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Introduction. Neutropenia, which is an abnormally low concentration of neutrophils in the blood, is one of the common side effects in patients receiving radio- or chemotherapy. Neutropenia usually leads to higher risks of severe bacterial and fungal infections. Such medicines as colonystimulating factor filgrastim (and its conjugates) are used to prevent and treat neutropenia in oncology patients. Immunogenicity is a potential concern for any biological product, thus, its assessment is one of the most critical necessities during the development and registration of such products.Aim. The main aim of this study was to validate the ELISA method for anti-pegfilgrastim antibodies detection in human serum samples and to apply the validated method to pegfilgrastim drugs immunogenicity assessment.Materials and methods. To assess pegfilgrastim immunogenicity, the commercial ELISA kit «PEGylated Filgrastim (Neulasta®) ADA ELISA» was used for screening, confirmatory and titer assay. Moreover, to confirm the chosen commercial kit suits the study aims it was revalidated. The absorbance values were obtained using plate immunoassay analyzer Stat Fax 3200, plate washing was performed using an automatic twochannel plate washer.Results and discussion. The ELISA method for anti-pegfilgrastim antibodies determination in human serum samples was validated and applied to the analytical part of the comparative, multicenter, blind, randomized study of pegfilgrastim efficacy and safety in patients with breast cancer, receiving myelosuppressive chemotherapy. Human serum samples were first screened for anti-drug antibodies, then «screening positive» samples were analyzed in confirmatory assay with % inhibition calculation for each sample. The «confirmed positive» samples were further characterized in titer assay.Conclusions. The ELISA method for anti-pegfilgrastim antibodies determination in human serum samples was successfully validated and applied for pegfilgrastim drugs immunogenicity assessment.

Parkinson’s disease (PD) is a progressive movement disorder characterized by tremors at rest, bradykinesia, and stifness. The alteration of handwriting (HW) faculties is one of the earliest motor symptoms in PD patients. This characteristic can be exploited to develop an automatic aid system for early detection of this pathologie. This article aims to assess the importance of diacritics and punctuation marks (DPM) in the PD patients and healthy controls (HCs) discrimination problem, by comparing the classification results obtained from three components: text carrying DPM, text without DPM, as well as only DPM. This work includes the Arabic manuscripts of 31 PD patients and 31 HCs. Furthermore, kinematic, mechanic, and inclination features were calculated for each component. Then, Adaboost models have been constructed on different feature sets, as well as on reduced sets formed in incremental manner using mRMR ranked-feature selection method. From the obtained results, it was concluded that the separating power of HW features in the classification problem of PD patients and HCs is present in all components of the Arabic text, but in varying degrees of importance. Despite the simple graphical nature of DPM, they are carrying of relevant diagnostic information, and effectively contributing to the improvement of PD detection performance. The highest accuracy of 93.54% was achieved for this component.

International audience

Nanopore sequencing of virus genomes represented by segmented RNA (e.g. rotaviruses) requires the development of specific approaches. Due to the massive use of rotavirus vaccines, the relevance of monitoring the genetic diversity of circulating strains of group A rotaviruses (RVA) increased. The WHO recommended method of multiplex type-specific PCR does not allow genotyping of all clinically significant strains of RVA and identifying inter-strain differences within the genotype. We have described a new principle of amplification of RVA gene segments using six primers for reverse transcription and one universal primer for PCR for nanopore sequencing. The amplification of RVA genome was tested on clinical samples and three phylogenetically distant laboratory RVA strains, Wa (G1P[8]), DS-1 (G2P[4]) and 568 (G3P[3]). The developed protocol of sample preparation and nanopore sequencing allowed obtaining full-length sequences for gene segments of RVA, including the diagnostically significant segments 9 (VP7), 4 (VP4) and 6 (VP6) with high accuracy and coverage. The accuracy of sequencing of the rotavirus genome exceeded 99.5 %, and the genome coverage varied for different strains from 59.0 to 99.6 % (on average 86 %). The developed approach of nanopore sequencing of RVA genome could be a prospective tool for epidemiological studies and surveillance of rotavirus infection.

Grapevine downy mildew caused by Plasmopara viticola is one of the most important diseases in vineyards. Oospores that overwinter in the leaf litter above the soil are the sole source of inoculum for primary infections of P. viticola; in addition to triggering the first infections in the season, the oospores in leaf litter also contribute to disease development during the season. In the current study, a quantitative polymerase chain reaction (qPCR) method that was previously developed to detect P. viticola DNA in fresh grapevine leaves was assessed for its ability to quantify P. viticola oospores in diseased, senescent grapevine leaves. The qPCR assay was specific to P. viticola and sensitive to decreasing amounts of both genomic DNA and numbers of P. viticola oospores used to generate qPCR standard curves. When the qPCR assay was compared to microscope counts of oospores in leaves with different levels of P. viticola infestation, a strong linear relationship (R2 = 0.70) was obtained between the numbers of P. viticola oospores per gram of leaves as determined by qPCR vs. microscopic observation. Unlike microscopic observation, the qPCR assay was able to detect significant differences between leaf samples with a low level of oospore infestation (25% infested leaves and 75% non-infested leaves) vs. samples without infestation, and this ability was not influenced by the weight of the leaf sample. The results indicate that the qPCR method is sensitive and provides reliable estimates of the number of P. viticola oospores in grapevine leaves. Additional research is needed to determine whether the qPCR method is useful for quantifying P. viticola oospores in grapevine leaf litter.

