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Policies to improve air quality need to be based on effective plans for reducing anthropogenic emissions. In 2020, the outbreak of COVID-19 pandemic resulted in significant reductions of anthropogenic pollutant emissions, offering an unexpected opportunity to observe their consequences on ambient concentrations. Taking the national lockdown occurred in Italy between March and May 2020 as a case study, this work tries to infer if and what lessons may be learnt concerning the impact of emission reduction policies on air quality. Variations of NO 2 , O 3 , PM 10 and PM 2.5 concentrations were calculated from numerical model simulations obtained with business as usual and lockdown specific emissions. Both simulations were performed at national level with a horizontal resolution of 4 km, and at local level on the capital city Rome at 1 km resolution. Simulated concentrations showed a good agreement with in-situ observations, confirming the modelling systems capability to reproduce the effects of emission reductions on ambient concentration variations, which differ according to the individual air pollutant. We found a general reduction of pollutant concentrations except for ozone, that experienced an increase in Rome and in the other urban areas, and a decrease elsewhere. The obtained results suggest that acting on precursor emissions, even with sharp reductions like those experienced during the lockdown, may lead to significant, albeit complex, reduction patterns for secondary pollutant concentrations. Therefore, to be more effective, reduction measures should be carefully selected, involving more sectors than those related to mobility, such as residential and agriculture, and integrated on different scales., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 Turkish National Committee for Air Pollution Research and Control. Production and hosting by Elsevier B.V. All rights reserved.)

Objectives: To investigate the association between long-term exposure to airborne pollutants and the incidence of SARS-CoV-2 up to March 2021 in a prospective study of residents in Varese city., Methods: Citizens of Varese aged ≥18 years as of 31 December 2019 were linked by residential address to 2018 average annual exposure to outdoor concentrations of PM 2.5 , PM 10 , NO 2 , NO and ozone modelled using the Flexible Air quality Regional Model (FARM) chemical transport model. Citizens were further linked to regional datasets for COVID-19 case ascertainment (positive nasopharyngeal swab specimens) and to define age, sex, living in a residential care home, population density and comorbidities. We estimated rate ratios and additional numbers of cases per 1 µg/m 3 increase in air pollutants from single- and bi-pollutant Poisson regression models., Results: The 62 848 residents generated 4408 cases. Yearly average PM 2.5 exposure was 12.5 µg/m 3 . Age, living in a residential care home, history of stroke and medications for diabetes, hypertension and obstructive airway diseases were independently associated with COVID-19. In single-pollutant multivariate models, PM 2.5 was associated with a 5.1% increase in the rate of COVID-19 (95% CI 2.7% to 7.5%), corresponding to 294 additional cases per 100 000 person-years. The association was confirmed in bi-pollutant models; excluding subjects in residential care homes; and further adjusting for area-based indicators of socioeconomic level and use of public transportation. Similar findings were observed for PM 10 , NO 2 and NO. Ozone was associated with a 2% decrease in disease rate, the association being reversed in bi-pollutant models., Conclusions: Long-term exposure to low levels of air pollutants, especially PM 2.5 , increased the incidence of COVID-19. The causality warrants confirmation in future studies; meanwhile, government efforts to further reduce air pollution should continue., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Background/aim: The relationship between air pollution and respiratory morbidity has been widely addressed in urban and metropolitan areas but little is known about the effects in non-urban settings. Our aim was to assess the short-term effects of PM10 and PM2.5 on respiratory admissions in the whole country of Italy during 2006-2015., Methods: We estimated daily PM concentrations at the municipality level using satellite data and spatiotemporal predictors. We collected daily counts of respiratory hospital admissions for each Italian municipality. We considered five different outcomes: all respiratory diseases, asthma, chronic obstructive pulmonary disease (COPD), lower and upper respiratory tract infections (LRTI and URTI). Meta-analysis of province-specific estimates obtained by time-series models, adjusting for temperature, humidity and other confounders, was applied to extrapolate national estimates for each outcome. At last, we tested for effect modification by sex, age, period, and urbanization score. Analyses for PM 2.5 were restricted to 2013-2015 cause the goodness of fit of exposure estimation., Results: A total of 4,154,887 respiratory admission were registered during 2006-2015, of which 29% for LRTI, 12% for COPD, 6% for URTI, and 3% for asthma. Daily mean PM 10 and PM 2.5 concentrations over the study period were 23.3 and 17 μg/m 3 , respectively. For each 10 μg/m 3 increases in PM 10 and PM 2.5 at lag 0-5 days, we found excess risks of total respiratory diseases equal to 1.20% (95% confidence intervals, 0.92, 1.49) and 1.22% (0.76, 1.68), respectively. The effects for the specific diseases were similar, with the strongest ones for asthma and COPD. Higher effects were found in the elderly and in less urbanized areas., Conclusions: Short-term exposure to PM is harmful for the respiratory system throughout an entire country, especially in elderly patients. Strong effects can be found also in less urbanized areas., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Fractures of the pelvic ring and acetabulum generally result after high energy trauma. Pelvic fractures, especially, are considered complex injuries from a therapeutic point of view, in relation to the frequent coexistence of skeletal and / or parenchymal lesions affecting other areas, and the abundant bleeding invariably associated with the latter. The systematic study of these injuries, starting from the 1950s, has led to a significant prognostic improvement, while generally remaining a non-negligible degree of disability. The knowledge of the characteristics of the lesions and of the classification systems, as well as an accurate assessment of the anatomo-functional repercussions, represent therefore the fundamental prerequisites for the correct assessment of physical damage. Herein, we aim to examine whether the medico-legal assessment parameters of physical damage being used in Italy and Europe are appropriate and consistent with the complexity of similar injuries., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest to declare that are relevant to the content of this article., (Copyright © 2021. Published by Elsevier Ltd.)

Background: Pharmacological therapies of proven efficacy in coronavirus disease 2019 (COVID-19) are still lacking. We have identified IFNβ-1a as the most promising drug to be repurposed for COVID-19. The rationale relies on the evidence of IFNβ anti-viral activity in vitro against SARS-CoV-2 and animal models resembling SARS-CoV-2 infection and on a recent clinical trial where IFNβ was indicated as the key component of a successful therapeutic combination., Methods: This is a randomized, controlled, open-label, monocentric, phase II trial (INTERCOP trial). One hundred twenty-six patients with positive swab detection of SARS-CoV-2, radiological signs of pneumonia, and mild-to-moderate disease will be randomized 2:1 to IFNβ-1a in addition to standard of care vs standard of care alone. No other anti-viral drugs will be used as part of the regimens, both in the control and the intervention arms. IFNβ-1a will be administered subcutaneously at the dose of 44 mcg (equivalent to 12 million international units) three times per week, at least 48 h apart, for a total of 2 weeks. The primary outcome is the time to negative conversion of SARS-CoV-2 nasopharyngeal swabs. Secondary outcomes include improvement or worsening in a clinical severity score measured on a 7-point ordinal scale (including transfer to intensive care unit and death), oxygen- and ventilator-free days, mortality, changes in pulmonary computed tomography severity score, hospital stay duration, reduction of viral load measured on nasopharyngeal swabs, number of serious adverse events, and changes in biochemical markers of organ dysfunction. Exploratory outcomes include blood cell counts, cytokine and inflammatory profile, peripheral mRNA expression profiles of interferon-stimulated genes, and antibodies to SARS-CoV-2 and to IFNβ-1a. INTERCOP is the first study to specifically investigate the clinical benefits of IFNβ-1a in COVID-19 patients., Discussion: Potential implications of this trial are multifaceted: should the primary outcome be fulfilled and the treatment be safe, one may envisage that IFNβ-1a be used to reduce the infectivity of patients with mild-to moderate disease. In case IFNβ-1a reduced the duration of hospital stay and/or ameliorated the clinical status, it may become a cornerstone of COVID-19 treatment., Trial Registration: EudraCT 2020-002458-25. Registered on May 11, 2020 ClinicalTrials.gov Identifier: NCT04449380.

