Pupillometric analysis for assessment of gene therapy in Leber Congenital Amaurosis patients

Background: Objective techniques to assess the amelioration of vision in patients with impaired visual function are needed to standardize efficacy assessment in gene therapy trials for ocular diseases. Pupillometry has been investigated in several diseases in order to provide objective information about the visual reflex pathway and has been adopted to quantify visual impairment in patients with Leber Congenital Amaurosis (LCA). In this paper, we describe detailed methods of pupillometric analysis and a case study on three Italian patients affected by Leber Congenital Amaurosis (LCA) involved in a gene therapy clinical trial at two follow-up time-points: 1 year and 3 years after therapy administration. Methods: Pupillary light reflexes (PLR) were measured in patients who had received a unilateral subretinal injection in a clinical gene therapy trial. Pupil images were recorded simultaneously in both eyes with a commercial pupillometer and related software. A program was generated with MATLAB software in order to enable enhanced pupil detection with revision of the acquired images (correcting aberrations due to the inability of these severely visually impaired patients to fixate), and computation of the pupillometric parameters for each stimulus. Pupil detection was performed through Hough Transform and a non-parametric paired statistical test was adopted for comparison. Results: The developed program provided correct pupil detection also for frames in which the pupil is not totally visible. Moreover, it provided an automatic computation of the pupillometric parameters for each stimulus and enabled semi-automatic revision of computerized detection, eliminating the need for the user to manually check frame by frame. With reference to the case study, the amplitude of pupillary constriction and the constriction velocity were increased in the right (treated eye) compared to the left (untreated) eye at both follow-up time-points, showing stability of the improved PLR in the treated eye. Conclusions: Our method streamlined the pupillometric analyses and allowed rapid statistical analysis of a range of parameters associated with PLR. The results confirm that pupillometry is a useful objective measure for the assessment of therapeutic effect of gene therapy in patients with LCA

Acute demyelinating neuropathy associated with rituximab treatment in a patient with relapsing nephrotic syndrome

We encountered a 63-year-old woman who experienced acute onset of demyelinating polyneuropathy (AIDP) after rituximab infusions to treat her nephrotic syndrome (NS

FAStEN: an efficient adaptive method for feature selection and estimation in high-dimensional functional regressions

Functional regression analysis is an established tool for many contemporary scientific applications. Regression problems involving large and complex data sets are ubiquitous, and feature selection is crucial for avoiding overfitting and achieving accurate predictions. We propose a new, flexible, and ultra-efficient approach to perform feature selection in a sparse high dimensional function-on-function regression problem, and we show how to extend it to the scalar-on-function framework. Our method combines functional data, optimization, and machine learning techniques to perform feature selection and parameter estimation simultaneously. We exploit the properties of Functional Principal Components, and the sparsity inherent to the Dual Augmented Lagrangian problem to significantly reduce computational cost, and we introduce an adaptive scheme to improve selection accuracy. Through an extensive simulation study, we benchmark our approach to the best existing competitors and demonstrate a massive gain in terms of CPU time and selection performance without sacrificing the quality of the coefficients' estimation. Finally, we present an application to brain fMRI data from the AOMIC PIOP1 study

Validazione di uno strumento per valutare la partecipazione alle attività extracurriculari in area STEM. Il questionario Science Activities Evaluation Engagement (SAEE)

In this study, we present a new questionnaire, the Science Activities Evaluation Engagement (SAEE) instrument, for the evaluation of the students’ engagement in STEM oriented extra-curricular activities. The questionnaire was administered to about 1000 secondary school students who participated in the activities of the Piano Nazionale Lauree Scientifiche in Biology, Chemistry and Physics. Through an exploratory and confirmatory factor analysis, it was possible to validate a four-factor structure of the instrument: Satisfaction with the followed activities; Utility of the activities; Difficulties in following the activities; Involvement of close people. The obtained factor structure shows a good model fit, with each of the obtained scales showing an excellent reliability. Criterion validity was established through the academic motivation scale. The proposed instrument shows also an adequate convergent validity and a sufficient discriminant validity. Implications of the study for the evaluation of Third Mission activities of the Italian universities are also briefly discussed

Catalytic Dehydration of Fructose to 5-Hydroxymethylfurfural in Aqueous Medium over Nb2O5-Based Catalysts

The catalytic dehydration of fructose to 5-hydroxymethylfurfural (HMF) in water was performed in the presence of pristine Nb2O5 and composites containing Nb and Ti, Ce or Zr oxides. In all experiments, fructose was converted to HMF using water as the solvent. The catalysts were characterized by powder X-ray diffraction, scanning electron microscopy, N2 physical adsorption, infrared and Raman spectroscopy and temperature-programmed desorption of NH3. Experimental parameters such as fructose initial concentration, volume of the reacting suspension, operation temperature, reaction time and amount of catalyst were tuned in order to optimize the catalytic reaction process. The highest selectivity to HMF was ca. 80% in the presence of 0.5 g\ub7L 121 of bare Nb2O5, Nb2O5-TiO2 or Nb2O5-CeO2 with a maximum fructose conversion of ca. 70%. However, the best compromise between high conversion and high selectivity was reached by using 1 g\ub7L 121 of pristine Nb2O5. Indeed, the best result was obtained in the presence of Nb2O5, with a fructose conversion of 76% and a selectivity to HMF of 75%, corresponding to the highest HMF yield (57%). This result was obtained at a temperature of 165\ub0 in an autoclave after three hours of reaction by using 6 mL of 1 M fructose suspension with a catalyst amount equal to 1 g\ub7L 121

