[Clinical analysis of early-onset infantile epileptic encephalopathy associated with synonymous variant of the ARHGEF9 gene].

OBJECTIVE: To explore the clinical characteristics of a child with early-onset infantile epileptic encephalopathy type 8 associated with synonymous variant of ARHGEF9 gene. METHODS: Clinical data of the patient was summarized. The child and his parents were subjected to trio-whole exome sequencing. RESULTS: The child has presented with global developmental delay, epilepsy, impulsive behavior, hypersensitivity to sound, and mental retardation. He was found to harbor a de novo synonymous variant c.741C>T (p.Cys247Cys) of the ARHGEF9 gene. RNA splicing analysis confirmed that the variant has led to abnormal splicing of exon 5, resulting in a 55-bp deletion. CONCLUSION: The clinical features of ARHGEF9 gene-related early-onset infantile epileptic encephalopathy type 8 includes mental and motor developmental delay, epilepsy, auditory allergy, and hyperactivity impulsivity. For synonymous variant, in vitro study and transcriptional experiment may be carried out to evaluate its functional and splicing effect. Above finding has enriched the phenotypic and genotypic spectrum of the ARHGEF9 gene.

Self-calibrated 3D differential phase contrast microscopy with optimized illumination.

3D phase imaging recovers an object's volumetric refractive index from intensity and/or holographic measurements. Partially coherent methods, such as illumination-based differential phase contrast (DPC), are particularly simple to implement in a commercial brightfield microscope. 3D DPC acquires images at multiple focus positions and with different illumination source patterns in order to reconstruct 3D refractive index. Here, we present a practical extension of the 3D DPC method that does not require a precise motion stage for scanning the focus and uses optimized illumination patterns for improved performance. The user scans the focus by hand, using the microscope's focus knob, and the algorithm self-calibrates the axial position to solve for the 3D refractive index of the sample through a computational inverse problem. We further show that the illumination patterns can be optimized by an end-to-end learning procedure. Combining these two, we demonstrate improved 3D DPC with a commercial microscope whose only hardware modification is LED array illumination.

Performance of Deep Learning and Genitourinary Radiologists in Detection of Prostate Cancer Using 3-T Multiparametric Magnetic Resonance Imaging.

BACKGROUND: Several deep learning-based techniques have been developed for prostate cancer (PCa) detection using multiparametric magnetic resonance imaging (mpMRI), but few of them have been rigorously evaluated relative to radiologists' performance or whole-mount histopathology (WMHP). PURPOSE: To compare the performance of a previously proposed deep learning algorithm, FocalNet, and expert radiologists in the detection of PCa on mpMRI with WMHP as the reference. STUDY TYPE: Retrospective, single-center study. SUBJECTS: A total of 553 patients (development cohort: 427 patients; evaluation cohort: 126 patients) who underwent 3-T mpMRI prior to radical prostatectomy from October 2010 to February 2018. FIELD STRENGTH/SEQUENCE: 3-T, T2-weighted imaging and diffusion-weighted imaging. ASSESSMENT: FocalNet was trained on the development cohort to predict PCa locations by detection points, with a confidence value for each point, on the evaluation cohort. Four fellowship-trained genitourinary (GU) radiologists independently evaluated the evaluation cohort to detect suspicious PCa foci, annotate detection point locations, and assign a five-point suspicion score (1: least suspicious, 5: most suspicious) for each annotated detection point. The PCa detection performance of FocalNet and radiologists were evaluated by the lesion detection sensitivity vs. the number of false-positive detections at different thresholds on suspicion scores. Clinically significant lesions: Gleason Group (GG) ≥ 2 or pathological size ≥ 10 mm. Index lesions: the highest GG and the largest pathological size (secondary). STATISTICAL TESTS: Bootstrap hypothesis test for the detection sensitivity between radiologists and FocalNet. RESULTS: For the overall differential detection sensitivity, FocalNet was 5.1% and 4.7% below the radiologists for clinically significant and index lesions, respectively; however, the differences were not statistically significant (P = 0.413 and P = 0.282, respectively). DATA CONCLUSION: FocalNet achieved slightly lower but not statistically significant PCa detection performance compared with GU radiologists. Compared with radiologists, FocalNet demonstrated similar detection performance for a highly sensitive setting (suspicion score ≥ 1) or a highly specific setting (suspicion score = 5), while lower performance in between. LEVEL OF EVIDENCE: 3 TECHNICAL EFFICACY STAGE: 2.

