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Sang-Jin Park,1,* Seung Ro Han,2,3,* Yun Hee Kang,2,3,* Eun-Jin Lee,1 Eu-Gene Kim,1 Hyobong Hong,4 Jae-Chan Jeong,4 Myung-Shin Lee,2,3 Seung-Hoon Lee,2,5 Dae-Yong Song1 1Department of Anatomy and Neuroscience, Eulji University School of Medicine, Daejeon, Korea; 2Eulji Biomedical Science Research Institute, Eulji University School of Medicine, Daejeon, Korea; 3Department of Microbiology and Immunology, Eulji University School of Medicine, Daejeon, Korea; 4Artifcial Intelligence Research Laboratory, Electronics and Telecommunications Research Institute (ETRI), Daejeon, Korea; 5Department of Neurosurgery, Eulji University School of Medicine, Daejeon, Korea*These authors contributed equally to this workCorrespondence: Seung-Hoon Lee, Department of Neurosurgery, Eulji University School of Medicine, Daejeon, Korea, Tel +82-42-259-1612, Fax +82-42-259-1669, Email nslsh@eulji.ac.kr Dae-Yong Song, Department of Anatomy and Neuroscience, Eulji University School of Medicine, Daejeon, Korea, Tel +82-42-259-1622, Fax +82-42-259-1669, Email dysong@eulji.ac.krPurpose: Magnetic particle imaging (MPI) is an emerging radiation-free, non-invasive three-dimensional tomographic technology that can visualize the concentrations of superparamagnetic iron oxide nanoparticles (SPIONs). To verify the applicability of the previously proposed point-of-care testing MPI (PoCT-MPI) in medical diagnosis and therapeutics, we imaged SPIONs in animal tumor models.Methods: CT26 or MC38 mouse colon carcinoma cells (2 × 106 cells) were subcutaneously injected into the right flank of BALB/c mice. SPIONs were either injected directly into the tumor lesions in the intratumoral group or through tail veins in the intravenous group. CT26 and MC38 tumor models were examined both intratumorally and intravenously to confirm the biological availability of SPIONs using PoCT-MPI.Results: Signals were observed in the tumor lesions from day 1 to day 7. This is the first study to successfully image the pathological region and show the biodistribution of SPIONs in CT26 tumor models using the recently developed PoCT-MPI technology. Furthermore, MC38 tumor models were examined, resulting in similar images to those of the CT26 tumor model in both intratumoral and intravenous groups.Conclusion: The present study demonstrates the biological applicability of PoCT-MPI, which promises to be a powerful diagnostic and therapeutic technique in biomedical imaging.Keywords: colon cancer, syngeneic mouse tumor model, point-of-care testing MPI, diagnostics

Background: There is a need for clinically actionable prognostic and predictive tools to guide the management of oligometastatic castration-sensitive prostate cancer (omCSPC)., Methods: This is a multicenter retrospective study to assess the prognostic and predictive performance of a multimodal artificial intelligence biomarker (MMAI; the ArteraAI Prostate Test) in men with omCSPC (n = 222). The cohort also included 51 patients from the STOMP and ORIOLE phase 2 clinical trials which randomized patients to observation versus metastasis-directed therapy (MDT). MMAI scores were computed from digitized histopathology slides and clinical variables. Overall survival (OS) and time to castration-resistant prostate cancer (TTCRPC) were assessed for the entire cohort from time of diagnosis. Metastasis free survival (MFS) was assessed for the trial cohort from time of randomization., Results: In the overall cohort, patients with a high MMAI score had significantly worse OS (HR = 6.46, 95 % CI = 1.44-28.9; p = 0.01) and shorter TTCRPC (HR = 2.07, 95 % CI = 1.15-3.72; p = 0.015). In a multivariable Cox model, MMAI score remained the only variable significantly associated with OS (HR = 6.51, 95 % CI = 1.32-32.2; p = 0.02). In the subset of patients randomized in the STOMP and ORIOLE trials, high MMAI score corresponded to improved MFS with MDT (p = 0.039) compared to patients with a low score, with p interaction  = 0.04., Conclusion: The ArteraAI MMAI biomarker is prognostic for OS and TTCRPC among patients with omCSPC and may predict for response to MDT. Further work is needed to validate the MMAI biomarker in a broader mCSPC cohort., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: PTT declares a consulting/advisory role and patent with Natsar Pharmaceuticals (Compounds and methods of use in ablative radiotherapy. Patent filed 3/9/2012. PCT/US2012/028475. PCT/WO/2012/122471) licensed with royalties to Natsar Pharmaceuticals. Consulting/advisory role and research funding with Reflexion Medical and Bayer Health. Consulting/advisory role with Regeneron, Dendreon, Noxopharm, Janssen, Myovant Sciences, AstraZeneca, Pfizer, Lantheus. FYF is a consultant for Janssen, Astellas Pharma, Serimmune, Foundation Medicine, Exact Sciences, Bristol-Myers Squibb, and Varian Medical Systems; advisor and stock options at Artera Inc; stock options for serving on the advisory boards from BlueStar Genomics and SerImmune. APK receives research funding from Advanced Accelerator Applications/Novartis (Inst), Merck (Inst), Bayer (Inst), Novartis Pharmaceuticals UK Ltd. PO reports a relationship with Janssen, Advanced Accelerator Applications, Curium, Bayer and MSD that includes: consulting or advisory. Piet Ost reports a relationship with Bayer and Varian that includes: funding grants. EC, TNS, TJR, TT, H-CH, SAH, RY, and AE are employed by Artera Inc. All remaining authors have declared no conflicts of interest., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Provisional Tic Disorder (PTD) is common in childhood. The received wisdom among clinicians is that PTD is short-lived and mild, with at most a few tics, and rarely includes complex tics, premonitory phenomena or comorbid illnesses. However, such conclusions come from clinical experience, with biased ascertainment and limited follow-up., Methods: Prospective study of 89 children with tics starting 0-9 months ago (median 4 months), fewer than half from clinical sources. Follow-up at 12 (± 24, 36, 48) months after the first tic., Results: At study entry, many children had ADHD (39), an anxiety disorder (27), OCD (9) or enuresis (17). All had at least two current tics, with a mean total since onset of 6.9 motor and 2.0 phonic tics. Forty-one had experienced a complex tic, and 69 could suppress some tics. Tics were clinically meaningful: 64 had tics severe enough for a clinical trial, and 76 families sought medical attention for the tics. At 12 months, 79 returned, and 78 still had tics. Of these, 29 manifested no tics during history and extended examination, but only via audio-visual monitoring when the child was seated alone. Only 12/70 now had plans to see a doctor for tics. Most who returned at 2-4 years still had tics known to the child and family, but medical impact was low., Conclusions: Our results do not contradict previous data, but overturn clinical lore. The data strongly argue against the longstanding but arbitrary tradition of separating tic disorders into recent-onset versus chronic., Competing Interests: Declaration of competing interest No relevant conflicts., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Whole-genome sequencing (WGS) analyses have found higher genetic burden in autistic females compared to males, supporting higher liability threshold in females. However, genomic evidence of sex differences has been limited to European ancestry to date and little is known about how genetic variation leads to autism-related traits within families across sex., Methods: To address this gap, we present WGS data of Korean autism families (n = 2255) and a Korean general population sample (n = 2500), the largest WGS data of East Asian ancestry. We analyzed sex differences in genetic burden and compared with cohorts of European ancestry (n = 15,839). Further, with extensively collected family-wise Korean autism phenotype data (n = 3730), we investigated sex differences in phenotypic scores and gene-phenotype associations within family., Results: We observed robust female enrichment of de novo protein-truncating variants in autistic individuals across cohorts. However, sex differences in polygenic burden varied across cohorts and we found that the differential proportion of comorbid intellectual disability and severe autism symptoms mainly drove these variations. In siblings, males of autistic females exhibited the most severe social communication deficits. Female siblings exhibited lower phenotypic severity despite the higher polygenic burden than male siblings. Mothers also showed higher tolerance for polygenic burden than fathers, supporting higher liability threshold in females., Conclusions: Our findings indicate that genetic liability in autism is both sex- and phenotype-dependent, expanding the current understanding of autism's genetic complexity. Our work further suggests that family-based assessments of sex differences can help unravel underlying sex-differential liability in autism., (© 2024. The Author(s).)

Introduction: Holmium laser enucleation of the prostate (HoLEP) is an increasingly utilized surgical intervention for benign prostatic hyperplasia (BPH) with lower urinary tract symptoms (LUTS). It is unclear how pre-HoLEP voiding performance (including pre-HoLEP incontinence) affects post-HoLEP urinary symptom performance and recovery which challenges effective patient counseling. Methods: This is a single-institution retrospective analysis of 266 patients who underwent HoLEP. Pre-HoLEP continence status was determined by patient report. Continence (severity and bother, severity broken into urge and stress) and LUTS (total IPSS score and QoL) were assessed preoperatively and 1 week (1wk), 1 month (1m), 3 months (3m), and 1-year (1y) post-HoLEP using the Michigan Incontinence Symptom Index (MISI) and International Prostate Symptom Score (IPSS), respectively. Primary outcome measures were MISI differences between groups at each time point. Results: Of the 376 patients who underwent HoLEP from two surgeons from 11/6/2020 to 12/18/2023, 266 were included in the study. Inclusion criteria were patients undergoing HoLEP during this period. There were no exclusion criteria. A total of 178 participants were continent and 88 were incontinent pre-HoLEP. Average age at time of HoLEP was 70.3 and 70.8 respectively, average preoperative prostate size measured by ultrasound or axial imaging was 109.0 g and 113.7 g, respectively. Based on MISI stress (#1-3) and urge (#4-6) items, pre-HoLEP Stress:Urge ratio in continent pre-HoLEP patients was 1.29:3.02. In the incontinent pre-HoLEP group, Stress:Urge was 2.45:6.18. MISI scores were statistically similar between cohorts at 1wk. Preop incontinent patients had a statistical and clinically significant improvement in MISI severity score at 1y post-HoLEP (5.62 n = 11 vs 10.170 n = 50, p = 0.013). IPSS total scores were statistically similar between cohorts at 1m and IPSS QoL scores were statistically similar at preop. At preop evaluation, urge symptoms were worse than stress symptoms in all cohorts. Conclusions: Preoperative incontinence should not be considered a predictor of poor intermediate or long-term post-HoLEP outcomes. Pre-HoLEP incontinence is likely largely urge-related.

