Development of a cardiac patch for the regeneration of infarcted hearts

Previously held under moratorium from 13 June 2019 until 28 July 2021The inflammation that occurs after cardiac ischemia/reperfusion leads to high levels of oxidative stress, which produces deleterious effects that ultimately limit regeneration of the myocardium. This stress response can be prolonged, thereby affecting various stages of cardiac repair remodelling. Efforts to control such remodelling and stimulate cardiac tissue regeneration have therefore included the use of antioxidant or anti-inflammatory drug strategies. To date, such approaches have involved delivery of the drugs orally or by injection. The use of a scaffold that can be placed onto the heart immediately following surgery would allow sustained delivery of high concentrations of drug in situ, directly targeting the affected area. Moreover, implantation of such a material has the potential to encourage cell infiltration into the matrix, thereby promoting regeneration. The ultimate aim of this project was to develop a cardiac scaffold loaded with a drug with antioxidant and anti-inflammatory activity. Pyruvate is a well characterised anti-inflammatory and antioxidant drug. It has been added to cardioplegia by some surgical groups for its potential cardioprotective effects, although the therapeutic value of sustained delivery of this drug into the myocardium following cardiac surgery has not been investigated. Ethyl Pyruvate (EP) is a more stable form of this drug and was therefore the drug selected for investigation in the present study. Various alginate scaffolds were developed as drug delivery vehicles, with EP release characterised in vitro. Alginate gels prepared with (1-2%) low viscosity high guluronate alginate and crosslinked with 1:1 (0.6-1%) calcium chloride solution provided sustained release of about 2,000 – 3,000 µM of EP over 28-days period, characterised by an initial burst of about 85% of EP released in the first week, and the remaining EP was released over the following weeks.Since it is likely that an optimal scaffold for cardiac regeneration will have a porous structure with interconnected pores to allow cell infiltration and proliferation, a series of macro-porous alginate scaffolds were developed. Different methods were used to prepare the scaffolds and thus different EP release profiles were obtained. Overall, the scaffolds prepared with 1% low viscosity high guluronate alginate and double crosslinked with 1:1 (0.4-1%) calcium gluconate solution and 0.2 M calcium chloride bath and prepared with one cycle of free-drying (method 6) released about 5,000- 5,500 µg over 28 days (with 88-98% drug loading efficiency), the highest compared to the other formulations. The potential therapeutic benefits of such EP release were then investigated in vitro. When primary rat cardiac fibroblast cells were exposed to hydrogen peroxide (150 μM) in the presence of EP (1,000 – 20,000 μM), EP improved cell viability as measured by alamarBlue assay. Moreover, at (1,000 - 10,000 μM), EP significantly increased cell viability compared to the control. In contrast, EP had no protective effect on the cells that had been previously exposed to H2O2 (150 μM) for 24 hours. Alginate macro-porous scaffolds (prepared using method 6), which showed high porosity, the best EP release profiles and the highest EP loading efficiency, were then tested in a cardiac fibroblasts culture and cell viability was measured by Neutral Red assay after 5 days. In order to improve cell attachment in the scaffolds prepared in this study, Arginine-Glycine-Aspartic acid modified RGD alginate was also used to prepared the scaffolds for the cardiac fibroblast study. Cells seeded onto the RGD- Alginate + EP scaffolds presented higher cell viability compared to the scaffolds without EP, demonstrating that the cells benefit from the structure of the scaffold, as well as from the presence of EP. This study has demonstrated for the first time that alginate represents a suitable delivery system for providing sustained release of EP. The protective effective of this drug on cardiac fibroblasts shown here, combined with the promising cell viability observed within the delivery scaffold, mean that this approach has significant potential for future development towards clinical evaluation.The inflammation that occurs after cardiac ischemia/reperfusion leads to high levels of oxidative stress, which produces deleterious effects that ultimately limit regeneration of the myocardium. This stress response can be prolonged, thereby affecting various stages of cardiac repair remodelling. Efforts to control such remodelling and stimulate cardiac tissue regeneration have therefore included the use of antioxidant or anti-inflammatory drug strategies. To date, such approaches have involved delivery of the drugs orally or by injection. The use of a scaffold that can be placed onto the heart immediately following surgery would allow sustained delivery of high concentrations of drug in situ, directly targeting the affected area. Moreover, implantation of such a material has the potential to encourage cell infiltration into the matrix, thereby promoting regeneration. The ultimate aim of this project was to develop a cardiac scaffold loaded with a drug with antioxidant and anti-inflammatory activity. Pyruvate is a well characterised anti-inflammatory and antioxidant drug. It has been added to cardioplegia by some surgical groups for its potential cardioprotective effects, although the therapeutic value of sustained delivery of this drug into the myocardium following cardiac surgery has not been investigated. Ethyl Pyruvate (EP) is a more stable form of this drug and was therefore the drug selected for investigation in the present study. Various alginate scaffolds were developed as drug delivery vehicles, with EP release characterised in vitro. Alginate gels prepared with (1-2%) low viscosity high guluronate alginate and crosslinked with 1:1 (0.6-1%) calcium chloride solution provided sustained release of about 2,000 – 3,000 µM of EP over 28-days period, characterised by an initial burst of about 85% of EP released in the first week, and the remaining EP was released over the following weeks.Since it is likely that an optimal scaffold for cardiac regeneration will have a porous structure with interconnected pores to allow cell infiltration and proliferation, a series of macro-porous alginate scaffolds were developed. Different methods were used to prepare the scaffolds and thus different EP release profiles were obtained. Overall, the scaffolds prepared with 1% low viscosity high guluronate alginate and double crosslinked with 1:1 (0.4-1%) calcium gluconate solution and 0.2 M calcium chloride bath and prepared with one cycle of free-drying (method 6) released about 5,000- 5,500 µg over 28 days (with 88-98% drug loading efficiency), the highest compared to the other formulations. The potential therapeutic benefits of such EP release were then investigated in vitro. When primary rat cardiac fibroblast cells were exposed to hydrogen peroxide (150 μM) in the presence of EP (1,000 – 20,000 μM), EP improved cell viability as measured by alamarBlue assay. Moreover, at (1,000 - 10,000 μM), EP significantly increased cell viability compared to the control. In contrast, EP had no protective effect on the cells that had been previously exposed to H2O2 (150 μM) for 24 hours. Alginate macro-porous scaffolds (prepared using method 6), which showed high porosity, the best EP release profiles and the highest EP loading efficiency, were then tested in a cardiac fibroblasts culture and cell viability was measured by Neutral Red assay after 5 days. In order to improve cell attachment in the scaffolds prepared in this study, Arginine-Glycine-Aspartic acid modified RGD alginate was also used to prepared the scaffolds for the cardiac fibroblast study. Cells seeded onto the RGD- Alginate + EP scaffolds presented higher cell viability compared to the scaffolds without EP, demonstrating that the cells benefit from the structure of the scaffold, as well as from the presence of EP. This study has demonstrated for the first time that alginate represents a suitable delivery system for providing sustained release of EP. The protective effective of this drug on cardiac fibroblasts shown here, combined with the promising cell viability observed within the delivery scaffold, mean that this approach has significant potential for future development towards clinical evaluation

