ALK-rearranged mesenchymal neoplasms: a clinicopathological and molecular study of eight additional cases of an emerging group of tyrosine kinase fusion mesenchymal tumours.

AIMS: Mesenchymal neoplasms characterised by ALK fusions mainly include inflammatory myofibroblastic tumour (IMT) and epithelioid fibrous histiocytoma (EFH). Most recently, ALK-rearranged mesenchymal tumours that are not IMT or EFH have been reported. Our aim is to further characterise eight such neoplasms, with a detailed clinicopathological, immunohistochemical and molecular analysis. METHODS: Clinicopathological features were assessed and partner agnostic targeted RNA-sequencing on clinically validated platforms was performed. RESULTS: The patients consisted of seven males and one female with a median age of 47 years (28 -59 years). The tumours ranged in size from 2.0 to 10.0 cm (mean=3.0 cm) and involved superficial and deep soft tissue (n=6) and visceral locations (n=2). Of the seven patients with follow-up (9-130 months), two developed distant metastases and five had no disease recurrence or metastasis. The tumours demonstrated diverse architectures and variable cellularity and cellular morphologies. The main constitutive cells appeared in elongated spindled in three, primitive to ovoid in two and round to epithelioid in three cases. We expanded the histopathological spectrum to include mildly to moderately cellular spindled to stellate cells in a multinodular growth in a prominent myxoid and vascularised stroma (n=2). All tumours expressed ALK(D5F3); seven were positive for S100 protein and six were positive for CD34. By fluorescence in situ hybridisation, ALK rearrangement was identified in all eight tumours. ALK fusion partners were identified by RNA-sequencing in all cases, including previously reported: EML4 (n=3), DCTN (n=1), CLIP1 (n=1) and PLEKHH2 (n=1), and also two novel fusion partners: TKT (n=1) and MMP2 (n=1). CONCLUSIONS: Our study expands the clinicopathological and molecular spectrum of ALK-rearranged mesenchymal neoplasms.

ALK-rearranged renal cell carcinoma: a multi-institutional study of nine cases with expanding the morphologic and molecular genetic spectrum.

ALK-rearranged renal cell carcinoma (ALK-RCC) is very rare, molecularly defined RCC subtype in the recently published 5th edition World Health Organization classification of tumors. In this study, we describe 9 ALK-RCCs from a clinicopathologic, immunohistochemical, and molecular genetic aspect, supporting and extending upon the observations by previous studies regarding this rare subgroup of RCC. There were six male and three female patients with ages ranging from 14 to 59 years (mean, 34.4 years). None of the patients had sickle cell trait. The diagnosis was based on radical or partial nephrectomy specimen for eight patients and on biopsy specimen for one. Tumor size ranged from 2.5 to 7.2 cm (mean, 2.8 cm). Follow-up was available for 6/9 patients (6 to 36 months); five had no tumor recurrence or metastasis and one developed lung metastasis at 24 months. The patient was subsequently treated with resection of the metastatic tumor followed by crizotinib targeted therapy, and he was alive without tumor 12 months later. Histologically, the tumors showed a mixed growth of multiple patterns, including papillary, solid, tubular, tubulocystic, cribriform, and corded, often set in a mucinous background. The neoplastic cells had predominantly eosinophilic cytoplasm. Focally, clear cytoplasm with polarized nuclei and subnuclear vacuoles (n=1), and pale foamy cytoplasm (n=1) were observed on the tumor cells. The biopsied tumor showed solid growth of elongated tubules merging with bland spindle cells. Other common and uncommon features included: psammomatous microcalcifications (n=5), rhabdoid cells (n=4), prominent intracytoplasmic vacuoles (n=4), prominent chronic inflammatory infiltrate (n=3), signet ring-cell morphology (n=2), and pleomorphic cells (n=2). By immunohistochemistry, all 9 tumors were diffusely positive for ALK(5A4) and 4/8 tested cases showed reactivity for TFE3 protein. By fluorescence in-situ hybridization analysis, ALK rearrangement was identified in all the 9 tumors; none of the tested tumors harbored TFE3 rearrangement (0/4) or gains of chromosomes 7 and 17 (0/3). ALK fusion partners were identified by RNA-sequencing in all 8 cases analyzed, including EML4 (n=2), STRN (n=1), TPM3 (n=1), KIF5B (n=1), HOOK1 (n=1), SLIT1(n=1), and TPM1(3'UTR) (n=1). Our study further expands the morphologic and molecular genetic spectrum of ALK-RCC.

