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Burning rate plays a crucial role in determining the performance of solid rocket motors (SRMs). In the traditional approach for solid propellant propulsion, technical activities regarding burning rates are developed at three different operational levels: (i) Strand burners or laboratory-scale devices in general; (ii) Small-scale motors (SSMs); And (iii) full-size or end-item rocket motors. While strand burners are extensively used for propellant development (formulation exploration, ingredients screening, performance verification, and production control) and relatively little is done experimentally at the full-size motor level (being large-scale experimentation too expensive and dangerous), a lot is usually carried out at SSM level to obtain burning rate information under motor operating conditions. In the introductory part of this work, burning rate fundamentals are recalled and burning rate measurement devices are quickly summarized. Then, a survey of subscale motors is conducted and several automated procedures to deduce burning rate from SSM testing are analyzed. Data reduction methods commonly used by leading European companies are based on the thickness-over-time (TOT) definition. Attention is dedicated to procedures used in Italy and France for quality control of the European space launchers (solid propellant boosters of Ariane family and core solid rocket motors of VEGA family). In addition, automated data reduction methods based on mass balance (MB) and often used in USA are investigated. Specific features and general trends of the tested industrial procedures are pointed out. Since for any tests the actual burning rates are unknown, results can only be compared based on the statistical quality of the deduced ballistic data. Mainly reproducibility, ease of application, and suitability for automated computer implementation are of interest to industrial users. The effects of test variability, input data quality, and data reduction methods on result reproducibility are discussed with reference to fire tests of the successful Ariane-5 solid boosters. The systematic analysis of industrial data conducted in this work suggests that improving the actual mix reproducibility and quality of experimental data is more important than perfecting the current data reduction methods. Moreover, the international trends suggest that the fundamental TOT procedures are being replaced by MB procedures or advanced TOT procedures with burning times evaluated using pressure integrals.

Background and purposeClinical outcomes of multiple sclerosis (MS) patients affected by coronavirus disease 2019 (COVID-19) have been thoroughly investigated, but a further analysis on main signs and symptoms and their risk factors still needs attention. The objective of this study was to group together and describe based on similarity the most common signs and symptoms of COVID-19 in MS patients and identify all factors associated with their manifestation.MethodLogistic and linear regression models were run to recognize factors associated with each pooled group of symptoms and their total number.ResultsFrom March 2020 to November 2021, data were collected from 1354 MS patients with confirmed infection of COVID-19. Ageusia and anosmia was less frequent in older people (odds ratio [OR] 0.98; p = 0.005) and more in smoker patients (OR 1.39; p = 0.049). Smoke was also associated with an incremental number of symptoms (OR 1.24; p = 0.031), substance abuse (drugs or alcohol), conjunctivitis and rash (OR 5.20; p = 0.042) and the presence of at least one comorbidity with shortness of breath, tachycardia or chest pain (OR 1.24; p = 0.008). Some disease-modifying therapies were associated with greater frequencies of certain COVID-19 symptoms (association between anti-CD20 therapies and increment in the number of concomitant symptoms: OR 1.29; p = 0.05). Differences in frequencies between the three waves were found for flu-like symptoms (G1, p = 0.024), joint or muscle pain (G2, p = 0.013) and ageusia and anosmia (G5, p

Background and purposeSome studies have shown that air pollution, often assessed by thin particulate matter with diameter below 2.5 µg/m3 (PM2.5), may contribute to severe COVID-19 courses, as well as play a role in the onset and evolution of multiple sclerosis (MS). However, the impact of air pollution on COVID-19 has never been explored specifically amongst patients with MS (PwMS). This retrospective observational study aims to explore associations between PM2.5 and COVID-19 severity amongst PwMS.MethodsData were retrieved from an Italian web-based platform (MuSC-19) which includes PwMS with COVID-19. PM2.5 2016-2018 average concentrations were provided by the Copernicus Atmospheric Monitoring Service. Italian patients inserted in the platform from 15 January 2020 to 9 April 2021 with a COVID-19 positive test were included. Ordered logistic regression models were used to study associations between PM2.5 and COVID-19 severity.ResultsIn all, 1087 patients, of whom 13% required hospitalization and 2% were admitted to an intensive care unit or died, were included. Based on the multivariate analysis, higher concentrations of PM2.5 increased the risk of worse COVID-19 course (odds ratio 1.90; p = 0.009).ConclusionsEven if several other factors explain the unfavourable course of COVID-19 in PwMS, the role of air pollutants must be considered and further investigated.

