MDGA2 Constrains Glutamatergic Inputs Selectively onto CA1 Pyramidal Neurons to Optimize Neural Circuits for Plasticity, Memory, and Social Behavior.

Synapse organizers are essential for the development, transmission, and plasticity of synapses. Acting as rare synapse suppressors, the MAM domain containing glycosylphosphatidylinositol anchor (MDGA) proteins contributes to synapse organization by inhibiting the formation of the synaptogenic neuroligin-neurexin complex. A previous analysis of MDGA2 mice lacking a single copy of Mdga2 revealed upregulated glutamatergic synapses and behaviors consistent with autism. However, MDGA2 is expressed in diverse cell types and is localized to both excitatory and inhibitory synapses. Differentiating the network versus cell-specific effects of MDGA2 loss-of-function requires a cell-type and brain region-selective strategy. To address this, we generated mice harboring a conditional knockout of Mdga2 restricted to CA1 pyramidal neurons. Here we report that MDGA2 suppresses the density and function of excitatory synapses selectively on pyramidal neurons in the mature hippocampus. Conditional deletion of Mdga2 in CA1 pyramidal neurons of adult mice upregulated miniature and spontaneous excitatory postsynaptic potentials, vesicular glutamate transporter 1 intensity, and neuronal excitability. These effects were limited to glutamatergic synapses as no changes were detected in miniature and spontaneous inhibitory postsynaptic potential properties or vesicular GABA transporter intensity. Functionally, evoked basal synaptic transmission and AMPAR receptor currents were enhanced at glutamatergic inputs. At a behavioral level, memory appeared to be compromised in Mdga2 cKO mice as both novel object recognition and contextual fear conditioning performance were impaired, consistent with deficits in long-term potentiation in the CA3-CA1 pathway. Social affiliation, a behavioral analog of social deficits in autism, was similarly compromised. These results demonstrate that MDGA2 confines the properties of excitatory synapses to CA1 neurons in mature hippocampal circuits, thereby optimizing this network for plasticity, cognition, and social behaviors.

Development and validation of a novel multiplex digital PCR assay for identification of pathogens in cerebrospinal fluid of children with bacterial meningitis.

BACKGROUND AND AIMS: Identifying the pathogens of bacterial meningitis (BM) is crucial for its diagnosis and treatment. The aim of this study is to develop and validate a novel method for detecting pathogens in cerebrospinal fluid (CSF) of children with BM using a digital polymerase chain reaction (dPCR) assay. MATERIALS AND METHODS: A novel multiplex dPCR assay method has been developed and validated. The diagnostic performance of the dPCR assay was compared with that of synchronous CSF culture, and the factors affecting its performance were analyzed. RESULTS: A total of 69 children with BM were enrolled prospectively. The sensitivity of the dPCR assay was 94.44 %, specificity was 100 %, coincidence rate was 98.55 %, Kappa value was 0.959, and net reclassification improvement was 61.11 %. Compared with the CSF culture assay, the dPCR assay had higher sensitivity in different bacterial groups. Multiple factors affected its performance, including previous use of antibiotics, sampling time, BM complications, and levels of inflammatory biomarkers in CSF and blood (all P < 0.05). Patients who required intensive care and died had a higher bacterial DNA loads identified by dPCR assay (both P < 0.05). CONCLUSION: This novel assay has better pathogen detection ability than CSF culture. Its performance was influenced by sampling time, previous use of antibiotics, and disease severity.

Biopsy-free AI-aided precision MRI assessment in prediction of prostate cancer biochemical recurrence.

BACKGROUND: To investigate the predictive ability of high-throughput MRI with deep survival networks for biochemical recurrence (BCR) of prostate cancer (PCa) after prostatectomy. METHODS: Clinical-MRI and histopathologic data of 579 (train/test, 463/116) PCa patients were retrospectively collected. The deep survival network (iBCR-Net) is based on stepwise processing operations, which first built an MRI radiomics signature (RadS) for BCR, and predicted the T3 stage and lymph node metastasis (LN+) of tumour using two predefined AI models. Subsequently, clinical, imaging and histopathological variables were integrated into iBCR-Net for BCR prediction. RESULTS: RadS, derived from 2554 MRI features, was identified as an independent predictor of BCR. Two predefined AI models achieved an accuracy of 82.6% and 78.4% in staging T3 and LN+. The iBCR-Net, when expressed as a presurgical model by integrating RadS, AI-diagnosed T3 stage and PSA, can match a state-of-the-art histopathological model (C-index, 0.81 to 0.83 vs 0.79 to 0.81, p > 0.05); and has maximally 5.16-fold, 12.8-fold, and 2.09-fold (p < 0.05) benefit to conventional D'Amico score, the Cancer of the Prostate Risk Assessment (CAPRA) score and the CAPRA Postsurgical score. CONCLUSIONS: AI-aided iBCR-Net using high-throughput MRI can predict PCa BCR accurately and thus may provide an alternative to the conventional method for PCa risk stratification.