Independent and Joint Effects of Prenatal Incense-Burning Smoke Exposure and Children's Early Outdoor Activity on Preschoolers' Obesity.

Incense burning is a significant source of indoor air pollution in many Asian regions. There is emerging evidence that maternal prenatal exposure to incense-burning smoke may be a risk factor for childhood obesity. We aimed to extend this new line of research by investigating the independent and joint effect of incense-burning smoke exposure, and children's outdoor activity in early life, on preschoolers' obesity. A total of 69,637 mother-child dyads were recruited from all kindergartens in the Longhua District of Shenzhen, China. Information on sociodemographic characteristics, maternal exposure to incense-burning smoke (IBS) during pregnancy, and frequency and duration of outdoor activity at the age of 1-3 years was collected by a self-administered questionnaire. In addition, the heights and weights of the children were measured by the research team. Logistic regression models and cross-over analyses were conducted to investigate the independent and combined effects of maternal exposure to incense-burning smoke during pregnancy and children's early outdoor activity on obesity in preschoolers. We found that prenatal exposure to incense-burning smoke increased the risk of the presence of obesity in preschoolers' (AOR = 1.13, 95% CI = 1.03-1.23). Additionally, lower frequencies (<3 times/week) or shorter durations (<60 min/time) of outdoor activity from the age of 1-3 years were significantly associated with the presence of obesity, with AORs of 1.24 (95% CI =1.18-1.32) and 1.11 (95% CI = 1.05-1.17), respectively. Furthermore, the cross-over analysis showed that prenatal exposure to IBS combined with a lower frequency of early outdoor activity (AOR = 1.47, 95% CI = 1.31-1.66) or a shorter duration of outdoor activity during ages of 1-3 years (AOR = 1.22, 95% CI = 1.07-1.39) increased the risk of obesity in preschoolers. Finally, additive interactions between prenatal exposure to IBS and postnatal outdoor activity on obesity were identified. Our study indicates that maternal exposure to incense-burning smoke during pregnancy and early lower postanal outdoor activity may independently and jointly increase the risk of obesity among preschoolers.

Revealing the Genetic Diversity of Chinese Chlamydia trachomatis Strains Directly from Clinical Samples through Selective Whole-Genome Amplification.

BACKGROUND: Chlamydia trachomatis is the causative agent of most prevalent bacterial sexually transmitted infection globally. Whole-genome sequencing is essential for molecular Chlamydia surveillance; however, its application is hampered by the pathogen's low abundance in clinical specimens and the expensive, labor-intensive nature of existing enrichment methodologies for Chlamydia. METHODS: We developed a targeted whole-genome amplification tool termed SWTICH, by integrating phi29 DNA polymerase-mediated amplification with meticulously designed primer sets to enrich Chlamydia trachomatis genome, followed by whole-genome sequencing. This method underwent evaluation through testing synthetic and clinical specimens. RESULTS: SWITCH demonstrated robust ability to achieve up to 98.3% genomic coverage of Chlamydia trachomatis from as few as 26.4 genomic copies present in synthetic specimens and exhibited excellent performance across diverse Chlamydia trachomatis serovars. Utilizing SWITCH, we directly generated 21 Chlamydia genomes from 26 clinical samples, enabling us to gain insights into the genetic relationships and phylogeny of current Chlamydia strains circulating in the country. Remarkably, this study marked the first instance of generating Chinese Chlamydia genomes directly from clinical samples. CONCLUSIONS: SWITCH represents a practical, cost-efficient approach to enrich Chlamydia genome directly from clinical specimens, offering an efficient avenue for molecular surveillance of Chlamydia.

MED15::TFE3 fusion renal cell carcinoma with extensive cystic change: A clinicopathologic and molecular genetic study of 2 cases, with an emphasis on differential diagnosis.