Resume Le syndrome respiratoire aigu severe coronavirus 2 (SARS-CoV-2) infecte les cellules hotes par les recepteurs de l’angiotensine, conduisant a une pneumonie liee au COVID-19. A un niveau cardiaque, le virus a un double impact ; en effet, l’infection sera plus grave si l’hote possede des comorbidites cardiovasculaires, et le virus peut causer des lesions cardiovasculaires pouvant engager le pronostic vital. Les therapeutiques associees au COVID-19 peuvent avoir des effets indesirables cardiovasculaires. Une attention particuliere doit etre accordee a la protection cardiovasculaire pendant l’infection au COVID-19.

Background Lung cancer is a major cause of death worldwide. However, few data on incidence, histologic types and mortality rates of lung cancer were available for Algeria. Methods LuCaReAl is an ongoing descriptive, non-interventional, national, multicenter, prospective and longitudinal study conducted in Algeria, among oncologists and pulmonologists in public community and university hospitals. Median and interquartile ranges are displayed. Results Between July 2016 and July 2017, 897 patients were included. Overall incidence of lung cancer was 3.4 [3.2;3.6] cases per 100,000 inhabitants; overall incidence by sex was 5.8 [5.4;6.2] for males and 1.0 [0.8;1.1] for females. Adenocarcinoma was the most common histologic type of cancer. Most tumors were diagnosed at Stage IV. Conclusion The first results from the LuCaReAl study in Algeria showed that most patients are diagnosed with lung cancer at an advanced stage. The ongoing follow-up will next provide data on the survival and mortality rates.

Oncolytic viruses, including live attenuated measles virus (MV) vaccine strains, have recently been shown as promising therapeutic agents against human malignancies. In this study, the oncolytic potential of the attenuated vaccine strain Leningrad-16 (L-16) of MV was evaluated in a panel of human metastatic melanoma cell lines. The L-16 measles virus was shown to replicate within melanoma cells mediating direct cell killing of tumor cells, although all melanoma cell lines varied in regard to their ability to respond to L-16 MV infection, as revealed by the different pattern of the Interferon Stimulated Gene expression, cytokine release and mechanisms of cell death. Furthermore, the statistically significant L-16 measles virus related tumor growth inhibition was demonstrated in a melanoma xenograft model. Therefore, L-16 MV represents an appealing oncolytic platform for target delivery of therapeutic genes along with other attenuated measles virus strains.

Background: The use of mobile technologies for data capture and transmission has the potential to streamline clinical trials, but researchers lack methods for collecting, processing, and interpreting data from these tools. Objectives: To assess the performance of a technical platform for collecting and transmitting data from six mobile technologies in the clinic and at home, to apply methods for comparing them to clinical standard devices, and to measure their usability, including how willing subjects were to use them on a regular basis. Methods: In part 1 of the study, conducted over 3 weeks in the clinic, we tested two device pairs (mobile vs. clinical standard blood pressure monitor and mobile vs. clinical standard spirometer) on 25 healthy volunteers. In part 2 of the study, conducted over 3 days both in the clinic and at home, we tested the same two device pairs as in part 1, plus four additional pairs (mobile vs. clinical standard pulse oximeter, glucose meter, weight scale, and activity monitor), on 22 healthy volunteers. Results: Data collection reliability was 98.1% in part 1 of the study and 95.8% in part 2 (the percentages exclude the wearable activity monitor, which collects data continuously). In part 1, 20 of 1,049 overall expected measurements were missing (1.9%), and in part 2, 45 of 1,083 were missing (4.2%). The most common reason for missing data was a single malfunctioning spirometer (13 of 20 total missed readings) in part 1, and that the subject did not take the measurement (22 of 45 total missed readings) in part 2. Also in part 2, a higher proportion of at-home measurements than in-clinic readings were missing (12.6 vs. 2.7%). The data from this experimental study were unable to establish repeatability or agreement for every mobile technology; only the pulse oximeter demonstrated repeatability, and only the weight scale demonstrated agreement with the clinical standard device. Most mobile technologies received high “willingness to use” ratings from the patients on the questionnaires. Conclusions: This study demonstrated that the wireless data transmission and processing platform was dependable. It also identified three critical areas of study for advancing the use of mobile technologies in clinical research: (1) if a mobile technology captures more than one type of endpoint (such as blood pressure and pulse), repeatability and agreement may need to be established for each endpoint to be included in a clinical trial; (2) researchers need to develop criteria for excluding invalid device readings (to be identified by algorithms in real time) for the population studied using ranges based on accumulated subject data and established norms; and (3) careful examination of a mobile technology’s performance (reliability, repeatability, and agreement with accepted reference devices) during pilot testing is essential, even for medical devices approved by regulators.

