBJECTIVES: The aim of this study was to investigate the efficacy and safety of the Litos drug-coated balloon (DCB) versus plain old balloon angioplasty (POBA) for reduction of late lumen loss (LLL) in patients with critical limb ischemia undergoing below-the-knee (BTK) intervention. BACKGROUND: Restenosis after balloon angioplasty of BTK arteries approximates 70%. Previous studies of DCBs in BTK arteries produced conflicting results. METHODS: ACOART-BTK (Evaluation of the Use of ACOTEC Drug-Eluting Balloon Litos® in Below-the-Knee Arteries to Treat Critical Limb Ischemia) is a randomized controlled single-center study. Inclusion criteria were critical limb ischemia (Rutherford class ≥4) and significant stenosis or occlusion >40 mm of at least 1 BTK vessel with distal runoff successfully treated with angioplasty. Six-month angiographic LLL was the primary endpoint. Occlusive restenosis at 6 months and clinically driven target lesion revascularization at 12 months were secondary endpoints. RESULTS: From January 2016 through January 2019, 105 patients with 129 BTK lesions were enrolled in the study. Mean lesion length was 168 ± 109 mm in the DCB group and 187 ± 113 mm in the POBA group (p = 0.30). Almost 70% of lesions were occluded at baseline in both groups. On 6-month angiography, mean LLL was 0.51 ± 0.60 mm in the DCB group and 1.31 ± 0.72 mm in the POBA group (p < 0.001); rates of occlusive restenosis were 8.6% and 48.4%, respectively (p < 0.001). Twelve-month clinically driven target lesion revascularization occurred in 6 of 62 DCB-treated lesions (10%) versus 27 of 66 POBA-treated lesions (41%) (p < 0.001). Complete healing at 12 months was observed in 42 of 47 DCB-treated limbs (89.4) versus 35 of 47 POBA-treated limbs (74.5%) (p = 0.05); no major amputations occurred. CONCLUSIONS: Litos DCBs strikingly reduced LLL, vessel reocclusion, and clinically driven target lesion revascularization compared with POBA in BTK angioplasty.

Influence of Positive End-Expiratory Pressure Titration on the Effects of Pronation in Acute Respiratory Distress Syndrome: A Comprehensive Experimental Study.

Prone position can reduce mortality in acute respiratory distress syndrome (ARDS), but several studies found variable effects on oxygenation and lung mechanics. It is unclear whether different positive end-expiratory pressure (PEEP) titration techniques modify the effect of prone position. We tested, in an animal model of ARDS, if the PEEP titration method may influence the effect of prone position on oxygenation and lung protection. In a crossover study in 10 piglets with a two-hit injury ARDS model, we set the "best PEEP" according to the ARDS Network low-PEEP table (BPARDS) or targeting the lowest transpulmonary driving pressure (BPDPL). We measured gas exchange, lung mechanics, aeration, ventilation, and perfusion with computed tomography (CT) and electrical impedance tomography in each position with both PEEP titration techniques. The primary endpoint was the PaO2/FiO2 ratio. Secondary outcomes were lung mechanics, regional distribution of ventilation, regional distribution of perfusion, and homogeneity of strain derived by CT scan. The PaO2/FiO2 ratio increased in prone position when PEEP was set with BPARDS [difference 54 (19-106) mmHg, p = 0.04] but not with BPDPL [difference 17 (-24 to 68) mmHg, p = 0.99]. The transpulmonary driving pressure significantly decreased during prone position with both BPARDS [difference -0.9 (-1.5 to -0.9) cmH2O, p = 0.009] and BPDPL [difference -0.55 (-1.6 to -0.4) cmH2O, p = 0.04]. Pronation homogenized lung regional strain and ventilation and redistributed the ventilation/perfusion ratio along the sternal-to-vertebral gradient. The PEEP titration technique influences the oxygenation response to prone position. However, the lung-protective effects of prone position could be independent of the PEEP titration strategy.

Drug-Eluting Balloon Versus Drug-Eluting Stent for Complex Femoropopliteal Arterial Lesions: The DRASTICO Study.