Rapid detection of telomerase expression of neuroblastoma in paraffin-embedded tissue: combination of in situ hybridisation and quantitative PCR.

Neuroblastoma is a heterogeneous paediatric malignant tumour. Telomere maintenance mechanism (TMM) by telomerase activation or alternative lengthening of telomeres (ALT) is a hallmark of high-risk neuroblastoma. However, the prior assays for telomerase, such as TERT expression by RNA sequencing or microarrays, may not be easy to perform in many histopathology laboratories in hospitals. The aims of this study are to assess the utility of ultrasensitive single-cell RNA in situ hybridisation (RNAscope), immunohistochemistry, and RT-qPCR on formalin-fixed, paraffin-embedded tumour samples as diagnostic tools for detecting TERT expression in neuroblastoma. In this study, we detected MYCN amplification in 22 of 222 cases (10%), TERT rearrangements in 18 of 220 cases (8%), and ALT activation in 39 of 222 cases (18%) using fluorescence in situ hybridisation (FISH). By RNA in situ hybridisation, 36 of 210 (17%) pretreatment neuroblastomas were found to have TERT overexpression, which was significantly associated with the high-risk group (33/78, 42%), TERT rearrangements (16/18, 89%), and MYCN amplification (13/22, 59%). None of the tumours with ALT showed TERT staining. In our study, 19 of the 55 MYCN non-amplified high-risk neuroblastomas displayed TERT mRNA expression, including 13 of the 14 TERT rearrangements, none of the 30 ALT-positive cases, and a significant proportion (6/11, 55%) that did not have the aforementioned genomic anomalies. RT-qPCR results correlated well with RNAscope levels (Spearman's rho=0.621, p<0.001, n=94). In conclusion, TERT RNA in situ hybridisation and RT-qPCR are suitable methods to evaluate TERT expression in neuroblastoma. The combination of detection of the genomic alterations and TERT mRNA expression is a powerful strategy for TMM activation detection, which can categorise neuroblastomas into multiple clinical subgroups for risk stratification in routine histopathology practice.

Neuroinflammation in Bilirubin Neurotoxicity.

Bilirubin neurotoxicity is a serious consequence of hyperbilirubinemia, which is the most common disease of the neonatal period. Clinically, bilirubin neurotoxicity can result in motor deficit, auditory dysfunction, cerebral palsy, seizure and neurodevelopmental diseases, amongst others. Bilirubin neurotoxicity is one of the major worldwide causes of neonatal brain injury, especially in poorer developing countries. However, the mechanisms of bilirubin neurotoxicity are still unclear. After the failure of attempts targeting neurons in many neurodegenerative disorders, neuroinflammation has become a significant target of research. Here, recent advances concerning neuroinflammation in bilirubin neurotoxicity are reported with a focus on the clinical characteristics of bilirubin neurotoxicity, including age-dependency, region-specificity and its yin-yang properties. Effects of neuroinflammation on blood brain interfaces and treatments targeting neuroinflammation in bilirubin neurotoxicity are also reviewed, which may promote the precision of future treatment of bilirubin neurotoxicity.

PI-RADSAI: introducing a new human-in-the-loop AI model for prostate cancer diagnosis based on MRI.