Background: Most models for outcome prediction in heart failure are under-utilized because complex or including non-routine clinical use variables. We aimed to develop a prognostic score for patients with stable heart failure, including only easily obtainable parameters., Methods: In 376 outpatients with heart failure (ejection fraction ≤40%), twelve variables were individually correlated with 5-year mortality. Those resulted significant predictors of cardiac and overall mortality were used to obtain a risk score. It was validated on a different sample of 325 patients previously enrolled in other clinical studies, according to tertiles of score., Results: Previous acute decompensated heart failure, atrial fibrillation, ejection fraction <30%, not-taking beta-blockers, chronic renal failure were the variables included in the final model. There was a significant difference in 5-year cardiac (P=0.004) and all-cause (P=0.003) mortality risk. Compared to the first tertile of the score, the second tertile and the third tertile had an increasing risk for cardiac cause admission (respectively, HR: 2.7; 95% CI: 1.5-4.9 and HR: 3.2; 95% CI: 1.7-6.1) and for heart failure worsening hospitalization (HR:4.3; 95% CI: 1.3-14.5 and HR: 3.8; 95% CI: 1.03-14.1) as well as the third tertile (respectively, HR:3.2; 95% CI: 1.7-6.1 and HR:3.8; 95% CI: 1.03-14.1.)., Conclusions: Our prognostic model, named OSR HF Risk Score, is a simple, quick, inexpensive tool for predicting patient outcome in 5 years. It might be used as an adjunctive tool in outpatients evaluation alongside more complex scores.

Background: Hand hygiene is the primary preventive measure against health care-associated infections in terms of cost-effectiveness. In 2005, the WHO proposed the "Global Patient Safety Challenge" campaign, with the aim of reducing the overall incidence of such infections, through multimodal programs and strategies, interactive training tools and standardised methods for monitoring compliance., Study Design: On the basis of project "Rimani", sponsored by the Health and Social Care Authority of Emilia-Romagna, the Istituto Ortopedico Gaetano Pini has implemented a project which seeks to increase healthcare staff's compliance with hand hygiene., Methods: A multidisciplinary working group was created to prepare the project documents. Starting from 5th April 2015, twenty operational units were asked to produce information and training material. On 5th May, during a conference, a committee selected the three best works. The material was distributed on a monthly basis to the various departments. In addition to the training, the specifically trained operators of the Medical Monitoring Department carried out direct hand washing tests, filling out appropriate checklists. Non-compliance relating to the technique recorded in 2014 and 2015 was compared and a statistical analysis was conducted using Student's t-test for paired data., Results: Three tests were carried out in 2014. Ninety-nine cases were monitored and 5 non-compliance cases were reported, concerning the execution of the procedural steps, the running time and closing the tap with one's hands at the end of the wash. In 2015 two tests, involving 30 operational units, were carried out. 60 observations were performed, and no non-conformities emerged concerning the technique. Statistical analysis showed a significant reduction of non-compliances between the 2014 and 2015 P = 0.000)., Conclusion: The results obtained agree with the main findings in literature. The comparison between the 2014 and 2015 tests shows a trend of improvement in the wash technique. This confirms the effectiveness of a multidisciplinary approach and recognises the active and participatory involvement suggested by the WHO.

Introduction: Defects of the Achilles tendon region represent a challenge for reconstructive surgeons. Several options are available but there is still no reconstructive ladder for this specific and tricky area. An up-to-date reconstructive ladder according to local and general conditions is proposed based on our multicentre experience and an extensive review of the English literature on PubMed., Materials and Methods: An extensive review of the English literature was performed on PubMed using the following key-words: "Achilles region", "heel", "soft-tissue reconstruction", "flaps", "grafts" and "dermal substitutes"., Results: A total of 69 complete papers were selected, covering the last thirty years' literature. Although most of the studies were based on limited case-series, local and general conditions were always reported. A comprehensive reconstructive ladder of all the available reconstructive techniques for the Achilles region has been created based on our personal multicentre experience and the results of the literature review., Conclusions: The reconstructive ladder is a concept that is still a mainstay in plastic surgery and guides decisions in the repair strategy for soft tissue defects. The optimal solution, according to the experience of the surgeon and the wishes of the patient, is the one that implies less sacrifice of the donor site. Perforator flaps should be the first-line option for small-to-moderate defects; the distally-based sural flap is the most reported for moderate-to-large defects of the Achilles region, and free flaps should be reserved mainly for complex and wide reconstructions., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Purpose: Reamer-irrigator-aspirator (RIA) is an innovative device that its indications have recently been expanded to the management of long bone infections., Methods: In this narrative review, we summarise the most important studies in the field and we present the current open questions pertaining to the use of RIA in the management of osteomyelitis of long bones., Results: The relevant literature is sparse and low quality. Nevertheless, the use of RIA for infected cases has yielded promising outcomes in specialised centres. Technical aspects that merit special attention in osteomyelitis of long bones are its inapplicability in small diameter long bones, the inadequate debridement of wide metaphyseal areas and the potential bleeding sequelae. The use of RIA in open fracture management to reduce infection risk has not gained acceptance. The antibiotic impregnated nails and rods constitute a complimentary strategy for the management of infections., Conclusions: The use of RIA for the management of long bone infections is an innovative and promising strategy. High quality studies are needed to shed light in its efficacy compared to conventional methods of management of osteomyelitis of long bones.

The prospective evidence for the associations of gamma glutamyltransferase (GGT) and alanine aminotransferase (ALT) with risk of cancer in the general population is uncertain. We conducted a systematic review and meta-analysis of published prospective observational studies evaluating the associations of baseline levels of GGT and ALT with risk of overall (incidence and/or mortality) and site-specific cancers. Relevant studies were identified in a literature search of MEDLINE, EMBASE, Web of Science, reference lists of relevant studies to April 2014 and email contact with investigators. Study specific relative risks (RRs) were meta-analyzed using random effects models. Fourteen cohort studies with data on 1.79 million participants and 57,534 cancer outcomes were included. Comparing top versus bottom thirds of baseline circulating GGT levels, pooled RRs (95% confidence intervals) were 1.32 (1.15-1.52) for overall cancer, 1.09 (0.95-1.24) for cancers of the breast and female genital organs, 1.09 (1.02-1.16) for cancers of male genital organs, 1.94 (1.35-2.79) for cancers of digestive organs and 1.33 (0.94-1.89) for cancers of respiratory and intrathoracic organs. For ALT, corresponding RRs for overall cancer were 0.96 (0.94-0.99) and 1.65 (1.52-1.79) in European and Asian populations, respectively. There was an increased risk of cancers of the digestive organs 2.44 (1.23-4.84). The pooled RR for overall cancer per 5 U/L increment in GGT levels was 1.04 (1.03-1.05). Available observational data indicate a positive log-linear association of GGT levels with overall cancer risk. The positive association was generally evident for site-specific cancers. There are geographical variations in the association of ALT and overall cancer., (© 2014 UICC.)