OBJECTIVES: TFE3-rearranged renal cell carcinomas (RCCs) harbor gene fusions between TFE3 and 1 of many partner genes. MED15::TFE3 fusion RCC is rare, often cystic, and easily misdiagnosed. METHODS: This study aimed to characterize 2 cases of MED15::TFE3 fusion RCC with extensive cystic change using fluorescence in situ hybridization and targeted RNA sequencing. RESULTS: Both patients were young adult women aged 29 and 35 years. Radiologically, both presented with a cystic Bosniak category II renal lesion. The cysts measured 9.3 cm and 4.8 cm in greatest dimension. Both patients underwent cyst enucleation, and neither had tumor recurrence or metastasis at 26 and 6 months of follow-up, respectively. Microscopically, both tumors were entirely cystic, with thick, fibrous cystic walls lined by small clusters of cells with clear to eosinophilic cytoplasm and uniform, round nuclei with inconspicuous nucleoli. There were also small aggregations of similar clear cells within the cystic walls. Foci of basement membrane-like material depositions were noted in 1 case; calcifications were observed in both cases. Both cases demonstrated nuclear positivity for PAX8 and TFE3 and cytoplasmic staining for Melan-A; HMB45, CAIX, and CK7 were negative. Fluorescence in situ hybridization revealed that both tumors were positive for TFE3 rearrangements. RNA sequencing identified MED15::TFE3 gene fusions in both cases. CONCLUSIONS: The main differential diagnosis of MED15::TFE3 fusion RCC includes multilocular cystic renal neoplasm of low malignant potential and atypical renal cysts. Molecular confirmation of TFE3 fusion is essential for establishing the correct diagnosis.

penA profile of Neisseria gonorrhoeae in Guangdong, China: Novel penA alleles are related to decreased susceptibility to ceftriaxone or cefixime.

BACKGROUND: Resistance to extended-spectrum cephalosporins (ESCs) has become a public health concern with the spread of Neisseria gonorrhoeae and increasing antimicrobial resistance. Mutation of penA, encoding penicillin-binding protein 2, represents a mechanism of ESC resistance. This study sought to assess penA alleles and mutations associated with decreased susceptibility (DS) to ESCs in N. gonorrhoeae. MATERIALS AND METHODS: In 2021, 347 gonococci were collected in Guangdong, China. Minimum inhibitory concentations (MICs) of ceftriaxone and cefixime were determined, and whole-genome sequencing and phylogenetic analysis were performed. Multi-locus sequence typing (MLST) and conventional resistance determinants such as penA, mtrR, PonA and PorB were analysed. penA was genotyped and sequence-aligned using PubMLST. RESULTS: Genome-wide phylogenetic analysis revealed that the prevalence of DS to ESCs was highest in Clade 11.1 (100.0%), Clade 2 (66.7%) and Clade 0 (55.7%), and the leading cause was strains with penA-60.001 or new penA alleles in clades. The penA phylogenetic tree is divided into two branches: non-mosaic penA and mosaic penA. The latter contained penA-60.001, penA-10 and penA-34. penA profile analysis indicated that A311V and T483S are closely related to DS to ESCs in mosaic penA. The new alleles NEIS1753_2840 and NEIS1753_2837 are closely related to penA-60.001, with DS to ceftriaxone and cefixime of 100%. NEIS1753_2660, a derivative of penA-10 (A486V), has increased DS to ceftriaxone. NEIS1753_2846, a derivative of penA-34.007 (G546S), has increased DS to cefixime. CONCLUSION: This study identified critical penA alleles related to elevated MICs, and trends of gonococcus-evolved mutated penA associated with DS to ESCs in Guangdong.

Relationship between bedtime, nighttime sleep duration, and anxiety symptoms in preschoolers in China.

Background: Sleep problems in preschoolers are becoming increasingly prominent, and the association between sleep status and anxiety symptoms has attracted growing attention. However, studies investigating the relationship between bedtime and nighttime sleep duration in preschoolers and their anxiety symptoms remain scant. We used the large sample data from the Longhua Cohort Study of Children in Shenzhen, China (LCCS) to analyze the association between bedtime and sleep in preschoolers and their anxiety symptoms. Methods: A cross-sectional study of 69,138 preschoolers in Longhua District, Shenzhen, China was conducted in 2022. Data on sociodemographic characteristics of families, bedtime, nighttime sleep duration of preschoolers, and their anxiety symptoms (measured by the Spence Preschool Children Anxiety Scale) were collected through a structured questionnaire completed by the parents. Using binary logistic regression models, the relationship between bedtime, nighttime sleep duration, and childhood anxiety symptoms was examined. Results: The bedtimes of preschoolers were concentrated between 21:01-22:00 (52.41%). Among the preschoolers, 38.70% had bedtimes later than 22:00, and 75.49% had insufficient nighttime sleep duration. The positive screening rate for anxiety symptoms among preschoolers was 3.50%. After adjusting for confounding factors using binary logistic regression models, compared with preschoolers with bedtime ≤21:00, The OR (95%CI) values of anxiety in preschoolers with bedtime ≥23:01, 22:01-23:00 and 21:01-22:00 were 2.86 (2.21-3.69), 1.51 (1.27-1.79) and 1.48 (1.26-1.76), respectively. Compared with those with sufficient nighttime sleep duration, the OR (95%CI) of children with nighttime sleep duration less than 9 h was 1.36 (1.23-1.51). Conclusion: An association exists between bedtime and nighttime sleep duration in preschoolers and their anxiety symptoms. Preschoolers with 21:00 for bedtime and a nighttime sleep duration of 10 h may have lower anxiety symptoms. These findings support the importance of adequate sleep for preventing anxiety symptoms in children.