Summary: Background: Atypical cartilaginous tumour (ACT) and high-grade chondrosarcoma (CS) of long bones are respectively managed with active surveillance or curettage and wide resection. Our aim was to determine diagnostic performance of X-rays radiomics-based machine learning for classification of ACT and high-grade CS of long bones. Methods: This retrospective, IRB-approved study included 150 patients with surgically treated and histology-proven lesions at two tertiary bone sarcoma centres. At centre 1, the dataset was split into training (n = 71 ACT, n = 24 high-grade CS) and internal test (n = 19 ACT, n = 6 high-grade CS) cohorts, respectively, based on the date of surgery. At centre 2, the dataset constituted the external test cohort (n = 12 ACT, n = 18 high-grade CS). Manual segmentation was performed on frontal view X-rays, using MRI or CT for preliminary identification of lesion margins. After image pre-processing, radiomic features were extracted. Dimensionality reduction included stability, coefficient of variation, and mutual information analyses. In the training cohort, after class balancing, a machine learning classifier (Support Vector Machine) was automatically tuned using nested 10-fold cross-validation. Then, it was tested on both the test cohorts and compared to two musculoskeletal radiologists' performance using McNemar's test. Findings: Five radiomic features (3 morphology, 2 texture) passed dimensionality reduction. After tuning on the training cohort (AUC = 0.75), the classifier had 80%, 83%, 79% and 80%, 89%, 67% accuracy, sensitivity, and specificity in the internal (temporally independent) and external (geographically independent) test cohorts, respectively, with no difference compared to the radiologists (p ≥ 0.617). Interpretation: X-rays radiomics-based machine learning accurately differentiates between ACT and high-grade CS of long bones. Funding: AIRC Investigator Grant.

IntroductionGiven its profound and transversal impact, the COVID-19 pandemic in 2020 marked a deep point of division in how people make sense of the world and their lives. The consequences of this event were remarkable, especially for populations already facing vulnerability, exclusion, and discrimination. In Italy, over 3 million people (5.2% of the entire population) have a disability due to health issues or severe limitations that prevent them from performing daily activities. Although the COVID-19 health emergency aggravated and amplified these problems, research and studies investigating the incidence of psychological distress and the role of psychological resources for people with disabilities in the aftermath of the pandemic are still to be implemented. For these reasons, the Department of Psychology conducted a study on behalf of the Italian Government to assess the impacts of the COVID-19 pandemic on the social, psychological, and economic wellbeing of Italians with disabilities.MethodsThe aim was to assess the consequences of the pandemic on this population, especially the impacts related to the lockdowns and preventive measures, and to evaluate the protective role that could be played by psychological resources such as resilience, future orientation, and career adaptability in a Life Design perspective. With the collaboration of local, regional, and national associations for people with disability, an anonymous, online self-report questionnaire was distributed to 403 persons with disabilities in Italy.ResultsResults showed a strong relationship between the levels of psychological resources and life satisfaction during the COVID-19 pandemic.DiscussionIn line with studies in international literature regarding the effects of the COVID-19 pandemic on people with disabilities, this research highlights the extension of this period’s impacts on this population’s psychological wellbeing. Moreover, this study amplifies the urgent call for action and research in promoting Life Design psychological resources, given their positive and protective role in preserving and increasing people’s wellbeing.