Introduction: Surgical site infections (SSIs) in orthopaedic surgery are a demanding complication for the patient and in terms of economics. Many guidelines (GLs) are available on antibiotic prophylaxis as an effective preventive measure; however, these GLs are often ignored in practice. A surveillance study of SSIs in arthroplasty, promoted by the Italian Study Group of Hospital Hygiene of the Italian Society of Public Health (SitI), showed a high percentage of non-adherence to GLs on antibiotic prophylaxis., Objectives: The purpose of this study was to review the existing GLs, share them within the hospital and then monitor their implementation., Materials and Methods: Information and training are considered to be great tools for implementation and sharing of GLs, which leads to significant improvements in clinical practice. A multidisciplinary team comprising infectious disease specialists, orthopaedic surgeons, nurse epidemiologists and public health specialists was established at the G. Pini Hospital in Milan to revise GLs, and to organise educational events for their implementation, sharing and dissemination. A checklist was devised for monitoring purposes., Results: GLs were presented to orthopaedic surgeons and nurse coordinators during two educational events. Meetings were organised in each unit to present the results of the surveillance of SSIs in arthroplasty and to discuss the reasons why the prophylaxis regimens adopted were not consistent with GLs. It was emphasised that the most important issue, on which there is consensus in the scientific literature, was related to the duration of prophylaxis beyond 24h. The review process for GLs was presented and pocket-sized GLs were given to surgeons. The importance of documenting on medical record any deviations from the GLs was emphasised., Conclusions: Any changes in behaviour in clinical practice must be monitored and evaluated regularly. The monitoring of GLs in terms of correct choice of drug, timing of administration and duration of prophylaxis is made using a special checklist on a representative sample of medical records., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Introduction: Non-union of long bones is a significant consequence of fracture treatment. The ideal classification for non-union of long bones would give sufficient significant information to the orthopaedic surgeon to enable good management of the treatment required and to facilitate the creation of comparable study groups for research purposes. The Non-Union Scoring System (NUSS) is a new scoring system to assist surgeons in the choice of the correct treatment in non-union surgery. The aim of this study was to determine the evidence supporting the use of the NUSS classification in the treatment of non-unions of long bones and to validate the treatment algorithm suggested by this scoring system., Materials and Methods: A total of 300 patients with non-union of the long bones were included in the clinical study., Results: A radiographic and clinical healing was reached in 60 of 69 non-unions (86%) in group 1 (0-25 points), in 102 of 117 non-unions (87%) in group 2 (26-50 points), and in 69 of 84 (82%) in group 3 (51-75 points). The mean time to clinical healing was 7.17 ± 1.85 months in group 1, 7.30 ± 1.72 months in group 2 and 7.60 ± 1.49 months in group 3. The mean time to radiographic healing was 8.78 ± 2.04 months in group 1, 9.02 ± 1.84 months in group 2 and 9.53 ± 1.40 months in group 3., Discussion: There are few articles in the scientific literature that examine the classification systems for non-union., Conclusions: A statistical analysis of the first results we have obtained with the use of NUSS showed significant rates of union in all the evaluated groups. This indicates that NUSS could be an appropriate scoring system to classify and stratify non-unions and to enable the surgeon to choose the correct treatment., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background: Acute compartment syndrome (ACS) is a clinical condition with potentially dramatic consequences, therefore, it is important to recognise and treat it early. Good management of ACS minimises or avoids the sequelae associated with a late diagnosis, and may also reduce the risk of malpractice claims. The aim of this article was to evaluate different errors ascribed to the surgeon and to identify how the damage was evaluated., Materials and Methods: A total of 66 completed and closed ACS cases were selected. The following were analysed for each case: clinical management before and after diagnosis of ACS, imputed errors, professional fault, damage evaluation and quantification. Particular attention was paid to distinguishing between impairment because of primary injury and iatrogenic impairment. Statistical analyses were performed using Fisher's exact test and Pearson's correlation., Results: The most common presenting symptom was pain. Delay in the diagnosis, and hence delay in decompression, was common in the study. A total of 48 out of 66 cases resolved with the verdict of iatrogenic damage, which varied from 12% to 75% of global capability of the person. A total of $394,780 out of $574,680 (average payment) derived from a medical error., Conclusions: ACS is a clinical emergency that requires continuous clinical surveillance from both medical and nursing staff. The related damage should be evaluated in two parts: damage deriving from the trauma, so that it is considered inevitable and independent from the surgeon's conduct, and damage deriving from a surgeon's error, which is eligible for an indemnity payment., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Introduction: The recent evolution of prosthesis technology has enabled the surgeon to replace entire limbs. These special prostheses, or megaprostheses, were developed for the treatment of severe oncological bone loss; however, the indications and applications of these devices have expanded to other orthopaedic and trauma situations. For some years, surgeons have been implanting megaprostheses in non-oncological conditions, such as acute trauma in severe bone loss and poor bone quality; post-traumatic failures, both aseptic and septic (represented by complex non-unions and critical size bone defects); major bone loss in prosthetic revision, both aseptic and septic; periprosthetic fractures with component mobilisation and poor bone stock condition. The purpose of this study was to evaluate retrospectively the complications during and after the implantation of megaprosthesis of the lower limb in post-traumatic and prosthetic bone loss, and to propose tips about how to avoid and manage such complications., Materials and Methods: All the complications and difficulties we have encountered during or after the implantation of megaprosthesis in non-oncology patients were evaluated retrospectively. A total of 72 patients were treated with large resection mono-and bi-articular prostheses between January 2008 and January 2014., Results: The main critical problems found in the study were: restoration of the correct length and rotation of the limb; reconstruction of the knee extensor mechanism; trochanteric reconstruction; stability/dislocation of the implant; mobility/range of motion (ROM) of the implant; skin cover; sepsis, and bone quality., Conclusion: Megaprosthesis in severe bone loss can be considered as an available solution for the orthopaedic surgeon in extreme, appropriately selected cases. This type of complex surgery must be performed in specialised centres where knowledge and technologies are present. Patients with severe bone loss should not be treated in the same way as oncology patients because life expectancy is definitely longer; therefore, the surgical technique and the system implantation must be extremely rigorous to ensure longevity of the prosthesis. The characteristics of the bone and soft tissue conditions in these patients are very different from those presented by oncology patients, which creates critical problems that the surgeon should be able to manage to avoid serious complications., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background: Defects of the Achilles tendon region still represent a tricky issue in lower limb surgery. Among the several reconstructive possibilities, local propeller perforator flaps have gained popularity in the last decade., Materials and Methods: We report our experience with eight patients affected by small-to-moderate soft-tissue defects of the Achilles tendon region, who underwent surgical reconstruction with local flaps based on posterior tibial perforator branches., Results: All patients healed successfully in terms of aesthetic and functional aspect. In only one case a transient venous congestion was observed and this resolved spontaneously., Conclusions: Although the surgical technique requires much care and skill, including an extremely gentle dissection of perforator vessels, local propeller flaps should be considered the first-line choice for reconstruction in small-to-medium size soft-tissue defects in the Achilles region., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Previous reports focusing on the high prevalence of voice disorders in teachers have suggested that vocal loading might be the main causal factor. The aim of our study was to assess the prevalence of voice disorders in a sample of primary school teachers and evaluate possible cofactors. Our sample was composed of 157 teachers (155 females, mean age 46 years). Participants were asked to complete two selfadministrated questionnaires: one with clinical data, and the second an Italian validated translation of VHI (voice handicap index). On the same day they also underwent a laryngostroboscopic exam and logopedic evaluation. The results were compared with those of a control group composed of accompanying individuals. Teachers presented a higher rate of abnormalities at laryngostroboscopic examination than the control group (51.6% vs. 16%, respectively). Among these, 7.1% presented nodules. In our sample, vocal fold disorders were not correlated with years of teaching, smoking, coffee consumption, or levels of anxiety. Our findings are in agreement with previous reports on the prevalence of pathologic disorders among teachers; nonetheless, the prevalence of nodules was lower than in previous investigations, and voice loading was not correlated with laryngostroboscopic findings. Current Italian law does not include any guidance regarding voice education and screening in subjects with high vocal loading. Our work stresses the need for such legislation.

Introduction: Clinical management of non-union of long bone fractures and segmental bone defect is a challenge for orthopaedic surgeons. The use of autologous bone graft (ABG) is always considered the gold standard treatment. Traditional techniques for harvesting ABG from iliac crest usually involve several complications, particularly at the donor site. The Reamer-Irrigator-Aspirator (RIA) is an intramedullary reaming system that generates a large volume of cancellous bone material in a single-step reaming process; this bone material can be collected and potentially used as an ABG source. Our interest is to compare the complications associated with the standard technique of harvesting from iliac crest with those of the innovative RIA harvesting device., Materials and Methods: A database of 70 patients with long bone non-unions was studied. The patients were divided into two groups according to the surgical harvesting technique used: RIA system ABG (35 patients) and iliac crest ABG (35 patients)., Results: At the 12-month follow-up, pain at the donor site was reported in no patients in the RIA system ABG group and five of 35 patients (14.28%) in the iliac crest ABG group. Local infections at the donor site were found in no patients in the RIA system ABG group compared with five patients (14.28%) in the iliac crest ABG group. There were no fractures in the RIA system ABG group and one case (2.85%) of anterior superior iliac spine (ASIS) dislocation in the iliac crest ABG group. No systemic infections were detected in either group., Discussion: We analysed the scientific literature on the use of RIA technique to collect ABG for use in patients with anthropic-oligotrophic non-unions, with a focus on the complications associated with this technique., Conclusion: RIA bone graft for the treatment of non-unions and segmental bone defect of long bones seems to be a safe and efficient procedure with low donor site morbidity., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Purpose: To study retinal function in asymptomatic Type 1 and Type 2 diabetic patients with nonproliferative diabetic retinopathy (NPDR) and no clinical signs of diabetic macular edema., Methods: Thirty-six consecutive Type 1 and Type 2 diabetic patients with nonproliferative diabetic retinopathy and no diabetic macular edema and 28 healthy controls underwent a complete ophthalmologic examination, including spectral domain optical coherence tomography and microperimetry., Results: Seventy-one eyes (17 patients with Type 1 and 19 with Type 2 diabetes) were tested, and data from 36 (17 Type 1 and 19 Type 2) eyes were analyzed. Mean best-corrected visual acuity was 0.00 ± 0.01 logMAR and 0.00 ± 0.02 logMAR for Type 1 and Type 2 diabetic patients, respectively (P = 0.075). Mean central foveal thickness was 234.5 ± 13.7 μm and 256.3 ± 12.7 μm for Type 1 and Type 2 diabetic patients, respectively (P = 0.04); the central foveal thickness was statistically different compared with the control groups (P = 0.04 and P = 0.01, respectively). Mean retinal sensitivity was 18.9 ± 0.5 dB and 17.7 ± 0.4 dB for Type 1 and Type 2 diabetic patients, respectively; it was statistically different compared with control groups (P < 0.0001 and P < 0.0001, respectively)., Conclusion: We demonstrated a significantly reduced sensitivity in both nonproliferative diabetic retinopathy groups without diabetic macular edema compared with healthy controls; this reduction was greater in Type 2 diabetic patients. Central foveal thickness was increased in all diabetic patients compared with healthy controls, despite the absence of diabetic macular edema.

