Scaling Properties of Atmospheric Wind Speed in Mesoscale Range

The scaling properties of turbulent flows are well established in the inertial sub-range. However, those of the synoptic-scale motions are less known, also because of the difficult analysis of data presenting nonstationary and periodic features. Extensive analysis of experimental wind speed data, collected at the Mauna Loa Observatory of Hawaii, is performed using different methods. Empirical Mode Decomposition, interoccurrence times statistics, and arbitrary-order Hilbert spectral analysis allow to eliminate effects of large-scale modulations, and provide scaling properties of the field fluctuations (Hurst exponent, interoccurrence distribution, and intermittency correction). The obtained results suggest that the mesoscale wind dynamics owns features which are typical of the inertial sub-range turbulence, thus extending the validity of the turbulent cascade phenomenology to scales larger than observed before

Knowledge translation in challenging healthcare environments: The PIOPPO experience at the National Centre of Oncological Hadrontherapy (CNAO Foundation).

Knowledge translation is the ability to translate concepts and ideas effectively among different stakeholders, leading to innovation and new knowledge. Translating knowledge is particularly challenging in the healthcare sector, which has been experiencing a shift from a centralized and sequential model of value creation to a more distributed and open model, where various stakeholders (including patients) act as co-creators of the outcome. According to management as well as the medical literature, knowledge translation in healthcare has been mainly seen as the translation of scientific research into clinical practice. However, different types of knowledge translation emerge, such as when multidisciplinary teams need to work together on a joint medical project. In this situation, multiple backgrounds, competencies, skills, and emotional feelings of the different stakeholders are a compelling barrier that prevents the effective transfer and sharing of knowledge. This is why knowledge translation needs a set of enablers to facilitate the transfer, sharing, and creation of new knowledge, innovation, and ideas. This paper investigates such a perspective by analyzing the PIOPPO project from the National Centre of Oncological Hadrontherapy (CNAO Foundation) in Pavia, Italy. The CNAO is one of the few dual-beam Hadrontherapy centres in the world that provides a beam that is able to irradiate patients with protons or carbon ions to treat radioresistant tumours. The PIOPPO project is an experimental phase 2 trial involving preoperative chemotherapy and carbon ion therapy to treat resectable and borderline-resectable pancreatic adenocarcinoma. The stakeholders involved in the PIOPPO trial have different characteristics, both in terms of competencies and emotions. The PIOPPO multidisciplinary team includes highly skilled professionals from several disciplines, which are not all related to medicine (from oncologists to physicists, from biologists to surgeons). Pancreatic cancer patients are also involved while experiencing a challenging personal time. The paper analyses the knowledge translation flows, instruments, and issues among such different stakeholders

Brainstem NTCP and dose constraints for carbon ion RT—Application and translation from Japanese to European RBE-weighted dose

Background and Purpose: The Italian National Center of Oncological Hadrontherapy (CNAO) has applied dose constraints for carbon ion RT (CIRT) as defined by Japan’s National Institute of Radiological Sciences (NIRS). However, these institutions use different models to predict the relative biological effectiveness (RBE). CNAO applies the Local Effect Model I (LEM I), which in most clinical situations predicts higher RBE than NIRS’s Microdosimetric Kinetic Model (MKM). Equal constraints therefore become more restrictive at CNAO. Tolerance doses for the brainstem have not been validated for LEM I-weighted dose (DLEM I). However, brainstem constraints and a Normal Tissue Complication Probability (NTCP) model were recently reported for MKM-weighted dose (DMKM), showing that a constraint relaxation to DMKM|0.7 cm3 <30 Gy (RBE) and DMKM|0.1 cm3 <40 Gy (RBE) was feasible. The aim of this work was to evaluate the brainstem NTCP associated with CNAO’s current clinical practice and to propose new brainstem constraints for LEM I-optimized CIRT at CNAO. Material and Methods: We reproduced the absorbed dose of 30 representative patient treatment plans from CNAO. Subsequently, we calculated both DLEM I and DMKM, and the relationship between DMKM and DLEM I for various brainstem dose metrics was analyzed. Furthermore, the NTCP model developed for DMKM was applied to estimate the NTCPs of the delivered plans. Results: The translation of CNAO treatment plans to DMKM confirmed that the former CNAO constraints were conservative compared with DMKM constraints. Estimated NTCPs were 0% for all but one case, in which the NTCP was 2%. The relationship DMKM/DLEM I could be described by a quadratic regression model which revealed that the validated DMKM constraints corresponded to DLEM I|0.7 cm3 <41 Gy (RBE) (95% CI, 38–44 Gy (RBE)) and DLEM I|0.1 cm3 <49 Gy (RBE) (95% CI, 46–52 Gy (RBE)). Conclusion: Our study demonstrates that RBE-weighted dose translation is of crucial importance in order to exchange experience and thus harmonize CIRT treatments globally. To mitigate uncertainties involved, we propose to use the lower bound of the 95% CI of the translation estimates, i.e., DLEM I|0.7 cm3 <38 Gy (RBE) and DLEM I|0.1 cm3 <46 Gy (RBE) as brainstem dose constraints for 16 fraction CIRT treatments optimized with LEM I.publishedVersio