BackgroundThe debate on how to manage women affected by multiple sclerosis (MS) during reproductive age is still open, as is the issue of fertility in such patients. Main issue regard the identification of the optimal window for pregnancy and how to deal with medical therapy before and during conception. The aim of this Delphi consensus was to collect the opinions of a multidisciplinary group, involving reproductive medicine specialists and neurologists with experience in the management of multiple sclerosis women with reproductive desire.MethodsFour experts plus scientific coordinators developed a questionnaire distributed online to 10 neurologists and later discussed the responses and amended a list of statements. The statements were then distributed via an online survey to 23 neurologists (comprising the first 10), who voted on their level of agreement/disagreement with each statement. Consensus was achieved if agreement or disagreement with a statement exceeded 66%.ResultsTwenty-one statements reached consensus after two rounds of voting, leading to the following main recommendations: (1) Fertility evaluation should be suggested to wMS, in case of the need to shorten time to pregnancy and before treatment switch in women on DMTs contraindicated in pregnancy, particularly in case of highly active disease and age > 35 years. (2) ART should not be discouraged in wMS, but the use of DMTs until pregnancy confirmation should be suggested; ART may be considered in order to reduce time to pregnancy in MS women with a reduced ovarian reserve and/or age > 35 years, but in case of an expected poor ART prognosis and the need for more than one ART cycle, a switch to a high-efficacy DMD before ART should be offered. (3) Oocyte cryopreservation may be considered in women with reduced ovarian reserve, with unpredictable time to complete diagnostic workup and achieve disease control; a risk/cost–benefit analysis must be performed in women >35 years, considering the diminished ovarian reserve.ConclusionThis consensus will help MS neurologists to support family planning in wMS, respecting MS therapeutic needs while also taking into account the safety and impact of advancing age on fertility.

ObjectiveThe addition of cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) to endocrine therapy impressively improved the outcome of patients with hormone receptor-positive metastatic breast cancer. Despite their great efficacy, not all patients respond to treatment and many of them develop acquired resistance. The aim of this retrospective study was to assess the role of [18F]-FDG PET/CT in predicting PFS and OS in breast cancer patients treated with CDK4/6i.Methods114 patients who performed an [18F]-FDG PET/CT scan before (PET1) and 2-6 months (PET2) after starting treatment were retrospectively enrolled. Metabolic response was evaluated by EORTC, PERCIST and Deauville Score and correlated to PFS and OS.ResultsIn patients who did not progress at PET2 (n = 90), PFS rates were not significantly different between classes of response by EORTC and PERCIST. Conversely, patients showing a Deauville score ≤3 had a longer PFS (median PFS 42 vs 21.0 months; p = 0.008). A higher total metabolic tumor volume at PET1 (TMTV1) was also associated with a shorter PFS (median 18 vs 42 months; p = 0.0026). TMTV1 and Deauville score were the only independent prognostic factors for PFS at multivariate analysis and their combination stratified the population in four definite classes of relapse risk. Conversely, the above parameters did not affect OS which was only influenced by a progressive metabolic disease at PET2 (3-years survival rate 29.8 vs 84.9%; p

Nowadays, society is characterized by enormous and rapid changes, erratic careers, gender discrimination, injustices, and inequities. Discrimination includes professional and educational segregation, the gender pay gap, stereotypical gender roles, and social expectations. In this context, phenomena called low fertility and fertility gap are increasing. Indeed, the birth rate necessary to ensure the replacement of the population is not reached, with severe repercussions at a social, environmental, and economic level. This study aimed to investigate 835 women’s perceptions of the desire for motherhood and the associated difficulties. Hierarchical multiple regression and thematic decomposition analyses first highlight a significant difference between the number of children women realistically plan and the ideal number of children they would like. Secondly, the results showed how the parenthood choice is connected to the perception of social and gender inequity. Finally, in a Life Design perspective, preventive actions will be described to support women to get back to the center of life choices, building dignified fair paths and family projects.

