PASIREOTIDE-INDUCED HYPERGLYCEMIA IN ACROMEGALY PATIENTS: EVALUATION OF PATHOPHISIOLOGICAL MECHANISMS AND EFFICACY OF ANTIDIABETIC TREATMENT

Pasireotide LAR (PAS) has a safety profile similar to first-generation somatostatin in analogues (SSA), except for a higher frequency of hyperglycaemia-related adverse events. However, consensus on the best management of PAS-induced hyperglycaemia in acromegalic patients has still to be defined. The current study aim at investigating the effects of long-term PAS treatment on glucose metabolism, besides GH and IGF-I control, by evaluating the clinical management of hyperglycemia adverse events in acromegalic patients followed in two Italian referral Centers, participating to the PAOLA study, a randomized, Phase III study assessing the efficacy and safety of PAS compared with patients with inadequately controlled acromegaly during first-generation SSA. Moreover, the role of metabolic parameters (weight, BMI, fasting glucose and HbA1c levels) and markers of disease activity (GH, IGF-I, duration of PAS treatment) were investigated as potential predictors of hyperglycemia development. A total of 31 patients (16 F/15 M, mean age 47.6 years) entered the present study, including 18 randomized to PAS (group 1), and 13 to continued treatment with octreotide LAR 30 mg or lanreotide Autogel 120 mg (group 2) for six months (core study). All patients in group 2 who remained uncontrolled at 6 months had the opportunity to switch to PAS in the extension phase. In all patients, fasting glucose and HbA1c were evaluated every 6 months, according to the study protocols. At baseline, pre-existing diabetes mellitus (DM) was found in five patients (27.7%) in group 1 and one (7.7%) in group 2 (p=0.34), whereas pre-existing prediabetes, defined as impaired glucose tolerance (IGT) or impaired fasting glucose (IFG), was seen in one patients (5.5%, IGT) in group 1 and in three patients (23.1%, 2 IGT, 1 IFG) in group 2 (p=0.34). Patients were treated with PAS for a mean time of 34 months (6-67 months). Hyperglycemia-related adverse events were reported in 15 patients (83.3%) in group 1, occurring after a mean time of 5 months (1-16 months). One patient required treatment discontinuation because of diabetes adverse event. Four out five patients with DM at baseline (80%) reported worsening of hyperglycemia during PAS treatment. One patient with IGT at baseline (100%) developed overt DM. Six (50%) and four (33.3%) patients with normal glucose tolerance (NGT) at baseline developed IFG and DM, respectively, during PAS treatment. In group 2, three (23%) patients reported hyperglycemia-related adverse events during the core phase (during first-generation SSA therapy), after a mean time of two months. Particularly, overt DM occurred in two patients (15.3%) with baseline NGT and in one patient (7.7%) with IGT at baseline. All cases were of mild severity, defined as grade 1. During the extension phase, nine patients (69.2%) reported hyperglycemia-related adverse events after a mean time of seven months (2-17 months) from the beginning of PAS treatment. One diabetic patient (33.3%) reported worsening hyperglycemia. Among patients with NGT at baseline, three (16.6%) developed pre-diabetes (2 IFG, 1 IGT), and two patients (15.3%) developed overt DM during PAS treatment. All cases reported in group 1 and 2 were of mild-to-moderate severity, defined as grade 2-3, and were judged to be related to PAS. The risk to develop hyperglycemia correlated neither with baseline BMI, weight, GH, IGF-I, glucose and HbA1c levels, or duration of PAS treatment (p=0.41). Similarly, glucose status did not significantly correlate with biochemical control at the last follow-up (p=0.66). At study entry, three patients (16.6%) in group 1 and one patient (7.7%) in group 2 were already treated with antidiabetic drugs. In group 1, starting of new antidiabetic treatment was required in eight patients (44.4 %) throughout the study, and metformin (MET) was the drug of choice in all these patients. Four (50%) out eight patients did not control glucose and HbA1c levels despite MET monotherapy, needing further therapies. In fact, MET was associated with DPP-4 inhibitor in one patient (25%), GLP-1 agonist in two patients (50%), and GLP-1 agonist and glargine insulin in one patient (25%) to control hyperglycemia. Two patients previously treated with antidiabetic drugs (1 patient with MET plus glargine insulin, and 1 patient with glargine insulin monotherapy) needed a dose adjustment to control hyperglycemia. In group 2, one patient (7.7%) started MET during the core phase. During the extension phase, starting of new antidiabetic treatment was required in seven patients (53.8%), and MET was the drug of choice in all these patients. Three (42.8%) out seven patients did not control glucose and HbA1c levels despite MET monotherapy, requiring further therapies. MET was associated with DPP-4 inhibitor in one patient (33.3%), GLP-1 agonist in two patients (33.3%), and GLP-1 agonist and detemir insulin in one patient (33.3%) to control hyperglycemia. The results of the present study confirm the known negative effect of PAS on glucose metabolism, however treatment intensification with DPP4 inhibitor and GLP-1 agonist resulted in good glycemic control in most patients. Further studies are needed to deeply evaluate the mechanism of PAS-induced hyperglycemia in acromegalyc patients, investigating the effect of PAS on insulin secretion and hepatic/peripheral insulin sensitivity