The rapid and precise detection of pathogenic agents is critical for public health and societal stability. The detection of biological warfare agents (BWAs) is especially vital within military and counter-terrorism contexts, essential in defending against biological threats. Traditional methods, such as polymerase chain reaction (PCR), are limited by their need for specific settings, impacting their adaptability and versatility. This study introduces a cell-free biosensor for BWA detection by converting the 16S rRNA of targeted pathogens into detectable functional protein molecules. The modular nature of this approach allows for the flexible configuration of pathogen detection, enabling the simultaneous identification of multiple pathogenic 16S rRNAs through customized reporter proteins for each targeted sequence. Furthermore, we demonstrate how this method integrates with techniques utilizing retroreflective Janus particles (RJPs) for facile and highly sensitive pathogen detection. The cell-free biosensor, employing RJPs to measure the reflection of non-chromatic white light, can detect 16S rRNA from BWAs at femtomolar levels, corresponding to tens of colony-forming units per milliliter of pathogenic bacteria. These findings represent a significant advancement in pathogen detection, offering a more efficient and accessible alternative to conventional methodologies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Anti-contactin-associated protein-like 2 (CASPR2) antibody encephalitis is an autoimmune disorder characterized by the presence of antibodies against the voltage-gated potassium channel. This leads to neurological symptoms, such as seizures, cognitive decline, and neuropathic pain, primarily affecting the limbic system. The prognosis of this disorder varies among individuals., Case Summary: The patient, a girl aged nine years and nine months, underwent treatment for 14 to 21 d. The main clinical manifestations were vomiting and unclear consciousness, positive pathological signs, normal cranial computed tomography and magnetic resonance imaging, and abnormal electroencephalogram. The child was discharged after receiving immunoglobulin and hormone treatment. Subsequent follow-up over a period of 15 months after discharge, conducted through telephone and outpatient visits, showed no recurrence of symptoms., Conclusion: Anti-CASPR2 antibody autoimmune encephalitis in children is rare, mainly manifested as convulsions, mental abnormalities, cognitive impairment, and neuropathic pain, among others. Timely evaluation for autoimmune encephalitis antibodies is crucial, especially in cases of recurrent central nervous system involvement in children., Competing Interests: Conflict-of-interest statement: There are no conflicts of interest in this study., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background: Salvage radiation therapy (SRT) is a mainstay of treatment for biochemical relapse following radical prostatectomy; however, few studies have examined genomic biomarkers in this context., Objective: We characterized the prognostic impact of previously identified deleterious molecular phenotypes-loss of PTEN, ERG expression, and TP53 mutation-for patients undergoing SRT., Design, Setting, and Participants: We leveraged an institutional database of 320 SRT patients with available tissue and follow-up. Tissue microarrays were used for genetically validated immunohistochemistry assays., Intervention: All men underwent SRT with or without androgen deprivation therapy OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Univariable and multivariable Cox-proportional hazard models assessed the association of molecular phenotypes with biochemical recurrence-free (bRFS) and metastasis-free (MFS) survival after SRT., Results and Limitations: Loss of PTEN (n = 123, 43%) and ERG expression (n = 118, 39%) were common in this cohort, while p53 overexpression (signifying TP53 missense mutation) was infrequent (n = 21, 7%). In univariable analyses, any loss of PTEN portended worse bRFS (hazard ratio [HR] 1.86; 95% confidence interval 1.36-2.57) and MFS (HR 1.89; 1.21-2.94), with homogeneous PTEN loss being associated with the highest risk of MFS (HR 2.47; 1.54-3.95). Similarly, p53 overexpression predicted worse bRFS (HR 1.95; 1.14-3.32) and MFS (HR 2.79; 1.50-5.19). ERG expression was associated with worse MFS only (HR 1.6; 1.03-2.48). On the multivariable analysis adjusting for known prognostic features, homogeneous PTEN loss remained predictive of adverse bRFS (HR 1.82; 1.12-2.96) and MFS (HR 2.08; 1.06-4.86). The study is limited by its retrospective and single-institution design., Conclusions: PTEN loss by immunohistochemistry is an independent adverse prognostic factor for bRFS and MFS in prostate cancer patients treated with SRT. Future trials will determine the optimal approach to treating SRT patients with adverse molecular prognostic features., Patient Summary: Loss of the PTEN tumor suppressor protein is associated with worse outcomes after salvage radiotherapy, independent of other clinical or pathologic patient characteristics., (Copyright © 2024 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Aim: Short tandem repeats (STRs) are repetitive DNA sequences and highly mutable in various human disorders. While the involvement of STRs in various genetic disorders has been extensively studied, their role in autism spectrum disorder (ASD) remains largely unexplored. In this study, we aimed to investigate genetic association of STR expansions with ASD using whole genome sequencing (WGS) and identify risk loci associated with ASD phenotypes., Methods: We analyzed WGS data of 634 ASD families and performed genome-wide evaluation for 12,929 STR loci. We found rare STR expansions that exceeded normal repeat lengths in autism cases compared to unaffected controls. By integrating single cell RNA and ATAC sequencing datasets of human postmortem brains, we prioritized STR loci in genes specifically expressed in cortical development stages. A deep learning method was used to predict functionality of ASD-associated STR loci., Results: In ASD cases, rare STR expansions predominantly occurred in early cortical layer-specific genes involved in neurodevelopment, highlighting the cellular specificity of STR-associated genes in ASD risk. Leveraging deep learning prediction models, we demonstrated that these STR expansions disrupted the regulatory activity of enhancers and promoters, suggesting a potential mechanism through which they contribute to ASD pathogenesis. We found that individuals with ASD-associated STR expansions exhibited more severe ASD phenotypes and diminished adaptability compared to non-carriers., Conclusion: Short tandem repeat expansions in cortical layer-specific genes are associated with ASD and could potentially be a risk genetic factor for ASD. Our study is the first to show evidence of STR expansion associated with ASD in an under-investigated population., (© 2024 The Authors. Psychiatry and Clinical Neurosciences published by John Wiley & Sons Australia, Ltd on behalf of Japanese Society of Psychiatry and Neurology.)

Background and Objective: Oligometastatic castration-sensitive prostate cancer (omCSPC) represents an early state in the progression of metastatic disease for which patients experience better outcomes in comparison to those with higher disease burden. Despite the generally more indolent nature, there is still much heterogeneity, with some patients experiencing a more aggressive clinical course unexplained by clinical features alone. Our aim was to investigate correlation of tumor genomics with the mode of progression (MOP) and pattern of failure (POF) following first treatment (metastasis-directed and/or systemic therapy) for omCSPC., Methods: We performed an international multi-institutional retrospective study of men treated for metachronous omCSPC who underwent tumor next-generation sequencing with at least 1 yr of follow-up after their first treatment. Descriptive MOP and POF results are reported with respect to the presence of genomic alterations in pathways of interest. MOP was defined as class I, long-term control (LTC; no radiographic progression at last follow-up), class II, oligoprogression (1-3 lesions), or class III, polyprogression (≥4 lesions). POF included the location of lesions at first failure. Genomic pathways of interest included TP53, ATM, RB1, BRCA1/2, SPOP, and WNT (APC, CTNNB1, RNF43). Genomic associations with MOP/POF were compared using χ 2 tests. Exploratory analyses revealed that the COSMIC mutational signature and differential gene expression were also correlated with MOP/POF. Overall survival (OS) was calculated via the Kaplan-Meier method from the time of first failure., Key Findings and Clinical Implications: We included 267 patients in our analysis; the majority had either one (47%) or two (30%) metastatic lesions at oligometastasis. The 3-yr OS rate was significantly associated with MOP (71% for polyprogression vs 91% for oligoprogression; p = 0.005). TP53 mutation was associated with a significantly lower LTC rate (27.6% vs 42.3%; p = 0.04) and RB1 mutation was associated with a high rate of polyprogression (50% vs 19.9%; p = 0.022). Regarding POF, bone failure was significantly more common with tumors harboring TP53 mutations (44.8% vs25.9%; p = 0.005) and less common with SPOP mutations (7.1% vs 31.4%; p = 0.007). Visceral failure was more common with tumors harboring either WNT pathway mutations (17.2% vs 6.8%, p = 0.05) or SPOP mutations (17.9% vs 6.3%; p = 0.04). Finally, visceral and bone failures were associated with distinct gene-expression profiles., Conclusions and Clinical Implications: Tumor genomics provides novel insight into MOP and POF following treatment for metachronous omCSPC. Patients with TP53 and RB1 mutations have a higher likelihood of progression, and TP53, SPOP, and WNT pathway mutations may have a role in metastatic organotropism., Patient Summary: We evaluated cancer progression after a first treatment for metastatic prostate cancer with up to five metastases. We found that mutations in certain genes were associated with the location and extent of further metastasis in these patients., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