ABSTRACT: Objectives: The aim of this study was to evaluate the impact of resistance mutations on efficacy of dolutegravir-based two-drug regimens (2DR). Methods: Virologically suppressed patients with HIV-1 switching to dolutegravir + lamivudine or rilpivirine or to a dolutegravir-based three-drug regimen (3DR) with pre-baseline genotype were selected. Virological failure (VF) was defined as one HIV-RNA viral load (VL) >200 cps/mL or two consecutive VL >50 cps/mL; treatment failure (TF) was defined as VF or treatment discontinuation (TD). Resistance was defined as at least low-level resistance to at least one drug of the current regimen. Propensity score matching was used to conduct adjusted analyses within a competing risks framework. Results: A total of 971 dolutegravir-based regimens were selected: 339 (34.9%) 2DR and 632 (65.1%) 3DR. The adjusted cumulative 48-week incidence of VF was 4.2% (90% CI 3.1%–5.3%) with 2DR and 4.7% (90% CI 3.5%–5.8%) with 3DR. The cumulative 48-week incidence of TF was 15.8% (90% CI 13.9%–17.9%) with 2DR and 24.5% (90% CI 22.2%–27.0%) with 3DR. For VF, the estimated hazard ratio (HR) for 2DR vs. 3DR was 1.02 (90% CI: 0.78–1.34), with evidence of effect modification by low-level resistance (HR 3.96, 90% CI: 2.10–7.46). The estimated HR of TF for 2DR vs. 3DR was 0.54 (90% CI: 0.48–0.60). The 48-week cumulative incidence of TD was 11.7% (8.7%, 14.6%) in 2DR and 19.6% (16.9%, 22.4%) in 3DR. Conclusions: Dolutegravir-based 2DR showed high virological efficacy and durability; however, past resistance increased the risk of VF, but not of TD or TF.

The pandemic increased world’s uncertainty, and led to deep change in daily habits, generating disorientation, and inevitably affecting people life and professional plans. Young adults and students’ future perspective and satisfaction with life were widely affected, especially for those facing school/ work transitions. Nevertheless, it was of primary importance for career guidance psychologists to intervene to support students despite having to navigate “on sight” and with little literature available. This paper will thus describe how the Life Design Psy-Lab, a career guidance service from Bicocca University (Milan, Italy) implemented a thematic online group intervention with 103 students enrolled. The intervention was based on the theoretical model of Life Design and was performed by career counselling psychologists. The intervention’s goal was to foster students’ development of skills and mindset to face complexity and unpredictability, shifting their time perception from an uncertain present to a more optimistic future scenario. The intervention’s impact was assessed using pre and post online questionnaires. Results show how students increased their precepted level in a set of skills to face change and complexity after participating to the intervention. In more detail, students’ precepted levels of career adaptability, courage, time perspective and resilience rose. Also, data show how the intervention strengthened students’ life satisfaction. This paper will thus contribute to expand the growing yet still newborn set of knowledge about career guidance interventions in times of COVID-19 emergency, specifically addressing the issue of design interventions that can improve young adults’ skills to visualize and project present and future for themselves, especially during uncertain times.

ObjectiveThe extent of response to neoadjuvant chemotherapy predicts survival in Ewing sarcoma. This study focuses on MRI radiomics of skeletal Ewing sarcoma and aims to investigate feature reproducibility and machine learning prediction of response to neoadjuvant chemotherapy.Materials and methodsThis retrospective study included thirty patients with biopsy-proven skeletal Ewing sarcoma, who were treated with neoadjuvant chemotherapy before surgery at two tertiary sarcoma centres. 7 patients were poor responders and 23 were good responders based on pathological assessment of the surgical specimen. On pre-treatment T1-weighted and T2-weighted MRI, 2D and 3D tumour segmentations were manually performed. Features were extracted from original and wavelet-transformed images. Feature reproducibility was assessed through small geometrical transformations of the regions of interest mimicking multiple manual delineations, and intraclass correlation coefficient >0.75 defined feature reproducibility. Feature selection also consisted of collinearity and significance analysis. After class balancing in the training cohort, three machine learning classifiers were trained and tested on unseen data using hold-out cross-validation.Results1303 (77%) 3D and 620 (65%) 2D radiomic features were reproducible. 4 3D and 4 2D features passed feature selection. Logistic regression built upon 3D features achieved the best performance with 85% accuracy (AUC=0.9) in predicting response to neoadjuvant chemotherapy.ConclusionCompared to 2D approach, 3D MRI radiomics of Ewing sarcoma had superior reproducibility and higher accuracy in predicting response to neoadjuvant chemotherapy, particularly when using logistic regression classifier.