Modelling Customers’ Perception of the Quality of Services Provided by Builders: A Case of Victoria, Australia

Consumer satisfaction is essential for quality assurance, business survival and economic prosperity. It can also be used as an indicator of the occurrence of defects in the houses delivered by builders. The objective of this study is to compare the quality of services provided by volume and small builders, and to develop a model for predicting the chance of occurrence of structural defects in houses. A list of home builders was obtained from Australia’s Housing Industry Association media release 2019. Thereafter, customer reviews of 10 volume builders and 107 small builders were obtained from publicly available data. Overall, 2336 reviews for volume-builders and 2037 reviews for small builders were analysed quantitatively. Further, using the scores provided by customers, the probability-based regression model for the structural integrity of residential buildings was developed. Generally, the research found that for volume-builders, customers have the highest satisfaction level for ‘customer service’ and the lowest satisfaction level for ‘plumbing and waterproofing’ work. However, for small builders, customers have the highest confidence in the ‘structural integrity’ of their buildings and the least confidence in projects ‘timeliness’. Clients can use the stochastic-based model to predict the probability that a builder could deliver a house with low structural defects. The model showed that if a customer service score for a particular builder is less than 3.3, then there is a higher chance of having structural defects. This research contributes to the body of knowledge by developing and validating the logistic regression model that can be used as a tool to assess the quality of services provided by home builders. Moreover, the research provides useful information which can assist builders to improve the quality of services they provide

Current role of computed tomography-guided transthoracic needle biopsy of metastatic lung lesions

AIM: As part of the Catania symposium on lung metastasectomy we reviewed our practice of computed tomography (CT)-guided percutaneous transthoracic needle biopsy of pulmonary metastatic lesions with particular emphasis on diagnostic accuracy and nature of complications lesions. MATERIALS & METHODS: 25 patients with metastatic lesions of the lung have been evaluated between May 2010 and February 2014. Inclusion criteria consisted of patients with histologically confirmed, metastatic disease of the lung, those receiving a CT-guided needle biopsy, were at least 18 years of age; and with adequate hepatic, renal and hematological function. We recorded also the size of the sampled lesions, their distance from the pleura, the complications encountered (pneumothorax and thoracostomy tube placement), the cytological diagnosis and the outcome in all the cases. RESULTS: CT-guided percutaneous transthoracic needle biopsy were performed on 23 of 25 patients with suspected lung metastases. 17 males and six females with a mean age of 71.4 years. The mean size of lesions was 4.2 cm (range: 1 to 17 cm). For CT-guided needle biopsy, an 18 gauge semi-automatic needle biopsy device was used. Of 23 biopsies, 20 (87%) yielded a correct diagnosis with specific histological typing for metastasis. Pneumothorax was the most common complication occurring in four cases (5.7%). CONCLUSION: CT-guided percutaneous transthoracic needle biopsy is a firm, useful and safe technique for the diagnosis of suspected pulmonary metastases as it avoids open biopsy in most cases