Aim: The prognostic utility of myocardial perfusion scintigraphy (MPS) in patients with angiographically normal coronary arteries has not been evaluated yet. Our aim was to determine the prognostic role of positive MPS in patients with angina, positive exercise test and smooth coronary arteries (syndrome X)., Methods: A total of 156 patients with angina, positive exercise test, positive MPS and normal coronary arteries and 172 patients with angina and positive exercise test who had negative MPS were selected for study. The primary endpoint was combined all-cause mortality and hospitalizations for cardiac causes. The secondary endpoint was hospitalization for cardiac causes., Results: Kaplan-Meier analysis showed a greater (p=0.001) incidence of the primary endpoint in patients with positive MPS, compared to those with negative MPS. Additionally, Kaplan-Meier analysis for cardiovascular hospitalization showed a significant difference (p=0.003) between the two groups. Cox regression analysis, adjusted for age, sex, BMI and antianginal therapy confirmed a significant risk increase for patients with positive MPS, with a hazard ratio (HR)=3.20 (CI 95%: 1.14-9.02; p=0.028). Cox analysis for cardiovascular hospitalization also showed a significant risk increase for patients with positive MPS (HR=3.19; CI 95%: 1.13-9.00; p=0.03). Finally, Cox analysis showed that patients with positive MPS tend to have a higher risk to remain symptomatic in the follow-up period (HR=1.614; CI 95%: 0.999-2.607; p=0.51)., Conclusions: This study shows that inducible myocardial hypoperfusion at MPS in patients with syndrome X could discriminate patients with a more severe prognosis, especially in terms of further hospitalization and symptomatic burden., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Aims: To evaluate the association between LOXIN, a new functional protective splicing isoform of the oxidized LDL receptor 1 (OLR1) gene, and the severity of coronary artery stenoses., Methods: We analyzed 100 consecutive patients with coronary artery disease (CAD) and 100 controls, all evaluated by a new molecular biology test using highly specific allele primers able to identify the single nucleotide variation (IVS4-14 A>G) in the OLR1 gene (Loxin Test - Technogenetics). All the patients and the controls underwent coronary angiography and, for quantitative evaluation, we used both vessel and stenosis score, and SYNTAX score to evaluate the severity of CAD. Moreover, we defined the prognostic localization of CAD as a critical stenosis (>50%) of the left main and/or proximal segment of left anterior descending artery (LAD). Finally, we evaluated a correlation with the presence of diabetes mellitus, dyslipidemia, hypertension, smoking and family history of CAD., Results: In this selected population, even though the 'AA nonrisk haplotype' is more frequent in the controls, we did not find any statistically significant correlation between the severity of CAD or the prognostic localization of critical stenosis and the difference of IVS4-14 A>G OLR1 genotype (P > 0.05). CAD patients showed significantly higher frequencies of dyslipidemia and smoking (P < 0.05) than controls, but no significant association was found between overall risk factors and the OLR1 polymorphism., Conclusion: In this selected population, we did not find any correlation of LOXIN with the severity or prognostic localization of CAD on left main and/or proximal LAD.

We explored the comprehension of the informed consent in 77 cancer patients previously enrolled in randomised phase II or phase III clinical trials, between March and July 2011, at the San Raffaele Scientific Institute in Milano. We asked participants to complete an ad hoc questionnaire and analysed their answers. Sixty-two per cent of the patients understood the purpose and nature of the trial they were participating in; 44% understood the study procedures and 40% correctly listed at least one of the major risks or complications related to their participation in the trial. We identified three factors associated with comprehension of the informed consent: age, education and type of tumour/investigator team. We suggest several possible improvements of how to obtain informed consent that will increase patient awareness, as well as the validity and effectiveness of the clinical trials.

Objective: To determine the efficacy of core decompression (CD) technique combined with recombinant morphogenetic proteins, autologous mesenchymal stem cells (MSCs) and xenograft bone substitute into the necrotic lesion of the femoral head on clinical symptoms and on the progression of osteonecrosis of the femoral head., Patients and Methods: A total of 38 patients (40 hips) with early stage osteonecrosis of the femoral head were studied over a 4-year period., Results: CD technique combined with recombinant morphogenetic proteins, autologous MSCs and xenograft bone substitute was associated with a significant reduction in both pain and joint symptoms and reduced the incidence of fractural stages. At 36 months, 33 patients achieved clinical and radiographic healing., Conclusion: This long-term follow-up study confirmed that CD technique combined with recombinant morphogenetic proteins, autologous MSCs and xenograft bone substitute may be an effective treatment for patients with early stage osteonecrosis of the femoral head., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Introduction: The development of new megaprosthesis for the treatment of large bone defects provides important options to orthopaedic oncologic surgeons for the replacement of skeletal segments, such as the long bones of the upper and lower limbs and the relative joints. We implanted megaprosthesis using either a one-step or two-step technique depending on the patient's condition. The aim of this study was to evaluate retrospectively both clinical and radiological outcomes in patients who underwent lower limb megaprosthesis implant., Materials and Methods: A total of 32 patients were treated with mono- and bi-articular megaprosthesis subdivided as follows: proximal femur, distal femur, proximal tibia and total femur. The mean follow-up of patients was about 18 months (range 3 months to 5 years). Clinical and serial radiographic evaluations were conducted using standard methods (X-ray at 45 days, 3, 6, 12, 18 and 24 months) and blood parameters of inflammation were monitored for at least 2 months., Results: Although the mean length of follow-up was only 18 months, the first patients to enter the study were monitored for 5 years and showed encouraging clinical results, with good articulation of the segments, no somato-sensory or motor deficit and acceptable functional recovery. During surgery and, more importantly, in pre-operative planning, much attention should be given to the evaluation of the extensor apparatus, preserving it and, when necessary, reinforcing it with tendon substitutes., Discussion: Megaprosthesis in extreme cases of severe bone loss and prosthetic failure is a potential solution for the orthopaedic surgeon. In oncological surgery, the opportunity to restore functionality to the patient (although not ad integrum) is important for both the patient and the surgeon. The high mortality associated with cancer precludes long-term patient follow-up; therefore, there is a lack of certainty about the survival of this type of prosthesis and any medium- to long-term complications that may occur. Nevertheless, patients should be considered as an oncologic patient, not because of the disease, but because of the limited therapeutic options available., Conclusions: Megaprosthesis provides a valuable opportunity to restore functionality to patients with highly disabling diseases., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Beta-blockers have been shown to improve left ventricular (LV) function in patients with heart failure. The aim of this study is to non-invasively assess, by means of in vivo 31P-magnetic resonance spectroscopy (31P-MRS), the effects of beta-blockers on LV cardiac phosphocreatine and adenosine triphosphate (PCr/ATP) ratio in patients with heart failure. Ten heart failure patients on full medical therapy were beta-blocked by either carvedilol or bisoprolol. Before and after 3 months of treatment, exercise testing, 2D echocardiography, MRS, New York Heart Association (NYHA) class, ejection fraction (EF), maximal rate-pressure product and exercise metabolic equivalent system (METS) were evaluated. Relative concentrations of PCr and ATP were determined by cardiac 31P-MRS. After beta-blockade, NYHA class decreased (from 2.2 ± 0.54 to 1.9 ± 0.52, P = 0.05), whereas EF (from 33 ± 7 to 44 ± 6%, P = 0.0009) and METS (from 6.74 ± 2.12 to 8.03 ± 2.39, P = 0.01) increased. Accordingly, the mean cardiac PCr/ATP ratio increased by 33% (from 1.48 ± 0.22 to 1.81 ± 0.48, P = 0.03). Beta-blockade-induced symptomatic and functional improvement in patients with heart failure is associated to increased PCr/ATP ratio, indicating preservation of myocardial high-energy phosphate levels., (© 2012 The Authors Fundamental and Clinical Pharmacology © 2012 Société Française de Pharmacologie et de Thérapeutique. Published by John Wiley & Sons Ltd.)