Thermal Comfort and Climatic Potential of Ventilative Cooling in Italian Climates

The chapter describes several climate-correlated variables and suitable key performance indicators (KPIs) to define the local ventilative cooling potential. Furthermore, a methodology is presented to verify potential correlations between climate KPIs and indoor comfort parameters. The latter values are calculated by adopting dynamic energy simulations (EnergyPlus) and comfort models – both Fanger (ISO 7730) and the recently updated EU adaptive comfort approach (EN 16798-1) – considering a sample building unit. Simulations are run by using a parametric-enabling tool developed by the research unit to check correlations and is part of work performed for the PRELUDE project, co-funded by the EU, Horizon 2020 research and innovation programme under grant agreement No 958345. The approach is applied to the whole Italian territory considering typical yearly (hourly defined) meteorological conditions for all municipalities (about 8000 data points). Strong connections between climate and building KPIs are underlined together with the high potential of ventilative cooling in reducing discomfort and energy needs in the Italian territory

Populism and Negative Emotions within the Italian Politics: A Twitter-based Analysis

While conceptualizing populism as “a cultural-relational performative style” (Moffitt et al. 2016), this paper seeks to explore whether and the extent to which semantic categories of populism and the emotional frames of anger and fear are combined in the tweets posted by selected Italian politicians and political parties on their Twitter account. Methodologically, a combination of quantitative and qualitative approaches was adopted: Content Analysis, to pinpoint recurrent thematic patterns that are relevant to the research purpose; as well as approaches of Multiple Correspondence Analysis, to verify whether the combination of the chosen variables is recurrent within the Twitter corpus purposely built for the analysis. The same tools were used to explore differences in the use of populism and emotional frames on the basis of gender, provenance and the local versus national political activity of the politicians under analysis. Results have showed that there exists a correlation between the use of given semantic categories of populism (i.e. ‘Appeal to people’, ‘Ostracizing the others’, ‘Attacking the elite’) and the frame of anger. The combined use of these categories was mostly detected in the tweeting style of Italian politicians and parties that collocate on the right-wing political spectrum. Moreover, preliminary findings showed a significant difference in the degree of populism depending either on the national or local political activity

Simulated Versus Monitored Building Behaviours: Sample Demo Applications of a Perfomance Gap Detection Tool in a Northern Italian Climate

Green building technologies and design-correlated choices may significantly contribute to supporting the transition toward net energy flows in the built environment. Nevertheless, large discrepancies are underlined between standard simulated and monitored building behaviours requiring approaches able to simply correlate real building behaviours and simulated ones to further support coherent certification and/or optimization. The paper focusses on the application of a semi-automatic methodology to compare and evaluate thermal behaviours of buildings considering monitored and simulated data. The approach is based on a new Python tool developed by the authors, able to manage EnergyPlus inputs and perform multi-source KPIs calculations. The mentioned tool is used here to support semi-automatic model verifications of real weather data by optimizing model parameters to fit monitored behaviours. The approach is applied in this chapter to two demo buildings, a municipality school and a residential unit, located in the Turin metropolitan area of Piedmont, in Northwest Italy

Growth hormone nadir during oral glucose load depends on waist circumference, gender and age: normative data in 231 healthy subjects.