Preliminary analysis of site effects in the Ischia island: new insights from md 4.0 earthquake of 21 august 2017 and seismic noise data

On August 21, 2017, at 18:57 UTC, an earthquake of MD 4.0 occurred in Casamicciola, district of Ischia island. The damage caused by the earthquake was massive, with two victims and several buildings collapsed, and circumscribed to the areas of uptown Casamicciola, particularly in the Piazza Maio-La Rita area, and in a small area, called Fango, in Lacco Ameno. Medium and minor damages occurred in Piazza Bagni, in the area around the town hall of Casamicciola and in the Sentinella area. Even assuming the poor quality constructions and/or not in compliance with the anti-seismic regulations, such a level of damage has induced the scientific community to analyse the effects of local site amplifications, that usually are not negligible in volcanic areas. As a matter of fact the seismic station IOCA, located very close to the high damage areas, recorded a peak ground acceleration (PGA) of 2.6 m/s2. This paper is aimed to study the possible site amplification in the areas heavily affected by the August 21 earthquake in order to better understand the causes of these macroseismic effects and high damage levels already observed in the past.PublishedCentro Congressi della Stazione Marittima, Trieste, Italy6V. Pericolosità vulcanica e contributi alla stima del rischi

Markers of microbial translocation during pregnancy: differences among HIV+ women of African and European provenance.

Introduction: Microbial translocation (MT) markers are indicators of HIV-related immune activation, but reference values are mostly derived from European or North American populations and could be substantially different in populations living in developing countries. Here we evaluate possible differences in MT markers levels in HIV+ pregnant women of different geographical provenance. Methodology: This study is nested within an observational study of pregnant women with HIV in Italy. Women were dichotomized on the basis of provenance in two groups of European (n = 14) and African (n = 26) origin. Soluble CD14, lipopolysaccharide-binding protein (LBP) and intestinal-fatty acid binding protein (I-FABP) were measured in plasma samples collected between the first and second trimester of pregnancy. Results: Demographic and viroimmunological characteristics were similar between groups, although European women were more commonly smokers and HCV-coinfected. Irrespective of origin, LBP plasma levels were positively correlated with I-FABP (r = 0.467, p = 0.004) and sCD14 levels (r = 0.312 p = 0.060). Significantly higher levels of sCD14 (1885 vs. 1208 ng/mL, p = 0.005) LBP (28.5 vs. 25.3 µg/mL, p = 0.050) and I-FABP (573.4 vs. 358.2 pg/mL, p = 0.002) were observed in European compared with African women. A multivariable linear regression analysis, adjusted for smoking and HCV coinfection confirmed the association between sCD14 levels and women provenance (p = 0.03). Conclusions: Our observations indicate significant differences in soluble markers among women of different provenance. In the design and analysis of studies evaluating MT markers, population-specific reference values should be considered

Factors Associated With Response and Resistance to Cognitive Remediation in Schizophrenia: A Critical Review

Cognitive impairment is a central feature of schizophrenia and has shown to play a crucial role in the psychosocial function of the disorder. Over the past few years, several cognitive remediation (CR) interventions have been developed for schizophrenia, whose effectiveness has also been widely demonstrated by systematic reviews and meta-analysis studies. Despite these evidences, many questions remain open. In particular, the identification of CR response predictors in patients with schizophrenia is still a topic with equivocal findings and only a few studies have looked for the relationship between CR response or resistance and the biological, socio-demographic, clinical and cognitive features in schizophrenia. The current knowledge on positive or negative response predictors to CR treatment in schizophrenia include: age, duration of illness, premorbid adjustment, baseline cognitive performance, intrinsic motivation, hostility, disorganized symptoms, neurobiological reserve, genetic polymorphisms, the amounts of antipsychotics, the type of CR, etc. The aim of this review is to identify neurobiological, psychopathological, cognitive, and functional predictors of CR response or resistance in schizophrenia, taking into account both cognitive and functional outcome measures. The information obtained could be very useful in planning integrated and personalized interventions, also with a better use of the available resources

