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Purpose Various prognostic indexes have been proposed to improve physicians’ ability to predict survival time in advanced cancer patients admitted to palliative care (PC), but no optimal score has still been identified. The study therefore aims to develop and externally validate a new multivariable predictive model in this setting.Methods We developed the model on 1020 cancer patients prospectively enrolled to home care palliative care at VIDAS Milan, Italy, between May 2018 and February 2020 and followed-up to June 2020. The model was then validated among two separate samples of 544 home care and 247 hospice patients. Overall survival was considered as the primary outcome to develop and validate the model; Cox and flexible parametric Royston-Parmar regression models were used.Results Through a four-step modelling process, among 68 clinical factors considered, five predictors were included in the predictive model, i.e., rattle, heart rate, anorexia, liver failure, and the Karnofsky performance status. Patient’s survival probability at various time points was estimated. The predictive model showed a good calibration and moderate discrimination (area under the receiver operating characteristic curve between 0.72 and 0.79) in the home care validation set, but model calibration was suboptimal in hospice patients.Conclusions The new multivariable predictive model for palliative cancer patients’ survival (PACS model) includes clinical parameters routinely at patient’s admission to PC and can be easily used to facilitate immediate and appropriate clinical decisions for PC cancer patients in the home setting.

Objectives: The aim of this study was to assess the prevalence of delirium, using the Assessment Test for Delirium and Cognitive Impairment (4AT) in end-of-life palliative care patients. Subjects and Methods: This retrospective cross-sectional study was conducted on end-of-life patients in a hospice or at home. All patients were evaluated with the 4AT for the presence of delirium. Results: Of the 461 patients analyzed, 76 (16.5%) were inpatients and 83.5% (385) outpatients. The median age was 79.5 (72–86) years, and 51.0% were female. According to the 4AT score, 126 patients (27.3%) had delirium (A4T ≥4) at admission, 28 (36.8%) were inpatients, and 98 (25.5%) outpatients. Around 33.8% of the cancer inpatients had delirium, while 20.6% of the cancer outpatients had delirium. The prevalence of delirium varied according to the setting, clinical condition, and life expectancy. In addition, 55.0% (11) actively dying inpatients, within 3 days, had delirium, and 56.7% (17) outpatients had delirium; while among those with life expectancy longer than 4 days, 30.4% (17) inpatients and 22.8% (81) outpatients were with delirium. Conclusions: Our study confirms that delirium is common in cancer and noncancer palliative care patients. Further research on delirium in end-of-life palliative care patients should consider the complexity of palliative care of this population as well as of the characteristics of the settings.

Aim To describe the experience involving the early introduction of palliative care (PC) in oncological patients treated within the paediatric oncology unit of the Istituto Nazionale Tumori of Milan and compare this cohort with a cohort of patients resident in the same area treated before the introduction of early palliative care. Methods A virtual team was assembled in 2015. The PC providers operate outside the hospital. Conference calls were scheduled to discuss patients' problems. This sample was compared with the clinical records of patients residing in the same area who died between 2009 and 2014. Results Between January 2015 and April 2019, 41 patients residing in the Milan area mainly with CNS tumours or sarcomas were referred to the team. Comparing the results with the previous cohort, there was a rise in the number of patients dying at home or in a hospice and the duration of PC increased over time. From 2015, none of the patients died in an intensive care unit. Conclusion Patients managed by the virtual team were able to continue their cancer treatments, take part in Phase I trials and receive PC. All patients with a poor prognosis should have PC at an early stage.

To determine the use of preventive and symptomatic medications in a sample of end-of-life patients living at home. Palliative care physicians can improve the appropriate use of medications for patients living at home, but more than half still receive avoidable medications. Drugs for peptic ulcer and antithrombotics were the preventive medications most frequently prescribed. This study supports the need for an appropriate drug review and de-prescribing in this vulnerable population, because unnecessary or inappropriate prescribing has no additional therapeutic benefit and only raises costs. To determine the use of avoidable medications in end-of-life patients living at home when they were moved from the general practice setting to the palliative medicine physician (T1) and before death (T2). This retrospective longitudinal study describes the prevalence of end-of-life patients cared for at home between April 2016 and December 2018 receiving preventive and symptomatic drug treatments. Socio-demographic data, diagnosis and drug treatments for each patient were collected in a web-based Case Report Form. The study sample comprised 1565 end-of-life patients with a median age (25–75 percentile) of 79.8 (72.5–85.3 years). All patients were treated with symptomatic drugs, and there were significantly fewer patients from T1 to T2 with at least one preventive medication at end of life (92.1% and, 60.8%, p