Mining Interpretable AOG Representations From Convolutional Networks via Active Question Answering.

In this paper, we present a method to mine object-part patterns from conv-layers of a pre-trained convolutional neural network (CNN). The mined object-part patterns are organized by an And-Or graph (AOG). This interpretable AOG representation consists of a four-layer semantic hierarchy, i.e., semantic parts, part templates, latent patterns, and neural units. The AOG associates each object part with certain neural units in feature maps of conv-layers. The AOG is constructed with very few annotations (e.g., 3-20) of object parts. We develop a question-answering (QA) method that uses active human-computer communications to mine patterns from a pre-trained CNN, in order to explain features in conv-layers incrementally. During the learning process, our QA method uses the current AOG for part localization. The QA method actively identifies objects, whose feature maps cannot be explained by the AOG. Then, our method asks people to annotate parts on the unexplained objects, and uses answers to discover CNN patterns corresponding to newly labeled parts. In this way, our method gradually grows new branches and refines existing branches on the AOG to semanticize CNN representations. In experiments, our method exhibited a high learning efficiency. Our method used about 1/6- 1/3 of the part annotations for training, but achieved similar or better part-localization performance than fast-RCNN methods.

Extraction of an Explanatory Graph to Interpret a CNN.

This paper introduces an explanatory graph representation to reveal object parts encoded inside convolutional layers of a CNN. Given a pre-trained CNN, each filter1 in a conv-layer usually represents a mixture of object parts. We develop a simple yet effective method to learn an explanatory graph, which automatically disentangles object parts from each filter without any part annotations. Specifically, given the feature map of a filter, we mine neural activations from the feature map, which correspond to different object parts. The explanatory graph is constructed to organize each mined part as a graph node. Each edge connects two nodes, whose corresponding object parts usually co-activate and keep a stable spatial relationship. Experiments show that each graph node consistently represented the same object part through different images, which boosted the transferability of CNN features. The explanatory graph transferred features of object parts to the task of part localization, and our method significantly outperformed other approaches.

Effects of Psychological Factors on Modal Shift from Car to Dockless Bike Sharing: A Case Study of Nanjing, China.

The emergence of dockless bike sharing in recent years has reduced the usage of private cars, especially usage for short-distance trips (within 2 km). In this paper, a modified technology acceptance model (TAM) is proposed to investigate from the psychological perspective drivers' willingness to shift to dockless bike sharing. The modified TAM includes the perceived usefulness of dockless bike sharing, perceived ease-of-use of dockless bike sharing, perceived health of dockless bike sharing, attitudes toward dockless bike sharing, and willingness to shift to dockless bike sharing. Data are obtained through offline communications with car drivers. The results show that two-thirds of car drivers are willing to use dockless bike sharing in short-distance trips. Perceived health, perceived ease-of-use, and perceived usefulness have significant positive effects on people's attitudes toward dockless bike sharing. As expected, people's attitudes toward dockless bike sharing are positively correlated with their willingness to shift. Policy implications are discussed to prompt the modal shift from private cars to dockless bike sharing according to the results.

Joint Prostate Cancer Detection and Gleason Score Prediction in mp-MRI via FocalNet.

