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

Biological systems: from water radiolysis to carbon ion radiotherapy

International audienceHadron therapy is an innovative cancer treatment method based on the acceleration of light ions at high energy. In addition to their interesting profile of dose deposition, which ensures accurate targeting of localized tumors, carbon ions offer biological properties that lead to an efficient treatment for radio-and chemo-resistant tumors and to provide a boost for tumors in hypoxia. This paper is a short review of the progress in theoretical, experimental, fundamental and applied research, aiming at understanding the origin of the biological benefits of light ions better. As a limit of such a vast and multidisciplinary domain, this review adopts the point of view of the physicists, leaning on results obtained in connection with CIMAP's IRRABAT platform. 1. Introduction Interaction of fast ions with biological systems constitutes one aspect of the interdisciplinary researches performed with ion-beam facilities. This domain is as rich as it is complex since it encompasses several orders of magnitude in both space and time. The shortest space and time scale corresponds to atomic collisions, which may be as short as 10 −18 s for the interaction of fast ions with individual atoms. At the opposite end of this domain, late effects – like cancer induction, chromosomal instability or organ dysfunctions – may appear or remain several years after irradiations. While irradiations may be limited to a very localized region, the whole behavior of an organ may be affected, possibly leading to human death, in particular when the irradiation dose and spatial extension are high. Between these two extreme scales, stands a great number of mechanisms, including for instance: the transport of the primary ejected electrons, the relaxation of the ionized and excited molecules, which may lead to direct damage in biological targets and to radical species and associated biochemical reactions. These early physical and chemical stages are followed by numerous and complex cell responses, such as the triggering of mechanisms to check DNA, to repair its damage, to manage the oxidative stress or to induce cell death. The numerous biological endpoints that have been studied reveal the complexity and the diversity of this biological response. These endpoints may involve particular structures of cells at the molecular scale (tracking of protein activities, damage in DNA, protein or lipid) or at the sub-cellular scale (chromosomes, nucleus, membranes, mitochondria.. .) and may concern cell organization (3D cell culture, tissues, organs, body). The domain of low dose

Stellar photometry with Multi Conjugate Adaptive Optics

We overview the current status of photometric analyses of images collected with Multi Conjugate Adaptive Optics (MCAO) at 8-10m class telescopes that operated, or are operating, on sky. Particular attention will be payed to resolved stellar population studies. Stars in crowded stellar systems, such as globular clusters or in nearby galaxies, are ideal test particles to test AO performance. We will focus the discussion on photometric precision and accuracy reached nowadays. We briefly describe our project on stellar photometry and astrometry of Galactic globular clusters using images taken with GeMS at the Gemini South telescope. We also present the photometry performed with DAOPHOT suite of programs into the crowded regions of these globulars reaching very faint limiting magnitudes Ks ~21.5 mag on moderately large fields of view (~1.5 arcmin squared). We highlight the need for new algorithms to improve the modeling of the complex variation of the Point Spread Function across the field of view. Finally, we outline the role that large samples of stellar standards plays in providing a detailed description of the MCAO performance and in precise and accurate colour{magnitude diagrams.Comment: 17 pages, 12 figures, SPIE 201

Assessment of Geant4 Prompt-Gamma Emission Yields in the Context of Proton Therapy Monitoring

International audienceMonte Carlo tools have been long used to assist the research and development of solutions for proton therapy monitoring. The present work focuses on the prompt-gamma emission yields by comparing experimental data with the outcomes of the current version of Geant4 using all applicable proton inelastic models. For the case in study and using the binary cascade model, it was found that Geant4 overestimates the prompt-gamma emission yields by 40.2 ± 0.3%, even though it predicts the prompt-gamma profile length of the experimental profile accurately. In addition, the default implementations of all proton inelastic models show an overestimation in the number of prompt gammas emitted. Finally, a set of built-in options and physically sound Geant4 source code changes have been tested in order to try to improve the discrepancy observed. A satisfactory agreement was found when using the QMD model with a wave packet width equal to 1.3 fm 2

Development of an in Vitro Rat Intestine Segmental Perfusion Model to Investigate Permeability and Predict Oral Fraction Absorbed