IR808@MnO nano-near infrared fluorescent dye's diagnostic value for malignant pleural effusion.

BACKGROUND: Malignant pleural effusion is mostly a complication of advanced malignant tumors. However, the cancer markers such as carbohydrate antigen 125 (CA 125), carbohydrate antigen 15-3 (CA 15-3), carbohydrate antigen 19-9 (CA 19-9), and cytokeratin fragment 21-1 (CYFRA 21-1) have low sensitivity and organ specificity for detecting malignant pleural effusion. RESEARCH QUESTION: Is IR808@MnO nano-near infrared fluorescent dye worthy for the diagnosis in differentiating benign and malignant pleural effusions. STUDY DESIGN AND METHODS: This experiment was carried out to design and characterize the materials for in vitro validation of the new dye in malignant tumor cells in the A549 cell line and in patients with adenocarcinoma pleural effusion. The dye was verified to possess tumor- specific targeting capabilities. Subsequently, a prospective hospital-based observational study was conducted, enrolling 106 patients and excluding 28 patients with unknown diagnoses. All patients underwent histopathological analysis of thoracoscopic biopsies, exfoliative cytological analysis of pleural fluid, and analysis involving the new dye. Statistical analyses were performed using Microsoft Excel, GraphPad Prism, and the R language. RESULTS: The size of IR808@MnO was 136.8 ± 2.9 nm, with peak emission at 808 nm, and it has near-infrared fluorescence properties. Notably, there was a significant difference in fluorescence values between benign and malignant cell lines (p < 0.0001). The malignant cell lines tested comprised CL1-5, A549, MDA-MB-468, U-87MG, MKN-7, and Hela, while benign cell lines were BEAS-2B, HUVEC, HSF, and VE. The most effective duration of action was identified as 30 min at a concentration of 5 µl. This optimal duration of action and concentration were consistent in patients with lung adenocarcinoma accompanied by pleural effusion and 5 µl. Of the 106 patients examined, 28 remained undiagnosed, 39 were diagnosed with malignant pleural effusions, and the remaining 39 with benign pleural effusions. Employing the new IR808@MnO staining method, the sensitivity stood at 74.4%, specificity at 79.5%, a positive predictive value of 69.2%, and a negative predictive value of 82.1%. The area under the ROC curve was recorded as 0.762 (95% CI: 0.652-0.872). The confusion matrix revealed a positive predictive value of 75.7%, a negative predictive value of 75.6%, a false positive rate of 22.5%, and a false negative rate of 26.3%. INTERPRETATION: The IR808@MnO fluorescent probe represents an efficient, sensitive, and user-friendly diagnostic tool for detecting malignant pleural fluid, underscoring its significant potential for clinical adoption.

A rapid isothermal CRISPR-Cas13a diagnostic test for genital herpes simplex virus infection.

Prompt diagnosis is essential for managing herpes simplex virus types 1 and 2 (HSV-1/2). Existing diagnostic methods are not widely available that required expensive or additional equipment for conducting examinations and result readouts, which can limit their utility in resource-constrained settings. We successfully developed a CRISPR-Cas13a-based assay for the detection and genotyping of HSV. Our assay demonstrated a high sensitivity of 96.15% and 95.15% for HSV-1 and HSV-2, respectively, with a specificity of 100% compared to a commercial qPCR assay when tested on 194 clinical samples. Remarkably, the assay enables a limit of detection of 1 copy/µL of viral DNA, facilitated by an enhanced input of RPA product and is designed for both mobile app integration and colorimetric interpretation, allowing for semiquantitative readings. These findings highlight the excellent performance of our CRISPR-based diagnostic in detecting HSV and its potential for point-of-care testing in resource-constrained settings.