BACKGROUND: This study aims to develop and validate an artificial intelligence (AI)-aided Prostate Imaging Reporting and Data System (PI-RADSAI) for prostate cancer (PCa) diagnosis based on MRI. METHODS: The deidentified MRI data of 1540 biopsy-naïve patients were collected from four centres. PI-RADSAI is a two-stage, human-in-the-loop AI capable of emulating the diagnostic acumen of subspecialists for PCa on MRI. The first stage uses a UNet-Seg model to detect and segment biopsy-candidate prostate lesions, whereas the second stage leverages UNet-Seg segmentation is trained specifically with subspecialist' knowledge-guided 3D-Resnet to achieve an automatic AI-aided diagnosis for PCa. RESULTS: In the independent test set, UNet-Seg identified 87.2% (628/720) of target lesions, with a Dice score of 44.9% (range, 22.8-60.2%) in segmenting lesion contours. In the ablation experiment, the model trained with the data from three centres was superior (kappa coefficient, 0.716 vs. 0.531) to that trained with single-centre data. In the internal and external tests, the triple-centre PI-RADSAI model achieved an overall agreement of 58.4% (188/322) and 60.1% (92/153) with a referential subspecialist in scoring target lesions; when one-point margin of error was permissible, the agreement rose to 91.3% (294/322) and 97.3% (149/153), respectively. In the paired test, PI-RADSAI outperformed 5/11 (45.5%) and matched the performance of 3/11 (27.3%) general radiologists in achieving a clinically significant PCa diagnosis (area under the curve, internal test, 0.801 vs. 0.770, p < 0.01; external test, 0.833 vs. 0.867, p = 0.309). CONCLUSIONS: Our closed-loop PI-RADSAI outperforms or matches the performance of more than 70% of general readers in the MRI assessment of PCa. This system might provide an alternative to radiologists and offer diagnostic benefits to clinical practice, especially where subspecialist expertise is unavailable.

Performance of Artificial Intelligence-Aided Diagnosis System for Clinically Significant Prostate Cancer with MRI: A Diagnostic Comparison Study.

BACKGROUND: The high level of expertise required for accurate interpretation of prostate MRI. PURPOSE: To develop and test an artificial intelligence (AI) system for diagnosis of clinically significant prostate cancer (CsPC) with MRI. STUDY TYPE: Retrospective. SUBJECTS: One thousand two hundred thirty patients from derivation cohort between Jan 2012 and Oct 2019, and 169 patients from a publicly available data (U-Net: 423 for training/validation and 49 for test and TrumpeNet: 820 for training/validation and 579 for test). FIELD STRENGTH/SEQUENCE: 3.0T/scanners, T2 -weighted imaging (T2 WI), diffusion-weighted imaging, and apparent diffusion coefficient map. ASSESSMENT: Close-loop AI system was trained with an Unet for prostate segmentation and a TrumpetNet for CsPC detection. Performance of AI was tested in 410 internal and 169 external sets against 24 radiologists categorizing into junior, general and subspecialist group. Gleason score >6 was identified as CsPC at pathology. STATISTICAL TESTS: Area under the receiver operating characteristic curve (AUC-ROC); Delong test; Meta-regression I2 analysis. RESULTS: In average, for internal test, AI had lower AUC-ROC than subspecialists (0.85 vs. 0.92, P < 0.05), and was comparable to junior (0.84, P = 0.76) and general group (0.86, P = 0.35). For external test, both AI (0.86) and subspecialist (0.86) had higher AUC than junior (0.80, P < 0.05) and general reader (0.83, P < 0.05). In individual, it revealed moderate diagnostic heterogeneity in 24 readers (Mantel-Haenszel I2  = 56.8%, P < 0.01), and AI outperformed 54.2% (13/24) of readers in summary ROC analysis. In multivariate test, Gleason score, zonal location, PI-RADS score and lesion size significantly impacted the accuracy of AI; while effect of data source, MR device and parameter settings on AI performance is insignificant (P > 0.05). DATA CONCLUSION: Our AI system can match and to some case exceed clinicians for the diagnosis of CsPC with prostate MRI. EVIDENCE LEVEL: 3 TECHNICAL EFFICACY: Stage 2.

Early life exposure to chronic unpredictable stress induces anxiety-like behaviors and increases the excitability of cerebellar neurons in zebrafish.