The prevalence of tick-borne pathogens (TBP), Orientia tsutsugamushi, Rickettsia and Borrelia spp. in wild small animals, namely wild rodents, is now widely investigated. This study is to present the prevalence and distribution of O. tsutsugamushi, Rickettsia and Borrelia spp. in wild small animals and ticks collected from Gyeonggi and Gangwon provinces, Republic of Korea (ROK) in 2014. A total of 131 wild small animals, rodents and shrews, and 2,954 ticks were collected from Gyeonggi and Gangwon provinces from May to November 2014. The wild small animals (KR1-9) and ticks (K1-17) were grouped in accordance with capture dates and locations. Among the wild small animals, a total of 393 tissues and blood samples were extracted from six selected small animal series (KR1-3, KR6-8). Also, each date and location-grouped ticks were identified for its species and pooled according to the stage of development. Molecular identification for Rickettsia, Orientia, and Borrelia species was performed using polymerase chain reaction (PCR). To detect TBPs among wild small animals and ticks, primer sets targeting the 56 kDa protein encoding gene of Orientia spp., outer membrane protein B gene (OmpB) of Rickettsia spp., and 5S-23S intergenic spacer region (IGS) gene of Borrelia spp. were used. Of the 393 wild small animals' blood and tissue samples, 199 (50.6%) were positive for Orientia spp., 158 (40.2%) were positive for Borrelia spp., and 55 (14.0%) were positive for Rickettsia spp. Moreover, a total of 14 tick pools (n = 377) was positive for Rickettsia spp. (n=128, 34.0%) and Borrelia spp. (n=33, 8.8%). High prevalence of Orientia spp. and Rickettsia spp. in rodents and shrews were observed. This study presents significant insights by presenting data collected in 2014 that the prevalence of TBP was already high in mid 2010s. This study highlights the sustainable routine surveillance model for TBP.

Background: Volumetric modulated arc therapy (VMAT) machine parameter optimization (MPO) remains computationally expensive and sensitive to input dose objectives creating challenges for manual and automatic planning. Reinforcement learning (RL) involves machine learning through extensive trial-and-error, demonstrating performance exceeding humans, and existing algorithms in several domains., Purpose: To develop and evaluate an RL approach for VMAT MPO for localized prostate cancer to rapidly and automatically generate deliverable VMAT plans for a clinical linear accelerator (linac) and compare resultant dosimetry to clinical plans., Methods: We extended our previous RL approach to enable VMAT MPO of a 3D beam model for a clinical linac through a policy network. It accepts an input state describing the current control point and predicts continuous machine parameters for the next control point, which are used to update the input state, repeating until plan termination. RL training was conducted to minimize a dose-based cost function for prescription of 60 Gy in 20 fractions using CT scans and contours from 136 retrospective localized prostate cancer patients, 20 of which had existing plans used to initialize training. Data augmentation was employed to mitigate over-fitting, and parameter exploration was achieved using Gaussian perturbations. Following training, RL VMAT was applied to an independent cohort of 15 patients, and the resultant dosimetry was compared to clinical plans. We also combined the RL approach with our clinical treatment planning system (TPS) to automate final plan refinement, and creating the potential for manual review and edits as required for clinical use., Results: RL training was conducted for 5000 iterations, producing 40 000 plans during exploration. Mean ± SD execution time to produce deliverable VMAT plans in the test cohort was 3.3 ± 0.5 s which were automatically refined in the TPS taking an additional 77.4 ± 5.8 s. When normalized to provide equivalent target coverage, the RL+TPS plans provided a similar mean ± SD overall maximum dose of 63.2 ± 0.6 Gy and a lower mean rectum dose of 17.4 ± 7.4 compared to 63.9 ± 1.5 Gy (p = 0.061) and 21.0 ± 6.0 (p = 0.024) for the clinical plans., Conclusions: An approach for VMAT MPO using RL for a clinical linac model was developed and applied to automatically generate deliverable plans for localized prostate cancer patients, and when combined with the clinical TPS shows potential to rapidly generate high-quality plans. The RL VMAT approach shows promise to discover advanced linac control policies through trial-and-error, and algorithm limitations and future directions are identified and discussed., (© 2024 The Authors. Medical Physics published by Wiley Periodicals LLC on behalf of American Association of Physicists in Medicine.)

Purpose: This study investigates gender-based disparities in health-related quality of life (HRQOL) outcomes among kidney stone patients and explores potential contributing factors. Methods: A retrospective review of medical records at the University of Rochester Medical Center was conducted on 2199 new urolithiasis patients who completed the Wisconsin Stone Quality of Life Questionnaire (WISQOL) standardized on a 0 to 100 scale. Demographic and clinical data were collected. Statistical analyses included univariate tests, chi-squared tests, and multivariate linear regression. Results: Of the 2199 kidney stone patients, 1085 (49.3%) were women. Women reported significantly lower quality of life (QoL) scores compared with men (71.6 vs 80.7; p  < 0.001), and this persisted across all domains, including social impact (80.2 vs 86.9; p  < 0.001), emotional impact (67.3 vs 77.1; p  < 0.001), disease impact (67.3 vs 77.1; p  < 0.001), and impact vitality (62.6 vs 72.9; p  < 0.001). Female gender was identified as an independent predictor of diminished QoL scores, along with younger age, symptomatic status, number of surgeries, and presence of a psychosocial comorbidity. Conclusions: Our findings suggest that women with kidney stones experience lower HRQOL compared with men, even accounting for clinical and demographic factors. Although this study provides preliminary insights, additional research is needed to validate these findings in broader and more varied populations.

Ribonucleotide reductases (RNRs) are essential enzymes that catalyze the de novo transformation of nucleoside 5'-di(tri)phosphates [ND(T)Ps, where N is A, U, C, or G] to their corresponding deoxynucleotides. Despite the diversity of factors required for function and the low sequence conservation across RNRs, a unifying apparatus consolidating RNR activity is explored. We combine aspects of the protein subunit simplicity of class II RNR with a modified version of Escherichia coli class la photoRNRs that initiate radical chemistry with light to engineer a mimic of a class II enzyme. The design of this RNR involves fusing a truncated form of the active site containing α subunit with the functionally important C-terminal tail of the radical-generating β subunit to render a chimeric RNR. Inspired by a recent cryo-EM structure, a [Re] photooxidant is located adjacent to Y 356 [β], which is an essential component of the radical transport pathway in class I RNRs. Combination of this RNR photochimera with cytidine diphosphate (CDP), adenosine triphosphate (ATP), and light resulted in the generation of Y 356 • along with production of deoxycytidine diphosphate (dCDP) and cytosine. The photoproducts reflect an active site chemistry consistent with both the consensus mechanism of RNR and chemistry observed when RNR is inactivated by mechanism-based inhibitors in the active site. The enzymatic activity of the RNR photochimera in the absence of any β metallocofactor highlights the adaptability of the 10-stranded αβ barrel finger loop to support deoxynucleotide formation and accommodate the design of engineered RNRs., Competing Interests: Competing interests statement:The authors declare no competing interest.

Purpose: Emerging data suggest that metastasis-directed therapy (MDT) improves outcomes in patients with oligometastatic castration-sensitive prostate cancer (omCSPC). Prostate-specific membrane antigen positron emission tomography (PSMA-PET) can detect occult metastatic disease, and PSMA response has been proposed as a biomarker for treatment response. Herein, we identify and validate a PSMA-PET biomarker for metastasis-free survival (MFS) following MDT in omCSPC., Methods and Materials: We performed an international multi-institutional retrospective study of patients with omCSPC, defined as ≤3 lesions, treated with metastasis-directed stereotactic ablative radiation who underwent PSMA-PET/computed tomography (CT) before and after (median, 6.2 months; range, 2.4-10.9 months) treatment. Pre- and post-MDT PSMA-PET/CT maximum standardized uptake value (SUV max ) was measured for all lesions, and PSMA response was defined as the percent change in SUV max of the least responsive lesion. PSMA response was both evaluated as a continuous variable and dichotomized into PSMA responders, with a complete/partial response (at least a 30% reduction in SUV max ), and PSMA nonresponders, with stable/progressive disease (less than a 30% reduction in SUV max ). PSMA response was correlated with conventional imaging-defined metastasis-free survival (MFS) via Kaplan-Meier and Cox regression analysis., Results: A total of 131 patients with 261 treated metastases were included in the analysis, with a median follow-up of 29 months (IQR, 18.5-41.3 months). After stereotactic ablative radiation, 70.2% of patients were classified as PSMA responders. Multivariable analysis demonstrated that PSMA response as a continuous variable was associated with a significantly worse MFS (hazard ratio = 1.003; 95% CI, 1.001-1.006; P = .016). Patients classified as PSMA responders were found to have a significantly improved median MFS of 39.9 versus 12 months ( P = .001) compared with PSMA nonresponders. Our study is limited as it is a retrospective review of a heterogenous population., Conclusions: After stereotactic ablative radiation, PSMA-PET response appears to be a radiographic biomarker that correlates with MFS in omCSPC. This approach holds promise for guiding clinical management of omCSPC and should be validated in a prospective setting., (© 2024 The Authors.)