Objectives: The aim of this cohort study was to retrospectively evaluate, in patients with chronic heart failure (CHF), the long term effect of trimetazidine (TMZ) on morbidity and mortality., Background: Previous small studies in patients with CHF have shown that TMZ can improve left ventricular function, exercise capacity and NYHA class compared to placebo. However, no data on the effects of TMZ on survival in patients with CHF have ever been produced., Methods: In this international multicentre retrospective cohort study data from 669 patients were analyzed. 362 patients were on TMZ due to symptom persistence despite up-titration of optimal CHF therapy, while the remaining patients continued conventional CHF therapy alone. Propensity score analysis was performed in order to minimize selection bias between the two groups., Results: Kaplan-Meier analysis for global mortality showed 11.3% improved global survival (p=0.015) and 8.5% improved survival for cardiovascular (CVD) death (p=0.050) in the TMZ group. Cox regression analysis for global mortality showed a significant risk reduction for TMZ treated patients with a hazard ratio (HR)=0.189 (confidence interval - CI 95%: 0.017-0.454; p=0.0002). TMZ also showed a good risk reduction profile for CVD death causes (HR=0.072, CI 95%: 0.019-0.268, p=0.0001). The rate of hospitalization for cardiovascular causes was reduced by 10.4% at 5 years (p<0.0005) with increased hospitalization-free survival of 7.8 months., Conclusion: TMZ is effective in reducing mortality and event-free survival in patients with CHF. The addition of TMZ on top of optimal medical therapy improves long term survival in CHF patients., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Objective: To relate therapeutic issues, comorbidities and functional parameters to mortality/morbidity of mild/moderate heart failure patients., Methods: From our heart failure clinic, 372 heart failure patients (269 men, aged 66 ± 11 years), with stable heart failure and ejection fraction 45% or less were recruited. Survival curves were estimated according to the Kaplan-Meier method. Associations of protective/risk factors with cardiovascular mortality/morbidity were also evaluated., Results: One hundred and two patients (27%) died (aged 70 ± 10 years at diagnosis, 76 ± 10 at death) during follow-up (overall mortality at 60 months: 19.2%; mean follow-up period: 67 ± 44 months). Cardiovascular deaths were 64 (63% of total deaths, 44 men, age at diagnosis 70 ± 9). Cardiovascular mortality at 60 months was 12%; standardized mortality ratio was 5.9 for women and 6.8 for men. The remaining 38 patients (37% of total deaths, 30 men, age at diagnosis 70 ± 10) died of noncardiovascular causes. Overall, noncardiovascular mortality at 60 months was 7.2%; mean survival time from diagnosis to death was 63 ± 69 months (median 42, Q1 = 27.5, Q3 = 77.7). Average cardiovascular admission rate was 1.63 ± 1.84 admissions/patient. At multivariate analysis, only previous history of myocardial infarction [hazard ratio: 3.62 (1.70-7.73)], class of ejection fraction at diagnosis [hazard ratio: 0.36 (0.32-0.60)], acute cardiac decompensation at any time [hazard ratio: 1.55 (1.32-1.84)], implanted defibrillator [hazard ratio: 0.11 (0.01-0.83)] and use of statins [hazard ratio: 0.08 (0.007-0.42)] were independently associated with cardiovascular mortality. Factors associated to higher annual cardiovascular morbidity were age at diagnosis, chronic renal failure, diabetes, cardiac decompensation at any time, female sex and diuretic therapy. Angiotensin-converting enzyme (ACE) inhibitors and/or angiotensin-receptor-blockers reduced annual cardiovascular morbidity., Conclusion: Survival in mild/moderate heart failure patients has consistently improved. Further improvements are warranted in terms of morbidity reduction.

Objective: To determinate the efficacy of "polytherapy", a surgical technique that utilize all the components of the diamond concept (mesenchymal stem cells, bone morphogenetic proteins and scaffold) versus a "monotherapy", a surgical technique that utilize only one component of the diamond conceptin the treatment of severe forearm non-unions., Methods: We studied a database of 52 patients with 52 forearm non-unions; we classified the patients with the NUSS SCORE and we divided the patients in two group according to the treatment received. So we distinguished a group of patients treated according to the principles of "monotherapy" (33 patients) and a group of patients treated according to the principles of "polytherapy" (19 patients). The minimum follow up was 12 months., Results: In the monotherapy group 21/33 non-unions (63.64%) went on to develop a radiographic and clinical healing within a period of 12 months, the calculated DASH SCORE showed a mean value of 55.15 points. In the polytherapy group 17/19 (89.47%) nonunions went on to develop clinical and radiographic healing within 12 months, and the average DASH score showed a mean value of 45.47 points., Conclusion: The polytherapy technique with the use of recombinant morphogenetic proteins, autologous MSCs and scaffold in the same surgical time appears to be an effective treatment for patients with severe forearm non-unions., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Fractures of the humerus in patients with total shoulder replacement are rare and difficult to treat. The treatment of periprosthetic humeral fractures depends on the location of the fracture in relation to the humeral stem and the stability of the stem/bone interface. We wished to determine the treatment outcomes in a series of patients managed in our institution with periprosthetic humeral fractures. We also carried out a review of the literature. Over a 5 year period, out of 10 patients, 7 were available at the final follow up with a mean age of 72 years (range 68-75). A fall from standing height was the most common mechanism of injury. All patients were found to have stable prosthesis in situ and were treated with angular stable plates and cerclage wiring. The mean time from the total shoulder replacement to injury (fracture) was 11.2 months (range 8-21). All fractures united without complications at a mean time of 5.1 months (range 4-6). The literature review revealed a limited number of publications reporting on the management of approximately 40 patients. The outcome noted in these patients is also presented., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Background: The aim of this study was to evaluate, according to functional response, the neuroendocrine and inflammatory status in patients with chronic heart failure before and after therapy with carvedilol., Methods and Results: Serum tumor necrosis factor-α (TNF-α) soluble receptors (sTNF-R1 and sTNF-R2), interleukin (IL)-10 and IL-18, chromogranin A (CgA) and brain natriuretic peptide (pro-BNP) were measured in 37 New York Heart Association class II to IV heart failure patients, at baseline and after 6 months of therapy with carvedilol. Patients were divided in two groups according to whether, following carvedilol, left-ventricular ejection fraction (LVEF) had increased by at least 5% (17 patients) or not (20 patients). Baseline LVEF was higher in nonresponders (38 ± 5 vs. 31 ± 7%, P = 0.002). In responders, LVEF increased from 31 ± 7 to 51 ± 7% (P < 0.0001), whereas in nonresponders it decreased from 38 ± 5 to 33 ± 7%, (P = 0.02). sTNF-R1 (P = 0.019) and sTNF-R2 (P = 0.025) increased in nonresponders, whereas they did not change in responders. After carvedilol, IL-10 was significantly higher in responders (P = 0.03). Conversely, no significant IL-18 and CgA changes were observed in either group. CgA was not significantly different between groups at baseline and after carvedilol in either group, whereas pro-BNP significantly increased in nonresponders (from 438 ± 582 to 1324 ± 1664 pg/ml, P = 0.04) and decreased in responders (from 848 ± 1221 to 420 ± 530 pg/ml, P = 0.08)., Conclusion: Increased inflammatory activation observed only in heart failure patients not improving left-ventricular function after carvedilol may indicate that inflammation, either as a direct cause or as a consequence, is associated with progressive ventricular dysfunction.

Type 2 diabetes is associated with risk of cancer. Hyperinsulinemia and insulin resistance may be the link with cancer, but whether this is independent of the diabetes status, obesity/visceral obesity and metabolic syndrome is uncertain and the present study wanted to address this issue. Fifteen-year all-cause, CVD and cancer mortality data were obtained through the Regional Health Registry in 2,011 out of 2,074 Caucasian middle-aged individuals of the Cremona Study, a population study on the prevalence of diabetes mellitus in Italy in which anthropometric and metabolic characteristics were collected. During the 15-year observation period, 495 deaths were registered: 221 CVD related and 180 cancer related. Age and sex were independently associated with all-cause, cancer and CVD mortality rates. Age- and sex-adjusted analysis showed that HOMA-IR, cigarette smoking and diabetes were independently associated with all-cause mortality; HOMA-IR, systolic blood pressure and fibrinogen were independently associated with CVD mortality; HOMA-IR and smoking habit were independently associated with cancer mortality. Individuals in the highest quintile of serum insulin had a 62% higher risk of cancer mortality (HR = 1.62 95% CI: 1.19-2.20; P < 0.0022) and 161% higher risk of gastrointestinal cancer mortality (HR = 2.61 95% CI: 1.73-3.94; P < 0.0001). Age- and sex-adjusted analysis showed that hyperinsulinemia/insulin resistance is associated with cancer mortality independently of diabetes, obesity/visceral obesity and the metabolic syndrome.

