Air Data Sensor Fault Detection with an Augmented Floating Limiter

Although very uncommon, the sequential failures of all aircraft Pitot tubes, with the consequent loss of signals for all the dynamic parameters from the Air Data System, have been found to be the cause of a number of catastrophic accidents in aviation history. This paper proposes a robust data-driven method to detect faulty measurements of aircraft airspeed, angle of attack, and angle of sideslip. This approach first consists in the appropriate selection of suitable sets of model regressors to be used as inputs of neural network-based estimators to be used online for failure detection. The setup of the proposed fault detection method is based on the statistical analysis of the residual signals in fault-free conditions, which, in turn, allows the tuning of a pair of floating limiter detectors that act as time-varying fault detection thresholds with the objective of reducing both the false alarm rate and the detection delay. The proposed approach has been validated using real flight data by injecting artificial ramp and hard failures on the above sensors. The results confirm the capabilities of the proposed scheme showing accurate detection with a desirable low level of false alarm when compared with an equivalent scheme with conventional “a priori set” fixed detection thresholds. The achieved performance improvement consists mainly in a substantial reduction of the detection time while keeping desirable low false alarm rates

Normalization of clonal diversity in gene therapy studies using shape constrained splines

Viral vectors are used to insert genetic material into semirandom genomic positions of hematopoietic stem cells which, after reinfusion into patients, regenerate the entire hematopoietic system. Hematopoietic cells originating from genetically modified stem cells will harbor insertions in specific genomic positions called integration sites, which represent unique genetic marks of clonal identity. Therefore, the analysis of vector integration sites present in the genomic DNA of circulating cells allows to determine the number of clones in the blood ecosystem. Shannon diversity index is adopted to evaluate the heterogeneity of the transduced population of gene corrected cells. However, this measure can be affected by several technical variables such as the DNA amount used and the sequencing depth of the library analyzed and therefore the comparison across samples may be affected by these confounding factors. We developed an advanced spline-regression approach that leverages on confounding effects to provide a normalized entropy index. Our proposed method was first validated and compared with two state of the art approaches in a specifically designed in vitro assay. Subsequently our approach allowed to observe the expected impact of vector genotoxicity on entropy level decay in an in vivo model of hematopoietic stem cell gene therapy based on tumor prone mice

Hematopoietic reconstitution dynamics of mobilized- and bone marrow-derived human hematopoietic stem cells after gene therapy

Mobilized peripheral blood is increasingly used instead of bone marrow as a source of autologous hematopoietic stem/progenitor cells for ex vivo gene therapy. Here, we present an unplanned exploratory analysis evaluating the hematopoietic reconstitution kinetics, engraftment and clonality in 13 pediatric Wiskott-Aldrich syndrome patients treated with autologous lentiviral-vector transduced hematopoietic stem/progenitor cells derived from mobilized peripheral blood (n = 7), bone marrow (n = 5) or the combination of the two sources (n = 1). 8 out of 13 gene therapy patients were enrolled in an open-label, non-randomized, phase 1/2 clinical study (NCT01515462) and the remaining 5 patients were treated under expanded access programs. Although mobilized peripheral blood- and bone marrow- hematopoietic stem/progenitor cells display similar capability of being gene-corrected, maintaining the engineered grafts up to 3 years after gene therapy, mobilized peripheral blood-gene therapy group shows faster neutrophil and platelet recovery, higher number of engrafted clones and increased gene correction in the myeloid lineage which correlate with higher amount of primitive and myeloid progenitors contained in hematopoietic stem/progenitor cells derived from mobilized peripheral blood. In vitro differentiation and transplantation studies in mice confirm that primitive hematopoietic stem/progenitor cells from both sources have comparable engraftment and multilineage differentiation potential. Altogether, our analyses reveal that the differential behavior after gene therapy of hematopoietic stem/progenitor cells derived from either bone marrow or mobilized peripheral blood is mainly due to the distinct cell composition rather than functional differences of the infused cell products, providing new frames of references for clinical interpretation of hematopoietic stem/progenitor cell transplantation outcome.</p

The stochastic route of haematopoiesis: modelling and inference methods in clonal tracking studies

Gene therapy is a novel clinical treatment for curing rare genetic diseases or moderating their effects. The success of this therapy depends on the ability of the modified stem cells to replace the faulty genes with functioning copies, called clones. This helps re-establishing the normal formation of blood cells, a process called haematopoiesis. Mathematical models of clonal dynamics provide useful insights on haematopoiesis and can support the design of safer and effective gene therapy strategies. In this work we propose a novel data-driven stochastic framework to shed light on the dynamics of haematopoiesis after a gene therapy treatment. First, we use a stochastic state-space model to describe how the modified stem cells differentiate into specific cell types. Subsequently, we employ a mixed-effects stochastic formulation to investigate if the growth of the cellular offspring is mainly guided by a few clones, a potential adverse event known as clonal dominance. Finally, we show how shape-constrained splines can be used to remove the effects of technical artefacts when quantifying the level of clonal diversity. Synthetic studies show that our methods outperform the state-of-the-art. The application of our framework on real clonal tracking datasets allowed to (i) infer the dynamics of cell differentiation in two preclinical studies and under three different genetic diseases, (ii) detect possible events of clonal dominance in two preclinical studies, and (iii) objectively compare clonal diversity under two different treatments in a preclinical safety study. Our proposed framework provides statistical support in gene therapy surveillance analyses

A mixed-effects stochastic model reveals clonal dominance in gene therapy safety studies