Lay Abstract: How non-autistic people think about autistic people impacts autistic people negatively. Many studies developed trainings to reduce autism stigma. The existing trainings vary a lot in terms of study design, content, and reported effectiveness. This means that a review studying how the studies have been conducted is needed. We also looked at the quality of these studies. We collected and studied 26 studies that tried to reduce stigma toward autistic people. The studies often targeted White K-12 students and college students. Most trainings were implemented once. Trainings frequently used video or computer. Especially, recent studies tended to use online platforms. The study quality was poor for most studies. Some studies made inaccurate claims about the intervention effectiveness. Studies did not sufficiently address study limitations. Future trainings should aim to figure out why and how interventions work. How intervention changes people's behavior and thoughts should be studied. Researchers should study whether the training can change the societal stigma. Also, researchers should use a better study design., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Standard of care management for synchronous metastatic castration-sensitive prostate cancer (mCSPC) includes androgen deprivation therapy with a second-generation antiandrogen therapy and/or docetaxel. Recently, randomized data have demonstrated that prostate-directed therapy (PDT) is associated with an improvement in overall survival (OS) among patients with low-volume metastatic disease. Tumor genomics represents an additional dimension to define the clinical trajectory of patients with mCSPC., Objective: To evaluate a high-risk (HiRi) genomic signature to predict the benefit from PDT., Design, Setting, and Participants: We performed a single-institution retrospective review of men with synchronous low-volume mCSPC who underwent DNA panel sequencing of their tumor. Patients were classified according to the presence of HiRi mutation including pathogenic mutations in TP53, ATM, BRCA1, BRCA2, or Rb1., Outcome Measurements and Statistical Analysis: The primary endpoint was to determine the effect of PDT on OS in patients with and without a HiRi mutation. A survival analysis was performed with the Kaplan-Meier method compared with log-rank test and multivariable Cox regression. The interaction between HiRi mutation and PDT was evaluated., Results and Limitations: A total of 101 patients with synchronous low-volume CSPC were included with a median follow-up of 44 mo. Approximately half of patients were found to have a HiRi pathogenic mutation (49%). Patients with HiRi mutations demonstrated median OS of 73 versus 66.8 mo (p = 0.3) for no PDT versus PDT. Conversely, patients without a HiRi mutation demonstrated a significant improvement in OS of 60 versus 105.3 mo (p < 0.001) for no PDT versus PDT. The p value for interaction for OS between PDT and HiRi mutation was statistically significant (p < 0.001). Limitations include the retrospective nature of the study., Conclusions: Here, we have identified a HiRi genomic biomarker that appears predictive for the lack of benefit from PDT in men with synchronous low-volume mCSPC. Further work validating these results is warranted., Patient Summary: In this report, we evaluated a high-risk genomic biomarker to predict the benefit from prostate-directed therapy for men with synchronous low-volume metastatic castration-sensitive prostate cancer. We found that men without a high-risk mutation appear to experience a greater clinical benefit from prostate-directed therapy than those with a high-risk mutation., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Predictive modeling strategies are increasingly studied as a means to overcome clinical bottlenecks in the diagnostic classification of autism spectrum disorder. However, while some findings are promising in the light of diagnostic marker research, many of these approaches lack the scalability for adequate and effective translation to everyday clinical practice. In this study, our aim was to explore the use of objective computer vision video analysis of real-world autism diagnostic interviews in a clinical sample of children and young individuals in the transition to adulthood to predict diagnosis. Specifically, we trained a support vector machine learning model on interpersonal synchrony data recorded in Autism Diagnostic Observation Schedule (ADOS-2) interviews of patient-clinician dyads. Our model was able to classify dyads involving an autistic patient (n = 56) with a balanced accuracy of 63.4% against dyads including a patient with other psychiatric diagnoses (n = 38). Further analyses revealed no significant associations between our classification metrics with clinical ratings. We argue that, given the above-chance performance of our classifier in a highly heterogeneous sample both in age and diagnosis, with few adjustments this highly scalable approach presents a viable route for future diagnostic marker research in autism., (© 2024. The Author(s).)

Purpose: Segmentation of the prostate and surrounding organs at risk from computed tomography is required for radiation therapy treatment planning. We propose an automatic two-step deep learning-based segmentation pipeline that consists of an initial multi-organ segmentation network for organ localization followed by organ-specific fine segmentation., Approach: Initial segmentation of all target organs is performed using a hybrid convolutional-transformer model, axial cross-attention UNet. The output from this model allows for region of interest computation and is used to crop tightly around individual organs for organ-specific fine segmentation. Information from this network is also propagated to the fine segmentation stage through an image enhancement module, highlighting regions of interest in the original image that might be difficult to segment. Organ-specific fine segmentation is performed on these cropped and enhanced images to produce the final output segmentation., Results: We apply the proposed approach to segment the prostate, bladder, rectum, seminal vesicles, and femoral heads from male pelvic computed tomography (CT). When tested on a held-out test set of 30 images, our two-step pipeline outperformed other deep learning-based multi-organ segmentation algorithms, achieving average dice similarity coefficient (DSC) of 0.836 ± 0.071 (prostate), 0.947 ± 0.038 (bladder), 0.828 ± 0.057 (rectum), 0.724 ± 0.101 (seminal vesicles), and 0.933 ± 0.020 (femoral heads)., Conclusions: Our results demonstrate that a two-step segmentation pipeline with initial multi-organ segmentation and additional fine segmentation can delineate male pelvic CT organs well. The utility of this additional layer of fine segmentation is most noticeable in challenging cases, as our two-step pipeline produces noticeably more accurate and less erroneous results compared to other state-of-the-art methods on such images., (© 2024 Society of Photo-Optical Instrumentation Engineers (SPIE).)

Gastric cancer is one of the most common malignant tumors in China. Currently, the surgery-based procedure is still the most acceptable strategy for treating gastric cancer. As an important part of standardized management, appropriate specimen processing following surgery is receiving more and more attention across the world. With the release of guidelines and consensus on the specimens processing after gastric cancer surgery, several centers in China have started to follow this standard procedure. However, due to differences in understanding the consensus and the degree of surgery practice, the results are variable. This paper will focus on reviewing every aspect of the processing procedure, with the hope that the concept and skill involved can be popularized in clinical operations. Hopefully this will help promote the development of high-quality gastric cancer surgery in China.

Objective: To explore the clinical characteristics, diagnosis, treatment, and follow-up of multisystem inflammatory syndrome in children (MIS-C) related to SARS-CoV-2 Omicron variant infection. Methods: A retrospective analysis was conducted on clinical data of 11 children with MIS-C, who were admitted to the Department of Pediatrics of Peking University First Hospital from December 2022 to January 2023. Clinical characteristics, treatment, and follow-up of MIS-C were summarized in this study. Results: The 11 cases contained 7 boys and 4 girls, with an age of 4.4 (2.0, 5.5) years on admission. All the patients had fever, with a duration of 7(5, 9) days. Other clinical manifestations included rash in 7 cases, conjunctival hyperemia in 5 cases, red lips and raspberry tongue in 3 cases, lymphadenopathy in 3 cases, and swollen fingers and toes in 2 cases. There were 8 cases of digestive symptoms, 8 cases of respiratory symptoms, and 3 cases of nervous system symptoms. Eight patients had multi-system injuries, and one of them had shock presentation. All 11 patients were infected with SARS-CoV-2 Omicron BF.7 variant. The laboratory examination results showed that all cases had elevated inflammatory indicators, abnormal coagulation function and myocardial damage. Six patients had elevated white blood cell counts, 5 cases had liver function abnormalities, 3 cases had kidney function abnormalities, and 8 cases had coronary artery involvement. All 11 patients received anti-infection treatment, of which 3 cases received only 2 g/kg intravenous immunoglobulin (IVIG), while the remaining 8 cases received a combination of IVIG and 2 mg/(kg·d) methylprednisolone. Among the 8 cases with coronary artery disease, 6 cases received low molecular weight heparin anticoagulation therapy. All patients were followed up in 2 weeks after being discharged, and their inflammatory markers had returned to normal by that time. The 8 cases with coronary artery disease and 3 cases with pneumonia showed significant improvement or back to normal at the 4-week follow-up. All patients had no new complications or comorbidities during follow-up of more than 3 months. Conclusions: MIS-C may present with Kawasaki disease-like symptoms, with or without gastrointestinal, neurological, or respiratory symptoms. Elevated inflammatory markers, abnormal coagulation function, and cardiac injury contribute to the diagnosis of MIS-C. IVIG and methylprednisolone were the primary treatments for MIS-C, and a favorable short-term prognosis was observed during a follow-up period of more than 3 months.