Anxiety is a common emotional disorder in children. To understand its underlying mechanisms, chronic unpredictable stress (CUS) has been established as a stress model in zebrafish. By using the tall tank test, the stress response reliability could be improved in adult fish which has not been confirmed in larvae. In addition, the increasing evidences have shown that cerebellum plays important roles in anxiety. Whether CUS will affect cerebellar neuronal activity remains unknown. We found that CUS exposure to larvae (from 10 to 17 days post fertilization) induced anxiety-like behaviors and social cohesion impairments within 1-2 d after CUS, including a prolonged freezing time, an increased time spent at the bottom of tank, an increased thigmotaxis index, and an increased interindividual distance. Our results showed that the four behavioral tests were homogeneous, especially the tall tank test either anxiety-like behaviors or the basal locomotion. Furthermore, we found that CUS enhanced the excitability of cerebellar neurons, as the amplitude, frequency, time to peak and half-width of spontaneous firing significantly decreased, as well as the amplitude of excitatory post-synaptic current when compared with the control group. CUS also activated hyperpolarization-activated cyclic nucleotide-gated and potassium channels of cerebellar neurons. Multiple linear regression analysis showed that the total distance in bottom (tall tank test) was correlated positively with outward Na+-K+ currents (r = 0.848, P = 0.016), and the thigmotaxis index (open field test) correlated with action potential amplitude (r = 0.854, P = 0.030). Altogether, early life CUS transiently induced an anxiety-like behavior which could be more accurately assessed by combining the tall tank test with other behavior tests in young zebrafish. CUS increased the excitability of cerebellar neurons might provide new targets to treat emotional diseases such as anxiety.

Efficacy, Retention Rate, and Influencing Factors of Ketogenic Diet Therapy in Children with Refractory Epilepsy: A Retrospective Study.

BACKGROUND: This study aimed to evaluate the efficacy and retention rate of a ketogenic diet (KD) and assess factors that influence the efficacy of KD therapy in children with refractory epilepsy (RE). METHODS: We retrospectively studied the efficacy and retention rate of 56 RE children who accepted KD therapy from January 2013 to December 2019. Patients who had a ≥50% reduction in seizure frequency were defined as responders. The retention rate was calculated as the proportion of children who continued KD/the total number of children who were followed up at the time of enrollment. We also analyzed the effects of different factors (such as gender, KD initial age, KD duration, the type of epilepsy syndrome, and others) on the efficacy of the KD. RESULTS: (1) The efficacy rates for the KD at 3, 6, 12, and 18 months were 51.8, 53.6, 39.2, and 23.2%, respectively. (2) The retention rates for the KD at 3, 6, 12 and 18 months were 100, 69.6, 41.1, and 23.2%, respectively. (3) There was no correlation between efficacy and gender, epilepsy onset age, the type of epilepsy syndrome, electroencephalogram improvement, or the number of antiseizure medications, while cranial magnetic resonance imaging (MRI) abnormalities, KD duration, and KD initial age affected its efficacy at 3 months. CONCLUSION: (1) KD therapy for refractory childhood epilepsy was effective and produced a high retention rate. (2) MRI abnormalities and the initial age and duration of KD influenced its short-term efficacy in RE children.

Case Report: De novo variant in myelin regulatory factor in a Chinese child with 46,XY disorder/difference of sex development, cardiac and urogenital anomalies, and short stature.

The myelin regulatory factor (MYRF; MIM# 608329) gene was first identified as a critical transcription factor involved in oligodendrocyte differentiation and central nervous system myelination. With the recent development of exome sequencing, pathogenic variants of MYRF had been considered as the cause of cardiac-urogenital syndrome (CUGS), 46,XY and 46,XX disorders/differences of sex development (DSDs), and nanophthalmos. Herein, we described a 4-year-7-month-old "girl" with ventricular septal defect, atrial septal defect, patent ductus arteriosus, severe pulmonary hypertension, moderate-to-severe tricuspid regurgitation, enlarged coronary sinus, left superior vena cava, and right lung hypoplasia at birth. Later, the patient developed short stature and amblyopia. Further examination revealed a karyotype 46,XY and visible uterus, whereas the presence of gonads were not explored. Laparoscopy revealed dysplasia of testicular gonad. Whole-exome sequencing (WES) was performed and a de novo heterozygous mutation in MYRF was identified, known as c.2817G > A/p. W939* (NM_001127392.3). Therefore, this case report presented multiple clinical manifestations with syndromic symptoms of CUGS, 46,XY DSD, and ocular symptoms. These new data expanded the phenotype of the MYRF variant and may benefit to characterize the phenotypes caused by the variants of this gene.

Clinical characteristics and associated factors of pediatric acute disseminated encephalomyelitis patients with MOG antibodies: a retrospective study in Hangzhou, China.