Gain-of-function defects of astrocytic Kir4.1 channels in children with autism spectrum disorders and epilepsy

Dysfunction of the inwardly-rectifying potassium channels Kir4.1 (KCNJ10) represents a pathogenic mechanism contributing to Autism-Epilepsy comorbidity. To define the role of Kir4.1 variants in the disorder, we sequenced KCNJ10 in a sample of affected individuals, and performed genotype-phenotype correlations. The effects of mutations on channel activity, protein trafficking, and astrocyte function were investigated in Xenopus laevis oocytes, and in human astrocytoma cell lines. An in vivo model of the disorder was also explored through generation of kcnj10a morphant zebrafish overexpressing the mutated human KCNJ10. We detected germline heterozygous KCNJ10 variants in 19/175 affected children. Epileptic spasms with dysregulated sensory processing represented the main disease phenotype. When investigated on astrocyte-like cells, the p.R18Q mutation exerted a gain-of-function effect by enhancing Kir4.1 membrane expression and current density. Similarly, the p.R348H variant led to gain of channel function through hindrance of pH-dependent current inhibition. The frequent polymorphism p.R271C seemed, instead, to have no obvious functional effects. Our results confirm that variants in KCNJ10 deserve attention in autism-epilepsy, and provide insight into the molecular mechanisms of autism and seizures. Similar to neurons, astrocyte dysfunction may result in abnormal synaptic transmission and electrical discharge, and should be regarded as a possible pharmacological target in autism-epilepsy. Supplementary information accompanies this paper in the files section.peer-reviewe

Pattern of care for re-irradiation in locally recurrent rectal cancer: a national survey on behalf of the AIRO gastrointestinal tumors study group

PurposeRadical resection (R0) represents the best curative treatment for local recurrence (LR) rectal cancer. Re-irradiation (re-RT) can increase the rate of R0 resection. Currently, there is a lack of guidelines on Re-RT for LR rectal cancer. The Italian Association of Radiation and clinical oncology for gastrointestinal tumors (AIRO-GI) study group released a national survey to investigate the current clinical practice of external beam radiation therapy in these patients.Material and methodsIn February 2021, the survey was designed and distributed to members of the GI working group. The questionnaire consisted of 40 questions regarding center characteristics, clinical indications, doses, and treatment techniques of re-RT for LR rectal cancer.ResultsA total of 37 questionnaires were collected. Re-RT was reported as an option for neoadjuvant treatment in resectable and unresectable disease by 55% and 75% of respondents, respectively. Long-course treatment with 30-40 Gy (1.8-2 Gy/die, 1.2 Gy bid) and hypofractionated regimen of 30-35 Gy in 5 fractions were used in most centers. A total dose of 90-100 Gy as EqD2 dose (& alpha;/& beta; = 5 Gy) was delivered by 46% of the respondents considering the previous treatment. Modern conformal techniques and daily image-guided radiation therapy protocols were used in 94% of centers.ConclusionOur survey showed that re-RT treatment is performed with advanced technology that allow a good management of LR rectal cancer. Significant variations were observed in terms of dose and fractionation, highlighting the need for a consensus on a common treatment strategy that could be validated in prospective studies