This study aimed to assess the accuracy of intraprostatic tumor volume measurements on prostate-specific membrane antigen-targeted 18 F-DCFPyL PET/CT made with various segmentation methods. An accurate understanding of tumor volumes versus segmentation techniques is critical for therapy planning, such as radiation dose volume determination and response assessment. Methods: Twenty-five men with clinically localized, high-risk prostate cancer were imaged with 18 F-DCFPyL PET/CT before radical prostatectomy. The tumor volumes and tumor-to-prostate ratios (TPRs) of dominant intraprostatic foci of uptake were determined using semiautomatic segmentation (applying SUV max percentage [SUV%] thresholds of SUV30%-SUV70%), adaptive segmentation (using adaptive segmentation percentage [A%] thresholds of A30%-A70%), and manual contouring. The histopathologic tumor volume (TV-Histo) served as the reference standard. The significance of differences between TV-Histo and PET-based tumor volume were assessed using the paired-sample Wilcoxon signed-rank test. The Spearman correlation coefficient was used to establish the strength of the association between TV-Histo and PET-derived tumor volume. Results: Median TV-Histo was 2.03 cm 3 (interquartile ratio [IQR], 1.16-3.36 cm 3 ), and median TPR was 10.16%. The adaptive method with an A40% threshold most closely determined the tumor volume, with a median difference of +0.19 (IQR, -0.71 to +2.01) and a median relative difference of +7.6%. The paired-sample Wilcoxon test showed no significant difference in PET-derived tumor volume and TV-Histo using A40%, A50%, SUV40%, and SUV50% threshold segmentation algorithms ( P > 0.05). For both threshold-based segmentation methods, use of higher thresholds (e.g., SUV60% or SUV70% and A50%-A70%) resulted in underestimation of tumor volumes, and use of lower thresholds (e.g., SUV30% or SUV40% and A30%) resulted in overestimation of tumor volumes relative to TV-Histo and TPR. Manual segmentation overestimated the tumor volume, with a median difference of +2.49 (IQR, 0.42-4.11) and a median relative difference of +130%. Conclusion: Segmentation of intraprostatic tumor volume and TPR with an adaptive segmentation approach most closely approximates TV-Histo. This information might be used to guide the primary treatment of men with clinically localized, high-risk prostate cancer., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)

Purpose: Despite well-informed work in several malignancies, the phenotypic effects of TP53 mutations in metastatic castration-sensitive prostate cancer (mCSPC) progression and metastasis are not clear. We characterized the structure-function and clinical impact of TP53 mutations in mCSPC., Patients and Methods: We performed an international retrospective review of men with mCSPC who underwent next-generation sequencing and were stratified according to TP53 mutational status and metastatic burden. Clinical outcomes included radiographic progression-free survival (rPFS) and overall survival (OS) evaluated with Kaplan-Meier and multivariable Cox regression. We also utilized isogenic cancer cell lines to assess the effect of TP53 mutations and APR-246 treatment on migration, invasion, colony formation in vitro, and tumor growth in vivo. Preclinical experimental observations were compared using t-tests and ANOVA., Results: Dominant-negative (DN) TP53 mutations were enriched in patients with synchronous (vs. metachronous) (20.7% vs. 6.3%, p < 0.01) and polymetastatic (vs. oligometastatic) (14.4% vs. 7.9%, p < 0.01) disease. On multivariable analysis, DN mutations were associated with worse rPFS (hazards ratio [HR] = 1.97, 95% confidence interval [CI]: 1.31-2.98) and overall survival [OS] (HR = 2.05, 95% CI: 1.14-3.68) compared to TP53 wild type (WT). In vitro, 22Rv1 TP53 R175H cells possessed stronger migration, invasion, colony formation ability, and cellular movement pathway enrichment in RNA sequencing analysis compared to 22Rv1 TP53 WT cells. Treatment with APR-246 reversed the effects of TP53 mutations in vitro and inhibited 22Rv1 TP53 R175H tumor growth in vivo in a dosage-dependent manner., Conclusions: DN TP53 mutations correlated with worse prognosis in prostate cancer patients and higher metastatic potential, which could be counteracted by APR-246 treatment suggesting a potential future therapeutic avenue., (© 2023 The Authors. The Prostate published by Wiley Periodicals LLC.)

Objective: Sibling relationships in early childhood can have a positive impact on children's social interaction and communication skills. Similarly, autistic children can benefit from interactions with their siblings, who can serve as readily available partners for social interaction. However, there is a lack of research on the effects of siblings based on specific characteristics of the sibling. Therefore, the aim of this study is to compare social interactions and communication skills of autistic children based on sibling status and characteristics., Methods: We conducted a retrospective data review involving 895 autistic children and their siblings at Seoul National University Bundang Hospital. Variety of diagnostic assessments or questionnaires were administered. Based on the characteristics of the data, Quade's test for nonparametric analysis of covariance was used to compare autism-related symptoms and levels of functioning of the autistic child according to 1) sibling status, 2) birth order, 3) sex, and 4) diagnosis of the sibling. Pearson correlation was used to explore associations between the sibling age gap and different clinical scores., Results: Having siblings was associated with fewer difficulties in restricted and repetitive behaviors. Based on the comparison of the Autism Diagnostic Interview-Revised scores, autistic children with multiple siblings demonstrated better nonverbal behaviors. Autistic children with autistic siblings experienced greater difficulties in social interactions and communications, such as peer relationships, sharing enjoyment, and engaging in social imitative play., Conclusion: The study revealed differences in social interactions and communication skills of autistic children based on sibling status, birth order, affected sibling, age gap, and sex.

Introduction: This study aimed to investigate the association between social vulnerability, as measured by the Centers for Disease Control and Prevention's Social Vulnerability Index (SVI), and the quality of life (QoL) of kidney stone patients using the validated Wisconsin Stone Quality of Life Questionnaire (WISQOL)., Methods: A retrospective analysis was conducted on medical records of new urolithiasis patients who completed the WISQOL at the University of Rochester Medical Center kidney stone clinic. The primary outcome was WISQOL score, which was measured across multiple domains. SVI was used to assess social vulnerability. Neighborhoods with high SVI were defined by a threshold greater than or equal to the 75th percentile nationally. Demographic and clinical data were collected. Statistical analyses, including univariate tests and multivariate linear regression, were performed to evaluate the relationships between social vulnerability and disease-specific QoL., Results: A total of 1718 patients were included in the study. One hundred five subjects (6.1%) were from neighborhoods of high social vulnerability. Patients residing in neighborhoods with high social vulnerability (SVI quartile) reported significantly lower QoL scores (69.1 vs 77.2; P = .001) and this persisted across all domains, including social impact (32.6 vs 35.1; P = .002), emotional impact (25.2 vs 27.5; P = .006), disease impact (28.5 vs 31.4; P = .001), and vitality (10.3 vs 11.2; P = .015). Younger age, female sex, and higher number of comorbidities were identified as independent predictors of lower QoL scores. However, non-White race and Latinx ethnicity did not exhibit a significant association with QoL scores., Conclusions: These findings highlight the negative impact of high social vulnerability on QoL, emphasizing the importance of considering socioeconomic factors in patient care. These results emphasize the need for targeted interventions to support vulnerable populations. While this study offers initial insights, further research is essential to corroborate these outcomes across larger and more diverse populations.

Background: Prostate cancer remains the most prevalent malignancy and the second-leading cause of cancer-related death in men in the USA. Radiation therapy, typically with androgen suppression, remains a mainstay in the treatment of intermediate- and high-risk, potentially lethal prostate cancers. However, local recurrence and treatment failure remain common. Basic and translational research has determined the potential for using androgen receptor (AR) ligands (e.g., dihydrotestosterone and flutamide) in the context of androgen-deprived prostate cancer to induce AR- and TOP2B-mediated DNA double-strand breaks (DSBs) and thereby synergistically enhance the effect of radiation therapy (RT). The primary aim of this study is to carry out pharmacodynamic translation of these findings to humans., Methods: Patients with newly diagnosed, biopsy-confirmed localized prostatic adenocarcinoma will be recruited. Flutamide, an oral non-steroidal androgen receptor ligand, will be administered orally 6-12 h prior to prostate biopsy (performed under anesthesia prior to brachytherapy seed implantation). Key study parameters will include the assessment of DNA double-strand breaks by γH2A.x foci and AR localization to the nucleus. The initial 6 patients will be treated in a single-arm run-in phase to assess futility by establishing whether at least 2 subjects from this group develop γH2A.x foci in prostate cancer cells. If this criterion is met, the study will advance to a two-arm, randomized controlled phase in which 24 participants will be randomized 2:1 to either flutamide intervention or placebo standard-of-care (with all patients receiving definitive brachytherapy). The key pharmacodynamic endpoint will be to assess whether the extent of γH2A.x foci (proportion of cancer cells positive and number of foci per cancer cell) is greater in patients receiving flutamide versus placebo. Secondary outcomes of this study include an optional, exploratory analysis that will (a) describe cancer-specific methylation patterns of cell-free DNA in plasma and urine and (b) assess the utility of serum and urine samples as a DNA-based biomarker for tracking therapeutic response., Discussion: This study will confirm in humans the pharmacodynamic effect of AR ligands to induce transient double-strand breaks when administered in the context of androgen deprivation as a novel therapy for prostate cancer. The findings of this study will permit the development of a larger trial evaluating flutamide pulsed-dose sequencing in association with fractionated external beam RT (+/- brachytherapy). The study is ongoing, and preliminary data collection and recruitment are underway; analysis has yet to be performed., Trial Registration: ClinicalTrials.gov NCT03507608. Prospectively registered on 25 April 2018., (© 2023. The Author(s).)