Earlier diagnosis, access to disease-modifying therapies (DMTs), and improved supportive care have favorably altered the disease course of multiple sclerosis (MS), leading to an improvement in long-term outcomes for people with MS (PwMS). This success has changed the medical characteristics of the population seen in MS clinics. Comorbidities and the accompanying polypharmacy, immune senescence, and the growing number of approved DMTs make selecting the optimal agent for an individual patient more challenging. Glatiramer acetate (GA), a moderately effective DMT, interacts only minimally with comorbidities, other medications, or immune senescence. We describe here several populations in which GA may represent a useful treatment option to overcome challenges due to advanced age or comorbidities (e.g., hepatic or renal disease, cancer). Further, we weigh GA's potential merits in other settings where PwMS and their neurologists must base treatment decisions on factors other than selecting the most effective DMT, e.g., family planning, conception and pregnancy, or the need for vaccination.

Exposomics is a novel concept that indicates the combination of all the external factors we are exposed to throughout our entire life, as the environment we live in, our lifestyle and behavior are able to have a notable influence on our health. The quantity and typology of environmental factors we are exposed to are clearly dependent on the geographical location of each individual, e.g. some areas are more polluted that others and even the social characteristics of a certain place can have an effect on the way we behave, exposing us to different levels of risk of developing certain diseases or exacerbating existing ones. In this context, the PULSE project, briefly described in this paper, is building an advanced system to identify the effect of a complex set of environmental and social exposures in the big cities, that represent the most complicated environment from this point of view, and mitigate health risk related to common diseases such as asthma, type 2 diabetes and cardiovascular diseases. This system is composed by several parts, most of which apply advanced spatial analytics and geographic information-based tools to estimate health risk in a precise way, providing both citizens and public health officers with tools to monitor it. This paper summarizes the work performed in the project using these analytics, and quickly describes some of the tools in which geographic information has been applied in the most innovative way.

Antiretroviral therapies have been tested with the goal of maintaining virological suppression with a particular attention in limiting drug-related toxicity. With this aim we designed the DUAL study: a randomized, open-label, multicenter, 96 weeks-long pilot exploratory study in virologically suppressed HIV-1+ patients with the aim of evaluating the immunovirological success and the impact on non-HIV related morbidity of switching to a dual therapy with darunavir-ritonavir (DRV/r) and rilpivirine (RPV). We recruited patients who received a PI/r-containing HAART for ≥6 months, HIV-RNA < 50 cp/mL for ≥3 months, eGFR > 60 mL/min/1,73m2, without DRV or RPV RAMs. We randomized patients in arm A: RPV + DRV/r QD or arm B: ongoing triple therapy. The primary endpoint has been defined as the percentage of patients with HIV-RNA < 50 cp/mL at week 48 (ITT). VACS index, Framingham CVD risk (FRS) and urinary RBP (uRBP) were calculated. We used Chi-square or Fisher statistics for categorical variables and Mann-Whitney U for continuous ones. Forty-one patients were enrolled (22 in arm A, 14 in arm B, plus 5 screening failures): 30 patients reached 96 weeks: 100% had HIV-RNA < 50 cp/mL in arm A versus 91.7% in arm B. Similar changes were observed in median CD4/mL between baseline and week 96 (+59 versus − 31, p: n.s.). Thirty-one in arm A and 23 in arm B adverse events took place, whereas only 1 was serious (arm A: turbinate hypertrophy, unrelated to HAART). Among the 6 discontinuations (3 in A, 3 in B), only 1 was related to adverse event (arm A: G3 depression, insomnia, weakness). VACS index, median FRS and median uRBP values did not vary from baseline to week 96. At 96-weeks all patients switched to a QD 2-drug regimen based on DRV/r + RPV maintained HIV-RNA suppression, but a single patient who showed a virological failure at week 4. CD4 counts increased overtime without significant differences between the two arms. The novel dual regimen was well tolerated with the same amount of discontinuation as the control arm. VACS index, FRS and uRBP did not differ between arms at week 96.