BACKGROUND: Drug-eluting technologies improve 12-month angiographic results of femoropopliteal (FP) interventions, but few data on the comparison between drug-coated balloons (DCBs) and drug-eluting stents (DES) are available. OBJECTIVES: The aim of this study was to compare, after balloon pre-dilation, a strategy of DCB followed by provisional self-expanding nitinol bare-metal stent implantation with a strategy of systematic DES implantation in patients at high risk for FP restenosis. METHODS: Patients presenting with either intermittent claudication or critical limb ischemia undergoing FP intervention were randomly assigned 1:1 to DCB or DES after successful target lesion pre-dilation. The primary endpoint was 12-month target lesion binary restenosis, assessed using Doppler ultrasound. Secondary endpoints were freedom from target lesion revascularization and from major amputation. RESULTS: A total of 192 patients, 96 in the DCB group and 96 in the DES group, with 240 lesions in 225 limbs, were included. Diabetes and critical limb ischemia were present in >50% in both groups. Mean lesion length was 14 cm, and baseline target lesion occlusion reached about 60% of cases in both groups. The systematic DES strategy yielded larger post-procedural minimal luminal diameter and a lower incidence of residual dissection compared to DCB, in which nitinol stents were used in only 21% of the lesions. Twelve-month target lesion restenosis was observed in 22% of DCB-treated versus 21% of DES-treated patients (p = 0.90). Clinically driven target lesion revascularization was necessary in 14% of DCB patients versus 17% of DES patients (p = 0.50). CONCLUSIONS: DCB was not superior to DES in the treatment of complex FP lesions in a high-risk population, yielding similar rate of restenosis and clinically driven target lesion revascularization. (Paclitaxel-Eluting Balloon Angioplasty With Provisional Use of Nitinol Stent Versus Systematic Implantation of Paclitaxel-Eluting Stent for the Treatment of Femoropopliteal De Novo Lesions; NCT01969630).

How complicated skin and soft tissue infections are treated in Italy: economic evaluation of inpatient intravenous antibiotic treatment in seven hospitals.

OBJECTIVES: Complicated skin and soft tissue infections (cSSTIs) are a common cause of morbidity at hospital level. This study aimed to evaluate the costs and outcomes of inpatient intravenous antibiotic therapy for the treatment of cSSTI in seven Italian hospitals. METHODS: A total of 307 patients were enrolled in a retrospective, multicentre, incidence-based, observational study. The target population consisted of hospitalised patients eligible to receive intravenous antibiotic therapy for cSSTI. Direct hospital costs were measured through a microcosting approach. RESULTS: Failure of initial antibiotic therapy occurred in 23% of patients. Average antibiotic treatment lasted 12.2 days; the average full cost of admission totalled euro5,530. If the initial antibiotic regimen fails to eradicate the infectious organism, the length of stay extends for 7 days and costs increase by euro2,850 per patient. Nevertheless, when taking into account the lower intensity of care during the last days of treatment, savings reduce costs to euro671 per patient. These could be increased by euro74 for each hospital day avoided because of faster antibiotic action. CONCLUSIONS: Efforts should be made to minimise the risk of selecting wrong antibiotics and to identify the quickest antibiotic in eradicating the infection.

All-cause and cardiovascular mortality in a consecutive series of patients with diabetic foot osteomyelitis.

BACKGROUND: Mortality in patients with type 2 diabetes and diabetic foot osteomyelitis (DFO) have been explored in few small studies with a short follow-up. Aim of the present study is to assess all-cause and cardiovascular mortality and predictors of mortality in a consecutive series of patients with DFO. RESEARCH DESIGN AND METHODS: Patients with a diagnosis of DFO, attending the Diabetic Foot Unit of San Donato Hospital in Arezzo between January 1st, 2012 and December 31st, 2013, were included in this retrospective study. Information on all-cause mortality up to December 1st, 2016, was obtained from the registry of the Local Health Unit of Arezzo, which contains updated records of all persons living in Tuscany. RESULTS: One hundred ninety-four patients were included in the study. During a mean period of observation of 2.8±1.4years, 73 (37.6%) died, with a yearly rate of 13.2%. Of the 73 deaths, 59 were attributable to cardiovascular causes. After adjusting for possible confounders in a Cox analysis, site of osteomyelitis (hindfoot vs mid/forefoot) was associated with a higher mortality, and surgical treatment with a lower mortality. CONCLUSIONS: Mortality in patients with DFO appears to be much higher than that reported in clinical series of patients with diabetic foot ulcers, particularly when hindfoot is affected.