Background In histopathological routine diagnostics, three-dimensional tissue samples are analyzed histologically and/or immunohistochemically in two-dimensional sectional planes due to the high expenditure of time and the lack of digitization possibilities. Aim Here, we demonstrate the application of three-dimensional reconstruction to solid tumors and analyze inter-/intratumoral heterogeneity with respect to epithelial-mesenchymal transition (EMT). Methods Tissue samples from pancreatic, lung, colorectal, and breast cancers as well as colorectal liver metastases were serially processed in 4μm sections. For individual analyses, alternating stains (cytokeratin AE1/3, zinc finger E‑box-binding homeobox 1 (ZEB1), eCadherin) were performed. Subsequently, the tumor cells were analyzed for their morphology (epitheloid amoeboid, mesenchymal) and the expression of ZEB1 and eCadherin. For statistical analysis, all tumor cell aggregates were hierarchically annotated and analyzed. Results Tumor buds are predominantly associated with the main tumor mass. Furthermore, a shutteling of eCadherin could be observed within tumor cell aggregates smaller than nine cells. ZEB1 is only increasingly expressed in tumor cell groups smaller than five cells. Conclusions The initial tumor budding and the subsequent decoupling of the tumor bud from the main tumor mass is most likely a two-part process. However, the EMT is not statistically significantly increased within the tumor bud detached from the main tumor mass. It could be shown that the currently valid and known definition of a tumor bud as a cell cluster of less than or equal to five cells cannot be completely classified in the concept of EMT represented by eCadherin and ZEB1.

Enteric viruses are the most common cause of acute gastroenteritis (AGE) in young children and a significant public health problem globally. Hospital admissions of children under 5 years of age with diarrhea are primarily associated with group A rotavirus (RVA) infection. In this retrospective study, the population structure of viruses linked to AGE etiology in young children hospitalized with AGE in Moscow was evaluated, and molecular characterization of RVA strains was performed. Fecal specimens were collected from children under 5 years old hospitalized with AGE between 2009 and 2014 in Moscow, Russia. Multiplex real-time reverse transcription PCR was used to detect enteric viruses and for G/[P]-genotyping of isolated RVAs. Sequencing of RVA VP7 and VP4 cDNA fragments was used to validate the data obtained by PCR-genotyping. The main causes for hospitalization of children with AGE were RVA (40.1%), followed by noroviruses (11.4%), while adenoviruses, astroviruses, sapoviruses, enteroviruses, and orthoreoviruses were detected in 4.7%, 1.9%, 1.4%, 1.2%, and 0.2% of samples tested, respectively. Nosocomial infections, predominantly associated with RVAs and noroviruses, were detected in 24.8% of cases and occurred significantly more frequently in younger infants. The predominant RVA genotype was G4P[8], detected in 38.7% of RVA-positive cases, whereas genotypes G1P[8], G9P[8], G3P[8], and G2P[4] were found in 11.8%, 6.6%, 4.2%, and 3.3% of cases, respectively. Together, the presence of circulating RVA strains with rare VP7 and VP4 gene variants (G6 and P[9]) highlights the need to conduct continuous epidemiological monitoring of RVA infection. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s12250-018-0043-0) contains supplementary material, which is available to authorized users.

The oncolytic potential of the attenuated mumps virus (MV) vaccine strain Leningrad-3 (L-3) was evaluated in a panel of four human metastatic melanoma cell lines. The lines were shown to be susceptible and permissive to MV infection. Efficient MV replication led to death of melanoma cells, but the effect differed among the cell lines. Possible mechanisms mediating the selectivity of MV L-3 towards the cell lines were explored. Replicative and oncolytic activity of MV was found to depend on the expression pattern of type I interferon genes. None of the melanoma cell lines showed induction of expression of the total spectrum of genes required to inhibit virus replication. Based on the results, MV L-3 was assumed to be a promising oncolytic agent for human melanoma cells.

Genetic aberrations in leukemia often lead to the formation of expressed chimeric genes, which should be assessed for proper diagnosis and therapy. Modern methods of molecular diagnostic mainly allow to identify already known fusion genes. RNAseq is an efficient tool for identification of rare and novel chimeric transcripts. Here we present the results of the whole transcriptome analysis of bone marrow samples from five patients with acute myeloblastic leukemia and one, with myelodysplastic syndrome. The wholetranscriptome analysis was performed using Illumina/Solexa approach. We found rare or unknown chimeric transcripts including ETV6-MDS1, MN1-ETV6, OAZ1-PTMA, and MLLT10-GRIA4. Each of these transcripts was confirmed by RT-PCR and Sanger sequencing.

Background Plasmodium falciparum Apical Membrane Antigen 1 Diversity Covering (PfAMA1-DiCo) candidate vaccine is a formulation of three recombinant variants of AMA1 designed to provide broader protection against parasites with varying AMA1 sequences. Methods In this staggered phase Ia/Ib randomized, double blind trial, healthy French adults received AMA1-DiCo with either Alhydrogel® (n = 15) or GLA-SE (n = 15). Following a safety assessment in French volunteers, GLA-SE was chosen for the phase Ib trial where healthy Burkinabe adults received either AMA1-DiCo/GLA-SE (n = 18) or placebo (n = 18). AMA1-DiCo (50 µg) was administered intramuscularly at baseline, Week 4 and 26. Results AMAI-DiCo was safe, well tolerated either with Alhydrogel® or GLA-SE. In European volunteers, the ratios of IgG increase from baseline were about 100 fold in Alhydrogel® group and 200–300 fold in GLA-SE group for the three antigens. In African volunteers, immunization resulted in IgG levels exceeding those observed for the European volunteers with a 4-fold increase. DiCo-specific IgG remained higher 26 weeks after the third immunization than at baseline in both European and African volunteers. Induced antibodies were reactive against whole parasite derived from different strains. Conclusion AMA1-DiCo vaccine was safe and immunogenic whatever the adjuvant although GLA-SE appeared more potent than Alhydrogel® at inducing IgG responses. Clinical Trials Registration. ClinicalTrials.gov NCT02014727; PACTR201402000719423.