BACKGROUND: To explore the clinical characteristics and related factors of children with acute disseminated encephalomyelitis (ADEM) with positive anti-myelin oligodendrocyte glycoprotein (MOG) antibody. METHODS: A retrospective study was conducted and enrolled pediatric ADEM patients who underwent serum MOG antibody detection from May 2017 to August 2020. The patients were divided into two groups: MOG- immunoglobulin G (IgG) positive (n = 35) and MOG-IgG negative (n = 50). We analyzed the clinical characteristics of MOG-IgG-positive ADEM pediatric patients and conducted a comparative analysis between the two groups. RESULTS: Thirty-five patients (21 males and 14 females) in the MOG-IgG-positive group with encephalopathy, multifocal neurological symptoms, and typical magnetic resonance imaging (MRI) abnormalities were enrolled. They usually had a favorable outcome, while some suffered from relapse. Compared to the MOG-IgG-negative group, MOG-IgG-positive ADEM patients had a longer disease duration (median: 10 vs. 6 days), more meningeal involvement (31.4% vs. 8%) and frontal lobe involvement (82.8% vs. 68%), higher relapse rates (14.3% vs. 2%), lower serum tumor necrosis factor (1-12.4 pg/ml, median 1.7 vs. 1-34 pg/ml, median 2.2) and interferon-gamma (1-9.4 pg/ml, median 1.3 vs. 1-64 pg/ml, median 3) (P < 0.05, respectively). Multivariate logistic regression analysis showed that the longer disease duration, meningeal involvement and frontal lobe involvement were the correlated factors of patients with ADEM with MOG antibody (P < 0.05). CONCLUSIONS: Our findings provide clinical evidence that MOG-IgG positivity is associated with longer disease duration, meningeal involvement, and frontal lobe involvement.

Validity of Broselow tape for estimating the weight of children in pediatric emergency: A cross-sectional study.

Objective: To assess the validity of the Broselow tape in estimating the weight of Chinese children in pediatric emergency. Methods: A cross-sectional study was conducted in the emergency department of the Children's Hospital of Zhejiang University School of Medicine (Hangzhou, Zhejiang Province, China) in March 2022. Broselow tape was used to estimate weight and its validity was compared with the advanced child life support (APLS) method. Results: The study included 442 children (mean age: 48 months; male-to-female ratio: 1.13:1). The < 10, 10-19 and > 19-kg groups included 44, 257, and 141 children, respectively. The color concordance rates of the Broselow tape-estimated weight in the three groups were 56.8, 57.2, and 68.1%, respectively. The percentage of weight estimations within 10% of actual weight were 65.8% (59.1, 65.8, and 68.1% for the <10, 10-19 and > 19-kg groups, respectively) and 44.8% (40.9, 50.6, and 35.5% for the < 10, 10-19 and > 19-kg groups, respectively) using the Broselow tape and the APLS method, respectively. The correlation between the Broselow tape estimated weight and actual weight was r = 0.931 (P < 0.0001, 95% CI: 0.918-0.943), while the correlation between actual weight and the APLS method calculated weight was r = 0.883 (P < 0.0001, 95% CI: 0.861-0.902). The mean percentage error using the Broselow tape was 1.0 ± 12.0% (P < 0.001 vs. -7.2 ± 17.2% of the APLS method). Conclusion: The Broselow tape may be an available method for predicting the weights of Chinese children in pediatric emergency.

Time-Dependent Diffusion MRI for Quantitative Microstructural Mapping of Prostate Cancer.