Objective  (i) To analyse the predictors of GH suppression after standard glucose load (oGTT) in the healthy population and (ii) to establish the 97th percentile of GH nadir post-oGTT according to these variables. Design  Analytical, retrospective. Measurements  GH nadir after oGTT. Subjects  Two hundred and thirty-one healthy subjects (113 women, 118 men 15-80 years) were studied. Results  The GH nadir after glucose load ranged from 0·01 (<assay detection limit) to 0·65 μg/l was higher in women and was inversely correlated with age, BMI, waist circumference, waist/hip, total cholesterol, triglycerides, basal and maximal glucose and basal insulin levels and directly correlated with basal GH levels, IGF-I SDS and HDL-cholesterol (P values ranging 0·004-<0·0001). On multistep regression analysis, the best predictors of nadir GH levels were waist circumference (t = -9·64, P < 0·0001), gender (t = -3·86, P = 0·0001) and age (t = -3·63, P = 0·0003). The results of comparative analysis among subjects grouped according to these variable showed different results in GH nadir in premenopausal women with waist circumference ≤88 cm (97th percentile 0·65 μg/l), in premenopausal women with waist circumference ≤88 cm and in men of any age with waist circumference ≤102 cm (97th percentile 0·33 μg/l) and in subjects of either gender and any age with waist circumference >88 cm in women and 102 cm in men (97th percentile 0·16 μg/l). Conclusions  The results of this study show that GH nadir after oGTT should be analysed according to gender, menopausal status and waist circumference. The GH cut-off should be limited to the assay used

A rare case of solitary brain Langerhans cell histiocytosis with intratumoral hemorrhage in a patient affected by Turner syndrome

Langerhans cell histiocytosis (LCH) is a rare disease involving clonal proliferation of cells with characteristics similar to bone marrow-derived Langerhans cells. The case of a young woman, affected by Turner syndrome and a solitary intraparenchymal LCH associated with an osteolytic lesion of the overlying skull, is presented

A novel mtDNA point mutation in tRNAVal is associated with hypertrophic cardiomyopathy and MELAS

Background. Pathological mutations of mitochondrial (mt) DNA may cause specific diseases such as cardiomyopathies or hearing loss, or syndromes such as mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episode (MELAS) syndrome. We describe a novel mtDNA mutation in a patient with severe hypertrophic cardiomyopathy associated with MELAS. The familial phenotype included 1) hypertrophic cardiomyopathy and MELAS, 2) clinically mild cardiac hypertrophy, and 3) deafness. Methods. The proband and her first degree relatives underwent echo and electrocardiograms, and biochemical tests. Magnetic resonance imaging of the brain was performed in the proband. mtDNA was fully analyzed by sequencing. DNA purification, polymerase chain reaction and direct automated sequencing were performed following standard procedures. Heteroplasmy of the novel mutation was quantified by densitometric analysis. Results. A novel G1644A transition affecting the tRNAVal was identified in the proband and maternal relatives. The mutation has been interpreted as pathological because the G at the 1644 position is a highly conserved base, is heteroplasmic with higher levels of mutant DNA in the proband than in the relatives, is located in the unique tRNAVal, is very close to a mutation described as causative of MELAS, and finally has not been found in 100 healthy controls. Conclusions. Although it is rare for patients with MELAS to be referred to cardiological evaluation because of coexisting cardiomyopathy, cardiologists should be aware of this association as well as of the non cardiac signs that may address the diagnosis to mtDNA defect-related disease in families with a variable phenotype. © 2004 CEPI Srl