Effects on the incidence of cardiovascular events of the addition of pioglitazone versus sulfonylureas in patients with type 2 diabetes inadequately controlled with metformin (TOSCA.IT): a randomised, multicentre trial.

BACKGROUND: The best treatment option for patients with type 2 diabetes in whom treatment with metformin alone fails to achieve adequate glycaemic control is debated. We aimed to compare the long-term effects of pioglitazone versus sulfonylureas, given in addition to metformin, on cardiovascular events in patients with type 2 diabetes. METHODS: TOSCA.IT was a multicentre, randomised, pragmatic clinical trial, in which patients aged 50-75 years with type 2 diabetes inadequately controlled with metformin monotherapy (2-3 g per day) were recruited from 57 diabetes clinics in Italy. Patients were randomly assigned (1:1), by permuted blocks randomisation (block size 10), stratified by site and previous cardiovascular events, to add-on pioglitazone (15-45 mg) or a sulfonylurea (5-15 mg glibenclamide, 2-6 mg glimepiride, or 30-120 mg gliclazide, in accordance with local practice). The trial was unblinded, but event adjudicators were unaware of treatment assignment. The primary outcome, assessed with a Cox proportional-hazards model, was a composite of first occurrence of all-cause death, non-fatal myocardial infarction, non-fatal stroke, or urgent coronary revascularisation, assessed in the modified intention-to-treat population (all randomly assigned participants with baseline data available and without any protocol violations in relation to inclusion or exclusion criteria). This study is registered with ClinicalTrials.gov, number NCT00700856. FINDINGS: Between Sept 18, 2008, and Jan 15, 2014, 3028 patients were randomly assigned and included in the analyses. 1535 were assigned to pioglitazone and 1493 to sulfonylureas (glibenclamide 24 [2%], glimepiride 723 [48%], gliclazide 745 [50%]). At baseline, 335 (11%) participants had a previous cardiovascular event. The study was stopped early on the basis of a futility analysis after a median follow-up of 57·3 months. The primary outcome occurred in 105 patients (1·5 per 100 person-years) who were given pioglitazone and 108 (1·5 per 100 person-years) who were given sulfonylureas (hazard ratio 0·96, 95% CI 0·74-1·26, p=0·79). Fewer patients had hypoglycaemias in the pioglitazone group than in the sulfonylureas group (148 [10%] vs 508 [34%], p<0·0001). Moderate weight gain (less than 2 kg, on average) occurred in both groups. Rates of heart failure, bladder cancer, and fractures were not significantly different between treatment groups. INTERPRETATION: In this long-term, pragmatic trial, incidence of cardiovascular events was similar with sulfonylureas (mostly glimepiride and gliclazide) and pioglitazone as add-on treatments to metformin. Both of these widely available and affordable treatments are suitable options with respect to efficacy and adverse events, although pioglitazone was associated with fewer hypoglycaemia events. FUNDING: Italian Medicines Agency, Diabete Ricerca, and Italian Diabetes Society.

Bridging the Gap between Theory and Practice in Integrated Care: The Case of the Diabetic Foot Pathway in Tuscany.

INTRODUCTION AND BACKGROUND: As diabetic foot (DF) care benefits from integration, monitoring geographic variations in lower limb Major Amputation rate enables to highlight potential lack of Integrated Care. In Tuscany (Italy), these DF outcomes were good on average but they varied within the region. In order to stimulate an improvement process towards integration, the project aimed to shift health professionals' focus on the geographic variation issue, promote the Population Medicine approach, and engage professionals in a community of practice. METHOD: Three strategies were thus carried out: the use of a transparent performance evaluation system based on benchmarking; the use of patient stories and benchmarking analyses on outcomes, service utilization and costs that cross-checked delivery- and population-based perspectives; the establishment of a stable community of professionals to discuss data and practices. RESULTS: The project enabled professionals to shift their focus on geographic variation and to a joint accountability on outcomes and costs for the entire patient pathways. Organizational best practices and gaps in integration were identified and improvement actions towards Integrated Care were implemented. CONCLUSION AND DISCUSSION: For the specific category of care pathways whose geographic variation is related to a lack of Integrated Care, a comprehensive strategy to improve outcomes and reduce equity gaps by diffusing integration should be carried out.