Spectral Graph Neural Network-Based Multi-Atlas Brain Network Fusion for Major Depressive Disorder Diagnosis.

Major Depressive Disorder (MDD) imposes a substantial burden within the healthcare domain, impacting millions of individuals worldwide. Functional Magnetic Resonance Imaging (fMRI) has emerged as a promising tool for the objective diagnosis of MDD, enabling the investigation of functional connectivity patterns in the brain associated with this disorder. However, most existing methods focus on a single brain atlas, which limits their ability to capture the complex, multi-scale nature of functional brain networks. To address these limitations, we propose a novel multi-atlas fusion method that incorporates early and late fusion in a unified framework. Our method introduces the concept of the holistic Functional Connectivity Network (FCN), which captures both intra-atlas relationships within individual atlases and inter-regional relationships between atlases with different brain parcellation scales. This comprehensive representation enables the identification of potential disease-related patterns associated with MDD in the early stage of our framework. Moreover, by decoding the holistic FCN from various perspectives through multiple spectral Graph Convolutional Neural Networks and fusing their results with decision-level ensembles, we further improve the performance of MDD diagnosis. Our approach is easily implemented with minimal modifications to existing model structures and demonstrates a robust performance across different baseline models. Our method, evaluated on public resting-state fMRI datasets, surpasses the current multi-atlas fusion methods, enhancing the accuracy of MDD diagnosis. The proposed novel multi-atlas fusion framework provides a more reliable MDD diagnostic technique. Experimental results show our approach outperforms both single- and multi-atlas-based methods, demonstrating its effectiveness in advancing MDD diagnosis.

Graph-Based Conditional Generative Adversarial Networks for Major Depressive Disorder Diagnosis With Synthetic Functional Brain Network Generation.

Major Depressive Disorder (MDD) is a pervasive disorder affecting millions of individuals, presenting a significant global health concern. Functional connectivity (FC) derived from resting-state functional Magnetic Resonance Imaging (rs-fMRI) serves as a crucial tool in revealing functional connectivity patterns associated with MDD, playing an essential role in precise diagnosis. However, the limited data availability of FC poses challenges for robust MDD diagnosis. To tackle this, some studies have employed Deep Neural Networks (DNN) architectures to construct Generative Adversarial Networks (GAN) for synthetic FC generation, but this tends to overlook the inherent topology characteristics of FC. To overcome this challenge, we propose a novel Graph Convolutional Networks (GCN)-based Conditional GAN with Class-Aware Discriminator (GC-GAN). GC-GAN utilizes GCN in both the generator and discriminator to capture intricate FC patterns among brain regions, and the class-aware discriminator ensures the diversity and quality of the generated synthetic FC. Additionally, we introduce a topology refinement technique to enhance MDD diagnosis performance by optimizing the topology using the augmented FC dataset. Our framework was evaluated on publicly available rs-fMRI datasets, and the results demonstrate that GC-GAN outperforms existing methods. This indicates the superior potential of GCN in capturing intricate topology characteristics and generating high-fidelity synthetic FC, thus contributing to a more robust MDD diagnosis.

Glutathione dynamics is a potential predictive and therapeutic trait for neoadjuvant chemotherapy response in bladder cancer.

Radical cystectomy with preoperative cisplatin-based neoadjuvant chemotherapy (NAC) is the standard care for muscle-invasive bladder cancers (MIBCs). However, the complete response rate to this modality remains relatively low, and current clinicopathologic and molecular classifications are inadequate to predict NAC response in patients with MIBC. Here, we demonstrate that dysregulation of the glutathione (GSH) pathway is fundamental for MIBC NAC resistance. Comprehensive analysis of the multicohort transcriptomes reveals that GSH metabolism and immune-response genes are enriched in NAC-resistant and NAC-sensitive MIBCs, respectively. A machine-learning-based tumor/stroma classifier is applied for high-throughput digitalized immunohistochemistry analysis, finding that GSH dynamics proteins, including glutaminase-1, are associated with NAC resistance. GSH dynamics is activated in cisplatin-resistant MIBC cells, and combination treatment with a GSH dynamics modulator and cisplatin significantly suppresses tumor growth in an orthotopic xenograft animal model. Collectively, these findings demonstrate the predictive and therapeutic values of GSH dynamics in determining the NAC response in MIBCs.