Purpose: The aims of the study are to develop and evaluate an in vitro rat intestine segmental perfusion model for the prediction of the oral fraction absorbed of compounds and to assess the ability of the model to study intestinal metabolism. Methods: The system consisted of a perfusion cell with a rat intestinal segment and three perfusion circulations (donor, receiver, and rinsing circulation). Lucifer yellow (LY) was applied as internal standard together with test compounds in the donor circulation. To validate the model, the permeability of eight noncongeneric passively absorbed drugs was determined. Intestinal N-demethylation of verapamil into norverapamil was followed in the donor and receiver circulations by high-performance liquid chromatography analysis. Results: The in vitro model allowed ranking of the tested compounds according to their in vivo absorption potential. The Spearman's correlation coefficient between the oral fraction absorbed in humans and the ratio of permeation coefficient of test compound to the permeation coefficient of LY within the same experiment was 0.98 (P < 0.01). Moreover, intestinal N-demethylation of verapamil, its permeation, and the permeation of its metabolite norverapamil could be assessed in parallel. Conclusions: Up to six permeation kinetics can be obtained per rat, and the method has shown to be a valuable tool to estimate human oral absorptio

Real-Time Online Monitoring of the Ion Range by Means of Prompt Secondary Radiations

International audiencePrompt secondary radiations such as gamma rays and protons can be used for ion-range monitoring during ion therapy either on an energy-slice basis or on a pencil-beam basis. We present a review of the ongoing activities in terms of detector developments, imaging, experimental and theoretical physics issues concerning the correlation between the physical dose and hadronic processe

Changes in Employment Uncertainty and the Fertility Intention-Realization Link: An Analysis Based on the Swiss Household Panel.

How do changes in employment uncertainty matter for fertility? Empirical studies on the impact of employment uncertainty on reproductive decision-making offer a variety of conclusions, ranging from gender and socio-economic differences in the effect of employment uncertainty on fertility intentions and behaviour, to the effect of employment on changes in fertility intentions. This article analyses the association between a change in subjective employment uncertainty and fertility intentions and behaviour by distinguishing male and female partners' employment uncertainty, and examines the variation in these associations by education. Using a sample of men and women living in a couple from the Swiss Household Panel (SHP 2002-2011), we examine through multinomial analysis how changes in employment uncertainty and selected socio-demographic factors are related to individual childbearing decisions. Our results show strong gendered effects of changes in employment uncertainty on the revision of reproductive decisions among the highly educated population

Cervical lymph node metastasis in adenoid cystic carcinoma of the larynx: a collective international review

Adenoid cystic carcinoma (AdCC) of the head and neck is a well-recognized pathologic entity that rarely occurs in the larynx. Although the 5-year locoregional control rates are high, distant metastasis has a tendency to appear more than 5 years post treatment. Because AdCC of the larynx is uncommon, it is difficult to standardize a treatment protocol. One of the controversial points is the decision whether or not to perform an elective neck dissection on these patients. Because there is contradictory information about this issue, we have critically reviewed the literature from 1912 to 2015 on all reported cases of AdCC of the larynx in order to clarify this issue. During the most recent period of our review (1991-2015) with a more exact diagnosis of the tumor histology, 142 cases were observed of AdCC of the larynx, of which 91 patients had data pertaining to lymph node status. Eleven of the 91 patients (12.1%) had nodal metastasis and, based on this low proportion of patients, routine elective neck dissection is therefore not recommended

The epidemiology of seasonal influenza after the 2009 influenza pandemic in Africa: a systematic review

Background: Influenza infection is a serious public health problem that causes an estimated 3 to 5 million cases and 250,000 deaths worldwide every year. The epidemiology of influenza is well-documented in high- and middle-income countries, however minimal effort had been made to understand the epidemiology, burden and seasonality of influenza in Africa. This study aims to assess the state of knowledge of seasonal influenza epidemiology in Africa and identify potential data gaps for policy formulation following the 2009 pandemic. Method: We reviewed articles from Africa published into four databases namely: MEDLINE (PubMed), Google Scholar, Cochrane Library and Scientific Research Publishing from 2010 to 2019. Results: We screened titles and abstracts of 2070 studies of which 311 were selected for full content evaluation and 199 studies were considered. Selected articles varied substantially on the basis of the topics they addressed covering the field of influenza surveillance (n=80); influenza risk factors and co-morbidities (n=15); influenza burden (n=37); influenza vaccination (n=40); influenza and other respiratory pathogens (n=22) and influenza diagnosis (n=5). Conclusion: Significant progress has been made since the last pandemic in understanding the influenza epidemiology in Africa. However, efforts still remain for most countries to have sufficient data to allow countries to prioritize strategies for influenza prevention and control