Mind the metal:a fragment library-derived zinc impurity binds the E2 ubiquitin-conjugating enzyme Ube2T and induces structural rearrangements

Efforts to develop inhibitors, activators, and effectors of biological reactions using small molecule libraries are often hampered by interference compounds, artifacts, and false positives that permeate the pool of initial hits. Here, we report the discovery of a promising initial hit compound targeting the Fanconi anemia ubiquitin-conjugating enzyme Ube2T and describe its biophysical and biochemical characterization. Analysis of the co-crystal structure led to the identification of a contaminating zinc ion as solely responsible for the observed effects. Zinc binding to the active site cysteine induces a domain swap in Ube2T that leads to cyclic trimerization organized in an open-ended linear assembly. Our study serves as a cautionary tale for screening small molecule libraries and provides insights into the structural plasticity of ubiquitin-conjugating enzymes

SECCA procedure for anal incontinence and antibiotic treatment: a case report of anal abscess

Background: Fecal Incontinence (FI) can seriously affect quality of life. The treatment of fecal incontinence starts conservatively but in case of failure, different surgical approaches may be proposed to the patient. Recently several not invasive approaches have been developed. One of these is the radiofrequency (RF) energy application to the internal anal sphincter. Case presentation: We report a rare case of an anal abscess related to a SECCA procedure in a 66-year-old woman affected by gas and FI for twenty years. Conclusions: The complications post-SECCA procedure reported in literature are generally not serious and often self-limited, such as bleeding or anal pain. This is a case of an anal abscess. We suggest that this finding could consolidate the importance of administering antibiotic therapy to patients and to run a full course of at least 6 days rather than a short-term (24 h) therapy, with the aim to minimize the incidence of this complication

Late Onset Cobalamin Disorder and Hemolytic Uremic Syndrome: A Rare Cause of Nephrotic Syndrome

Hemolytic uremic syndrome (HUS) is an unrare and severe thrombotic microangiopathy (TMA) caused by several pathogenetic mechanisms among which Shiga toxin-producing Escherichia coli infections and complement dysregulation are the most common. However, very rarely and particularly in neonates and infants, disorders of cobalamin metabolism (CblC) can present with or be complicated by TMA. Herein we describe a case of atypical HUS (aHUS) related to CblC disease which first presented in a previously healthy boy at age of 13.6 years. The clinical picture was initially dominated by nephrotic range proteinuria and severe hypertension followed by renal failure. The specific treatment with high dose of hydroxycobalamin rapidly obtained the remission of TMA and the complete recovery of renal function. We conclude that plasma homocysteine and methionine determinations together with urine organic acid analysis should be included in the diagnostic work-up of any patient with TMA and/or nephrotic syndrome regardless of age

The role of oxysterols in vascular aging.

The ageing endothelium progressively loses its remarkable and crucial ability to maintain homeostasis of the vasculature, as it acquires a proinflammatory phenotype. Cellular and structural changes gradually accumulate in the blood vessels, and markedly in artery walls. Most changes in aged arteries are comparable to those occurring during the atherogenic process, the latter being more marked: pro‐oxidant and proinflammatory molecules, mainly deriving from or triggered by oxidized low density lipoproteins (oxLDLs), are undoubtedly a major driving force of this process. Oxysterols, quantitatively relevant components of oxLDLs, are likely candidate molecules in the pathogenesis of vascular ageing, because of their marked pro‐oxidant, proinflammatory and proapoptotic properties. An increasing bulk of experimental data point to the contribution of a variety of oxysterols of pathophysiological interest, also in the age‐related genesis of endothelium dysfunction, intimal thickening due to lipid accumulation, and smooth muscle cell migration and arterial stiffness due to increasing collagen deposition and calcification. This review provides an updated analysis of the molecular mechanisms whereby oxysterols accumulating in the wall of ageing blood vessels may ‘activate’ endothelial and monocytic cells, through expression of an inflammatory phenotype, and ‘convince’ smooth muscle cells to proliferate, migrate and, above all, to act as fibroblast‐like cells. [Image: see text

The shapes of an epidemic: using Functional Data Analysis to characterize COVID-19 in Italy

We investigate patterns of COVID-19 mortality across 20 Italian regions and their association with mobility, positivity, and socio-demographic, infrastructural and environmental covariates. Notwithstanding limitations in accuracy and resolution of the data available from public sources, we pinpoint significant trends exploiting information in curves and shapes with Functional Data Analysis techniques. These depict two starkly different epidemics; an "exponential" one unfolding in Lombardia and the worst hit areas of the north, and a milder, "flat(tened)" one in the rest of the country -- including Veneto, where cases appeared concurrently with Lombardia but aggressive testing was implemented early on. We find that mobility and positivity can predict COVID-19 mortality, also when controlling for relevant covariates. Among the latter, primary care appears to mitigate mortality, and contacts in hospitals, schools and work places to aggravate it. The techniques we describe could capture additional and potentially sharper signals if applied to richer data