Objective: To determine whether prostate biopsy type affects spacer placement quality using a large sample of patients treated in the ambulatory setting., Methods: A retrospective cohort study was conducted on patients diagnosed with prostate cancer who underwent hydrogel spacer placement before primary radiation treatment between 2018 and 2023 after transperineal (TP) or transrectal (TR) prostate biopsy. Study outcomes were Spacer Quality Score (SQS) (0-2, with greater values indicating better placement), Rectal Wall Infiltration (RWI) (0-3, with lower values indicating lack of RWI), and the occurrence of other hydrogel complications., Results: A total of 395 patients were included. A pre-hydrogel TR biopsy was performed in 273 patients (69.1%), while TP biopsy was performed in 122 (30.9%). A SQS ≥1 occurred in 308 (77.9%) patients. A greater proportion of TP patients had a favorable SQS (≥1) compared to those who underwent TR (87.7 vs 73.5%, P <.002). An RWI score ≥2 was found in 180 (45.6%) patients. The proportion of patients with an unfavorable RWI score (≥2) did not differ significantly by type of biopsy performed. Patients who had an interval of >70 days between biopsy and hydrogel placement had significantly decreased odds of an RWI score ≥2 (odds ratio = 0.42, 95% confidence interval: 0.21-0.83). Only one infection was found after hydrogel placement., Conclusion: The quality of hydrogel placement was significantly better in men who had undergone TP biopsy. Rectal wall infiltration was more common than previously reported but did not differ between TP and TR biopsies., Competing Interests: Declaration of Competing Interest All authors have no competing interests.., (Copyright © 2023 Elsevier Inc. All rights reserved.)

In metastatic castration-sensitive prostate cancer (mCSPC), disease volume plays an integral role in guiding treatment recommendations, including selection of docetaxel therapy, metastasis-directed therapy, and radiation to the prostate. Although there are multiple definitions of disease volume, they have commonly been studied in the context of metastases detected via conventional imaging (CIM). One such numeric definition of disease volume, termed oligometastasis, is heavily dependent on the sensitivity of the imaging modality. We performed an international multi-institutional retrospective review of men with metachronous oligometastatic CSPC (omCSPC), detected via either advanced molecular imaging alone (AMIM) or CIM. Patients were compared with respect to clinical and genomic features using the Mann-Whitney U test, Pearson's χ 2 test, and Kaplan-Meier overall survival (OS) analyses with a log-rank test. A total of 295 patients were included for analysis. Patients with CIM-omCSPC had significantly higher Gleason grade group (p = 0.032), higher prostate-specific antigen at omCSPC diagnosis (8.0 vs 1.7 ng/ml; p < 0.001), more frequent pathogenic TP53 mutations (28% vs 17%; p = 0.030), and worse 10-yr OS (85% vs 100%; p < 0.001). This is the first report of clinical and biological differences between AMIM-detected and CIM-detected omCSPC. Our findings are particularly important for ongoing and planned clinical trials in omCSPC. PATIENT SUMMARY: Metastatic prostate cancer with just a few metastases only detected via newer scanning methods (called molecular imaging) is associated with fewer high-risk DNA mutations and better survival in comparison to metastatic cancer detected via conventional scan methods., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Detection of tumor biomarkers in body fluids is a significant advancement in cancer treatment because it allows diagnosis without invasive tissue biopsies. Nucleases have long been regarded as a potential class of biomarkers that can indicate the occurrence and progression of cancers. Among these, flap endonuclease 1 (FEN1) plays an important role in DNA replication and repair, and also overexpressed in abnormally proliferating cells such as cancer cells. FEN1 is thus considered to be a potential biomarker as well as a target for cancer therapy., Results: We developed a novel method for detecting FEN1 based on its specific endonuclease activity which incises bifurcated nucleic acids (flaps), in combination with in vitro transcription. Developed method uses a simple DNA structure (substrate DNA) carrying a short 5'-flap sequence, and a single-stranded sensor DNA encoding the Broccoli light-up aptamer. When the assay mixture was supplied with a FEN1-containing sample, the flap sequence encoding the sense sequence of T7 promoter was cleaved and released from the substrate DNA. Because the sensor DNA was designed to carry the Broccoli RNA aptamer under the antisense sequence of T7 promoter, hybridization of the excised flap onto the sensor DNA initiated the transcription of the Broccoli RNA aptamer, enabling determination of the FEN1 titer based on the fluorescence of transcribed Broccoli aptamer. By using a combination of FEN1-mediated generation of a short oligonucleotide and subsequent oligonucleotide-dependent in vitro transcription, this method could detect FEN1 in biological samples within 1 h., Significance and Novelty: Developed method enables the detection of FEN1 by a simple one-pot reaction. It can detect sub-nanomolar concentrations of FEN1 within an hour, and has the potential to be used for cancer diagnosis, prognosis, and drug screening. It also enables easy identification of compounds that inhibit FEN1 activity and is thus a versatile platform for screening anti-cancer drugs. We anticipate that the basic principles of this assay can be applied to detect other biomolecules, such as nucleic acids., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could influence the work reported in this study., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Parkinson's disease (PD) is an age-related chronic neurological disorder, mainly characterized by the pathological feature of α-synuclein (α-syn) aggregation, with the exact disease pathogenesis unclear. During the onset and progression of PD, synaptic dysfunction, including dysregulation of axonal transport, impaired exocytosis, and endocytosis are identified as crucial events of PD pathogenesis. It has been reported that over-expression of α-syn impairs clathrin-mediated endocytosis (CME) in the synapses. However, the underlying mechanisms still needs to be explored. In this study, we investigated the molecular events underlying the synaptic dysfunction caused by over-expression of wild-type human α-syn and its mutant form, involving series of proteins participating in CME. We found that excessive human α-syn causes impaired fission and uncoating of clathrin-coated vesicles during synaptic vesicle recycling, leading to reduced clustering of synaptic vesicles near the active zone and increased size of plasma membrane and number of endocytic intermediates. Furthermore, over-expressed human α-syn induced changes of CME-associated proteins, among which synaptojanin1 (SYNJ1) showed significant reduction in various brain regions. Over-expression of SYNJ1 in primary hippocampal neurons from α-syn transgenic mice recovered the synaptic vesicle density, clustering and endocytosis. Using fluorescence-conjugated transferrin, we demonstrated that SYNJ1 re-boosted the CME activity by restoring the phosphatidylinositol-4,5-bisphosphate homeostasis. Our data suggested that over-expression of α-syn disrupts synaptic function through interfering with vesicle recycling, which could be alleviated by re-availing of SYNJ1. Our study unrevealed a molecular mechanism of the synaptic dysfunction in PD pathogenesis and provided a potential therapeutic target for treating PD., (© 2023 The Authors. Journal of Neurochemistry published by John Wiley & Sons Ltd on behalf of International Society for Neurochemistry.)

From November 2021 to September 2022, we conducted four field surveys on macroinvertebrates and water environmental factors in Xinyang section of the Huaihe River main stream. We analyzed the structure and spatiotemporal distribution characteristics of the functional feeding groups of macroinvertebrates, and evaluated river water quality. A total of 73 macroinvertebrate species were collected in the basin, belonging to 42 families, 7 classes, and 3 phyla. The dominant species of macroinvertebrates changed significantly in different months, with Exopalaemon modestus being the absolute advantage species in the basin in July and September 2022. In different sampling months, the functional feeding group of macroinvertebrates was mainly dominated by shredders, accounting for 35.9%. The results of redundancy analysis showed that the main environmental factors affecting the distribution of functional feeding groups of macroinvertebrates varied across different months, with conductivity in February, temperature in July, and oxidation-reduction potential in September and November. The evaluation based on the biolo-gical index and Shannon index of macroinvertebrates indicated that water quality in the investigated section was at a light pollution level.