Background Recently developed time-dependent diffusion MRI has potential in characterizing cellular tissue microstructures; however, its value in imaging prostate cancer (PCa) remains unknown. Purpose To investigate the feasibility of time-dependent diffusion MRI-based microstructural mapping for noninvasively characterizing cellular properties of PCa and for discriminating between clinically significant PCa and clinically insignificant disease. Materials and Methods Men with a clinical suspicion of PCa were enrolled prospectively between October 2019 and August 2020. Time-dependent diffusion MRI data were acquired with pulsed and oscillating gradient diffusion MRI sequences at an equivalent diffusion time of 7.5-30 msec on a 3.0-T scanner. Time-dependent diffusion MRI-based microstructural parameters, including cell diameter, intracellular volume fraction, cellularity, and diffusivities, were estimated with a two-compartment model. These were compared for different International Society of Urological Pathology grade groups (GGs), and their performance in discriminating clinically significant PCa (GG >1) from clinically insignificant disease (benign and GG 1) was determined with a linear discriminant analysis. The fitted microstructural parameters were validated by means of correlation with histopathologic measurements. Results In the 48 enrolled men, the time-dependent diffusion MRI measurements showed that higher GG was correlated with higher intracellular volume fraction and higher cellularity (intracellular volume fraction = 0.22, 0.36, 0.34, 0.37, and 0.40 in GGs 1-5, respectively; P < .001 at one-way analysis of variance), while lower cell diameter was found at higher GGs (diameter = 23.4, 18.3, 19.2, 17.9, and 18.5 µm in GGs 1-5, respectively; P = .002). Among all measurements derived from time-dependent diffusion MRI, cellularity achieved the highest diagnostic performance, with an accuracy of 92% (44 of 48 participants) and area under the receiver operating characteristic curve of 0.96 (95% CI: 0.87, 0.99) in discriminating clinically significant PCa from clinically insignificant disease. Microstructural mapping was supported by positive correlations between time-dependent diffusion MRI-based and pathologic examination-based intracellular volume fraction (r = 0.83; P < .001). Conclusion Time-dependent diffusion MRI-based microstructural mapping correlates with pathologic findings and demonstrates promise for characterizing prostate cancer. © RSNA, 2022 Online supplemental material is available for this article. See also the editorial by Chatterjee and Oto in this issue.

RtNet: a deep hybrid neural network for the identification of acute rejection and chronic allograft nephropathy after renal transplantation using multiparametric MRI.

BACKGROUND: Reliable diagnosis of the cause of renal allograft dysfunction is of clinical importance. The aim of this study is to develop a hybrid deep-learning approach for determining acute rejection (AR), chronic allograft nephropathy (CAN) and renal function in kidney-allografted patients by multimodality integration. METHODS: Clinical and magnetic resonance imaging (MRI) data of 252 kidney-allografted patients who underwent post-transplantation MRI between December 2014 and November 2019 were retrospectively collected. An end-to-end convolutional neural network, namely RtNet, was designed to discriminate between AR, CAN and stable renal allograft recipient (SR), and secondarily, to predict the impaired renal graft function [estimated glomerular filtration rate (eGFR) ≤50 mL/min/1.73 m2]. Specially, clinical variables and MRI radiomics features were integrated into the RtNet, resulting in a hybrid network (RtNet+). The performance of the conventional radiomics model RtRad, RtNet and RtNet+ was compared to test the effect of multimodality interaction. RESULTS: Out of 252 patients, AR, CAN and SR was diagnosed in 20/252 (7.9%), 92/252 (36.5%) and 140/252 (55.6%) patients, respectively. Of all MRI sequences, T2-weighted imaging and diffusion-weighted imaging with stretched exponential analysis showed better performance than other sequences. On pairwise comparison of resulting prediction models, RtNet+ produced significantly higher macro-area-under-curve (macro-AUC) (0.733 versus 0.745; P = 0.047) than RtNet in discriminating between AR, CAN and SR. RtNet+ performed similarly to the RtNet (macro-AUC, 0.762 versus 0.756; P > 0.05) in discriminating between eGFR ≤50 mL/min/1.73 m2 and >50 mL/min/1.73 m2. With decision curve analysis, adding RtRad and RtNet to clinical variables resulted in more net benefits in diagnostic performance. CONCLUSIONS: Our study revealed that the proposed RtNet+ model owned a stable performance in revealing the cause of renal allograft dysfunction, and thus might offer important references for individualized diagnostics and treatment strategy.

A clinical available decision support scheme for optimizing prostate biopsy based on mpMRI.