Energy simulation platform supporting building design and management

The paper describes specific usage scenarios of an innovative platform, interfacing users, monitoring, and simulations for building energy simulations and the computation of key performance indicators to support, in an interoperable and open vision, design and management choices exploiting the enabling capabilities of ICT in architecture. The modularity of the proposed solution allows the development of pre-defined usage scenarios for professionals: impact of modifications in technological design choices, model calibration, and performance gap between simulated and monitored building data. The paper faces some new architectural usage scenarios of the tool, considering its enabling capabilities, and focuses on the tool’s components developed and tested in the EU H2020 E-DYCE project

Usability of a Hybrid System Combining P300-Based Brain-Computer Interface and Commercial Assistive Technologies to Enhance Communication in People With Multiple Sclerosis

Brain-computer interface (BCI) can provide people with motor disabilities with an alternative channel to access assistive technology (AT) software for communication and environmental interaction. Multiple sclerosis (MS) is a chronic disease of the central nervous system that mostly starts in young adulthood and often leads to a long-term disability, possibly exacerbated by the presence of fatigue. Patients with MS have been rarely considered as potential BCI end-users. In this pilot study, we evaluated the usability of a hybrid BCI (h-BCI) system that enables both a P300-based BCI and conventional input devices (i.e., muscular dependent) to access mainstream applications through the widely used AT software for communication "Grid 3." The evaluation was performed according to the principles of the user-centered design (UCD) with the aim of providing patients with MS with an alternative control channel (i.e., BCI), potentially less sensitive to fatigue. A total of 13 patients with MS were enrolled. In session I, participants were presented with a widely validated P300-based BCI (P3-speller); in session II, they had to operate Grid 3 to access three mainstream applications with (1) an AT conventional input device and (2) the h-BCI. Eight patients completed the protocol. Five out of eight patients with MS were successfully able to access the Grid 3 via the BCI, with a mean online accuracy of 83.3% (+/- 14.6). Effectiveness (online accuracy), satisfaction, and workload were comparable between the conventional AT inputs and the BCI channel in controlling the Grid 3. As expected, the efficiency (time for correct selection) resulted to be significantly lower for the BCI with respect to the AT conventional channels (Z = 0.2, p &lt; 0.05). Although cautious due to the limited sample size, these preliminary findings indicated that the BCI control channel did not have a detrimental effect with respect to conventional AT channels on the ability to operate an AT software (Grid 3). Therefore, we inferred that the usability of the two access modalities was comparable. The integration of BCI with commercial AT input devices to access a widely used AT software represents an important step toward the introduction of BCIs into the AT centers' daily practice

Autologous fibrin sealant (Vivostat®) in the neurosurgical practice: Part I: Intracranial surgical procedure

Background: Hemorrhages, cerebrospinal fluid (CSF) fistula and infections are the most challenging postoperative complications in Neurosurgery. In this study, we report our preliminary results using a fully autologous fibrin sealant agent, the Vivostat® system, in achieving hemostasis and CSF leakage repair during cranio-cerebral procedures. Methods: From January 2012 to March 2014, 77 patients were studied prospectively and data were collected and analyzed. Autologous fibrin sealant, taken from patient's blood, was prepared with the Vivostat® system and applied on the resection bed or above the dura mater to achieve hemostasis and dural sealing. The surgical technique, time to bleeding control and associated complications were recorded. Results: A total of 79 neurosurgical procedures have been performed on 77 patients. In the majority of cases (98%) the same autologous fbrin glue provided rapid hemostasis and dural sealing. No patient developed allergic reactions or systemic complications in association with its application. There were no cases of cerebral hematoma, swelling, infection, or epileptic seizures after surgery whether in the immediate or in late period follow-up. Conclusions: In this preliminary study, the easy and direct application of autologous fibrin sealant agent helped in controlling cerebral bleeding and in providing prompt and efficient dural sealing with resolution of CSF leaks. Although the use of autologous fibrin glue seems to be safe, easy, and effective, further investigations are strongly recommended to quantify real advantages and potential limitations