Purpose: To evaluate the association between the severity and angiographic localization of coronary artery stenoses and clinical control of major traditional risk factors (RF)., Methods: We analyzed 500 patients without known cardiovascular disease, undergoing coronary angiography for the diagnosis of coronary artery disease (CAD), with one or more major traditional RF, all in optimal clinical control. For the quantitative evaluation of CAD, we used a vessel and stenosis score to evaluate the severity of CAD. Moreover, we defined the prognostic localization of CAD as a critical stenosis (≥50%) of the left main (LM) and/or the proximal segment of the left anterior descending coronary artery (LAD)., Results: The presence of RF was as follows: one in 14.2%, two in 40.6%, three in 35%, and more than three in 10.2% of the patients. Prognostic localization of critical stenosis on the proximal segment of LAD and/or LM was found in 174 patients (34.8%). The severity of CAD and prognostic localization of critical stenosis was not correlated with all of the conventional RF evaluated or their association (P>0.05)., Conclusion: In this population with optimally controlled traditional RF, the severity of CAD or prognostic localization on LM and/or proximal LAD was not correlated with the major RF analyzed., (© 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins.)

Objectives: We undertook a historical cohort study to compare, in terms of morbidity, mortality and long-term survival associated with lung cancer resection, a group of patients with previous lymphoproliferative disorders and a group without a hematological history., Methods: We identified 29 patients with a previous lymphoproliferative disorder who underwent lung cancer resection. These subjects (Group-A) were matched with 87 patients without a hematological history who underwent pulmonary resection during the same period (Group-B)., Results: We found no significant difference between the two groups in length of hospitalization, comorbidities, spirometric parameters, type of surgery, histology, neoadjuvant chemotherapy, morbidity, mortality, median survival (Group-A = 37 months; Group-B = 52 months) and 5-year survival (Group-A = 37%; Group-B = 42%). The mean age of Group-A patients was significantly lower than that of Group-B patients (62 vs 66 years; p = 0.024). Group-A patients had a well differentiated lung cancer more frequently than Group-B patients (p = 0.001). Group-A patients had transitory bacteraemies more frequently than Group-B patients (p = 0.005). Multivariate Cox regression analysis showed that age (p = 0.01) and lung cancer stage (p = 0.04) were significantly associated with survival., Conclusions: Patients with lymphoproliferative disorders had a lower age and more differentiated lung cancers than those without lymphoproliferative disorders. Patients with lymphoproliferative disorders and those without a hematological history had similar morbidity, mortality and long-term survival after pulmonary resection. Distinguishing patients with and without a lymphoproliferative disorder seems to be of limited value in the decision-making process of evaluating the indications for surgical treatment of lung cancer., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Objectives: This study sought to assess the prevalence of normal levels of high sensitivity C-reactive protein (hsCRP) at the very onset of ST-segment elevation myocardial infarction (STEMI)., Background: Levels of hsCRP ≥2 mg/l identify individuals who benefit from lipid lowering and possibly anti-inflammatory agents, but how many patients develop infarction in spite of hsCRP levels <2 mg/l and thus would be ineligible for these treatments?, Methods: We studied 887 patients with unequivocally documented STEMI as the first manifestation of coronary disease and 887 matched control subjects from urban areas of Italy, Scotland, and China. Blood samples were obtained before reperfusion strategies <6 h from symptoms onset in order to limit acute event-related increases., Results: hsCRP values were similar in samples obtained <2 h, 2 to 4 h, and 4 to 6 h from symptoms onset in all ethnic groups, consistent with the delayed hsCRP elevation after myocardial necrosis and thus indicative of pre-infarction levels. Median hsCRP values were significantly higher in patients than in control subjects: 2.49 (interquartile range [IQR]: 1.18 to 5.55) mg/l versus 1.32 (IQR: 0.58 to 3.10) mg/l (p < 0.0001), which is consistent with previous findings. However, 41% of patients had hsCRP levels <2 mg/l and conversely, 37% of control subjects had values ≥2 mg/l., Conclusions: The measurement of hsCRP, with a 2 mg/l cutoff, would not have predicted 41% of unequivocally documented STEMIs in 3 ethnic groups without evidence of previous coronary disease, thus indicating both its limitations as an individual prognostic marker and as an indicator of a generalized inflammatory pathogenetic component of STEMI. New specific prognostic and therapeutic approaches should be found for such a large fraction of patients at risk., (Copyright © 2011 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

With an aging and more active older population, an increased incidence of elderly trauma patients, including severely injured geriatric patients, is anticipated. Poorer functional outcomes and increased mortality and morbidity rates in these patients compared to their younger counterparts may be inevitable due to the associated pre-existing medical conditions and the reduced physiological reserves and compensatory mechanisms secondary to aging. However, mortality and complication rates can be reduced, and outcomes can be improved, when prompt and aggressive treatment is provided. Knowledge of the specific issues, challenges and the distinctive injury patterns of this unique trauma population is important when treating elderly polytrauma patients. In the herein study, the special needs of these patients and the current concepts on their management are summarised. Research in this field is ongoing in order to develop advanced management strategies to optimise outcomes. Overall, these patients should not be treated as "older adults", but as a special population with special considerations and the trauma care should be tailored to meet their specific needs.

Objective: Trimetazidine may have beneficial effects on left ventricular (LV) function in patients with systolic heart failure. The authors assessed whether long-term addition of trimetazidine to conventional treatment could improve, along with LV function, resting whole body energy metabolism in patients with chronic systolic heart failure., Design: Single blind randomised study., Setting: University Hospital., Patients: 44 patients with systolic heart failure receiving full medical treatment., Interventions: Indirect calorimetry and two-dimensional echocardiography at baseline and after 3 months., Main Outcome Measures: Whole body resting energy expenditure (REE), percentage of predicted REE, LV ejection fraction (EF), NYHA class, quality of life., Results: Trimetazidine increased EF compared with conventional therapy alone (from 35±8% to 42±11% vs from 35±7% to 36±6%; p=0.02, analysis of variance for repeated measures). NYHA class and quality of life also improved compared with conventional therapy (p<0.0001). REE (from 1677±264 to 1580±263 kcal/day) and percentage of predicted REE (based on the Harris-Benedict equation: from 114±10% to 108±9%) decreased in the trimetazidine group, but not in the control group (REE from 1679±304 to 1690±337 kcal/day and percentage of predicted REE from 113±12% to 115±14%). The variation was different between groups (p=0.03 and 0.023, respectively)., Conclusions: In patients with systolic heart failure, improvement in functional class and LV function induced by middle-term trimetazidine therapy is paralleled by a reduction in whole body REE. The beneficial cardiac effects of trimetazidine may be also mediated by a peripheral metabolic effect.