PEComa with ASPSCR1::TFE3 fusion: expanding the molecular genetic spectrum of TFE3-rearranged PEComa with an emphasis on overlap with alveolar soft part sarcoma.

AIMS: Mesenchymal neoplasms involving TFE3 gene fusions are diverse, mainly include alveolar soft part sarcoma (ASPS) that is characterised by ASPSCR1::TFE3 fusion, and a small subset of perivascular epithelioid cell tumours (PEComas) referred to as TFE3-rearranged PEComa, that most frequently harbours SFPQ::TFE3 fusion. Historically, ASPS and TFE3-rearranged PEComa are considered two distinctive entities despite their known morphological overlap. However, recent studies have suggested a potential histogenetic relationship between them, and several neoplasms that showed morphological features more closely fit PEComa rather than ASPS but harboured ASPSCR1::TFE3 fusion have been documented. In this study, we report three cases of PEComa with ASPSCR1::TFE3 fusion. METHODS AND RESULTS: Clinicopathological features were assessed and partner agnostic targeted next-generation sequencing on clinically validated platforms were performed. The patients are two females and one male with age at presentation ranging from 21 to 51 years. All three tumours were located in the viscera (rectum, kidney and cervix). On a relatively limited follow-up period (range = 9-15 months), all patients are alive without evidence of recurrent or metastatic disease. The neoplasms were composed of tight nested architecture of epithelioid clear cells separated by a delicate vascular network, two of which were associated with sheets of plump spindle cells, and none showed significant discohesive tumour morphology. Immunohistochemically, in addition to TFE3 protein, all three neoplasms demonstrated co-expression of melan-A and smooth muscle actin. RNA-sequencing identified ASPSCR1::TFE3 fusion in all three cases that were confirmed by subsequent fluorescence in-situ hybridisation analyses. CONCLUSIONS: Our study expands the molecular genetic spectrum of TFE3-rearranged PEComa and further indicates its close relationship to ASPS.

SMARCB1/INI1-deficient epithelioid and myxoid neoplasms in paratesticular region: Expanding the clinicopathologic and molecular spectrum.

SMARCB1/INI1-deficient soft tissue tumors with epithelioid and myxoid features are diverse and mainly include soft tissue myoepithelial tumor, extraskeletal myxoid chondrosarcoma, and the recently described myoepithelioma-like tumor of the vulvar region and myxoepithelioid tumor with chordoid features. Because of their overlapping features, the accurate diagnosis and classification of these tumors are often challenging. Herein, we report two unique cases of SMARCB1/INI1-deficient soft tissue neoplasm with epithelioid and myxoid features occurring in male paratesticular region. The first case was a 52-year-old man presented with an intermittent painful left paratesticular mass for 1 year. The second case was a 41-year-old man presented with a painless paratesticular mass on the right side for 3 months. Both patients underwent an orchiectomy. After 6 and 26 months of follow-up, both were alive with no evidence of recurrence or metastasis. In both cases, the tumor was relatively well-demarcated and showed monomorphic round to epithelioid cells arranged in a nested, trabecular, reticular, and corded pattern, setting in a myxohyalinized and vascularized matrix. The tumor cells showed relatively uniform round nuclei with vesicular chromatin and variably prominent nucleoli. No rhabdoid cells were identified. Mitoses numbered 3 and 2 per 10 high-power fields. Tumor necrosis or lymphovascular invasion was absent. Immunohistochemically, both tumors expressed epithelial membrane antigen (focal), calponin (focal), and CD99. SMARCB1/INI1 expression was deficient in both cases. In addition, case 1 diffusely expressed pan-cytokeratin, and case 2 diffusely expressed CD34 and synaptophysin. Molecular genetically, case 1 showed SMARCB1 homozygous deletion as detected by fluorescence in-situ hybridization (FISH), and case 2 demonstrated SMARCB1 copy number deletions by next-generation sequencing and SMARCB1 monoallelic deletion by FISH. Both cases lacked EWSR1 rearrangements by FISH. The overall clinicopathologic profiles of the two cases made it difficult to classify them as one of the established categories of SMARCB1/INI1-deficient mesenchymal tumors. Our study further expands the clinicopathologic and molecular spectrum of SMARCB1/INI1-deficient epithelioid and myxoid neoplasms and highlights the challenges to diagnose these tumors.

An isothermal CRISPR-based diagnostic assay for Neisseria gonorrhoeae and Chlamydia trachomatis detection.

