Hymenoptera venom allergy is an epidemiologically underestimated condition and a major cause of morbidity worldwide. Preventing future allergic reactions in patients who experience a systemic ...reaction is based on the correct management of the emergency followed by an accurate diagnosis, prescription of adrenaline autoinjectors, and, where indicated, specific venom immunotherapy. Some epidemiological studies highlight our poor knowledge of this disease and the frequent inadequacy of its management. Moreover, they emphasize the importance of such a life-saving treatment as specific immunotherapy. The availability of high-quality hymenoptera venom extracts for diagnostic and therapeutic use has dramatically improved the prognosis and quality of life of allergic patients. Subcutaneous venom immunotherapy is currently the most effective form of allergen-based immunotherapy, with a carry-over effect lasting up to several years after its interruption. This report on the management of hymenoptera venom-allergic children and adults was prepared by a panel of Italian experts. The main objective of this consensus document is to review the scientific evidence related to diagnosis, therapy, and management of patients allergic to hymenoptera venom. Thus, we can improve our knowledge of the disease and promote good clinical practices. The present document provides practical suggestions for correct diagnosis, prescription of emergency therapy and immunotherapy, and strategies for patient care.
New precision medicine therapies are urgently required for glioblastoma (GBM). However, to date, efforts to subtype patients based on molecular profiles have failed to direct treatment strategies. We ...hypothesised that interrogation of the GBM tumour microenvironment (TME) and identification of novel TME-specific subtypes could inform new precision immunotherapy treatment strategies.
A refined and validated microenvironment cell population (MCP) counter method was applied to >800 GBM patient tumours (GBM-MCP-counter). Specifically, partition around medoids (PAM) clustering of GBM-MCP-counter scores in the GLIOTRAIN discovery cohort identified three novel patient clusters, uniquely characterised by TME composition, functional orientation markers and immune checkpoint proteins. Validation was carried out in three independent GBM-RNA-seq datasets. Neoantigen, mutational and gene ontology analysis identified mutations and uniquely altered pathways across subtypes. The longitudinal Glioma Longitudinal AnalySiS (GLASS) cohort and three immunotherapy clinical trial cohorts treatment with neoadjuvant/adjuvant anti-programmed cell death protein 1 (PD-1) or PSVRIPO were further interrogated to assess subtype alterations between primary and recurrent tumours and to assess the utility of TME classifiers as immunotherapy biomarkers.
TMEHigh tumours (30%) displayed elevated lymphocyte, myeloid cell immune checkpoint, programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 transcripts. TMEHigh/mesenchymal+ patients featured tertiary lymphoid structures. TMEMed (46%) tumours were enriched for endothelial cell gene expression profiles and displayed heterogeneous immune populations. TMELow (24%) tumours were manifest as an ‘immune-desert’ group. TME subtype transitions upon recurrence were identified in the longitudinal GLASS cohort. Assessment of GBM immunotherapy trial datasets revealed that TMEHigh patients receiving neoadjuvant anti-PD-1 had significantly increased overall survival (P = 0.04). Moreover, TMEHigh patients treated with adjuvant anti-PD-1 or oncolytic virus (PVSRIPO) showed a trend towards improved survival.
We have established a novel TME-based classification system for application in intracranial malignancies. TME subtypes represent canonical ‘termini a quo’ (starting points) to support an improved precision immunotherapy treatment approach.
•Studying the IDHwt GBM tumour microenvironment (TME) transcriptome reveals three distinct GBM subtypes: TMEHigh, TMEMed, TMELow.•Novel TME subtypes are dynamic and evolve across primary and recurrent GBMs.•Interrogation of retrospective trial datasets suggest patient response to immunotherapies could be TME subtype specific.•TMEHigh, Med, Low GBMs manifest specific vulnerabilities which may direct novel combinatorial treatment strategies.•In the future, patient assignment to TME subtypes may support precision immunotherapy treatment in IDHwt GBM.
•The code structure is presented.•The performed validation is outlined.•Results are critically discussed assessing code accuracy.•Conclusions are drawn and ground for future work identified.
Liquid ...Metal cooled Fast Reactors, and notably Heavy Liquid Metal cooled systems, are promising options for achieving, in a relatively short term, the various advantages brought about by Small Modular Reactors (SMRs). To increase safety, natural circulation in the primary circuit to cool the core, even at rated power, is also considered, possibly bringing the core thermal exchange dynamics inside the mixed convection regime. To address, at the outset of the design process, thermal-hydraulics aspects, suitable tools must be employed, like the sub-channel code ANTEO+. ANTEO+ was, however, specifically built for the forced convection regime, trying to maximize modeling efficiency inside that regime; to make it applicable also for these SMRs concepts, its validity domain has been extended to the mixed convection regime. In this work, such extension process is outlined, presenting the new code structure, including the solved set of equations and models in the new anticipated application domain. A thorough validation for sub-channel and clad outer temperatures is also presented, confirming the ability of ANTEO+ in reproducing experimental data, homogeneously, in its new anticipated validity domain, with a relatively high degree of accuracy when compared to a reference tool like COBRA-IV-I-MIT. The need for Heavy Liquid Metal-cooled experiments dedicated to validation for sub-channel tools has also been highlighted so to greatly enhance confidence in the final code accuracy assessment, ultimately easing its use in the design phase.