Introduction: The gold standard for restoring bone defects is still considered to be autologous bone grafting. However, clinical benefits are not guaranteed and donor-site complications and morbidity is not infrequent. Research is on-going for the development of alternative bone substitutes of both biological and synthetic origin. The purpose of this study was to evaluate the type of materials used and their efficacy for the treatment of large bone defects in traumatology and orthopaedic surgery., Materials and Method: A literature review was carried out of Embase and PubMed databases. Inclusion criteria were articles in English language focusing on the use of bone substitutes in trauma and orthopaedic surgery for the treatment of bone defects and included details on the structural, biological or biomechanical properties of the pure product. Furthermore, based on two clinical challenges, fracture non-union and impaction grafting we elaborated on the use of polytherapy for large bone defects as guided by the diamond concept., Results: All the products indicated in this manuscript possess osteoconductive activities but have different resorption times and biomechanical properties. Bone graft substitute materials are used for a wide range of clinical applications even when the level of clinical evidence is low. The size and location of the defect and the local biological and mechanical environment as well as the biomechanical characteristics of the material determine the type of device that can be implanted in a bone defect., Conclusion: Proper assessment of the biological and mechanical environment and accurate patient selection are necessary to judge the extent of therapy the injury warrants. A sound understanding of various aspects of biomaterial properties and their relation and influence towards bone healing is of utmost importance. We suggest the application of polytherapy for the treatment of large bone defects and advocate the use of the diamond concept as a guideline., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Study Design: Randomized clinical trial., Objectives: To determine the efficacy of trunk balance exercises for individuals with chronic low back pain., Background: The majority of exercises focusing on restoring lumbopelvic stability propose targeting the feedforward control of the lumbopelvic region. Less attention has been paid to feedback control during balance adjustments., Methods: Seventy-nine patients were randomly allocated to 2 different groups. The experimental group performed trunk balance exercises in addition to standard trunk flexibility exercises. The control group performed strengthening exercises in addition to the same standard trunk flexibility exercises. The primary outcome measures were pain intensity (visual analogue scale), disability (Roland-Morris Questionnaire), and quality of life (12-Item Short-Form Health Survey). Secondary outcomes were painful positions, use of analgesic drugs, and referred pain. Analysis of variance and relative risk were used to analyze the data for the primary and secondary outcome measures, respectively. The number of participants reaching the minimal clinically important difference in the 2 groups for each outcome measure was compared using relative risk., Results: A significant difference in scores on the Roland-Morris Questionnaire (P = .011) and the physical component of the 12-Item Short-Form Health Survey (P = .048), and in the number of participants reaching the minimal clinically important difference for the Roland-Morris Questionnaire (relative risk, 1.79; 95% confidence interval [CI]: 1.05, 3.04) and the secondary outcome of painful positions (relative risk, 1.37; 95% CI: 1.03, 1.83) were found in favor of the experimental treatment., Conclusions: Trunk balance exercises combined with flexibility exercises were found to be more effective than a combination of strength and flexibility exercises in reducing disability and improving the physical component of quality of life in patients with chronic low back pain.

Background: 31-Phosphorus-magnetic resonance spectroscopy may provide pathophysiological insights into the high-energy phosphate metabolism of the myocardium as measured by phosphocreatine to adenosine triphosphate (PCr/ATP) ratio. Aim of the present study was to determine in vivo the relation between cardiac PCr/ATP ratio and heart rate in normal male subjects., Methods: One hundred twelve apparently healthy, young male individuals (age 34 ± 10 years) were prospectively evaluated. They underwent cardiac cine magnetic resonance imaging to assess left ventricular (LV) function and morphology and 3D-ISIS (31)P-magnetic resonance spectroscopy of the LV to assess the PCr/ATP ratio (a recognized in vivo marker of myocardial energy metabolism). Data were analyzed after segregation by tertiles of the resting PCr/ATP ratio., Results: A significant inverse association between PCr/ATP ratios and resting heart rate was observed (Spearman ρ: r=-0.37; P < .0001). PCr/ATP ratios were also inversely associated with body mass index, diastolic blood pressure, wall mass and with insulin resistance, but in multiple regression analysis heart rate was found to be independently related to PCr/ATP., Conclusions: The present study shows that resting heart rate is proportionally lower across tertiles of increasing PCr/ATP ratio of the LV in apparently healthy young male individuals, supporting the hypothesis that heart rate is a major determinant of cardiac energy stores. These findings may explain the prognostic role of heart rate in the general population as evidenced by previous large epidemiological studies., (Copyright © 2011 Mosby, Inc. All rights reserved.)

Unlabelled: A fatty liver, which is a common feature in insulin-resistant states, can lead to chronic liver disease. It has been hypothesized that a fatty liver can also increase the rates of non-hepatic-related morbidity and mortality. Therefore, we wanted to determine whether the fatty liver index (FLI), a surrogate marker and a validated algorithm derived from the serum triglyceride level, body mass index, waist circumference, and γ-glutamyltransferase level, was associated with the prognosis in a population study. The 15-year all-cause, hepatic-related, cardiovascular disease (CVD), and cancer mortality rates were obtained through the Regional Health Registry in 2011 for 2074 Caucasian middle-aged individuals in the Cremona study, a population study examining the prevalence of diabetes mellitus in Italy. During the 15-year observation period, 495 deaths were registered: 34 were hepatic-related, 221 were CVD-related, 180 were cancer-related, and 60 were attributed to other causes. FLI was independently associated with the hepatic-related deaths (hazard ratio = 1.04, 95% confidence interval = 1.02-1.05, P < 0.0001). Age, sex, FLI, cigarette smoking, and diabetes were independently associated with all-cause mortality. Age, sex, FLI, systolic blood pressure, and fibrinogen were independently associated with CVD mortality; meanwhile, age, sex, FLI, and smoking were independently associated with cancer mortality. FLI correlated with the homeostasis model assessment of insulin resistance (HOMA-IR), a surrogate marker of insulin resistance (Spearman's ρ = 0.57, P < 0.0001), and when HOMA-IR was included in the multivariate analyses, FLI retained its association with hepatic-related mortality but not with all-cause, CVD, and cancer-related mortality., Conclusion: FLI is independently associated with hepatic-related mortality. It is also associated with all-cause, CVD, and cancer mortality rates, but these associations appear to be tightly interconnected with the risk conferred by the correlated insulin-resistant state., (Copyright © 2011 American Association for the Study of Liver Diseases.)

Purpose: To identify by noninvasive means early retinal abnormalities that may predict diabetic macular edema., Methods: The authors analyzed retrospectively data from consecutive patients with Type 1 (n = 16) or Type 2 (n = 23) diabetes who presented for routine follow-up of early retinopathy, had no clinical signs or symptoms of diabetic macular edema, and were evaluated with spectral-domain optical coherence tomography. Age- and gender-matched nondiabetic subjects provided normative data., Results: Spectral-domain optical coherence tomography revealed in the macular region of diabetic patients small hyporeflective areas (median diameter, 55 μm) contained within discrete retinal layers that we named micropseudocysts (MPCs). Micropseudocysts are associated with vascular leakage. The patients showing MPCs had more frequently systemic hypertension and increased central foveal thickness than those without MPCs. The association with increased central foveal thickness was only in the patients with Type 2 diabetes., Conclusion: Macular MPCs in patients with mild diabetic retinopathy appear to reflect leakage and can precede macular thickening. The association of MPCs with increased central foveal thickness in patients with Type 2 diabetes, but not in patients with Type 1 diabetes, points to a greater tendency to retinal fluid accumulation in patients with Type 2 diabetes. Studies in larger cohorts will determine the usefulness of MPCs in strategies to abort diabetic macular edema.

The incidence of long bone non-unions has been estimated to range between 5 and 10%. Autologous bone graft usually harvested from the iliac crest continues to be the gold standard for biological enhancement of atrophic non-unions. However, its use has been hampered by minor and major donor site complications. Moreover despite possessing the properties of osteogenecity, osteoconductivity and some osteoinductivity the overall results of treatment have not been consistent with disappointing success rates at times. The concept of polytherapy for the treatment of non-unions, namely the simultaneous application of the three fundamental elements of the diamond concept, osteoprogenitor cells, growth factor and osteoconductive scaffold, appears to be an attractive alternative but more studies are desirable to validate this strategy., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Background: Pancreatic cancer causes severe pain in 50 to 70% of patients and is often difficult to treat. Celiac plexus block (CPB) is thought to be a safe and effective technique for reducing the severity of pain., Objectives: To determine the efficacy and safety of celiac plexus neurolysis in reducing pancreatic cancer pain, and to identify adverse effects and differences in efficacy between the different techniques., Search Strategy: We searched Cochrane CENTRAL, MEDLINE, GATEWAY and EMBASE from 1990 to December 2010., Selection Criteria: Randomised controlled trials (RCTs) of CPB by the percutaneous approach or endoscopic ultrasonography (EUS)-guided neurolysis in adults with pancreatic cancer at any stage, with a minimum of four weeks follow-up., Data Collection and Analysis: We recorded details of study design, participants, disease, setting, outcome assessors, pain intensity (visual analogue scale (VAS)) and methods of calculation., Main Results: The search identified 102 potentially eligible studies. Judged from the information in the title and abstract six of these concerning the percutaneous block, involving 358 participants, fulfilled the inclusion criteria and were included in the review. All were RCTs in which the participants were followed for at least four weeks. We excluded studies published only as abstracts. We identified one RCT comparing EUS-guided or computed tomography (CT) -guided CPB but its aim was to assess efficacy in controlling chronic abdominal pain associated with chronic pancreatitis rather than pancreatic cancer, so it was excluded.For pain (VAS) at four weeks the mean difference was -0.42 in favour of CPB (95% confidence interval (CI) -0.70 to - 0.13, P = 0.004, fixed-effect model). At eight weeks the mean difference was -0.44 (95% CI -0.89 to - 0.01, random-effects model). At eight weeks there was significant heterogeneity (I(2) = 89%).Opioid consumption was significantly lower in the CPB group than the control group (P < 0.00001). , Authors' Conclusions: Although statistical evidence is minimal for the superiority of pain relief over analgesic therapy, the fact that CPB causes fewer adverse effects than opioids is important for patients. Further studies and RCTs are recommended to demonstrate the potential efficacy of a less invasive technique under EUS guidance.