Solid-State Structural Transformation in Zn(II) Metal-Organic Frameworks in a Single-Crystal-to-Single-Crystal Fashion.

Solid-state structural transformation is an interesting methodology used to prepare various metal-organic frameworks (MOFs) that are challenging to prepare in direct synthetic procedures. On the other hand, solid-state [2 + 2] photoreactions are distinctive methodologies used for light-driven solid-state transformations. Meanwhile, most of these photoreactions explored are quantitative in nature, in addition to them being stereo-selective and regio-specific in manner. In this work, we successfully synthesized two photoreactive novel binuclear Zn(II) MOFs, [Zn2(spy)2(tdc)2] (1) and [Zn2(spy)4(tdc)2] (2) (where spy = 4-styrylpyridine and tdc = 2,5-thiophenedicarboxylate) with different secondary building units. Both MOFs are interdigitated in nature and are 2D and 1D frameworks, respectively. Both the compounds showed 100% and 50% photoreaction upon UV irradiation, as estimated from the structural analysis for 1 and 2, respectively. This light-driven transformation resulted in the formation of 3D, [Zn2(rctt-ppcb)(tdc)2] (3), and 2D, [Zn2(spy)2(rctt-ppcb)(tdc)2] (4) (where rctt = regio, cis, trans, trans; ppcb = 1,3-bis(4'-pyridyl)-2,4-bis(phenyl)cyclobutane), respectively. These solid-state structural transformations were observed as an interesting post-synthetic modification. Overall, we successfully transformed novel lower-dimensional frameworks into higher-dimensional materials using a solid-state [2 + 2] photocycloaddition reaction.

Intercellular cross-talk through lineage-specific gap junction of cancer-associated fibroblasts related to stromal fibrosis and prognosis.

Stromal fibrosis in cancer is usually associated with poor prognosis and chemotherapy resistance. It is thought to be caused by fibroblasts; however, the exact mechanism is not yet well understood. The study aimed to identify lineage-specific cancer-associated fibroblast (CAF) subgroup and their associations with extracellular matrix remodeling and clinical significances in various tumor types using single-cell and bulk RNA sequencing data. Through unsupervised clustering, six subclusters of CAFs were identified, including a cluster with exclusively high gap junction protein beta-2 (GJB2) expression. This cluster was named GJB2-positive CAF. It was found to be a unique subgroup of terminally differentiated CAFs associated with collagen gene expression and extracellular matrix remodeling. GJB2-positive CAFs showed higher communication frequency with vascular endothelial cells and cancer cells than GJB2-negative CAFs. Moreover, GJB2 was poorly expressed in normal tissues, indicating that its expression is dependent on interaction with other cells, including vascular endothelial cells and cancer cells. Finally, the study investigated the clinical significance of GJB2 signature score for GJB2-positive CAFs in cancer and found a correlation with poor prognosis. These results suggest that GJB2-positive CAF is a unique fibroblast subtype involved in extracellular matrix remodeling, with significant clinical implications in cancer.

Homo- and Heteromultinuclear Pseudocapsules Assembled from Calix[6]-mono-crown-5 and Alkali Metal Ions.