BACKGROUND: Combined MRI/Ultrasound fusion targeted biopsy (TBx) and systematic biopsy (SBx) results in better prostate cancer (PCa) detection relative to either TBx or SBx alone, while at the cost of higher number of biopsy cores and greater detection of clinically insignificant PCa. We therefore developed and evaluated a simple decision support scheme for optimizing prostate biopsy based on multiparametric (mp) MRI assessment. METHODS: Total 229 patients with suspicion of PCa underwent mpMRI before combined TBx/SBx were retrospectively included. Impacts of MRI characteristics such as Prostate Imaging-Reporting and Data System (PI-RADS) score, lesion size, zonal origination, and location on biopsy performance were evaluated. A clinically available decision support scheme relying on mpMRI assessment was subsequently developed as a triage test to optimize prostate biopsy process. Cost (downgrade, upgrade, and biopsy core)-to-Effectiveness (detection rate) was systemically compared. RESULTS: TBx achieved comparable detection rate to combined TBx/SBx in diagnosis of PCa and clinically significant PCa (csPCa) (PCa, 59% [135/229] vs 60.7% [139/229]; csPCa, 45.9% [105/229] vs 47.2% [108/229]; p-values > 0.05) and outperformed SBx (PCa, 42.4% [97/229]; csPCa, 28.4% [65/229]; p-values < 0.001). Specially, in personalized decision support scheme, TBx accurately detected all PCa (72.5% [74/102]) in PI-RADS 5 and larger (≥1 cm) PI-RADS 3-4 observations, adding SBx to TBx only resulted in 1.4% (1/74) upgrading csPCa. For smaller (<1 cm) PI-RADS 3-4 lesions, combined TBx/SBx resulted in relatively higher detection rate (51.2% [65/127] vs 48.0% [61/127]) and lower upgrading rate (30.6% [15/49] vs 36.7% [18/49]) than TBx. CONCLUSIONS: The benefit of SBx added to TBx was largely restricted to smaller PI-RADS score 3-4 lesions. Using our personalized strategy of solo TBx for PI-RADS 5 and larger (≥1 cm) PI-RADS score 3-4 lesions would avoid excess SBx in 44.5% (102/229) of all biopsy-naïve patients without compromising detection rate.

Poly(I:C)-exposed zebrafish shows autism-like behaviors which are ameliorated by fabp2 gene knockout.

Introduction: Autism spectrum disorder (ASD) is a group of neurodevelopmental disorders mainly representing impaired social communication. The etiology of ASD includes genetic and environmental risk factors. Rodent models containing ASD risk gene mutations or environmental risk factors, such as exposure to maternal inflammation, show abnormal behavior. Although zebrafish conserves many important brain structures of humans and has sophisticated and fine behaviors in social interaction, it is unknown whether the social behaviors of their offspring would be impaired due to exposure to maternal inflammation. Methods: We exposed zebrafish to maternal immune activation (MIA) by injection with polyinosinic:polycytidylic acid [poly(I:C)], and screened their behaviors through social behavioral tests such as social preference and shoaling behavior tests. We compared phenotypes resulted from different ways of poly(I:C) exposure. RNA sequencing was performed to explore the differential expression genes (DEGs). Gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) and protein-protein interaction (PPI) network analysis was performed with the detected DEGs to find the concentrated pathways. Finally, we knocked out the fatty acid-binding protein 2 (fabp2), a key node of the concentrated PPI network, to find its rescues on the altered social behavior. Results: We reported here that MIA offspring born to mothers injected with poly(I:C) exhibited impaired social approach and social cohesion that mimicked human ASD phenotypes. Both maternal exposure and direct embryo exposure to poly(I:C) resulted in activations of the innate immune system through toll-like receptors 3 and 4. RNA-sequencing results from MIA brain tissues illustrated that the numbers of overexpressed genes were significantly more than that of underexpressed genes. GO and KEGG analyses found that MIA-induced DEGs were mainly concentrated in complement and coagulation cascade pathways. PPI network analyses suggested that villin-1 (vil1) pathway might play a key role in MIA-induced ASD. Knockout of fabp2 in F0 zebrafish rescued the social behavior deficits in MIA offspring. Conclusions: Overall, our work established an ASD model with assessable behavior phenotype in zebrafish and provided key insights into environmental risk factor in ASD etiology and the influence of fabp2 gene on ASD-like behavior.

miR-485's anti-drug resistant epilepsy effects by regulating SV2A/PSD-95 and targeting ABCC1 and neuronal signaling-transduction proteins in hippocampus of rats.