Delirium is a neuropsychiatric syndrome associated with negative outcomes, including worsening of cognitive and functional status and an increased burden on patients and caregivers. Medications with anticholinergic effect have been associated with delirium symptoms, but the relationship is still debated. To assess the relation between delirium and anticholinergic load according to the hypothesis that the cumulative anticholinergic burden increases the risk of delirium. This retrospective cross-sectional study was conducted in a sample of end-of-life patients in a hospice or living at home between February and August 2019. Delirium was diagnosed on admission using the 4 ‘A’s Test (4AT) and each patient’s anticholinergic burden was measured with the Anticholinergic Cognitive Burden (ACB) scale. Of the 461 eligible for analysis, 124 (26.9%) had delirium. Anticholinergic medications were associated with an increased risk of delirium in univariate (OR (95% CI) 1.26 (1.16–1.38), p < 0.0001) and multivariate models adjusted for age, sex, dementia, tumors, Karnofsky Performance Status (KPS) score, days of palliative assistance, and setting (OR (95% CI) 1.16 (1.05–1.28), p < 0.0001). Patients with delirium had a greater anticholinergic burden than those without, with a dose-effect relationship between total ACB score and delirium. Patients who scored 4 or more had 2 or 3 times the risk of delirium than those not taking anticholinergic drugs. The dose-response relationship was maintained in the multivariate model. Anticholinergic drugs may influence the development of delirium due to the cumulative effect of multiple medications with modest antimuscarinic activity.

Background: The aim of pharmacotherapy in people at the end of life should be symptom control, more than prolonging life. Drugs for disease prevention should therefore be discouraged, but this is not the usual practice. The prevalence of unnecessary preventive drugs at the end of life is not well described, although some studies suggest it is common. Methods: This retrospective longitudinal study describes the prevalence of patients receiving preventive and symptomatic drug treatments at admission (T1) and before death (T2) in an Italian hospice. All adults admitted to the VIDAS hospice between March 2015 and February 2017 were included in the analysis. Results: The study sample comprised 589 end-of-life patients with a mean age of 75.3 (12.1) years. The mean number of drugs decreased from admission to the hospice to the time of death (mean [standard deviation]: 9.7 [3.4] and 8.7 [3.0]). All patients were appropriately treated with symptomatic drugs at T1 and T2, while there were significantly fewer patients from T1 to T2 with at least 1 preventive medication that could be considered for deprescription at the end of life (511, 86.8% and 286, 48.6%; P < .0001). Conclusions: Hospice admission can be associated with a definite reduction in the use of commonly prescribed preventive medications. However, about half of end-of-life patients can be prescribed avoidable medications. Drugs for peptic ulcer and gastroesophageal reflux disease and antithrombotics were the potentially avoidable preventive medications most frequently prescribed at admission to the hospice and before death.

Few studies regarding palliative sedation (PS) have been carried out in home care (HC) setting. A comparison of PS rate and practices between hospice (HS) and HC is also lacking.Comparing HC and HS settings for PS rate, patient clinical characteristics before and during PS, decision-making process, and clinical aspects of PS.About 38 HC/HS services in Italy participated in a multicenter observational longitudinal study. Consecutive adult cancer patients followed till death during a four-month period and undergoing PS were eligible. Symptom control and level of consciousness were registered every eight hours to death.About 4276 patients were screened, 2894 followed till death, and 531 (18%) underwent PS. PS rate was 15% in HC and 21% in HS (P 0.001). Principal refractory symptoms were delirium (54%) and dyspnea (45%), respectively, more common in HC (P 0.001) and HS (P = 0.03). Informed consent was not obtained in 72% of patients but achieved by 96% of families. Midazolam was the most used drug (94% HS vs. 75% HC; P 0.001) mainly by continuous infusion (74% HC vs. 89% HS; P 0.001). PS duration was less than 48 hours in 67% of patients. Hydration during PS was less frequent in HC (27% vs. 49%; P 0.001). In the eight hours before death, consciousness level was unrousable to mild physical stimulation in 81% and symptom control complete in 89% of cases.Our results show feasibility of PS in HC and HS and suggest setting differences in rates, indications, and practice of PS, possibly related to patients' selection or care organization.

International audience; In mammals, neuroepithelial cells play an essential role in embryonic neurogenesis, whereas glial stem cells are the principal source of neurons at post-embryonic stages. By contrast, neuroepithelial-like stem/progenitor (NE) cells have been shown to be present throughout life in teleosts. We used 3-dimensional (3D) reconstructions of cleared transgenic wdr12:GFP medaka brains to demonstrate that this cell type is widespread in juvenile and to identify new regions containing NE cells. We established the gene expression profile of optic tectum (OT) NE cells by cell sorting followed by RNA-seq. Our results demonstrate that most OT NE cells are indeed active stem cells and that some of them exhibit long G2 phases. We identified several novel pathways (e.g., DNA repair pathways) potentially involved in NE cell homeostasis. In situ hybridization studies showed that all NE populations in the post-embryonic medaka brain have a similar molecular signature. Our findings highlight the importance of NE progenitors in medaka and improve our understanding of NE-cell biology. These cells are potentially useful not only for neural stem cell studies, but also for improving the characterization of neurodevelopmental diseases, such as microcephaly. This article is protected by copyright. All rights reserved.