Background: Air pollution is an important and interventionable risk factor for cardiovascular disease. Air pollution exposure, even for a short-term exposure, is conspicuously relevant to increased risk of myocardial infarction (MI) mortality and clinical evidence has shown that air pollution particulate matter (PM) induces the aggravation of AMI. 3,4-benzo[a]pyrene (BaP), an extremely toxic polycyclic aromatic hydrocarbon (PAH) and a common component of PM, is listed as one of the main objects of environmental pollution monitoring. Both epidemiological and toxicological studies suggest that BaP exposure may be associated with cardiovascular disease. Since PM is significantly associated with the increased risk of MI mortality, and BaP is an important component of PM associated with cardiovascular disease, we intend to investigate the effect of BaP on MI models., Methods: The MI mouse model and the oxygen and glucose deprivation (OGD) H9C2 cell model were used to investigate the effect of BaP in MI injury. The involvement of mitophagy and pyroptosis in regulating deterioration of cardiac function and aggravation of MI injury induced by BaP was comprehensively evaluated., Results: Our study shows that BaP exacerbates MI injury in vivo and in vitro, a result based on BaP-induced NLRP3-related pyroptosis. In addition, BaP can inhibit PINK1/Parkin dependent mitophagy through the aryl hydrocarbon receptor (AhR), thus the mitochondrial permeability transition pore (mPTP) was induced to open., Conclusion: Our results suggest a role for the BaP from air pollution in MI injury aggravation and reveal that BaP aggravates MI injury by activating NLRP3-related pyroptosis via the PINK1/Parkin-mitophagy-mPTP opening axis., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Introduction: Self-limited epilepsy with centrotemporal spikes is a transient developmental epilepsy with a seizure onset zone localized to the centrotemporal cortex that commonly impacts aspects of language function. To better understand the relationship between these anatomical findings and symptoms, we characterized the language profile and white matter microstructural and macrostructural features in a cohort of children with SeLECTS., Methods: Children with active SeLECTS (n = 13), resolved SeLECTS (n = 12), and controls (n = 17) underwent high-resolution MRIs including diffusion tensor imaging sequences and multiple standardized neuropsychological measures of language function. We identified the superficial white matter abutting the inferior rolandic cortex and superior temporal gyrus using a cortical parcellation atlas and derived the arcuate fasciculus connecting them using probabilistic tractography. We compared white matter microstructural characteristics (axial, radial and mean diffusivity, and fractional anisotropy) between groups in each region, and tested for linear relationships between diffusivity metrics in these regions and language scores on neuropsychological testing., Results: We found significant differences in several language modalities in children with SeLECTS compared to controls. Children with SeLECTS performed worse on assessments of phonological awareness (p = 0.045) and verbal comprehension (p = 0.050). Reduced performance was more pronounced in children with active SeLECTS compared to controls, namely, phonological awareness (p = 0.028), verbal comprehension (p = 0.028), and verbal category fluency (p = 0.031), with trends toward worse performance also observed in verbal letter fluency (p = 0.052), and the expressive one-word picture vocabulary test (p = 0.068). Children with active SeLECTS perform worse than children with SeLECTS in remission on tests of verbal category fluency (p = 0.009), verbal letter fluency (p = 0.006), and the expressive one-word picture vocabulary test (p = 0.045). We also found abnormal superficial white matter microstructure in centrotemporal ROIs in children with SeLECTS, characterized by increased diffusivity and fractional anisotropy compared to controls (AD p = 0.014, RD p = 0.028, MD p = 0.020, and FA p = 0.024). Structural connectivity of the arcuate fasciculus connecting perisylvian cortical regions was lower in children with SeLECTS (p = 0.045), and in the arcuate fasciculus children with SeLECTS had increased diffusivity (AD p = 0.007, RD p = 0.006, MD p = 0.016), with no difference in fractional anisotropy (p = 0.22). However, linear tests comparing white matter microstructure in areas constituting language networks and language performance did not withstand correction for multiple comparisons in this sample, although a trend was seen between FA in the arcuate fasciculus and verbal category fluency (p = 0.047) and the expressive one-word picture vocabulary test (p = 0.036)., Conclusion: We found impaired language development in children with SeLECTS, particularly in those with active SeLECTS, as well as abnormalities in the superficial centrotemporal white matter as well as the fibers connecting these regions, the arcuate fasciculus. Although relationships between language performance and white matter abnormalities did not pass correction for multiple comparisons, taken together, these results provide evidence of atypical white matter maturation in fibers involved in language processing, which may contribute to the aspects of language function that are commonly affected by the disorder., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Metastatic castration-sensitive prostate cancer (mCSPC) is commonly classified into high- and low-volume subgroups which have demonstrated differential biology, prognosis, and response to therapy. Timing of metastasis has similarly demonstrated differences in clinical outcomes; however, less is known about any underlying biologic differences between these disease states. Herein, we aim to compare transcriptomic differences between synchronous and metachronous mCSPC and identify any differential responses to therapy., Patients and Methods: We performed an international multi-institutional retrospective review of men with mCSPC who completed RNA expression profiling evaluation of their primary tumor. Patients were stratified according to disease timing (synchronous versus metachronous). The primary endpoint was to identify differences in transcriptomic profiles between disease timing. The median transcriptomic scores between groups were compared with the Mann-Whitney U test. Secondary analyses included determining clinical and transcriptomic variables associated with overall survival (OS) from the time of metastasis. Survival analysis was carried out with the Kaplan-Meier method and multivariable Cox regression., Results: A total of 252 patients were included with a median follow-up of 39.6 months. Patients with synchronous disease experienced worse 5-year OS (39% versus 79%; P < 0.01) and demonstrated lower median androgen receptor (AR) activity (11.78 versus 12.64; P < 0.01) and hallmark androgen response (HAR; 3.15 versus 3.32; P < 0.01). Multivariable Cox regression identified only high-volume disease [hazard ratio (HR) = 4.97, 95% confidence interval (CI) 2.71-9.10; P < 0.01] and HAR score (HR = 0.51, 95% CI 0.28-0.88; P = 0.02) significantly associated with OS. Finally, patients with synchronous (HR = 0.47, 95% CI 0.30-0.72; P < 0.01) but not metachronous (HR = 1.37, 95% CI 0.50-3.92; P = 0.56) disease were found to have better OS with AR and non-AR combination therapy as compared with monotherapy (P value for interaction = 0.05)., Conclusions: We have demonstrated a potential biologic difference between metastatic timing of mCSPC. Specifically, for patients with low-volume disease, those with metachronous low-volume disease have a more hormone-dependent transcriptional profile and exhibit a better prognosis than synchronous low-volume disease., Competing Interests: Disclosure PAS reports stocks from Merck and Pfizer. AH reports employment, stock/other ownership interests with Veracyte. YL reports employment with Veracyte. VF reports travel/accommodations/expenses covered by Ipsen. AH reports honoraria, travel/accommodations/expenses covered by UroToday; consulting/advisory role with AstraZeneca and MSD. DYS is a consultant for Isoray; also reports being a consultant and carrying out research for BioProtect. AES reports consulting/advisory role for and receiving honoraria from Astellas Pharma; is on the speaker’ bureau and reports receiving honoraria from Tempus; reports receiving honoraria from Bayer, Janssen Biotech, Blue Earth Diagnostics, Decipher Biosciences, Myovant Sciences, and Lantheus Medical Imaging. FF reports carrying out consulting/advisory role for Janssen Biotech, Astellas Pharma, Foundation Medicine, Exact Sciences, Bristol-Myers Squibb, Varian Medical Systems, Novartis, Roivant, Bayer, Myovant Sciences, Tempus, and POINT Biopharma; reports performing consulting/advisory role or has stock/other ownership interests in Serimmune, BlueStar Genomics, and Artera; and receives research funding from Zenith Epigenetics. DS reports consulting/advisory role with AstraZeneca, Bayer, Boston Scientific, Janssen, Novartis, Myovant, Pfizer, GammaTile, Elekta, and Varian. KP reports consulting/advisory role with CUE Biopharma, GloriousMed Technology, and Akrevia Therapeutics; reports leadership, travel/accommodations/expenses, and stock/other ownership interests with CUE Biopharma; stock/other ownership interests with Keystone Biopharma; stock/other ownership interests with Medsyn Biopharma, Oncopia Therapeutics; and research funding from Progenics. SG reports consulting/advisory role with Bayer, MSD Oncology, Amgen, Pfizer, Bristol-Meyers Squibb, Telix Pharmaceuticals, AAA HealthCare, Orion, Novartis, Modra Pharmaceuticals, Myriad Genetics, AstraZeneca, TOLREMO, Silvio Grasso Consulting, WebMD/Medscape, ESMO, Swiss Academy of Multidisciplinary Oncology, Swiss group for Clinical Cancer Research, German-speaking European School of Oncology, Radiotelevisione Svizzera Italiana, and ProteoMediX; also reports travel/accommodations/expenses covered by AstraZeneca. GA reports consulting/advisory role, speakers’ bureau, travel/accommodations/expenses, honoraria, research funding from Janssen-Cilag; consulting/advisory role with Veridex, Novartis, Millennium; consulting/advisory role, speakers’ bureau, travel/accommodations/expenses covered by Ventana Medical Systems; consulting/advisory role, speakers’ bureau, travel/accommodations/expenses, honoraria from Astellas Pharma; consulting/advisory role, travel/accommodations/expenses covered by Medivation, Abbott Laboratories, ESSA, Bayer, and Pfizer; consulting/advisory role and is on the speaker’s bureau for AstraZeneca; consulting/advisory role, speakers’ bureau, travel/accommodations/expenses covered by Ferring; is on the speakers’ bureau for Takeda, Sanofi, Ipsen; has received ICR rewards to inventors of abiraterone acetate (patent/royalty/other intellectual property); and reports research funding from Arno Therapeutics and Innocrin Pharma. NDJ reports honoraria, consulting/advisory role, speakers’ bureau, research funding, travel/accommodations/expenses covered by Sanofi and Janssen; honoraria, consulting/advisory role, speakers’ bureau, and research funding from Astellas Pharma; honoraria and consulting/advisory role with Bayer; consulting/advisory role with Clovis Oncology and EUSA Pharma; reports consulting/advisory role with and research funding from Pfizer; is on the speakers’ bureau for Pierre Fabre, Ferring, and Merck; is on the speakers’ bureau and received research funding from AstraZeneca; and research funding from Novartis. TL reports consulting/advisory role with Janssen Oncology; research funding from Ventana Medical Systems, Deep Bio, AIRA Matrix, and Exact Sciences. ED reports employment and stock/other ownership interests with Veracyte. CS reports consulting/advisory role and research funding from Sanofi, Janssen Biotech, Astellas Pharma, Bayer, and Pfizer; consulting/advisory role with Genentech/Roche, AstraZeneca, Amgen, Lilly, and POINT Biopharma; stock/other ownership interest, patents/royalties/other intellectual property with Leuchemix; patents/royalties/other intellectual property with Exelixis; and research funding from Dendreon. PTT reports consulting/advisory role with Astellas Pharma, Regeneron, GenomeDx, Dendreon, Noxopharm, Janssen, Myovant Sciences, AstraZeneca; research funding from Astellas Pharma; consulting/advisory role, travel/accommodations/expenses, honoraria, and research funding from RefleXion Medical; consulting/advisory role and research funding from Bayer Health; and patent (Compounds and Methods of Use in Ablative Radiotherapy. Patent filed 3/9/2012. PCT/US2012/028475. PCT/WO/2012/122471). PO reports consulting/advisory role with Janssen-Cilag, Bayer, Astellas Pharma, Curium Pharma, Telix Pharmaceuticals, and Novartis; research funding from Bayer and Varian Medical Systems; and travel/accommodations/expenses covered by Ferring. All other authors have declared no conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: The frequency, clinical characteristics, and associated symptoms of comorbid tic disorders in individuals with autism spectrum disorder (ASD) remain unclear., Methods: We included subsets of individuals from a larger genetic study who were diagnosed with ASD (n = 679; age: 4-18 years) and completed the Yale Global Tic Severity Scale (YGTSS) questionnaire. Based on the YGTSS score, the individuals were divided into two groups: ASD only (n = 554) and ASD with tics (n = 125). Individuals were assessed using the verbal and non-verbal intelligence quotient (IQ), Vineland Adaptive Behavior Scale (VABS-2), Social Responsiveness Scale-2 (SRS-2), Child Behavior Checklists (CBCL), and Yale-Brown Obsessive-Compulsive Scale (YBOCS), followed by between-group comparisons. All statistical analyses were performed using the Statistical Package for the Social Sciences (SPSS) version 26., Results: Tic symptoms were observed in 125 (18.4%) participants; among them, most participants presented both motor and vocal tics (n = 40, 40.0%). The ASD with tics group had a significantly higher average age and full-scale IQ score than the ASD only group. After adjusting for age, the ASD with tics group had significantly higher scores in the SRS-2, CBCL, and YBOCS subdomains than the ASD only group. Furthermore, all variables except the non-verbal IQ and VABS-2 scores were positively correlated with the YGTSS total score. Finally, the proportion of tic symptoms was significantly higher among individuals with a higher IQ score (≥ 70)., Conclusions: The IQ score was positively correlated with the proportion of tic symptoms among individuals with ASD. Moreover, the severity of the core and comorbid symptoms of ASD was associated with the occurrence and severity of tic disorders. Our findings suggest the need for appropriate clinical interventions for individuals with ASD. Trial registration This study retrospectively registered participants., (© 2023. The Author(s).)