In this paper, we propose to characterize the on-line handwriting for the early detection of Parkinson’s disease. Thus, using kinematics, mechanical, and spatial features of handwriting, we are looking for the characterization of Parkinson’s disease. This paper describes the phase of the data acquisition which is currently carried out with in the Neurological department of UHC Hassan II of Fez. Following this paper, we have proposed an approach based on unsupervised learning techniques for analyzing on-line handwriting of 34 Parkinson’s disease patients and 34 Healthy Controls according to quantitative and qualitative features. Based on 230 computed features for each participant, our study has uncovered three different types of writers. The results show that the complications of fine motor abilities in Parkinson’s disease patients is especially characterized by a significant degradation in handwriting kinematic features.

Introduction/Background The breast cancer is a disease which is more alarming than it is generally more aggressive. The breast cancer ‘of the young woman’, is a cancer occurring at a person of less than 35 years. It is more difficult to diagnose, when it occurs before this age. The objective of this study is to describe the epidemiologic characteristics of the primitive breast cancer in woman of less than 35 years in Oran from 1996 up to 2014. Methodology It is a descriptive study of which the data were extracted from the Register from Cancer from Oran which is a register of population going back to 19 years and which is part of the regional network of the Algerian west. The coding of the localizations and morphologies of the tumors is done according to CIMO (CIMO3: International classification of the Diseases for Oncology, 3emerevision) and CIM 10 (International Classification of the Diseases, version 10). The seizure and the analysis are done by the Edge-reg4 (software bench by the CDC of Atlanta) and Ear-information version 6. Results Among the 21108 cancers all localizations notified during these 19 years, one finds 623 cases of breast cancer primitive cancer in woman of less than 35 years. The median age is of 30.94±0, 30 years with an extreme 16 years. The most frequent morphology is the canal carcinoma infiltrating followed by the infiltrating ductal Carcinoma and of the Carcinoma lobar SAI. Conclusion The breast cancer is the first female cancer: among 21108 of all cancer localizations notified during these 19 years with Oran, one retrouve4148 case (either 19.6%) including 623 case at the young woman (or 15,01%). Disclosure Nothing to disclose.

International audience; Radioisotope imaging is a powerful tool to understand the biological mechanisms in-vivo, especially in the brain of small animals, providing a significant model to study the human brain.In this context, we have developed and built a pixelated intracerebral positron probe to be embedded on awake and freely moving small animals, typically rats. This pixelated probe will represent a key instrument for neuroscientists to study neural mechanisms and correlate them to behavioral experiments.We describe in this paper the simulations carried out to design the intracerebral sensor, its architecture, and the detection of positrons in a volume with a couple of sensors assembled back-to-back. We also depict the architecture of the wireless acquisition system. Finally, we present the first measurements performed in real-time by this miniaturized probe with sealed radioactive sources and a 18F solution.Key words: Active pixel sensors / Animal behavior / CMOS Image sensors / Implants / Molecular imaging / Monte Carlo methods / Nuclear Imaging / Positron emission tomography

Parkinson's disease (PD) is the second most common neurodegenerative disease affecting significant portion of elderly population. One of the most frequent hallmarks and usually also the first manifestation of PD is deterioration of handwriting. Since the diagnosis of Parkinson's disease is difficult, researchers have worked to develop a support tool based on algorithms to separate healthy controls from PD patients. Online handwriting analysis is one of the methods that can be used to diagnose PD.In this study, we aimed to analyze the Arabic Handwriting of 18 Parkinson's disease (PD) patients and 18 age matched healthy controls. We focused on copying an Arabic text task. For each participant we have calculated 528 features, and the purpose of this study is to find a subset of selected handwriting features suitable for efficiently identifying subjects with PD. The selected features were fed to a support vector machine classifier with RBF kernel, whose aim is to identify the subjects suffering from PD. Robustness of this classifier is measured with three performance matrices i.e., accuracy, sensitivity, and specificity. The obtained results show almost 80% overall classification accuracy.

MLL is involved in fusion genes with more than 100 partner genes, approximately 80 of which have been characterized at the molecular level. MLL fusion genes are often found in infants (60-80% of acute lymphoblastic leukemia (ALL) cases and 40-50% of acute myeloblastic leukemia (AML) cases) and are appreciably rarer (8-10%) in children older than 1 year of age. MLL rearrangements are important markers in diagnosis and treatment choice. To identify the partner gene is of primary importance for prognosis and minimal residual disease monitoring. The structure of the fusion gene, including localization of the MLL breakpoints, is also informative. A method was developed to examine the fusion transcripts in order to identify the partner gene among the six most common ones and to establish the exon structure of the rearranged MLL. The method includes a multiplex reverse transcriptase-polymerase chain reaction (RT-PCR) to amplify and to fluorescently label a fusion transcript fragment and subsequent hybridization of the product on a biological microchip with immobilized oligonucleotides complementary to exons of MLL and its partner genes AFF1, MLLT1, MLLT3, MLLT4, MLLT10, and ELL. Hybridization results were verified by sequencing the RT-PCR products and, in some cases, performing long-distance inverse PCR (LDI-PCR). The study involved 38 bone marrow samples from ALL patients (including 33 children younger than 1 year of age) and 15 samples from AML patients (including 10 from children younger than 1 year of age). The main partner genes were AFF1 (49%), MLLT1 (27%), MLLT3 (12%), and MLLT10 (12%) in ALL and MLLT3 (80%), MLLT10 (10%), and MLLT4 (10%) in AML. Fusion gene transcripts most commonly included MLL exon 11 (58% of ALL cases and 50% of AML cases), suggesting a breakpoint in MLL intron 11.