Multi-parametric MRI (mp-MRI) is considered the best non-invasive imaging modality for diagnosing prostate cancer (PCa). However, mp-MRI for PCa diagnosis is currently limited by the qualitative or semi-quantitative interpretation criteria, leading to inter-reader variability and a suboptimal ability to assess lesion aggressiveness. Convolutional neural networks (CNNs) are a powerful method to automatically learn the discriminative features for various tasks, including cancer detection. We propose a novel multi-class CNN, FocalNet, to jointly detect PCa lesions and predict their aggressiveness using Gleason score (GS). FocalNet characterizes lesion aggressiveness and fully utilizes distinctive knowledge from mp-MRI. We collected a prostate mp-MRI dataset from 417 patients who underwent 3T mp-MRI exams prior to robotic-assisted laparoscopic prostatectomy. FocalNet was trained and evaluated in this large study cohort with fivefold cross validation. In the free-response receiver operating characteristics (FROC) analysis for lesion detection, FocalNet achieved 89.7% and 87.9% sensitivity for index lesions and clinically significant lesions at one false positive per patient, respectively. For the GS classification, evaluated by the receiver operating characteristics (ROC) analysis, FocalNet received the area under the curve of 0.81 and 0.79 for the classifications of clinically significant PCa (GS ≥ 3 + 4) and PCa with GS ≥ 4 + 3, respectively. With the comparison to the prospective performance of radiologists using the current diagnostic guideline, FocalNet demonstrated comparable detection sensitivity for index lesions and clinically significant lesions, only 3.4% and 1.5% lower than highly experienced radiologists without statistical significance.

Deep transfer learning-based prostate cancer classification using 3 Tesla multi-parametric MRI.

PURPOSE: The purpose of the study was to propose a deep transfer learning (DTL)-based model to distinguish indolent from clinically significant prostate cancer (PCa) lesions and to compare the DTL-based model with a deep learning (DL) model without transfer learning and PIRADS v2 score on 3 Tesla multi-parametric MRI (3T mp-MRI) with whole-mount histopathology (WMHP) validation. METHODS: With IRB approval, 140 patients with 3T mp-MRI and WMHP comprised the study cohort. The DTL-based model was trained on 169 lesions in 110 arbitrarily selected patients and tested on the remaining 47 lesions in 30 patients. We compared the DTL-based model with the same DL model architecture trained from scratch and the classification based on PIRADS v2 score with a threshold of 4 using accuracy, sensitivity, specificity, and area under curve (AUC). Bootstrapping with 2000 resamples was performed to estimate the 95% confidence interval (CI) for AUC. RESULTS: After training on 169 lesions in 110 patients, the AUC of discriminating indolent from clinically significant PCa lesions of the DTL-based model, DL model without transfer learning and PIRADS v2 score ≥ 4 were 0.726 (CI [0.575, 0.876]), 0.687 (CI [0.532, 0.843]), and 0.711 (CI [0.575, 0.847]), respectively, in the testing set. The DTL-based model achieved higher AUC compared to the DL model without transfer learning and PIRADS v2 score ≥ 4 in discriminating clinically significant lesions in the testing set. CONCLUSION: The DeLong test indicated that the DTL-based model achieved comparable AUC compared to the classification based on PIRADS v2 score (p = 0.89).

Antimicrobial activity of human ß-defensins against lactic acid bacteria.

In this study, we evaluated the antimicrobial activity of human ß-defensin-1 (hBD-1), human ß-defensin-2 (hBD-2) and human ß-defensin-3 (hBD-3) against three internationally common probiotic strains of lactic acid bacterium. Our results indicated that hBD-1, hBD-2 and hBD-3 at the range of 0.08-10 µg/mL do not have obvious antimicrobial activity against these strains. Viability of Bifidobacterium longum JDM301 (B. longum JDM301), Bifidobacterium lactis HN019 (B. lactis HN019) and Lactobacillus rhamnosus GG (LGG) were still very high even at concentration of 10 µg hBD/mL. Then, we explored the mechanism of resistance by using carbonyl cyanide 3-chlorophenylhydrazone (CCCP) to inhibit efflux pumps. In the presence of CCCP, hBD-1, hBD-2 and hBD-3 exhibited enhanced antibacterial effect against B. longum JDM301 and B. lactis HN019, but not against LGG. Efflux pumps in B. longum JDM301 and B. lactis HN019 may partly contribute to their resistance to hBD-1, hBD-2, and hBD-3.