The formation of pseudocapsule type homo- and heteromultinuclear complexes of calix[6]-mono-crown-5 (H4L) encapsulating from 4 to 6 alkali metal ions is reported. H4L reacts with KOH to yield a hexanuclear potassium(I) complex [K6(HL)2(CH3OH)2]·CHCl3 (1) in which two bowl-shaped tripotassium(I) complex units are linked in a rim-to-rim fashion via the interligand C-H···π interactions. In the same reaction condition, RbOH afforded a tetranuclear rubidium(I) complex [Rb4(H2L)2(CH3OH)2(µ-H2O)2]·6CHCl3 (2). In 2, again two bowl-shaped dirubidium(I) complex units are held together by two bridging water molecules and C-H···π interactions that act as a glue to generate such an elegant pseudocapsule. Interestingly, a mixture of KOH and RbOH yielded a heterotetranuclear complex [K2Rb2(H2L)2(CH3OH)2(µ-H2O)2]·6CHCl3 (3). Similarly, two heterodinuclear bowl units [KRb(H2L)] in 3 are held together by two bridging water molecules and C-H···π interactions to form a heteromultinuclear pseudocapsule. In each heterodinuclear K+/Rb+ bowl unit of 3, Rb+ occupies the center of the crown loop while K+ locates inside the calix rim. Consequently, the proposed host discriminates not only on the types and numbers of the metal ions but also on their positional preferences in forming pseudocapsules. Solution studies by nuclear magnetic resonance and electrospray ionization-mass support the heterometallic (K+/Rb+) complexation by showing the superior binding affinity of Rb+ over K+ toward the crown loop. These results demonstrate how the metal-driven pseudocapsules are formed and present a new perspective on the metallosupramolecules of the calixcrown scaffold.

Narcolepsy is associated with an increased risk of HLA-related autoimmune diseases: Evidence from a nationwide healthcare system data in South Korea.

STUDY OBJECTIVES: To determine the incidence rate of narcolepsy in South Korea and closely examine the relationship between narcolepsy, which is believed to be an autoimmune response, and other systemic autoimmune diseases. METHODS: We examined data from the South Korean nationwide health insurance claims database from 2010 to 2019. Our study included patients with narcolepsy as well as age- and sex-matched controls without narcolepsy. We estimated the incidence of narcolepsy and the odds ratio of narcolepsy and associated autoimmune comorbidities in South Korea. RESULTS: We identified 8710 patients with narcolepsy (59.8% men and 40.2% women). The incidence of narcolepsy was 0.05%. Patients with narcolepsy were at a significantly high risk of ankylosing spondylitis, rheumatoid arthritis, and Sjögren's syndrome, which diseases are known to be related to human leukocyte antigen (HLA) genes. CONCLUSIONS: Narcolepsy is closely related to systemic autoimmune diseases, particularly those related to HLA genes.

Whole-genome sequencing reveals an association between small genomic deletions and an increased risk of developing Parkinson's disease.

Single-nucleotide variants (SNVs) associated with Parkinson's disease (PD) have been investigated mainly through genome-wide association studies. However, other genomic alterations, including copy number variations, remain less explored. In this study, we conducted whole-genome sequencing of primary (310 PD patients and 100 healthy individuals) and independent (100 PD patients and 100 healthy individuals) cohorts from the Korean population to identify high-resolution small genomic deletions, gains, and SNVs. Global small genomic deletions and gains were found to be associated with an increased and decreased risk of PD development, respectively. Thirty significant locus deletions were identified in PD, with most being associated with an increased PD risk in both cohorts. Small genomic deletions in clustered loci located in the GPR27 region had high enhancer signals and showed the closest association with PD. GPR27 was found to be expressed specifically in brain tissue, and GPR27 copy number loss was associated with upregulated SNCA expression and downregulated dopamine neurotransmitter pathways. Clustering of small genomic deletions on chr20 in exon 1 of the GNAS isoform was detected. In addition, we found several PD-associated SNVs, including one in the enhancer region of the TCF7L2 intron, which exhibited a cis-acting regulatory mode and an association with the beta-catenin signaling pathway. These findings provide a global, whole-genome view of PD and suggest that small genomic deletions in regulatory domains contribute to the risk of PD development.

Community-based multi-site randomized controlled trial of behavioral activation for patients with negative symptoms of schizophrenia.