IMPORTANCE: A method for Neisseria gonorrhoeae (NG)/Chlamydia trachomatis (CT) detection is developed using multiplex-recombinase polymerase amplification and Cas12a/Cas13a. This method can detect NG and CT simultaneously with high sensitivity and specificity. This method has great potential to be further developed into larger-scale screening and point-of-care testing (POCT).

How does ESG performance affect stock returns? Empirical evidence from listed companies in China.

With the increasing attention to sustainable development, environmental, social, and corporate governance (ESG) investment has become an important vehicle for achieving carbon neutrality worldwide. In this paper, the impact of ESG performance on stock returns and the transmission mechanism are explored. A fixed effect model based on a panel unbalanced data of listed companies in China from 2011 to 2020 is selected for the empirical analysis. The results show that ESG performance of listed companies in China positively impacts stock returns. However, by distinguishing the ownership nature and region to which listed companies belong, this study finds that the relationship between ESG performance and stock returns is particularly significant for non-state-owned companies and those in the eastern region. Further, based on stakeholder theory, financial performance and corporate innovation ability are embedded into the relationship between ESG performance and stock returns. Both financial performance and corporate innovation ability play partial mediating roles in the correlation between ESG performance and stock returns. In addition, the relationship between ESG performance and corporate innovation ability is non-linear. This paper provides insight for emerging markets into cultivating the value investment concept of investors and improving the ESG information disclosure system.

Dissemination of Neisseria gonorrhoeae with decreased susceptibility to extended-spectrum cephalosporins in Southern China, 2021: a genome-wide surveillance from 20 cities.

BACKGROUND: Antimicrobial resistance (AMR) of untreatable gonococcal infection is an emerging threat, especially in Guangdong, a prosperous province in Southern China. METHODS: N.gonorrhoeae was isolated from 20 cities in Guangdong and determined antimicrobial susceptibility. Through whole-genome sequencing (WGS), multilocus sequence typing (MLST), N.gonorrhoeae multiantigen sequence typing (NG-MAST), and N.gonorrhoeae sequence typing for antimicrobial resistance (NG-STAR) were obtained based on the PubMLST database ( https://pubmlst.org/ ). Phylogenetic analysis was used for dissemination and tracking analysis. RESULTS: Antimicrobial susceptibility was performed on 347 isolates, and 50 isolates were identified as decreased susceptibility (DS) to cephalosporins. Of which 16.0% (8/50) were ceftriaxone DS, 38.0% (19/50) were cefixime DS, and 46.0% (23/50) were both ceftriaxone and cefixime DS. In all, the dual-resistant rate of the cephalosporin-DS isolates was 96.0% for penicillin and 98.0% for tetracycline-resistant, and 10.0% (5/50) were resistant to azithromycin. All cephalosporin-DS isolates were resistant to ciprofloxacin but sensitive to spectinomycin. The predominant MLSTs were ST7363 (16%, 8/50), ST1903 (14%, 7/50), ST1901 (12%, 6/50), and ST7365 (10%, 5/50). Besides some isolates that failed genotyping (NA), NG-STAR ST1143 (n = 6) and NG-MAST ST17748 (n = 4) were the most prevalent. Twelve isolates with mosaic penA-60.001 allele retained the most elevated cephalosporin MIC (Minimum Inhibitory Concentration). Phylogenetic analysis revealed that epidemic penA-60.001 clones, either domestic or foreign, had spread to nine cities in Guangdong, and 9/12 clones were from the Pearl River Delta region. CONCLUSIONS: N. gonorrhoeae with cephalosporins-DS was extensively disseminated in Guangdong, Southern China, requiring strict surveillance.

Effect of high-frequency repetitive transcranial magnetic stimulation over M1 for consciousness recovery after traumatic brain injury.