BackgroundScreening of atrial fibrillation (AF) for high-risk patients including all patients aged 65 years and older is important for prevention of risk of stroke. Different technologies such as modified blood pressure monitor, single lead ECG-based finger-probe, and smart phone using plethysmogram signal have been emerging for this purpose. All these technologies use irregularity of heartbeat duration as a feature for AF detection. We have investigated a normalization method of heartbeat duration for improved AF detection. MethodAF is an arrhythmia in which heartbeat duration generally becomes irregularly irregular. From a window of heartbeat duration, we estimate the possible rhythm of the majority of heartbeats and normalize duration of all heartbeats in the window based on the rhythm so that we can measure the irregularity of heartbeats for both AF and non-AF rhythms in the same scale. Irregularity is measured by the entropy of distribution of the normalized duration. Then we classify a window of heartbeats as AF or non-AF by thresholding the measured irregularity. The effect of this normalization is evaluated by comparing AF detection performances using duration with the normalization, without normalization, and with other existing normalizations. ResultsSensitivity and specificity of AF detection using normalized heartbeat duration were tested on two landmark databases available online and compared with results of other methods (with/without normalization) by receiver operating characteristic (ROC) curves. ROC analysis showed that the normalization was able to improve the performance of AF detection and it was consistent for a wide range of sensitivity and specificity for use of different thresholds. Detection accuracy was also computed for equal rates of sensitivity and specificity for different methods. Using normalized heartbeat duration, we obtained 96.38% accuracy which is more than 4% improvement compared to AF detection without normalization. ConclusionsThe proposed normalization method was found useful for improving performance and robustness of AF detection. Incorporation of this method in a screening device could be crucial to reduce the risk of AF-related stroke. In general, the incorporation of the rhythm-based normalization in an AF detection method seems important for developing a robust AF screening device. We investigate rhythm-based heartbeat normalization for improved atrial fibrillation detection.Heartbeat durations are normalized based on estimated rhythm of heartbeats in a window.It allows to measure irregularity of heartbeats for both AF and non-AF rhythms in the same scale.The normalization is found helpful for improving performance and robustness of AF detection.The normalization could be crucial for developing a clinically acceptable screening device.

Background Parkinson’s disease (PD) affects millions of people worldwide, and it is predicted that this pathology will gravely increase in the next few years. Unfortunately, there’s currently no cure for this disease, indeed an early diagnosis of Parkinson’s disease can help to better manage its symptoms and its evolution. One of the most frequent abilities and usually also the first manifestation of Parkinson’s disease is alteration of handwriting. New method We propose a novel method to detect Parkinson’s disease, based on the segmentation of the online handwritten text into lines. Indeed, we propose to compare Parkinson’s disease patients and healthy controls, based on the full dynamics of new temporal and spectral features. Three classifiers were used, K-Nearest Neighbors, Support Vector Machine and Decision Trees. The performances of these three classifiers were estimated using a stratified nested 10 cross-validation. All the models in this study have been evaluated using classification accuracy, balanced accuracy, sensitivity, specificity, F-Score and Matthews Correlation Coefficient. Results An accuracy of 92.86 % was obtained with Decision Trees classifier in the last line. The new categories of spectral and temporal features gave the best classification performances in comparison to the basic statistical features. Comparison with existing methods Previous studies have only focused on words or sentences. This is the first study to deal with the analysis of a text composed of several lines. Conclusion The last line discriminates at best between Parkinson’s disease patients and healthy controls. This obtained result has further strengthened our hypothesis concerning the fatigue occurring while writing in PD patients.

Parkinson's disease (PD) is the second most common neurodegenerative disease affecting significant portion of elderly population. One of the most frequent hallmarks and the first manifestation of PD is deterioration of handwriting. Since the diagnosis of Parkinson's disease is difficult, researchers have worked to develop a support tool based on algorithms to separate healthy controls from PD patients. On-line handwriting analysis is one of the methods that can be used to diagnose PD. In this study, we aimed to analyze the Arabic Handwriting of 28 Parkinson's disease patients and 28 healthy controls (HCs) who were the same age and have the same intellectual level. We focused on copying an Arabic text task. For each participant we have calculated 1482 features. Based on the most relevant features selected by the Pearson's coefficient correlation, the Hierarchical Ascendant Classification (HAC) was applied and generated 3 clusters of writers. The characterization of these clusters was carried out by using the quantitative and qualitative parameters. The obtained results show that the combination of these two aspects can discriminate at best PD patients from HCs.

Atrial fibrillation (AF) is a life-threatening arrhythmia that is often paroxysmal and asymptomatic. Therefore, there is a great impetus towards an automatic AF early detection for providing crucial evidence-based treatment. To this end, the existing supervised classification methods typically rely on a large training set built from the majority of ECG records. By contrast, in this paper, we focus on interpatient scenarios affected by the data shift problem between the training and test distributions referred to as source and target domains. The intrinsic discrepancy between the source target domains due to the generation of ECG data in varied acquisition conditions and from different devices renders the classification problem very challenging. To overcome this constraint and to enhance the AF detection system performance, we propose a classification system based on neural networks called an asymmetric domain adaptation neural network (ADANN). First, a denoising auto-encoder (DAE) is used to perform feature learning, and then extra fully connected hidden layers are employed to eliminate the data shift problem. The performances of the proposed AF detection system are evaluated and compared to those of state-of-the-art systems using a publicly available landmark database.