Epstein-Barr virus induces the differentiation of semi-mature dendritic cells from cord blood monocytes.

BACKGROUND: Epstein-Barr virus (EBV) is a tumorigenic virus which has effectively infected nearly all human beings with over 95% adult being seropositive. The persistence of latent EBV infection is not fully understood. Recent studies point towards a hypothesis of immune suppression and immune evasion involving regulatory T cells (Tregs) and dendritic cells (DCs). We sought to explore the mechanism of EBV suppression and immune evasion. METHODS: We compared the effects of EBV on cord blood (CB) and adult DCs differentiation and maturation including phenotype by flow cytometry, cytokine by ELISA and RT-PCR. And we evaluated the function of DC by co-culture DC and Treg by detection the expression of Foxp3, the phenotype and the cytokine profile of Tregs by flow cytometry. RESULTS: CB DCs derived from EBV-infected CB monocytes or from EBV-infected CB immature DCs (iDCs) displayed distinct phenotypes of "semi-mature" DCs with high expression of co-stimulatory molecules, such as CD40, CD80 and CD86 but low cytokine production, related to immune tolerance and homeostasis. While the EBV-infected adult iDCs resemble that of "pathogen-driven regulatory mature DCs" with high expression of co-stimulatory molecules, down-regulation of IL-12 secretion and up-regulation of IL-10 secretion, related to protection of host and immune evasion of pathogens. EBV infected cord blood monocytes-derived DCs drived Tregs development by driving the expression of Foxp3, increasing the expression of CTLA-4, decreasing the expression of GITR and promoted the generation of intracellular IL-2 and IL-10 by Tregs. CONCLUSION: Epstein-Barr virus induces the differentiation of semi-mature dendritic cells from cord blood monocytes. The differences between CB and adult DCs suggested that the developmental maturity of the cells may affect their immune responses to EBV infection.

Identification of sociodemographic and clinical factors associated with the levels of human ß-defensin-1 and human ß-defensin-2 in the human milk of Han Chinese.

Human milk provides infants with various immune molecules. The objective of the present study was to measure human ß-defensin-1 (hBD-1) and human ß-defensin-2 (hBD-2) levels in the colostrum and mature milk of healthy Han Chinese, to identify factors regulating milk hBD-1 and hBD-2 expression and to explore the potential protective effect of milk hBD-1 and hBD-2 on infants. A total of 100 mothers and their babies were recruited into the study. Sociodemographic characteristics and other factors were obtained by a questionnaire. Babies were followed up for a period of 6 months. Colostrum samples (n 100) and mature milk samples (n 82) were collected by hand expression. The hBD-1 and hBD-2 concentrations were measured by ELISA. The hBD-1 and hBD-2 levels differed in the colostrum and mature milk. In the colostrum, the concentration ranges of hBD-1 and hBD-2 were 1·04-12·81 µg/ml and 0·31-19·12 ng/ml, respectively. In mature milk, the hBD-1 and hBD-2 levels were 1·03-31·76 ng/ml and 52·65-182·29 pg/ml, respectively. Several independent factors influence their production. The multivariable analysis showed a strong association between pre-pregnancy BMI and hBD-1 levels in the colostrum (P=0·001), mode of delivery was significantly associated with hBD-2 levels in the colostrum (P=0·006) and gestational age was significantly associated with hBD-1 levels in mature milk (P= 0·010). During the first 6 months of life, the incidence rate of upper respiratory infection was found to be less in the high-colostrum hBD-1 group than in the low-colostrum hBD-1 group (χ²=4·995, P=0·025). The present study suggested that the abundance of hBD-1 in the colostrum may have a protective function against upper respiratory infection for infants younger than 6 months.