BACKGROUND: Negative symptoms are closely related to the poor prognosis of schizophrenia, for which there is no effective treatment to date. Behavioral activation (BA), which is an effective treatment for depression, is a behavioral approach that targets low levels of response-contingent positive reinforcement. This study aimed to explore BA as an effective intervention for relieving the negative symptoms of schizophrenia. METHODS: This was a randomized single-blind controlled trial. Eighty-four patients with schizophrenia were enrolled in community mental health settings. Excluding 14 patients who opted out of the study, 70 were randomly assigned to receive BA in addition to treatment-as-usual (BA + TAU) or treatment-as-usual (TAU) only. Negative symptoms were assessed using the Clinical Assessment Interview for Negative Symptoms (CAINS) and Brief Negative Symptom Scale (BNSS) at baseline, post-treatment, and 6-months follow-up. RESULTS: Significant differences between the BA + TAU and TAU only groups were observed in the measures of negative symptoms post-treatment. The total score of CAINS was significantly decreased after BA treatment (η2 = 0.13). The tendency of the BA + TAU treatment effect was also observed for the BNSS total score and PANSS negative symptom subscale (η2 = 0.10 and η2 = 0.11, respectively). However, the difference between the two groups was not sustained at the six-month follow-up. CONCLUSIONS: Our findings suggest that BA could be a promising time-limited and structured psychosocial intervention for schizophrenia-associated negative symptoms with the merit of easy dissemination. Further studies are needed to examine the factors involved in sustaining improvement.

Effects of Long-acting Injectable 3-Monthly Paliperidone Palmitate on the Clinical and Social Performance of Patients with Schizophrenia.

Objective: To investigate the effects of long-acting injectable 3-monthly paliperidone palmitate on the clinical and social functioning of patients with schizophrenia. Methods: This study enrolled patients with schizophrenia receiving long-acting injectable 1-monthly paliperidone palmitate for at least 4 months and who subsequently received 3-monthly paliperidone palmitate. Accordingly, 418 patients were followed up for 24 weeks. Their clinical symptoms and social functioning were measured using the Clinical Global Impression-Severity of Illness and Personal and Social Performance scales. Results: The Personal and Social Performance total score was significantly higher after 3-monthly paliperidone palmitate treatment than at baseline (baseline vs. week 24: 54.3 ± 18.0 vs. 61.0 ± 14.5 [mean ± standard deviation]; p < 0.001; Wilcoxon signed-rank test); the proportion of patients in the mildly ill group (scores 71-100) also increased significantly (baseline vs. week 24: 16.5% vs. 20.6%; p < 0.001; McNemar-Bowker test). The mean Clinical Global Impression-Severity of Illness score decreased significantly (baseline vs. week 24: 3.7 ± 1.0 vs. 3.4 ± 0.9; p < 0.001; Wilcoxon signed-rank test), as did the proportion of patients in the severely ill group (baseline vs. week 24: 4.1% vs. 2.1%; p < 0.001; McNemar-Bowker test). Conclusion: Continuous 3-monthly paliperidone palmitate treatment significantly enhances the personal and social performance of patients with schizophrenia and reduces the proportion of those with severe illness. These findings suggest that long-acting injectable antipsychotic administration at intervals longer than 1 month might improve the social functioning of and promote return to activities of daily living in patients with schizophrenia.

Clinicogenomic characteristics and synthetic lethal implications of germline homologous recombination-deficient hepatocellular carcinoma.

BACKGROUNDS AND AIMS: We performed an in-depth examination of pathogenic germline variants (PGVs) and somatic variants in DNA damage response (DDR) genes in hepatocellular carcinoma (HCC) to explore their clinical and genomic impacts. APPROACH AND RESULTS: We used a merged whole-exome or RNA sequencing data set derived from in-house ( n = 230) and The Cancer Genome Atlas ( n = 362) databases of multiethnic HCC samples. We also evaluated synthetic lethal approaches targeting mutations in homologous recombination (HR) genes using HCC cells selected from five genomic databases of cancer cell lines. A total of 110 PGVs in DDR pathways in 96 patients were selected. Of the PGV carriers, 44 were HR-altered and found to be independently associated with poorer disease-free survival after hepatectomy. The most frequently altered HR gene in both germline and somatic tissues was POLQ , and this variant was detected in 22.7% (10/44) and 23.8% (5/21) of all the corresponding carriers, respectively. PGVs in HR were significantly associated with upregulation of proliferation and replication-related genes and familial risk of HCC. Samples harboring PGVs in HR with loss of heterozygosity were most strongly correlated with the genomic footprints of deficient HR, such as mutation burden and denovoSig2 (analogous to Catalogue of Somatic Mutations in Cancer [COSMIC] 3), and poor outcome. Pharmacologic experiments with HCC cells defective in BRCA2 or POLQ suggested that tumors with this phenotype are synthetic lethal with poly(ADP-ribose) polymerase inhibitors. CONCLUSIONS: Our findings suggest that germline HR defects in HCC tend to confer a poor prognosis and result in distinctive genomic scarring. Tests of the clinical benefits of HR-directed treatments in the affected patients are needed.