Chorangioma is the most common benign tumor of the placenta. Tumors larger than 5 cm can cause adverse fetal outcomes. We describe the case of a term infant presenting with acute respiratory failure due to fetal heart insufficiency. In this particular case, the presence of a multifocal chorangiomatosis causing fetal heart failure was not diagnosed prenatally by ultrasound but first by the histopathological report of the placenta.

Automatic screening of atrial fibrillation (AF) in the out-of-clinic environment is potentially an effective method for early detection of this life-threatening arrhythmia which is often paroxysmal and asymptomatic. Different technologies such as modified blood pressure monitor, single lead ECG-based finger-probe, and smartphone using plethysmogram signal have been emerging for this purpose. All these technologies use irregularity of RR interval (RRI) as a feature for AF detection. For real-time applications scalar feature is extracted from RRI signal and classified with a threshold. In this work, we have introduced multi-parametric RRI feature yielding a multidimensional feature vector. We used machine learning technique to learn the optimal decision boundary. The proposed method was tested with a publicly available landmark database. Initial experiments show promising AF detection performances comparable to those of state-of-the-art methods. Development and implementation of such a method in existing screen devices such a smartphone could be important for prevention of AFrelated risk of stroke, dementia, and death.

Cancer cell invasion takes place at the cancer-host interface and is a prerequisite for distant metastasis. The relationships between current biological and clinical concepts such as cell migration modes, tumour budding and epithelial-mesenchymal transition (EMT) remains unclear in several aspects, especially for the 'real' situation in human cancer. We developed a novel method that provides exact three-dimensional (3D) information on both microscopic morphology and gene expression, over a virtually unlimited spatial range, by reconstruction from serial immunostained tissue slices. Quantitative 3D assessment of tumour budding at the cancer-host interface in human pancreatic, colorectal, lung and breast adenocarcinoma suggests collective cell migration as the mechanism of cancer cell invasion, while single cancer cell migration seems to be virtually absent. Budding tumour cells display a shift towards spindle-like as well as a rounded morphology. This is associated with decreased E-cadherin staining intensity and a shift from membranous to cytoplasmic staining, as well as increased nuclear ZEB1 expression.

Background: In UAE, stroke is the second leading cause of disability after RTA, where annually 8,000 to 10,000 patients get a stroke. Our aim is to identify the knowledge levels of stroke among Sharjah’s adult citizens.Methods: Using self-administered questionnaires, in a cross-sectional design, a non-probability convenience sampling method was used to enrol subjects. Eligible subjects were above 18 years of age, comprehended Arabic or English, and are currently residing in Sharjah. The questionnaire was 17 questions structured in 5 sections which included: demographics, general knowledge, knowledge of signs and symptoms, risk factors, and appropriate response towards stroke. SPSS V.22 was used to analyse the data. Percentages, means, and ANOVA were used. A P-value less than 0.05 was considered to be statistically significant.Results: The study included 426 subjects, mean age was 35.1 years, 65.2% were females. 51.8% of the subjects claimed they know what stroke is, out of whom 24.3% provided incorrect descriptions. The mean knowledge level of signs and symptoms was 55.4%, and of risk factors was 40.6%. Visual disturbance was the least identified of the five signs and symptoms (38.0%). Female gender, African American race, and age above 60, were the least identified of the 8 risk factors (4.7%, 3.5%, 19.8% respectively). Better knowledge was associated with increased age and higher education. Conclusion: The majority of the sample showed an average to low level of knowledge. Such results indicate the importance of implementing more awareness programs that target younger age groups in the community.

Objective To determine if inclusion/exclusion (I/E) criteria of clinical trial protocols can be represented as structured queries and executed using a secure federated research platform (InSite) on hospital electronic health records (EHR) systems, to estimate the number of potentially eligible patients. Methods Twenty-three clinical trial protocols completed during 2011–2017 across diverse disease areas were analyzed to construct queries that were executed with InSite using EHR records from 24 European hospitals containing records of >14 million patients. The number of patients matching I/E criteria of each protocol was estimated. Results All protocols could be formalized to some extent into a medical coding system (e.g. ICD-10CM, ATC, LOINC, SNOMED) and mapped to local hospital coding systems. The median number of I/E criteria of protocols tested was 29 (range: 14–47). A median of 55% (range 38–89%) of I/E criteria in each protocol could be transformed into a computable format. The median number of eligible patients identified was 26 per hospital site (range: 1–134). Conclusion Clinical trial I/E eligibility criteria can be structured computationally and executed as queries on EHR systems to estimate the patient recruitment pool at each site. The results further suggest that an increase in structured coded information in EHRs would increase the number of I/E criteria that could be evaluated. Additional work is needed on broader deployment of federated platforms such as InSite.

Tumor biology 39(5), [1]-11 (2017). doi:10.1177/1010428317705501, Published by Sage Publishing, London

In this study, a rapid quantitative method using TaqMan-based real-time reverse transcription-polymerase chain reaction (qPCR-RT) has been developed for estimating the titers of measles, mumps and rubella (MMR) viruses in infected cell culture supernatants. The qPCR-RT assay was demonstrated to be a specific, sensitive, efficient and reproducible method. For MMR viral samples obtained during MMR viral propagations in Vero cells at a different multiplicity of infection, titers determined by the qPCR-RT assay have been compared with estimates of infectious virus obtained by a traditional commonly used method for MMR viruses - 50% cell culture infective dose (CCID(50)) assay, in paired samples. Pearson analysis evidenced a significant correlation between both methods for a certain period after viral inoculation. Furthermore, the established qPCR-RT assay was faster and less-laborious. The developed method could be used as an alternative method or a supplementary tool for the routine titer estimation during MMR vaccine production.