BACKGROUND: The brain area stimulated during repetitive transcranial magnetic stimulation (rTMS) treatment is important in altered states of consciousness. However, the functional contribution of the M1 region during the treatment of high-frequency rTMS remains unclear. OBJECTIVE: The aim of this study was to examine the clinical [the Glasgow coma scale (GCS) and the coma recovery scale-revised (CRS-R)] and neurophysiological (EEG reactivity and SSEP) responses in vegetative state (VS) patients following traumatic brain injury (TBI) before and after a protocol of high-frequency rTMS over the M1 region. METHODS: Ninety-nine patients in a VS following TBI were recruited so that their clinical and neurophysiological responses could be evaluated in this study. These patients were randomly allocated into three experimental groups: rTMS over the M1 region (test group; n = 33), rTMS over the left dorsolateral prefrontal cortex (DLPFC) (control group; n = 33) and placebo rTMS over the M1 region (placebo group; n = 33). Each rTMS treatment lasted 20 min and was carried out once a day. The duration of this protocol was a month with 20 treatments (5 times per week) occurring with that time. RESULTS: We found that the clinical and neurophysiological responses improved after treatment in the test, control, and placebo groups; the improvement was highest in the test group compared to that in the control and placebo groups. CONCLUSIONS: Our results demonstrate an effective method of high-frequency rTMS over the M1 region for consciousness recovery after severe brain injury.

Critical window for the association between early electronic screen exposure and hyperactive behaviors in preschool children.

Electronic screens have become an integral part of modern life, accompanied with growing concerns for children's neuropsychological development. This study aimed to evaluate the associations between measures of early life screen exposure and hyperactive behaviors among preschool children. The study also aimed to investigate their cumulative effects and the critical window for these associations. A cross-sectional survey was conducted among 52 625 mother-child dyads at preschools in LongHua District of Shenzhen, China. A self-administered structured questionnaire was used to assess socio-demographic characteristics, duration of children's electronic screen exposure in each of the first 3 years following birth and the presence of current hyperactive behaviors. A series of logistic regression models were used to examine the relationship between previous screen time and current hyperactive behaviors. A crossover analysis was used to explore the critical window for a significant relationship between screen time and hyperactive behaviors. We found that exposure to electronic screens in the first 3 years of life was associated with hyperactive behaviors in preschool children. A cumulative effect was shown in children with an average daily screen time less than 60 min, with adjusted ORs increasing from 1.262 to 1.989 as screen exposure years increased from 1 to 3 years. A critical window was identified in that children in the first 2 years after birth were vulnerable to electronic screen exposure. Exposure to televisions, mobile phones, and computers were all related to elevated risks for hyperactive behaviors. In conclusion, early screen exposure appears to increase the risk for hyperactive behaviors in preschool children with the presence of a cumulative effect, a critical window and different electronic screens having similar effects.

Recurrent PRDM10 Fusions in Superficial CD34-Positive Fibroblastic Tumors : A Clinicopathologic and Molecular Study of 10 Additional Cases of an Emerging Novel Entity.

OBJECTIVES: Superficial CD34-positive fibroblastic tumor (SCD34FT) is a rare mesenchymal neoplasm. The genetic alterations of SCD34FT have yet to be determined. Recent studies suggest it overlaps with PRDM10-rearranged soft tissue tumor (PRDM10-STT). METHODS: This study aimed to characterize a series of 10 cases of SCD34FT using fluorescence in situ hybridization (FISH) and targeted next-generation sequencing (NGS). RESULTS: The study recruited 7 men and 3 women aged between 26 and 64 years. The tumors were located in the superficial soft tissues of the thigh (8 cases), foot, and back (1 case each), ranging in size from 1.5 to 7 cm. The tumors were composed of sheets and fascicles of plump spindled to polygonal cells, with glassy cytoplasm and pleomorphic nuclei. Mitotic activity was absent or low. Common and uncommon stromal findings included foamy histiocytic infiltrates, myxoid changes, peripheral lymphoid aggregates, large ectatic vessels, arborizing capillary vasculature, and hemosiderin deposition. All tumors expressed CD34, and 4 demonstrated focal cytokeratin immunoexpression. In 7 of 9 (77.8%) cases analyzed, FISH identified PRDM10 rearrangement. Targeted NGS revealed a MED12::PRDM10 fusion in 4 of 7 cases tested. Follow-up showed no recurrence or metastasis. CONCLUSIONS: We demonstrate recurrent PRDM10 rearrangements in SCD34FT and provide additional evidence of a close relationship to PRDM10-STT.

Parent-child interactions in early life mediating association between prenatal maternal stress and autistic-like behaviors among preschoolers.