Online proton therapy monitoring: Clinical test of a Silicon-photodetector-based in-beam PET

Particle therapy exploits the energy deposition pattern of hadron beams. The narrow Bragg Peak at the end of range is a major advantage but range uncertainties can cause severe damage and require online verification to maximise the effectiveness in clinics. In-beam Positron Emission Tomography (PET) is a non-invasive, promising in-vivo technique, which consists in the measurement of the β+ activity induced by beam-tissue interactions during treatment, and presents the highest correlation of the measured activity distribution with the deposited dose, since it is not much influenced by biological washout. Here we report the first clinical results obtained with a state-of-the-art in-beam PET scanner, with on-the-fly reconstruction of the activity distribution during irradiation. An automated time-resolved quantitative analysis was tested on a lacrimal gland carcinoma case, monitored during two consecutive treatment sessions. The 3D activity map was reconstructed every 10 s, with an average delay between beam delivery and image availability of about 6 s. The correlation coefficient of 3D activity maps for the two sessions (above 0.9 after 120 s) and the range agreement (within 1 mm) prove the suitability of in-beam PET for online range verification during treatment, a crucial step towards adaptive strategies in particle therapy

Localization of anatomical changes in patients during proton therapy with in-beam PET monitoring: a voxel-based morphometry approach exploiting Monte Carlo simulations

Purpose: In-beam positron emission tomography (PET) is one of the modalities that can be used for in vivo noninvasive treatment monitoring in proton therapy. Although PET monitoring has been frequently applied for this purpose, there is still no straightforward method to translate the information obtained from the PET images into easy-to-interpret information for clinical personnel. The purpose of this work is to propose a statistical method for analyzing in-beam PET monitoring images that can be used to locate, quantify, and visualize regions with possible morphological changes occurring over the course of&nbsp;treatment. Methods: We selected a patient treated for squamous cell carcinoma (SCC) with proton therapy, to perform multiple Monte Carlo (MC) simulations of the expected PET signal at the start of treatment, and to study how the PET signal may change along the treatment course due to morphological changes. We performed voxel-wise two-tailed statistical tests of the simulated PET images, resembling the voxel-based morphometry (VBM) method commonly used in neuroimaging data analysis, to locate regions with significant morphological changes and to quantify the&nbsp;change. Results: The VBM resembling method has been successfully applied to the simulated in-beam PET images, despite the fact that such images suffer from image artifacts and limited statistics. Three dimensional probability maps were obtained, that allowed to identify interfractional morphological changes and to visualize them superimposed on the computed tomography (CT) scan. In particular, the characteristic color patterns resulting from the two-tailed statistical tests lend themselves to trigger alarms in case of morphological changes along the course of&nbsp;treatment. Conclusions: The statistical method presented in this work is a promising method to apply to PET monitoring data to reveal interfractional morphological changes in patients, occurring over the course of treatment. Based on simulated in-beam PET treatment monitoring images, we showed that with our method it was possible to correctly identify the regions that changed. Moreover we could quantify the changes, and visualize them superimposed on the CT scan. The proposed method can possibly help clinical personnel in the replanning procedure in adaptive proton therapy treatments

In-vivo range verification analysis with in-beam PET data for patients treated with proton therapy at CNAO