SummaryLimited data are available regarding the risk for venous thromboembolism (VTE) and VTE prophylaxis use in hospitalised medically ill patients. We analysed data from the global ENDORSE survey to evaluate VTE risk and prophylaxis use in this population according to diagnosis, baseline characteristics, and country. Data on patient characteristics, VTE risk, and prophylaxis use were abstracted from hospital charts. VTE risk and prophylaxis use were evaluated according to the 2004 American College of Chest Physicians (ACCP) guidelines. Multivariable analysis was performed to identify factors associated with use of ACCP-recommended prophylaxis. Data were evaluated for 37,356 hospitalised medical patients across 32 countries. VTE risk varied according to medical diagnosis, from 31.2% of patients with gastrointestinal/hepatobiliary diseases to 100% of patients with acute heart failure, active non-infectious respiratory disease, or pulmonary infection (global rate, 41.5%). Among those at risk for VTE, ACCP-recommended prophylaxis was used in 24.4% haemorrhagic stroke patients and 40–45% of cardiopulmonary disease patients (global rate, 39.5%). Large differences in prophylaxis use were observed among countries. Markers of disease severity, including central venous catheters, mechanical ventilation, and admission to intensive care units, were strongly associated with use of ACCP-recommended prophylaxis. In conclusion, VTE risk varies according to medical diagnosis. Less than 40% of at-risk hospitalised medical patients receive ACCP-recommended prophylaxis. Prophylaxis use appears to be associated with disease severity rather than medical diagnosis. These data support the necessity to improve implementation of available guidelines for evaluating VTE risk and providing prophylaxis to hospitalised medical patients.

Background: The new technological platform developed by the Electronic Health Records for Clinical Research (EHR4CR) European research project (2011-2016) has been specially designed to enable the trustworthy reuse of health data contained in hospital-based electronic health records (EHR) for enhancing and speeding up clinical research scenarios. In particular, protocol feasibility assessments, patient identification for recruitment, and clinical data exchange for study conduct, in accordance with data privacy, ethical and legal requirements. The objective of our study was to assess the financial impact of adopting these advanced solutions compared to current practices, from the perspective of the primary sponsors of clinical trials in Europe. Methods: Considering a scalable implementation of EHR4CR solutions in up to 5-10% of Phase II, III and IV clinical trials to be commercially sponsored in Europe over 5 years, two potential market sizes were defined. The first has a European initial scope (i.e., for European clinical trials only), and the second has a European subsequent broader scope (also including European arms of global studies). Based on expert opinions, the EHR4CR initial scope target market was estimated to be 30% of the broader scope. Direct costs to clinical research sponsors were estimated under current practices, and with the EHR4CR platform. Uncertainty was managed using 100,000 Monte Carlo simulations. Results: Compared to current practices, the potential average 5-year savings with EHR4CR solutions for Phase II, III and IV commercially sponsored clinical trials in Europe were estimated at €175.5 m for the European initial scope market, and at €585.3 m for the European broader scope market. These results were confirmed by robust probabilistic sensitivity analyses. Conclusions: Compared to current practices, EHR4CR solutions appear cost-saving for primary sponsors of clinical trials. These results suggest that the potential for savings would increase with a broader adoption of EHR4CR solutions in Europe, and beyond.

An increasing body of literature is addressing the immuno-modulating functions of miRNAs which include paracrine signaling via exosome-mediated intercellular miRNA. In view of the recent evidence of intake and bioavailability of dietary miRNAs in humans and animals we explored the immuno-modulating capacity of plant derived miRNAs. Here we show that transfection of synthetic miRNAs or native miRNA-enriched fractions obtained from a wide range of plant species and organs modifies dendritic cells ability to respond to inflammatory agents by limiting T cell proliferation and consequently dampening inflammation. This immuno-modulatory effect appears associated with binding of plant miRNA on TLR3 with ensuing impairment of TRIF signaling. Similarly, in vivo, plant small RNAs reduce the onset of severity of Experimental Autoimmune Encephalomyelities by limiting dendritic cell migration and dampening Th1 and Th17 responses in a Treg-independent manner. Our results indicate a potential for therapeutic use of plant miRNAs in the prevention of chronic-inflammation related diseases.

Introduction The widespread adoption of electronic health records (EHR) provides a new opportunity to improve the efficiency of clinical research. The European EHR4CR ( Electronic Health Records for Clinical Research ) 4-year project has developed an innovative technological platform to enable the re-use of EHR data for clinical research. The objective of this cost–benefit assessment (CBA) is to assess the value of EHR4CR solutions compared to current practices, from the perspective of sponsors of clinical trials. Materials and methods A CBA model was developed using an advanced modeling approach. The costs of performing three clinical research scenarios (S) applied to a hypothetical Phase II or III oncology clinical trial workflow (reference case) were estimated under current and EHR4CR conditions, namely protocol feasibility assessment (S1), patient identification for recruitment (S2), and clinical study execution (S3). The potential benefits were calculated considering that the estimated reduction in actual person–time and costs for performing EHR4CR S1, S2, and S3 would accelerate time to market (TTM). Probabilistic sensitivity analyses using Monte Carlo simulations were conducted to manage uncertainty. Results Should the estimated efficiency gains achieved with the EHR4CR platform translate into faster TTM, the expected benefits for the global pharmaceutical oncology sector were estimated at €161.5 m (S1), €45.7 m (S2), €204.5 m (S1 + S2), €1906 m (S3), and up to €2121.8 m (S1 + S2 + S3) when the scenarios were used sequentially. Conclusions The results suggest that optimizing clinical trial design and execution with the EHR4CR platform would generate substantial added value for pharmaceutical industry, as main sponsors of clinical trials in Europe, and beyond.