Generalized Lymphatic Anomaly as a Differential Diagnosis of Lytic Lesions

Generalized lymphatic anomaly (GLA) is an infrequent multiorgan disease characterized by the presence of abnormal proliferation of lymphatic vessels. The diagnosis requires histological confirmation, and the treatment is controversial. We are presenting a case of a 28-year-old male patient who was diagnosed with an extragonadal mediastinal nonseminomatous germ cell tumor. He underwent chemotherapy, and during this treatment, radiologic findings evidenced lytic lesions. Multiple biopsies were performed, which revealed the presence of abnormal lymphatic vessels, characteristic of GLA. There are different etiologies of osteolytic lesions, and on some occasions, they mimic a tumoral entity. The clinical suspicion of GLA is the first step in approaching the diagnosis, particularly in young adult patients

Long-Term Drug Survival and Effectiveness of Secukinumab in Patients with Moderate to Severe Chronic Plaque Psoriasis: 42-Month Results from the SUPREME 2.0 Study

Purpose: SUPREME, a phase IIIb study conducted in Italy, demonstrated safety and high efficacy of secukinumab for up to 72 weeks in patients with moderate-to-severe plaque-type psoriasis. SUPREME 2.0 study aimed to provide real-world data on the long-term drug survival and effectiveness of secukinumab beyond 72 weeks.Patients and Methods: SUPREME 2.0 is a retrospective observational chart review study conducted in patients previously enrolled in SUPREME study. After the end of the SUPREME study, eligible patients continued treatment as per clinical practice, and their effectiveness and drug survival data were retrieved from medical charts.Results: Of the 415 patients enrolled in the SUPREME study, 297 were included in SUPREME 2.0; of which, 210 (70.7%) continued secukinumab treatment throughout the 42-month observation period. Patients in the biologic-naive cohort had higher drug survival than those in the biologic-experienced cohort (74.9% vs 61.7%), while HLA-Cw6-positive and HLA-Cw6-negative patients showed similar drug survival (69.3% and 71.9%). After 42 months, Psoriasis Area and Severity Index (PASI) 90 was achieved by 79.6% of patients overall; with a similar proportion of biologic-naive and biologic-experienced patients achieving PASI90 (79.8% and 79.1%). The mean absolute PASI score reduced from 21.94 to 1.38 in the overall population, 21.90 to 1.24 in biologic-naive and 22.03 to 1.77 in biologic-experienced patients after 42 months. The decrease in the absolute PASI score was comparable between HLA-Cw6-positive and HLA-Cw6-negative patients. The baseline Dermatology Life Quality Index scores also decreased in the overall patients (10.5 to 2.32) and across all study sub-groups after 42 months. Safety was consistent with the known profile of secukinumab, with no new findings. Conclusion: In this real-world cohort study, secukinumab showed consistently high long-term drug survival and effectiveness with a favourable safety profile

Long-Term Drug Survival and Effectiveness of Secukinumab in Patients with Moderate to Severe Chronic Plaque Psoriasis: 42-Month Results from the SUPREME 2.0 Study

Purpose: SUPREME, a phase IIIb study conducted in Italy, demonstrated safety and high efficacy of secukinumab for up to 72 weeks in patients with moderate-to-severe plaque-type psoriasis. SUPREME 2.0 study aimed to provide real-world data on the long-term drug survival and effectiveness of secukinumab beyond 72 weeks. Patients and Methods: SUPREME 2.0 is a retrospective observational chart review study conducted in patients previously enrolled in SUPREME study. After the end of the SUPREME study, eligible patients continued treatment as per clinical practice, and their effectiveness and drug survival data were retrieved from medical charts. Results: Of the 415 patients enrolled in the SUPREME study, 297 were included in SUPREME 2.0; of which, 210 (70.7%) continued secukinumab treatment throughout the 42-month observation period. Patients in the biologic-naïve cohort had higher drug survival than those in the biologic-experienced cohort (74.9% vs 61.7%), while HLA-Cw6–positive and HLA-Cw6–negative patients showed similar drug survival (69.3% and 71.9%). After 42 months, Psoriasis Area and Severity Index (PASI) 90 was achieved by 79.6% of patients overall; with a similar proportion of biologic-naïve and biologic-experienced patients achieving PASI90 (79.8% and 79.1%). The mean absolute PASI score reduced from 21.94 to 1.38 in the overall population, 21.90 to 1.24 in biologic-naïve and 22.03 to 1.77 in biologic-experienced patients after 42 months. The decrease in the absolute PASI score was comparable between HLACw6–positive and HLA–Cw6-negative patients. The baseline Dermatology Life Quality Index scores also decreased in the overall patients (10.5 to 2.32) and across all study sub-groups after 42 months. Safety was consistent with the known profile of secukinumab, with no new findings. Conclusion: In this real-world cohort study, secukinumab showed consistently high long-term drug survival and effectiveness with a favourable safety profile