Clinical characteristics and genetic profiles of 44 patients with severe combined immunodeficiency (SCID): report from Shanghai, China (2004-2011).

Severe combined immunodeficiency (SCID), a rare type of genetic associated immune disorder, is poorly characterized in mainland China. We retrospectively reviewed 44 patients with SCID who received treatment from 2004 to 2011 in Shanghai, China, and herein summarize their clinical manifestations and immunological and preliminary genetic features. The male-to-female ratio was 10:1. Twenty five patients presented with X-SCID symptoms. Only one patient was diagnosed before the onset of symptoms due to positive family history. The mean time of delay in the diagnosis of X-SCID was 2.69 months (range, 0.5-8.67). Thirty-seven of the 44 patients died by the end of 2011 with the mean age of death being 7.87 months (range, 1.33-31). Six patients received hematopoietic stem cell transplantation (HSCT); only one of them survived, who was transplanted twice. The time between onset and death was shorter in the HSCT-treated group compared with the untreated group (2.87 ± 1.28 and 3.34 ± 0.59 months, respectively), probably due to active infections during transplantation. Bacillus Calmette-Guérin (BCG) complications occurred in 14 of the 34 patients who received BCG vaccination. Transfusion-induced graft-versus-host disease occurred in 5 patients. Total 20 mutations in interleukin-2 receptor subunit gamma (IL2RG) were identified in 22 patients, including 11 novel mutations. Most patients were misdiagnosed before referred to our SCID Center. Therefore, establishing more diagnostic centers dedicated to the care of PID and accessible by primary immunodeficiency patients will facilitate early, correct diagnosis and better care of SCID in China.

Partially hydrolyzed cow's milk formula has a therapeutic effect on the infants with mild to moderate atopic dermatitis: a randomized, double-blind study.

OBJECTIVE: The allergy-preventing effect of partially hydrolyzed cow's milk formula (phCMF) in infants at high risk of atopic dermatitis (AD) has been demonstrated in many studies. However, the therapeutic potential of phCMF in treating the infants with AD has not been reported. We sought to assess such therapeutic efficacy of phCMF in infants with mild to moderate AD. METHODS: From 2006 to 2008, 113 infants <6 months of age with AD were randomized to receive either partially hydrolyzed cow's milk formula (phCMF) or conventional cow's milk formula (CMF) in a double-blind clinical trial. Assessments were made at enrollment and at weeks 4, 8, and 12. The severity of AD was assessed using two scoring systems: Standard guideline for management (diagnosis, severity scoring, and therapy) of AD by the Japanese Dermatological Association Scoring System (JDASS) and the SCORing Atopic Dermatitis (SCORAD). Growth status of the infants was evaluated. Allergy profile was assessed by measuring total blood eosinophils (EOS), total/specific IgE, Th1/Th2 cytokine profiles, and the percentage of regulatory T cells. RESULTS: After follow-up for 12 wk, 27 infants (23.89%) dropped off study. Analysis was performed on 86 infants by the end of 12-wk observation. The AD severity scores were significantly reduced in the phCMF group (n = 56) compared with CMF group (n = 30) after 12 wk (p < 0.05). The severity scores of phCMF group were significantly reduced at weeks 4, 8, and 12 compared to enrollment (p < 0.05). In contrast, no significant improvement was observed for CMF group at any of those time points (p > 0.05). The number of AD flare-ups was significantly decreased in the phCMF group (p = 0.002). Th1/Th2 ratio in phCMF was significantly increased compared with CMF group (p = 0.041). The growth rates did not differ significantly between these feeding groups at any assessed time point (p > 0.05) and were in the normal range. CONCLUSION: This study suggests a novel therapeutic effect of phCMF in treating infants with mild to moderate AD during the first 6 months of their life without affecting their nutritional status.