Morphological changes that may arise through a treatment course are probably one of the most significant sources of range uncertainty in proton therapy. Non-invasive in-vivo treatment monitoring is useful to increase treatment quality. The INSIDE in-beam Positron Emission Tomography (PET) scanner performs in-vivo range monitoring in proton and carbon therapy treatments at the National Center of Oncological Hadrontherapy (CNAO). It is currently in a clinical trial (ID: NCT03662373) and has acquired in-beam PET data during the treatment of various patients. In this work we analyze the in-beam PET (IB-PET) data of eight patients treated with proton therapy at CNAO. The goal of the analysis is twofold. First, we assess the level of experimental fluctuations in inter-fractional range differences (sensitivity) of the INSIDE PET system by studying patients without morphological changes. Second, we use the obtained results to see whether we can observe anomalously large range variations in patients where morphological changes have occurred. The sensitivity of the INSIDE IB-PET scanner was quantified as the standard deviation of the range difference distributions observed for six patients that did not show morphological changes. Inter-fractional range variations with respect to a reference distribution were estimated using the Most-Likely-Shift (MLS) method. To establish the efficacy of this method, we made a comparison with the Beam's Eye View (BEV) method. For patients showing no morphological changes in the control CT the average range variation standard deviation was found to be 2.5&nbsp;mm with the MLS method and 2.3&nbsp;mm with the BEV method. On the other hand, for patients where some small anatomical changes occurred, we found larger standard deviation values. In these patients we evaluated where anomalous range differences were found and compared them with the CT. We found that the identified regions were mostly in agreement with the morphological changes seen in the CT scan

Cholangiocarcinoma: A position paper by the Italian Society of Gastroenterology (SIGE), the Italian Association of Hospital Gastroenterology (AIGO), the Italian Association of Medical Oncology (AIOM) and the Italian Association of Oncological Radiotherapy (AIRO)

The incidence of Cholangiocellular carcinoma (CCA) is increasing, due to a sharp increase of the intrahepatic form. Evidence-ascertained risk factors for CCA are primary sclerosing cholangitis, Opistorchis viverrini infection, Caroli disease, congenital choledocal cist, Vater ampulla adenoma, bile duct adenoma and intra-hepatic lithiasis. Obesity, diabetes, smoking, abnormal biliary-pancreatic junction, bilio-enteric surgery, and viral cirrhosis are emerging risk factors, but their role still needs to be validated. Patients with primary sclerosing cholangitis should undergo surveillance, even though a survival benefit has not been clearly demonstrated. CCA is most often diagnosed in an advanced stage, when therapeutic options are limited to palliation. Diagnosis of the tumor is often difficult and multiple imaging techniques should be used, particularly for staging. Surgery is the standard of care for resectable CCA, whilst liver transplantation should be considered only in experimental settings. Metal stenting is the standard of care in inoperable patients with an expected survival >4 months. Gemcitabine or platinum analogues are recommended in advanced CCA whilst there are no validated neo-adjuvant treatments or second-line chemotherapies. Even though promising results have been obtained in CCA with radiotherapy, further randomized controlled trials are needed. (C) 2010 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved

Evolution of Turbulence in the Kelvin-Helmholtz Instability in the Terrestrial Magnetopause

The dynamics occurring at the terrestrial magnetopause are investigated by using Geotail and THEMIS spacecraft data of magnetopause crossings during ongoing Kelvin–Helmholtz instability. Properties of plasma turbulence and intermittency are presented, with the aim of understanding the evolution of the turbulence as a result of the development of Kelvin–Helmholtz instability. The data have been tested against standard diagnostics for intermittent turbulence, such as the autocorrelation function, the spectral analysis and the scale-dependent statistics of the magnetic field increments. A quasi-periodic modulation of different scaling exponents may exist along the direction of propagation of the Kelvin–Helmholtz waves along the Geocentric Solar Magnetosphere coordinate system (GSM), and it is visible as a quasi-periodic modulation of the scaling exponents we have studied. The wave period associated with such oscillation was estimated to be approximately 6.4 Earth Radii ( R E ). Furthermore, the amplitude of such modulation seems to decrease as the measurements are taken further away from the Earth along the magnetopause, in particular after X ( G S M ) ≲ − 15 R E . The observed modulation seems to persist for most of the parameters considered in this analysis. This suggests that a kind of signature related to the development of the Kelvin–Helmholtz instabilities could be present in the statistical properties of the magnetic turbulence