The advancement of the design of the Advanced Lead-cooled Fast Reactor European Demonstrator (ALFRED) beyond the conceptual phase, passes through the analysis of the impact of uncertainties, notably ...to what concerns safety-related conditions. Compliancy of plant safety to Design Extension Conditions is, according to IAEA and in line with the meaning itself of these beyond-design conditions, usually investigated by best estimates only. Due however to the demonstration nature of ALFRED, it was decided to assess the actual safety performances of this system even in ultimate conditions. To this regard, the emphasis was put on unprotected events like the UTOP (unprotected transient of over-power) and ULOOP (unprotected loss of offsite power, resulting from the combination of a loss of flow and loss of heat sink under unprotected conditions), pinpointed as the most challenging situations sought for the plant. The purpose of the present work, which has been divided in three parts, was then to assess the ultimate ALFRED safety margins against failure of the key core components and systems (Part III). To target this objective, the evaluation of uncertainties coming, on one hand, from nuclear data was performed at first, to retrieve their impact on the reactivity coefficients, thereby on the transient behavior driven by the latter (Part I); then, uncertainties from material properties, fabrication procedures, operation and measurement, and computational tools were propagated to assess their influence on the thermal-hydraulics of the system (Part II). In this work the efforts of Parts I and II are merged together and the effect of uncertainties on safety margins and salient parameters assessed. The retrieved uncertainties are propagated to the expected number of pins experiencing fuel melting during an UTOP and to the clad time-to-failure during an ULOOP. The former has been found to be quite affected by uncertainties, but still under limits not directly posing hazards to the people and the environment, even when extremely conservative assumptions are put forward; the latter shows a milder response to uncertainties, but always guaranteeing more than an order of magnitude of safety margin relative to WENRA recommendations.
•The general objectives and rationales for stress-testing the ALFRED design are presented.•A summary of the uncertainty quantification results of previous Parts is presented.•The methodology for propagating uncertainties on safety margins during the UTOP and ULOOP is explained.•Results are presented and discussed.
Automation synthesis modules review Boschi, S.; Lodi, F.; Malizia, C. ...
Applied radiation and isotopes,
June 2013, 2013-Jun, 2013-6-00, 20130601, Letnik:
76
Journal Article
Recenzirano
The introduction of 68Ga labelled tracers has changed the diagnostic approach to neuroendocrine tumours and the availability of a reliable, long-lived 68Ge/68Ga generator has been at the bases of the ...development of 68Ga radiopharmacy. The huge increase in clinical demand, the impact of regulatory issues and a careful radioprotection of the operators have boosted for extensive automation of the production process. The development of automated systems for 68Ga radiochemistry, different engineering and software strategies and post-processing of the eluate were discussed along with impact of automation with regulations.
► Generators availability and robust chemistry boosted for the huge diffusion of 68Ga radiopharmaceuticals. ► Different technological approaches for 68Ga radiopharmaceuticals will be discussed. ► Generator eluate post processing and evolution to cassette based systems were the major issues in automation. ► Impact of regulations on the technological development will be also considered.
The role of mechanical ventilation and catheters in favouring Acinetobacter baumannii infections needs to be better understood. This study evaluated the adherence of 19 isolates of different hospital ...clusters of A. baumannii to abiotic surfaces and epithelial cells (HEp‐2). Of the hydrophobic isolates, 80% adhered to polystyrene, indicating a close relationship between hydrophobicity and adherence. All isolates adhered to epithelial cells to different degrees, and 73·7% showed an aggregated pattern. Analysis of the serum resistance of catheter‐tip isolates showed that all were resistant. These worrisome results showed that the high capacity of A. baumannii to adhere to surfaces and survive in human serum could hinder treatment and control of this pathogen.
Significance and Impact of the Study: Acinetobacter baumannii can colonize inpatients and health workers. The ability to survive in hostile environments allows this bacterium to persist in intensive care units, causing serious infections with high mortality. This study describes, for the first time, the aggregated adherence pattern of a majority of A. baumannii isolates to human epithelial cells, which can favour human colonization. The bacterium was also able to adhere to polystyrene in medical devices and escape the host's defence responses. We believe that this information can help to understand certain factors in the virulence of A. baumannii, enabling its control.
Data about food-induced anaphylaxis in Italy are missing.
It was the aim of this study to detect the main foods/food allergens causing anaphylaxis in Italy.
The frequency of anaphylaxis and the ...relative importance of many offending foods were assessed in 1,110 adult patients with food allergy diagnosed by common criteria at 19 allergy centres scattered throughout Italy from 1 January to 31 December 2007.