Objective: To assess the ischemic threshold and stress-induced left ventricular dysfunction after high fat (HFM) and high carbohydrate (HCM) meals in patients with stable coronary disease., Methods: Twelve patients (68 ± 7 years) underwent stress (treadmill exercise testing) echocardiography after fasting (8h), after HFM and HCM (2h). Time to 1mm ST-segment depression (time to 1mm) and stress wall motion score index (WMSI) were evaluated. Before eating and just before exercise testing glucose, insulin, triglycerides, total cholesterol and FFA levels were measured., Results: Results are expressed as medians (Q1-Q3). HFM did not affect exercise variables compared to fasting, whereas HCM reduced the ischemic threshold [time to 1mm from 376 (343-493) to 297 (180-420) s, p = 0.003]. Compared to fasting [1.47 (1.31-1.66)], stress WMSI was higher after HCM [1.56 (1.44-1.69)] (p = 0.04) but not after HFM [1.56 (1.30-1.63)]. Glycemia and insulinemia were significantly higher after HCM, compared to fasting and HFM., Conclusions: In patients with coronary disease, exercise testing after a high carbohydrate meal results in a lower ischemic threshold and greater ischemia magnitude. Conversely, compared to fasting, a high fat meal does not induce additional detrimental effects. Hyperglycemia and hyperinsulinemia were the only metabolic determinants identified as potential metabolic mechanisms of this phenomenon., (Copyright © 2009 Elsevier Ireland Ltd. All rights reserved.)

Purpose: To evaluate the efficacy and safety of intravitreal ranibizumab (Lucentis) in patients with treatment-naive retinal vein occlusion., Design: Prospective, consecutive, non-comparative, interventional case series., Participants: Seventeen eyes of 17 consecutive patients with naive retinal vein occlusion. METHODS; Consecutive patients were recruited and received, on demand, intravitreal 0.5 mg of ranibizumab; nine had central retinal vein occlusion (CRVO) and eight had branch retinal vein occlusion (BRVO). Pre- and postoperative clinical evaluation included measurement of best corrected visual acuity (BCVA) for distance, and near vision (MNREAD time, reading fluency), contrast sensitivity, colour fundus photography, fluorescein angiography and optical coherence tomography (OCT). All subjects were followed for a minimum of 12 months., Main Outcome Measures: Change in BCVA, contrast sensitivity, angiographic leakage, OCT central macular thickness (CMT), number of treatments., Results: Patients with CRVO had mean pre-treatment BCVA of 20/240 (1.08 ± 0.25 logarithm of the minimum angle of resolution (logMAR)) and final BCVA of 20/46 (0.36 ± 0.16 logMAR), with significant improvement at 1 year of follow-up (p<0.0001). At 12 months mean BCVA improved to 36.7 letters, with a gain of 6.4 lines, and OCT showed that the mean CMT was 271 μm, with a mean reduction of 360 μm (p<0.0001) from baseline (mean 631 μm). Patients with BRVO had mean pre-treatment BCVA of 20/126 (0.80 ± 0.29 logMAR) and final BCVA of 20/50 (0.41 ± 0.23 logMAR) (p<0.0001). The mean OCT CMT was 278 μm, with a mean reduction of 275 μm (p<0.0001) from baseline (mean 553 μm). Contrast sensitivity, MNREAD time and reading fluency improved significantly in the treated eyes. No ocular or systemic side effects were observed. Eyes with CRVO received an average of 3.0 injections (range 2-4) and those with BRVO 3.6 (range 3-4)., Conclusions: Intravitreal ranibizumab for the management of naive CRVO or BRVO can favourably modify the course of the occlusion, indicating that short- and long-term blockade of vascular endothelial growth factor (VEGF)-A may restore the integrity of the inner blood-retinal barrier, reduce CMT and significantly improve visual function, with a good safety profile. Further prospective long-term studies are warranted to confirm the efficacy, safety and optimal treatment regimen for intravitreal ranibizumab.

Polytherapy, namely the simultaneous application of three fundamental elements necessary for bone regeneration (growth factors, osteogenic cells and osteoconductive scaffolds) seems to lead to a very high success rate in the treatment of complex non-union (NU) cases and critical bone defects. NU are reported in 5-10% of long bone fractures. The use of autologous bone grafts has been long-considered the gold standard for the treatment of these cases. However the harvesting procedure from the iliac crest increases surgery time and presents some donor site complications which may be elevated. In recent years, surgeons have some alternatives to autologous grafting such as: application of organic or synthetic bone substitute, application of mesenchymal stromal cells (MSC) or growth factors (GF). In the literature there are many studies available about their application in monotherapy, but unfortunately the healing rate doesn't exceed 90%. Polytherapy seems to be a logical option to improve the healing rate, nevertheless, there are not still extensive studies that validate this strategy and moreover, some questions are not resolved.

Objective: Some obese individuals have normal insulin sensitivity. It is controversial whether this phenotype is associated with increased all-cause mortality risk., Research Design and Methods: Fifteen-year all-cause mortality data were obtained through the Regional Health Registry for 2,011 of 2,074 Caucasian middle-aged individuals of the Cremona Study, a population study on the prevalence of diabetes in Italy. Individuals were divided in four categories according to BMI (nonobese: <30 kg/m²; obese: ≥30 kg/m²) and estimated insulin resistance (insulin sensitive: homeostasis model assessment of insulin resistance <2.5; insulin resistant ≥2.5)., Results: Obese insulin-sensitive subjects represented 11% (95% CI 8.1-14.5) of the obese population. This phenotype had similar BMI but lower waist circumference, blood pressure, fasting glucose, triglycerides, and fibrinogen and higher HDL cholesterol than obese insulin-resistant subjects. In the 15-year follow-up, 495 deaths (cardiovascular disease [CVD]: n = 221; cancer: n = 180) occurred. All-cause mortality adjusted for age and sex was higher in the obese insulin-resistant subjects (hazard ratio 1.40 [95% CI 1.08-1.81], P = 0.01) but not in the obese insulin-sensitive subjects (0.99 [0.46-2.11], P = 0.97) when compared with nonobese insulin-sensitive subjects. Also, mortality for CVD and cancer was higher in the obese insulin-resistant subjects but not in the obese insulin-sensitive subjects when compared with nonobese insulin-sensitive subjects., Conclusions: In contrast to obese insulin-resistant subjects, metabolically healthy obese individuals are less common than previously thought and do not show increased all-cause, cancer, and CVD mortality risks in a 15-year follow-up study.

The aim of this study was to estimate the diagnostic sensitivity of thyroid autoantibodies in individuals with a case-mix of subjects with thyroid disease representing that of the general population. We measured thyroid microsome (TMA), thyroid peroxidase (TPO), thyroglobulin (TGA) and thyroid-stimulating hormone (TSH) receptor (TRA) autoantibodies in subjects in the bottom (hyperthyroid end) and top (hypothyroid end) four percentiles of the TSH distribution from among participants in a population-based survey of individuals aged ≥40 years (the Cremona Study). TMA and TPO were the most sensitive autoantibodies in subjects in both the bottom percentiles (19.8% and 18.5%, respectively) and the top percentiles (51.2% and 53.8%, respectively) of the TSH distribution. TMA and TPO showed good agreement (kappa statistics 87.8%, 95% CI 80.1-95.5%) at both ends of the TSH distribution. TGA were the next most sensitive marker, although seldom detected if TMA or TPO were not present. TRA were detected only at the extremes of the TSH distribution (1st percentile, 31.8%; 100th percentile, 25.0%). We conclude that, among a case-mix of individuals with thyroid disease representing that of the general population, TMA and TPO are the most sensitive markers of thyroid disease. TGA only marginally increased the diagnostic sensitivity of TMA and TPO. TRA are sensitive markers of thyroid disease only at the extremes of thyroid function.