AIM: Drug-resistant epilepsy (DRE), most subsequently developing refractory epilepsy, causes a significant burden to the society. microRNAs have been demonstrated as key regulators and therapeutic targets in epilepsy. Accordingly, the aim of the present study was to test whether miR-485 could be a potential target for DRE. METHODS AND RESULTS: An in vivo DRE model was developed in Sprague-Dawley rats by lithium chloride-pilocarpine and screened by antiepileptic drugs. We found that miR-485-5p in hippocampus was significant downregulated at early stage and recovered to normal level at late stage of DRE. Overexpression of miR-485-5p in dentate gyrus (DG) of hippocampus in DRE rats could significantly decrease the frequency of seizures and the numbers of epileptiform spikes of hippocampal DG neuron, and could specifically decrease SV2A expression without affecting PSD-95 expression in DG. Furthermore, miR-485-5p overexpression could significantly downregulate the expression of efflux transporter related to multidrug resistance (ABCC1) in hippocampus at late stage of DRE. Finally, a specific expression pattern of neuronal signaling-transduction proteins (LRP4, MDM4, p53, and TMBIM1) for DRE was observed, and miR-485-5p overexpression could modulate these proteins' expression levels toward normal in hippocampus both at early and late stage of DRE. CONCLUSION: Collectively, these results suggest that miR-485 was a potential target for anti-DRE, and this effects might be partially via miR-485-5p/homeostatic-synaptic plasticity-molecule axis and/or targeting efflux transporter (ABCC1) and other neuronal signaling-transduction proteins (LRP4, MDM4, p53, and TMBIM1).

Integration of clinicopathologic identification and deep transferrable image feature representation improves predictions of lymph node metastasis in prostate cancer.

BACKGROUND: Accurate identification of pelvic lymph node metastasis (PLNM) in patients with prostate cancer (PCa) is crucial for determining appropriate treatment options. Here, we built a PLNM-Risk calculator to obtain a precisely informed decision about whether to perform extended pelvic lymph node dissection (ePLND). METHODS: The PLNM-Risk calculator was developed in 280 patients and verified internally in 71 patients and externally in 50 patients by integrating a set of radiologists' interpretations, clinicopathological factors and newly refined imaging indicators from MR images with radiomics machine learning and deep transfer learning algorithms. Its clinical applicability was compared with Briganti and Memorial Sloan Kettering Cancer Center (MSKCC) nomograms. FINDINGS: The PLNM-Risk achieved good diagnostic discrimination with areas under the receiver operating characteristic curve (AUCs) of 0.93 (95% CI, 0.90-0.96), 0.92 (95% CI, 0.84-0.97) and 0.76 (95% CI, 0.62-0.87) in the training/validation, internal test and external test cohorts, respectively. If the number of ePLNDs missed was controlled at < 2%, PLNM-Risk provided both a higher number of ePLNDs spared (PLNM-Risk 59.6% vs MSKCC 44.9% vs Briganti 38.9%) and a lower number of false positives (PLNM-Risk 59.3% vs MSKCC 70.1% and Briganti 72.7%). In follow-up, patients stratified by the PLNM-Risk calculator showed significantly different biochemical recurrence rates after surgery. INTERPRETATION: The PLNM-Risk calculator offers a noninvasive clinical biomarker to predict PLNM for patients with PCa. It shows improved accuracy of diagnosis support and reduced overtreatment burdens for patients with findings suggestive of PCa. FUNDING: This work was supported by the Key Research and Development Program of Jiangsu Province (BE2017756) and the Suzhou Science and Technology Bureau-Science and Technology Demonstration Project (SS201808).

A 6-Year-Old Boy With a Mediastinal Mass.

CASE PRESENTATION: A 6-year-old boy was referred to our hospital with an anterior mediastinal mass. This was discovered by chest radiography performed when the boy was examined after being caught by an elevator door about 2 weeks earlier. The patient had been born full term without any complications during pregnancy or delivery. No clinical symptoms were observed during this presentation, and he had no history of previous infections.

[Principles and suggestions on biosafety protection of biological specimen preservation during prevalence of COVID-19].

Coronavirus disease 2019 (COVID-19) is a grade B infectious disease caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). In pace with the spreading of the disease, biosafety risk of the biological specimen preservation in biobanks has been significantly increased and biosafety protection during biological specimen preservation become increasingly important. According to the related national rules and the corresponding guidelines of Chinese Medical Association, this paper introduced the etiology about SARS-CoV-2, epidemiology about COVID-19, and the biosafety protection principles of individuals and biological specimen storage places in the process of personal protection, protection of collection, transport, handling, preservation, detection, post-detection disposal and emergencies of biological specimen. Emphasized to carry out a strict biosafety-risk assessment on biological specimen basing on virus load information, infectivity, and sample type (possible contact transmission, aerosol transmission, and fecal oral transmission).