Abstract Suppressor of Lin‐12‐like (C. elegans) (SEL1L) participates in the endoplasmic reticulum‐associated protein degradation pathway, malignant transformation and stem cell biology. We explored the role of SEL1L in 110 adult gliomas, of different molecular subtype and grade, in relation to cell proliferation, stemness, glioma‐associated microglia/macrophages (GAMs), prognostic markers and clinical outcome. SEL1L protein expression was assessed by immunohistochemistry and Western blotting. Genetic and epigenetic alterations were detected by molecular genetics techniques. SEL1L was overexpressed in anaplastic gliomas (World Health Organization [WHO] grade III) and in glioblastoma (GB, WHO grade IV) with the highest labelling index (LI) in the latter. Immunoreactivity was significantly associated with histological grade (p = 0.002) and cell proliferation index Ki‐67/MIB‐1 (p = 0.0001). In GB, SEL1L co‐localised with stemness markers Nestin and Sox2. Endothelial cells and vascular pericytes of proliferative tumour blood vessels expressed SEL1L suggesting a role in tumour neo‐vasculature. GAMs consistently expressed SEL1L. SEL1L overexpression was significantly associated with TERT promoter mutations (p = 0.0001), EGFR gene amplification (p = 0.0013), LOH on 10q (p = 0.0012) but was mutually exclusive with IDH1/2 mutations (p = 0.0001). SEL1L immunoreactivity correlated with tumour progression and cell proliferation, conditioning poor patient survival and response to therapy. This study emphasises SEL1L as a potential biomarker for the most common subgroup of TERT mutant/EGFR amplified/IDH‐WT GBs.

IntroductionAlemtuzumab is highly effective in the treatment of patients with relapsing multiple sclerosis (PwRMS) and selectively targets the CD52 antigen, with a consequent profound lymphopenia, particularly of CD4+ T lymphocytes. However, the immunological basis of its long-term efficacy has not been clearly elucidated.MethodsWe followed up 29 alemtuzumab-treated RMS patients over a period of 72 months and studied the immunological reconstitution of their CD4+ T cell subsets by means of phenotypic and functional analysis and through mRNA-related molecule expression, comparing them to healthy subject (HS) values (rate 2:1).ResultsIn patients receiving only two-course alemtuzumab, the percentage of CD4+ lymphocytes decreased and returned to basal levels only at month 48. Immune reconstitution of the CD4+ subsets was characterized by a significant increase (p < 0.001) in Treg cell percentage at month 24, when compared to baseline, and was accompanied by restoration of the Treg suppressor function that increased within a range from 2- to 6.5-fold compared to baseline and that persisted through to the end of the follow-up. Furthermore, a significant decrease in self-reactive myelin basic protein-specific Th17 (p < 0.0001) and Th1 (p < 0.05) cells reaching HS values was observed starting from month 12. There was a change in mRNA of cytokines, chemokines, and transcriptional factors related to Th17, Th1, and Treg cell subset changes, consequently suggesting a shift toward immunoregulation and a reduction of T cell recruitment to the central nervous system.ConclusionsThese data provide further insight into the mechanism that could contribute to the long-term 6-year persistence of the clinical effect of alemtuzumab on RMS disease activity.

Genome-wide association studies identified over 200 risk loci for multiple sclerosis (MS) focusing on common variants, which account for about 50% of disease heritability. The goal of this study was to investigate whether low-frequency and rare functional variants, located in MS-established associated loci, may contribute to disease risk in a relatively homogeneous population, testing their cumulative effect (burden) with gene-wise tests. We sequenced 98 genes in 588 Italian patients with MS and 408 matched healthy controls (HCs). Variants were selected using different filtering criteria based on allelic frequency and in silico functional impacts. Genes showing a significant burden (n = 17) were sequenced in an independent cohort of 504 MS and 504 HC. The highest signal in both cohorts was observed for the disruptive variants (stop-gain, stop-loss, or splicing variants) located in EFCAB13, a gene coding for a protein of an unknown function (p < 10–4). Among these variants, the minor allele of a stop-gain variant showed a significantly higher frequency in MS versus HC in both sequenced cohorts (p = 0.0093 and p = 0.025), confirmed by a meta-analysis on a third independent cohort of 1298 MS and 1430 HC (p = 0.001) assayed with an SNP array. Real-time PCR on 14 heterozygous individuals for this variant did not evidence the presence of the stop-gain allele, suggesting a transcript degradation by non-sense mediated decay, supported by the evidence that the carriers of the stop-gain variant had a lower expression of this gene (p = 0.0184). In conclusion, we identified a novel low-frequency functional variant associated with MS susceptibility, suggesting the possible role of rare/low-frequency variants in MS as reported for other complex diseases.