A range of studies have shown that prenatal maternal stress (PNMS) exposure is associated with offspring autistic-like behaviors, however the potential pathways remain unexplored. This study aimed to evaluate the mediating role of parent-child interactions in early life in the association between PNMS exposure and preschoolers' autistic-like behaviors. Data from 65,928 child-parent dyads were obtained via a primary caregiver-reported questionnaire administered as part of the Longhua Child Cohort Study. To strengthen confidence in the reliability of the results, the analyses were initially conducted on a random selection of 70% of the total sample, and then validated on the remaining 30% of the sample. Analysis of covariance and multiple linear models were employed to estimate the associations between PNMS exposure, parent-child interactions in early life, and children's autistic-like behaviors. The results showed that PNMS exposure was positively associated with the presence of autistic-like behaviors at preschool age. The total indirect effect of the frequency of positive parent-child interactions in early life accounted for 9.69% or 8.99% of the variance of the association. Our findings indicate that parent-child interactions in early life might function as potential mediators of the association between PNMS and the increased risk of offspring autistic-like behaviors.

Uterine Tumor Resembling Ovarian Sex Cord Tumor With Aggressive Histologic Features Harboring a GREB1-NCOA2 Fusion: Case Report With a Brief Review.

Uterine tumor resembling ovarian sex cord tumor (UTROSCT) is a rare mesenchymal neoplasm, of uncertain lineage, that shows predominantly sex cord-like differentiation with a broad range of histologic appearances and polyphenotypic immunohistochemical features. Although generally having a favorable prognosis, a subset can recur/metastasize. Most recently, several studies of UTROSCT have described novel fusion genes involving ESR1 and GREB1 as the 5 partner, and NCOA1-3 as the 3 partner. Genotype and phenotype correlation has suggested that GREB1 -rearranged tumors may have a higher tendency to behave aggressively. Herein, we report a UTROSCT with aggressive histologic features harboring a GREB1-NCOA2 fusion. A 51-yr-old woman presented with menometrorrhagia and progressive dysmenorrhea and was found to have a submucous uterine lesion by ultrasonography. Gross examination of the hysterectomy specimen showed an 8.5-cm, polypoid, soft, intracavitary mass. Histologic examination revealed a deeply invasive neoplasm composed of uniform round to plump spindle cells, arranged predominantly in diffuse sheets and fascicles and focally in anastomosing cords patterns. Groups of rhabdoid tumor cells were occasionally noted. Worrisome features, including increased mitotic figures (up to 3/10 high power fields), geographic necrosis, and lymphovascular invasion, were evident. Immunohistochemical analysis showed variable positivity for epithelial, smooth muscle, neuroendocrine, and sex cord markers, as well as hormone receptors. RNA sequencing revealed an in-frame fusion between exon 3 of GREB1 and exon 14 of NCOA2 . Fluorescence in situ hybridization analyses confirmed rearrangements of both the GREB1 and NCOA2 loci. Our case lends further supports that GREB1 -rearranged UTROSCTs frequently exhibit aggressive histological features with inconspicuous sex cord-like differentiation.

Recurrent RET fusions in fibrosarcoma-like neoplasms in adult viscera: expanding the clinicopathological and genetic spectrum.

AIMS: RET-fused mesenchymal neoplasms mostly affect the soft tissue of paediatric patients. Given their responsiveness to selective RET inhibitors, it remains critical to identify those extraordinary cases occurring in the visceral organs of adults. In this study, we report three RET-rearranged spindle-cell tumours occurring in the visceral organs of adults. METHODS AND RESULTS: Clinicopathological features were assessed and partner agnostic targeted next-generation sequencing on clinically validated platforms were performed. The patients were 18, 53, and 55 years old and included one male and two females. The tumours were located in the kidney (case 1), small intestine (case 2), and ureter (case 3), with maximum diameters of 14, 5, and 1 cm, respectively. Histologically, all tumours displayed a morphological spectrum typical of fibrosarcoma, including moderately to highly cellular, nonpleomorphic, ovoid to spindle-shaped cells arranged in long fascicles or haphazardly within collagenised to myxohyaline stroma. Foci of irregular alveolar oedema-like structures and areas with microcystic and reticular arrangements were identified in the renal tumour. Staghorn-type vessels and foci of band-like stromal hyalinisation were observed in the small intestine tumour. Cases 1 and 2 were high-grade and pursed a highly aggressive clinical course, while case 3 was of intermediate grade with no tumour recurrence or metastasis 14 years after surgery. All three tumours expressed CD34, which was coexpressed with S100 protein in cases 2 and 3. Molecular genetic testing revealed PRKAR1A::RET, KIF5B::RET, and SPECC1L::RET in-frame gene fusions. CONCLUSION: Our study expands the clinicopathological and genetic spectrum of mesenchymal neoplasms associated with RET fusions.