Abstract Background Mathematical models of haematopoiesis can provide insights on abnormal cell expansions (clonal dominance), and in turn can guide safety monitoring in gene therapy clinical applications. Clonal tracking is a recent high-throughput technology that can be used to quantify cells arising from a single haematopoietic stem cell ancestor after a gene therapy treatment. Thus, clonal tracking data can be used to calibrate the stochastic differential equations describing clonal population dynamics and hierarchical relationships in vivo. Results In this work we propose a random-effects stochastic framework that allows to investigate the presence of events of clonal dominance from high-dimensional clonal tracking data. Our framework is based on the combination between stochastic reaction networks and mixed-effects generalized linear models. Starting from the Kramers–Moyal approximated Master equation, the dynamics of cells duplication, death and differentiation at clonal level, can be described by a local linear approximation. The parameters of this formulation, which are inferred using a maximum likelihood approach, are assumed to be shared across the clones and are not sufficient to describe situation in which clones exhibit heterogeneity in their fitness that can lead to clonal dominance. In order to overcome this limitation, we extend the base model by introducing random-effects for the clonal parameters. This extended formulation is calibrated to the clonal data using a tailor-made expectation-maximization algorithm. We also provide the companion  package RestoreNet, publicly available for download at https://cran.r-project.org/package=RestoreNet . Conclusions Simulation studies show that our proposed method outperforms the state-of-the-art. The application of our method in two in-vivo studies unveils the dynamics of clonal dominance. Our tool can provide statistical support to biologists in gene therapy safety analyses

Campagna oceanografica ANOMCITY_2012

Obiettivo della Campagna Oceanografica ANOMCITY_2012 era quello di studiare gli effetti dell’inquinamento da metalli pesanti in aree marine antistanti un numero discreto di siti ad elevato impatto antropico (centri urbani e Siti di Interesse Nazionale), ovvero: Gioia Tauro, Milazzo, Augusta, Gela, Catania e Taranto e condizioni meteo estremamente difficili non hanno permesso il campionamento dell’area antistante Brindisi, al fine di valutarne lo stato reale della contaminazione, la sua storia e possibile evoluzione. La scelta delle aree investigate è stata guidata dalla specificità della tipologia di inquinamento propria di ogni sito e soprattutto al l’importanza, in termini quantitativi, di tale impatto su scala bacinale - regionale. L’attività di campionamento ha visto il prelievo di acqua, sedimenti tramite benna e box corer e prelievi di particolato organico tramite retinate bongo in “ventagli” spaziali disegnati nella aree prospicienti i centri di interesse, ad una distanza compresa tra 1 e 10 miglia da costa. La campionatura è stata preceduta da analisi multibeam dei fondali per opportuna identificazione di aree di possibile trasferimento di inquinanti da costa verso il mare aperto. Lo studio ad alta risoluzione della morfobatimetria del fondo delle aree di potenziale trasferimento di sedimenti contaminati e/o acque di fondo dall’ambiente costiero a quello profondo rappresenta un contributo chiave alla comprensione dei reali processi che contribuiscono alla genesi di fenomeni di antropizzazione a scale differenti. Per un numero discreto di aree per cui non erano disponibili dati per ricostruzioni ad alta risoluzione del DTM del fondo marino (Gioia Ta uro, Milazzo e Taranto), sono state acquisiti dati per la cartografia del fondo tramite indagine side scan sonare multibeam, utili all’individuazione di specifici sistemi geomorfologici potenzialmente in grado di trasferire contaminanti dall’area costiera a quella profonda. Le attività di campionatura del fondale e della colonna d’acqua, che costituiscono la parte preponderante della campagna oceanografica, sono state confinate alle aree marine antistanti i siti di interesse nazionale scelti, e distribuite su tre - cinque transetti di circa 10 Miglia Nautiche ciascuno

Mortality and risk factors of vaccinated and unvaccinated COVID-19 frail patients treated with anti-SARS-CoV-2 monoclonal antibodies. A real-world study

Background: There is a scarcity of data on outcomes and predictors of therapeutic failure of mAbs in frail COVID-19 patients. Methods: Prospective study including consecutive COVID-19 outpatients referred by primary care physicians for mAbs treatment. Outcomes evaluated were 60-day mortality, time to SARS-CoV-2 clearance, need for hospitalization, and O2-therapy. Results: Among 1026 COVID-19 patients enrolled, 60.2% received casirivamab/imdevimab and 39.8% sotrivimab. Median age was 63 years, 52.4% were males and median time from positive nasopharyngeal swab to mAbs administration was 3 days [IQR, 2-5]. 78.1% were vaccinated. Overall, 60-day mortality was 2.14%. No differences in outcomes were observed between the two mAbs used. No difference was observed in mortality between vaccinated and unvaccinated patients (p=0.925), although lower rate of hospitalization (p&lt;0.005), less need for O2-therapy (p&lt;0.0001) and reduced nasopharyngeal swab negativity time (p&lt;0.0001) were observed in vaccinated. Early administration of mAbs was associated with lower mortality (p&lt;0.007), while corticosteroid use worsened prognosis (p&lt;0.004). Independent predictors associated with higher mortality were older age (p&lt;0.0001), presence of active haematological malignancies (p&lt;0.0001), renal failure (p&lt;0.041) and need for O2-therapy (p&lt;0.001). Conclusion: This study shows similar effectiveness among mAbs used regardless of vaccination status and identifies COVID-19 patients in whom mAbs have poor activity