Display Omitted EHR4CR has designed a secure platform to optimise clinical trial protocols.The EHRCR platform facilitates patient identification and recruitment.The EHR4CR platform uses state of the art security and has robust information governance policies.The EHR4CR platform does not require the extraction or communication of any patient level data from hospitals.Proof-of-concept demonstrators have been built and evaluated. ObjectivesTo describe the IMI EHR4CR project which is designing and developing, and aims to demonstrate, a scalable, widely acceptable and efficient approach to interoperability between EHR systems and clinical research systems. MethodsThe IMI EHR4CR project is combining and extending several previously isolated state-of-the-art technical components through a new approach to develop a platform for reusing EHR data to support medical research. This will be achieved through multiple but unified initiatives across different major disease areas (e.g. cardiovascular, cancer) and clinical research use cases (protocol feasibility, patient identification and recruitment, clinical trial execution and serious adverse event reporting), with various local and national stakeholders across several countries and therefore under various legal frameworks. ResultsAn initial instance of the platform has been built, providing communication, security and terminology services to the eleven participating hospitals and ten pharmaceutical companies located in seven European countries. Proof-of-concept demonstrators have been built and evaluated for the protocol feasibility and patient recruitment scenarios. The specifications of the clinical trial execution and the adverse event reporting scenarios have been documented and reviewed. ConclusionsThrough a combination of a consortium that brings collectively many years of experience from previous relevant EU projects and of the global conduct of clinical trials, of an approach to ethics that engages many important stakeholders across Europe to ensure acceptability, of a robust iterative design methodology for the platform services that is anchored on requirements of an underlying Service Oriented Architecture that has been designed to be scalable and adaptable, EHR4CR could be well placed to deliver a sound, useful and well accepted pan-European solution for the reuse of hospital EHR data to support clinical research studies.

We report the rapid and dramatic efficacy of propranolol in 8 infants with infantile hepatic hemangiomas. The degree of response varied from a significant improvement to a complete resolution of hepatic lesions. Heart failure and hypothyroidism resolved, and hepatomegaly decreased. No side-effects of the drug were noted.

Anaplastic large cell lymphoma, ALK-(+), is an aggressive type of T-cell lymphoma characterized by large cells with bizarre morphologic features, prominent sinusoidal invasion and expression of CD30 and ALK antigens. The majority of patients present with advanced clinical stage have nodal and extranodal involvements and complain of B-symptoms. The disease is most frequent in the first three decades of life with a median age of 35 years. The development of ALCL-ALK(+) in infants is very rare, with only very few case reports in the literature. We report two cases of male infants who presented with fever and a progressive leukemoid reaction. The leukocytosis was mainly neutrophilic and monocytic without lymphoma cells, and in one case the neutrophils were severely toxic. Extensive workup for infections and acute leukemia did not reveal any cause. The diagnosis of ALCL-ALK(+) was established after demonstration of enlarged neck and abdominal lymph nodes in the first and second patients, respectively, when they underwent histologic evaluation. Although rare, our cases show that ALCL-ALK(+) is still a likely cause of a leukemoid reaction in infants in a manner similar to infectious diseases, and a survey of lymph nodes enlargement would prevent delay in diagnosis.

Background In HCV-infected patients with advanced liver disease, the direct antiviral agents-associated clinical benefits remain debated. We compared the clinical outcome of patients with a previous history of decompensated cirrhosis following treatment or not with direct antiviral agents from the French ANRS CO22 HEPATHER cohort. Methods We identified HCV patients who had experienced an episode of decompensated cirrhosis. Study outcomes were all-cause mortality, liver-related or non-liver-related deaths, hepatocellular carcinoma, liver transplantation. Secondary study outcomes were sustained virological response and its clinical benefits. Results 559 patients met the identification criteria, of which 483 received direct antiviral agents and 76 remained untreated after inclusion in the cohort. The median follow-up time was 39.7 (IQR: 22.7–51) months. After adjustment for multivariate analysis, exposure to direct antiviral agents was associated with a decrease in all-cause mortality (HR 0.45, 95% CI 0.24–0.84, p = 0.01) and non-liver-related death (HR 0.26, 95% CI 0.08–0.82, p = 0.02), and was not associated with liver-related death, decrease in hepatocellular carcinoma and need for liver transplantation. The sustained virological response was 88%. According to adjusted multivariable analysis, sustained virological response achievement was associated with a decrease in all-cause mortality (HR 0.29, 95% CI 0.15–0.54, p Conclusion Treatment with direct antiviral agents is associated with reduced risk for mortality. The sustained virological response was 88%. Thus, direct antiviral agents treatment should be considered for any patient with HCV-related decompensated cirrhosis. Trial registration: ClinicalTrials.gov registry number: NCT01953458.