The quantitative and systematic analysis of embryonic cell dynamics from in vivo 3D+time image data sets is a major challenge at the forefront of developmental biology. Despite recent breakthroughs in the microscopy imaging of living systems, producing an accurate cell lineage tree for any developing organism remains a difficult task. We present here the BioEmergences workflow integrating all reconstruction steps from image acquisition and processing to the interactive visualization of reconstructed data. Original mathematical methods and algorithms underlie image filtering, nucleus centre detection, nucleus and membrane segmentation, and cell tracking. They are demonstrated on zebrafish, ascidian and sea urchin embryos with stained nuclei and membranes. Subsequent validation and annotations are carried out using Mov-IT, a custom-made graphical interface. Compared with eight other software tools, our workflow achieved the best lineage score. Delivered in standalone or web service mode, BioEmergences and Mov-IT offer a unique set of tools for in silico experimental embryology., Quantitative analysis of embryonic cell dynamics from large data sets remains a major challenge in the field of developmental biology. Here the authors develop software and a workflow to reconstruct cell lineage trees from 3D time lapse imaging data sets from several developing organisms including zebrafish, tunicates and sea urchins.

Regionalization is a critical, highly conserved step in the development of the vertebrate brain. Discrepancies exist in how regionalization of the anterior vertebrate forebrain is conceived since the “preoptic area” is proposed to be a part of the telencephalon in tetrapods but not in teleost fish. To gain insight into this complex morphogenesis, formation of the anterior forebrain was analyzed in 3D over time in zebrafish embryos, combining visualization of proliferation and differentiation markers, with that of developmental genes. We found that the region containing the preoptic area behaves as a coherent morphogenetic entity, organized around the optic recess and located between telencephalon and hypothalamus. This optic recess region (ORR) makes clear borders with its neighbor areas and expresses a specific set of genes (dlx2a, sim1a and otpb). We thus propose that the anterior forebrain (secondary prosencephalon) in teleosts contains three morphogenetic entities (telencephalon, ORR and hypothalamus), instead of two (telencephalon and hypothalamus). The ORR in teleosts could correspond to “telencephalic stalk area” and “alar hypothalamus” in tetrapods, resolving current inconsistencies in the comparison of basal forebrain among vertebrates.

International audience; Embryogenesis is a dynamic process with an intrinsic variability whose understanding requires the integration of molecular, genetic, and cellular dynamics. Biological circuits function over time at the level of single cells and require a precise analysis of the topology, temporality, and probability of events. Integrative developmental biology is currently looking for the appropriate strategies to capture the intrinsic properties of biological systems. The "-omic" approaches require disruption of the function of the biological circuit; they provide static information, with low temporal resolution and usually with population averaging that masks fast or variable features at the cellular scale and in a single individual. This data should be correlated with cell behavior as cells are the integrators of biological activity. Cellular dynamics are captured by the in vivo microscopy observation of live organisms. This can be used to reconstruct the 3D + time cell lineage tree to serve as the basis for modeling the organism's multiscale dynamics. We discuss here the progress that has been made in this direction, starting with the reconstruction over time of three-dimensional digital embryos from in toto time-lapse imaging. Digital specimens provide the means for a quantitative description of the development of model organisms that can be stored, shared, and compared. They open the way to in silico experimentation and to a more theoretical approach to biological processes. We show, with some unpublished results, how the proposed methodology can be applied to sea urchin species that have been model organisms in the field of classical embryology and modern developmental biology for over a century.

International audience; We present nonlinear diffusion equations, numerical schemes to solve them and their application for filtering 3D images obtained from laser scanning microscopy (LSM) of living zebrafish embryos, with a goal to identify the optimal filtering method and its parameters. In the large scale applications dealing with analysis of 3D+time embryogenesis images, an important objective is a correct detection of the number and position of cell nuclei yielding the spatio-temporal cell lineage tree of embryogenesis. The filtering is the first and necessary step of the image analysis chain and must lead to correct results, removing the noise, sharpening the nuclei edges and correcting the acquisition errors related to spuriously connected subregions. In this paper we study such properties for the regularized Perona-Malik model and for the generalized mean curvature flow equations in the level-set formulation. A comparison with other nonlinear diffusion filters, like tensor anisotropic diffusion and Beltrami flow, is also included. All numerical schemes are based on the same discretization principles, i.e. finite volume method in space and semi-implicit scheme in time, for solving nonlinear partial differential equations. These numerical schemes are unconditionally stable, fast and naturally parallelizable. The filtering results are evaluated and compared first using the Mean Hausdorff distance between a gold standard and different isosurfaces of original and filtered data. Then, the number of isosurface connected components in a region of interest (ROI) detected in original and after the filtering is compared with the corresponding correct number of nuclei in the gold standard. Such analysis proves the robustness and reliability of the edge preserving nonlinear diffusion filtering for this type of data and lead to finding the optimal filtering parameters for the studied models and numerical schemes. Further comparisons consist in ability of splitting the very close objects which are artificially connected due to acquisition error intrinsically linked to physics of LSM. In all studied aspects it turned out that the nonlinear diffusion filter which is called geodesic mean curvature flow (GMCF) has the best performance.