Background: Novel treatments and trial designs remain a high priority for bacillus Calmette-Guerin (BCG)-unresponsive non-muscle-invasive bladder cancer (NMIBC) patients., Objective: To evaluate the safety and preliminary efficacy of anti-PD-L1 directed therapy with durvalumab (D), durvalumab plus BCG (D + BCG), and durvalumab plus external beam radiation therapy (D + EBRT)., Design, Setting, and Participants: A multicenter phase 1 trial was conducted at community and academic sites., Intervention: Patients received 1120 mg of D intravenously every 3 wk for eight cycles. D + BCG patients also received full-dose intravesical BCG weekly for 6 wk with BCG maintenance recommended. D + EBRT patients received concurrent EBRT (6 Gy × 3 in cycle 1 only)., Outcome Measurements and Statistical Analysis: Post-treatment cystoscopy and urine cytology were performed at 3 and 6 -mo, with bladder biopsies required at the 6-mo evaluation. The recommended phase 2 dose (RP2D) for each regimen was the primary endpoint. Secondary endpoints included toxicity profiles and complete response (CR) rates., Results and Limitations: Twenty-eight patients were treated in the D (n = 3), D + BCG (n = 13), and D + EBRT (n = 12) cohorts. Full-dose D, full-dose BCG, and 6 Gy fractions × 3 were determined as the RP2Ds. One patient (4%) experienced a grade 3 dose limiting toxicity event of autoimmune hepatitis. The 3-mo CR occurred in 64% of all patients and in 33%, 85%, and 50% within the D, D + BCG, and D + EBRT cohorts, respectively. Twelve-month CRs were achieved in 46% of all patients and in 73% of D + BCG and 33% of D + EBRT patients., Conclusions: D combined with intravesical BCG or EBRT proved feasible and safe in BCG-unresponsive NMIBC patients. Encouraging preliminary efficacy justifies further study of combination therapy approaches., Patient Summary: Durvalumab combination therapy can be safely administered to non-muscle-invasive bladder cancer patients with the goal of increasing durable response rates., (Copyright © 2023 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Objective: To investigate the predictive value of complete blood count (CBC) and inflammation marker on the recurrence risk in children with Henoch-Schönlein purpura (HSP)., Methods: One hundred and thirty-three children with HSP admitted to Cangzhou Central Hospital from February 2017 to March 2019 were enrolled. The clinical data of the children were collected, at the time of admission CBC and C-reactive protein (CRP) were detected. After discharge, the children were followed up for 1 year, the clinical data of children with and without recurrence were compared, and multivariate logistic regression was used to analyze the risk factors affecting HSP recurrence. Receiver operating characteristic (ROC) curve should be drawn and the predictive value of CBC and CRP on HSP recurrence should be analyzed., Results: In the follow-up of 133 children, 8 cases were lost and 39 cases recurred, with a recurrence rate of 31.20% (39/125). The age, skin rash duration, proportion of renal damage at the initial onset, percentage of neutrophils, percentage of lymphocytes, platelet count (PLT), mean platelet volume (MPV) and neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR), MPV/PLT ratio (MPR), and CRP level of patients with recurrence were statistically different from those without recurrence ( P <0.05). Multivariate logistic regression analysis showed that long skin rash duration, renal damage at the initial onset, increased PLR, high PLT, increased MPV and elevated CRP level were independent risk factors for recurrence in children with HSP ( P <0.05). The ROC curve analysis showed that the area under the curve (AUC) of the combination of the four blood and inflammation marker (PLT, MPV, PLR and CPR) in the early prediction of HSP recurrence was 0.898, which was higher than the initial renal damage (AUC=0.687) and persistent skin rash time (AUC=0.708), with a sensitivity of 84.62% and a specificity of 83.72%., Conclusion: Observation of CBC and CPR can predict the risk of HSP recurrence early and guide early clinical intervention.

Executive functioning (EF) is a cognitive process used to perform various daily activities throughout one's lifespan. Autistic adults without intellectual disabilities (ID) also experience difficulties with EF, which is closely associated with adaptive behaviors. For this reason, it is important to improve adaptive behaviors through enhanced use of EF for autistic adults to transition into adulthood successfully. This study aims to conduct a randomized controlled trial to evaluate the effectiveness of a newly developed and modified intervention program. Thirty autistic adults without ID were randomly assigned to the treatment or waitlist group. The participants and caregivers completed various assessments and self-report questionnaires to measure everyday EF and adaptive behaviors. We performed linear mixed-effect modeling to compare the two groups. Data collected at pre-, middle, post-, and follow-up based on participants who completed the program were used to explore changes across time. While there were significant differences in the EF utility-scale (F=5.46, p = .027) between the treatment and waitlist groups, no group x time interactions were detected in other measures. Everyday EF and adaptive behaviors improved when comparing measurements at different time points (p < .001). Our program is Korea's first evidence-based intervention to improve everyday EF and adaptive behaviors for autistic adults without ID., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Objective: To analyze the clinical and genetic characteristics of pediatric patients with dual genetic diagnoses (DGD). Methods: Clinical and genetic data of pediatric patients with DGD from January 2021 to February 2022 in Peking University First Hospital were collected and analyzed retrospectively. Results: Among the 9 children, 6 were boys and 3 were girls. The age of last visit or follow-up was 5.0 (2.7,6.8) years. The main clinical manifestations included motor retardation, mental retardation, multiple malformations, and skeletal deformity. Cases 1-4 were all all boys, showed myopathic gait, poor running and jumping, and significantly increased level of serum creatine kinase. Disease-causing variations in Duchenne muscular dystrophy (DMD) gene were confirmed by genetic testing. The 4 children were diagnosed with DMD or Becker muscular dystrophy combined with a second genetic disease, including hypertrophic osteoarthropathy, spinal muscular atrophy, fragile X syndrome, and cerebral cavernous malformations type 3, respectively. Cases 5-9 were clinically and genetically diagnosed as COL9A1 gene-related multiple epiphyseal dysplasia type 6 combined with NF1 gene-related neurofibromatosis type 1, COL6A3 gene-related Bethlem myopathy with WNT1 gene-related osteogenesis imperfecta type XV, Turner syndrome (45, X0/46, XX chimera) with TH gene-related Segawa syndrome, Chromosome 22q11.2 microduplication syndrome with DYNC1H1 gene-related autosomal dominant lower extremity-predominant spinal muscular atrophy-1, and ANKRD11 gene-related KBG syndrome combined with IRF2BPL gene-related neurodevelopmental disorder with regression, abnormal movement, language loss and epilepsy. DMD was the most common, and there were 6 autosomal dominant diseases caused by de novo heterozygous pathogenic variations. Conclusions: Pediatric patients with coexistence of double genetic diagnoses show complex phenotypes. When the clinical manifestations and progression are not fully consistent with the diagnosed rare genetic disease, a second rare genetic disease should be considered, and autosomal dominant diseases caused by de novo heterozygous pathogenic variation should be paid attention to. Trio-based whole-exome sequencing combining a variety of molecular genetic tests would be helpful for precise diagnosis.