Fifty-eight of 1,110 (5%) food-allergic patients experienced at least 1 episode of anaphylaxis. On average, they were older than other food-allergic patients (34 vs. 31 years; p < 0.05). The majority of anaphylactic episodes occurred in patients sensitized to lipid transfer protein (LTP; n = 19), followed by shrimp (n = 10), tree nuts (n = 9), legumes other than peanut (n = 4), and seeds (n = 2); peanut, spinach, celery, buckwheat, wheat, avocado, tomato, fish, meat, and Anisakis caused an anaphylactic reaction in single patients. Among LTP-hypersensitive patients, peach caused 13/19 anaphylactic episodes. Shrimp-allergic patients were significantly older than other patients with food-induced anaphylaxis (p < 0.05), whereas patients allergic to LTP experienced their anaphylactic episodes at a younger age (p < 0.001). The frequency of anaphylaxis among patients sensitized to LTP, shrimp or tree nuts did not differ between northern and central/southern Italy.
LTP is the most important allergen causing food-induced anaphylaxis in Italy, peach being the most frequently offending food. Peanut-induced anaphylaxis seems very uncommon. Geographic and environmental differences both between Italy and other countries and within Italy seem to play a relevant role in the pattern of sensitization to foods.
Abstract Introduction The fine detection of 11-nor-Δ9-tetrahydrocannabinol-9-carboxylic acid (THCCOOH) in hair matrix remains one of the most important topics in hair analysis. This relevance lies in ...the necessity to obtain evidence of effective drug consumption and dispel any doubt of environmental contamination. THCCOOH is the highest and mainly represented Δ9-THC metabolite, but its concentration in hair is very low. A sensitive method for quantitative determination of THCCOOH in hair was developed. As first step, the method was tested with different SPE/LLE conditions, but the best results were obtained with a simple ad hoc LLE extraction. The final method was fully validated, evaluating parameters like extraction recovery, linearity, specificity and sensitivity. More than one hundred hair samples were then analyzed with the validated method. Data analysis was performed so as to determine respective concentrations of the metabolite and active molecule. Methods Hair was washed and cut into small pieces (2–4 mm). Samples (20–50 mg) were spiked with deuterated internal standard (THC-d3 and THCCOOH-d3 ) and then hydrolyzed at 90 °C in 1 mL of 1 M NaOH for 15 min. THC was isolated by a LLE basic extraction with n-hexane:ethyl acetate (9:1). Next the aqueous solution was acidified (pH 4) adding concentrated acetic acid. THCCOOH was extracted with the same mixture. Dried extracts were derivatized with pentafluoropropionic anhydride and hexafluoroisopropanol and analyzed by GC/MS/MS (Agilent 7000B triple quadrupole) in NCI mode. Results The linear range of THCCOOH is 0.1–5 pg/mg, with good correlation coefficients ( r2 > 0.9993). This method has great sensitivity (LOD 0.01 pg/mg to LOQ 0.04 pg/mg), high recovery, reproducibility and robustness. Conclusions Based on these results, the method proved to be effective for the rapid determination of THC and THCCOOH in hair specimens.
Introduction: The fine detection of 11-nor- Delta 9-tetrahydrocannabinol-9-carboxylic acid (THCCOOH) in hair matrix remains one of the most important topics in hair analysis. This relevance lies in ...the necessity to obtain evidence of effective drug consumption and dispel any doubt of environmental contamination. THCCOOH is the highest and mainly represented Delta 9-THC metabolite, but its concentration in hair is very low. A sensitive method for quantitative determination of THCCOOH in hair was developed. As first step, the method was tested with different SPE/LLE conditions, but the best results were obtained with a simple ad hoc LLE extraction. The final method was fully validated, evaluating parameters like extraction recovery, linearity, specificity and sensitivity. More than one hundred hair samples were then analyzed with the validated method. Data analysis was performed so as to determine respective concentrations of the metabolite and active molecule. Methods: Hair was washed and cut into small pieces (2-4 mm). Samples (20-50 mg) were spiked with deuterated internal standard (THC-d3 and THCCOOH-d3) and then hydrolyzed at 90 degree C in 1 mL of 1 M NaOH for 15 min. THC was isolated by a LLE basic extraction with n-hexane: ethyl acetate (9: 1). Next the aqueous solution was acidified (pH 4) adding concentrated acetic acid. THCCOOH was extracted with the same mixture. Dried extracts were derivatized with pentafluoropropionic anhydride and hexafluoroisopropanol and analyzed by GC/MS/MS (Agilent 7000B triple quadrupole) in NCI mode. Results: The linear range of THCCOOH is 0.1-5 pg/mg, with good correlation coefficients (r2 > 0.9993). This method has great sensitivity (LOD 0.01 pg/mg to LOQ 0.04 pg/mg), high recovery, reproducibility and robustness. Conclusions: Based on these results, the method proved to be effective for the rapid determination of THC and THCCOOH in hair specimens.
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