We designed a strategy for extracting the shapes of cell membranes and nuclei from time lapse confocal images taken throughout early zebrafish embryogenesis using a partial-differential-equation-based segmentation. This segmentation step is a prerequisite for an accurate quantitative analysis of cell morphodynamics during embryogenesis and it is the basis for an integrated understanding of biological processes. The segmentation of embryonic cells requires live zebrafish embryos fluorescently labeled to highlight sub-cellular structures and designing specific algorithms by adapting classical methods to image features. Our strategy includes the following steps: the signal-to-noise ratio is first improved by an edge-preserving filtering, then the cell shape is reconstructed applying a fully automated algorithm based on a generalized version of the Subjective Surfaces technique. Finally we present a procedure for the algorithm validation either from the accuracy and the robustness perspective.

This paper is devoted to the segmentation of cell nuclei from time lapse confocal microscopy images, taken throughout early Zebrafish embryogenesis. The segmentation allows to identify and quantify the number of cells in the animal model. This kind of information is relevant to estimate important biological parameters such as the cell proliferation rate in time and space. Our approach is based on the active contour model without edges. We compare two different formulations of the model equation and evaluate their performances in segmenting nuclei of different shapes and sizes. Qualitative and quantitative comparisons are performed on both synthetic and real data, by means of suitable gold standard. The best approach is then applied on a number of time lapses for the segmentation and counting of cells during the development of a zebrafish embryo between the sphere and the shield stage.

We designed a set of procedures for achieving the tracking of cell nuclei and the identification of cell divisions in live zebrafish embryos using 3D+time images acquired by confocal laser scanning microscopy (CLSM). Our strategy includes image signal enhancement with feature preserving denoising algorithm, automated identification of the nuclei position, extraction of the optical flow from 3D images sequences and tracking of nuclei.

In this paper, we use partial-differential-equation-based segmentation to accurately extract the shapes of membranes and nuclei from time lapse confocal microscopy images, taken throughout early Zebrafish embryogenesis. This strategy is a prerequisite for an accurate quantitative analysis of cell shape and morphodynamics during organogenesis and is the basis for an integrated understanding of biological processes. This data will also serve for the measurement of the variability between individuals in a population. The segmentation of cellular structures is achieved by first using an edge-preserving image filtering method for noise reduction and then applying an algorithm for cell shape reconstruction based on the Subjective Surfaces technique.

The analysis of productivity and efficiency of manufacturing activities is a well-known field of research. The recent structural changes of the economic systems have contributed to move researchers’ attention from goods production activities to the services sector and among them to the banking activity, object of this study.

We report on the incidence of complications of 172 internal jugular vein retrograde catheterizations (IJVRCs) performed on 126 patients. Standard cannulation and X-ray control of the catheter tip placement were performed. Difficulties encountered during the manouvre were registered. Patients with a jugular catheter in place for more than one day had neck echography on catheter removal and one week later. Carotid artery puncture occured in 20 (12%) cases and lymphatic vessel puncture in one. In 13 (8%) cases IJVRC failed due to difficulties in advancing the guide. X-ray films documented catheter misplacement in 39 (23%) cases: loop into the internal jugular vein in 11 (6%); paravertebral venous plexus cannulated in one; other extracranial jugular afferent cannulated in 4 (2%); catheter tip into the jugular lumen in 10 (6%); catheter tip beyond the jugular bulb in 13 (8%). First neck echography documented: one perivascular hematoma (absent one week later); 3 (4%) jugular vein thrombosis (2 asymptomatic and absent one week later; one symptomatic and still evident one week later). Positive neck echography was not associated with difficulties, length of catheterization, diameter of the catheter. IJVRC is a simple and safe procedure with a low incidence of serious complications.

We discuss application of nonlinear PDE based methods to filtering of 3-D confocal images of embryogenesis. We focus on the mean curvature driven and the regularized Perona-Malik equations, where standard as well as newly suggested edge detectors are used. After presenting the related mathematical models, the practical results are given and discussed by visual inspection and quantitatively using the mean Hausdorff distance.