Characterization of immunocompetent cells in human milk of Han Chinese.

Immunocompetent cells in colostrum and mature breast milk (42 days after delivery) of 64 Chinese females of Han ethnic background were characterized. The total cell numbers in colostrum and mature breast milk were 593 ± 205 × 10(6)/L and 1.74 ± 0.97 × 10(6)/L, respectively. NK cell is the predominant lymphocyte subtype (12.69%). T cells in colostrum express CD40L and CD25 without stimulation, indicating memory T cells in nature. The CD45RA( +)CD45RO(+) subsets of CD4(+) T cells are present in both colostrum and mature human milk. The percentage of NK cells and the absolute number of CD4(+)CD45RO(+) T cells in colostrum of atopic mothers were significantly lower than those of mothers without atopy (P = .006 and .026, respectively). The absolute numbers of CD4( +) T lymphocytes and their expression of CD40L were significantly reduced in breast milk of mothers who had undergone cesarean section versus vaginal delivery (P < .05), indicating that atopy and cesarean delivery are associated with the phenotypes of lymphocytes in colostrum.

Distribution and clinical features of primary immunodeficiency diseases in Chinese children (2004-2009).

Two hundred and one patients have been diagnosed with primary immunodeficiency diseases (PIDs) in our center from January 2004 to December 2009. The male-to-female ratio was 5.29:1. Spectrums of PIDs were as follows: predominantly antibody deficiency disease was the most common category (94 patients, 48.2%), followed by other well-defined immunodeficiency syndromes (40 patients, 20.5%), combined T and B cell immunodeficiencies (33 patients, 16.9%), congenital defects of phagocyte number and/or function (21 patients, 10.8%), and diseases of immune dysregulation (six patients, 3.1%). Agammaglobulinemia was the most frequent disease type. The median of diagnosis lag was 18.0 months. Pneumonia was the most common manifestation of PID patients. Some manifestations were prone to concentrate in certain diseases. As for therapy, 99 patients (50.8%) received intravenous immunoglobulin replacement therapy; 13 patients received hematopoietic stem cell transplantation and nine of them were still alive. In this study, we sought to describe and analyze the distribution, clinical features, and therapy methods of PIDs among children diagnosed in our country and to compare with reports from other countries and regions.

A novel point mutation in CD18 causing leukocyte adhesion deficiency in a Chinese patient.

BACKGROUND: Leukocyte adhesion deficiency type 1 (LAD-1) is a rare, autosomal recessive inherited immunodeficiency disease characterized by recurrent severe bacterial infection, impaired pus formation, poor wound healing, associated with the mutation in the CD18 gene responsible for the ability of the leucocytes to migrate from the blood stream towards the site of inflammation. Correct and early diagnosis of LAD-1 is vital to the success of treatment and prevention of aggressive infections. The purpose of this study was to collect the clinical findings of the disease and to identify the genetic entity. METHODS: CD18 expression in the peripheral blood leukocytes from the patient, his parents and normal control was measured with flow cytometry. The entire coding regions of the CD18 gene were screened with direct sequencing genomic DNA. RESULTS: CD18 expression level on this patient's leukocyte surface was significantly decreased, with normal level in control group, his father and mother. Gene analysis revealed that this patient had a homozygous c.899A > T missense mutation in exon 8 of CD18 gene, causing the substitution of Asp to Val at the 300 amino acid. His parents were both heterozygous carriers while no such mutation was found in 50 normal controls. CONCLUSION: This study disclosed a novel point mutation Asp 300 Val located in a highly conserved region (HCR) of CD18 and confirmed the heterogeneity of the mutations causing LAD-1, indicating it was quite beneficial to establish correct and early diagnosis in children with severe LAD-1.