Machine Learning for Intelligent-Reflecting-Surface-Based Wireless Communication towards 6G: A Review.

An intelligent reflecting surface (IRS) is a programmable device that can be used to control electromagnetic waves propagation by changing the electric and magnetic properties of its surface. Therefore, IRS is considered a smart technology for the sixth generation (6G) of communication networks. In addition, machine learning (ML) techniques are now widely adopted in wireless communication as the computation power of devices has increased. As it is an emerging topic, we provide a comprehensive overview of the state-of-the-art on ML, especially on deep learning (DL)-based IRS-enhanced communication. We focus on their operating principles, channel estimation (CE), and the applications of machine learning to IRS-enhanced wireless networks. In addition, we systematically survey existing designs for IRS-enhanced wireless networks. Furthermore, we identify major issues and research opportunities associated with the integration of IRS and other emerging technologies for applications to next-generation wireless communication.

Efficient User-Serving Scheme in the User-Centric Cell-Free Massive MIMO System.

A cell-free massive multiple input multiple output (MIMO) system is an attractive network model that is in the spotlight in 5G and future communication systems. Despite numerous advantages, the cell-free massive MIMO system has a problem in that it is difficult to operate in reality due to its vast amount of calculation. The user-centric cell-free massive MIMO model has a more feasible and scalable benefit than the cell-free massive MIMO model. However, this model has the disadvantage that as the number of users in the area increases, there are users who do not receive the service. In this paper, the proposed scheme creates connections for unserved users under a user-centric scheme without additional access point (AP) installation and disconnection for existing users. A downlink user-centric cell-free massive MIMO system model in which the APs are connected to the central processing unit (CPU) and the APs and users are geographically distributed is considered. First, the downlink spectral efficiency formula is derived and applied to the user-centric cell-free massive MIMO system. Then, the proposed scheme and power control algorithm are applied to the derived formula. The simulation results show that the unserved users within the area disappear by using the proposed scheme, while the bit error rate (BER) performance and sum rate improve compared to the existing scheme. In addition, it is shown that the proposed scheme works well even with a very large number of users in the area, and a significant service performance improvement for the worst 10% of users and the overall improvement of per-user throughput for the bottom 70% of users are ensured.

The benefits of the earlier use of sacubitril/valsartan in de novo heart failure with reduced ejection fraction patients.

AIMS: We evaluated the clinical outcomes and trajectory of cardiac reverse remodelling according to the timing of sacubitril/valsartan (Sac/Val) use in patients with heart failure (HF) with reduced ejection fraction (HFrEF). METHODS AND RESULTS: Patients with de novo HFrEF who used Sac/Val between June 2017 and October 2019 were retrospectively enrolled. Patients were grouped into the earlier use group (initiation of Sac/Val < 3 months after the first HFrEF diagnosis) and the later use group (initiation of Sac/Val ≥ 3 months after the first HFrEF diagnosis). Primary outcome was a composite of HF hospitalization and cardiac death. Secondary outcomes were HF hospitalization, cardiac death, all-cause death, significant ventricular arrhythmia (ventricular tachycardia or ventricular fibrillation), and echocardiographic evidence of cardiac reverse remodelling including left ventricular ejection fraction (LVEF) change during follow-up. Among 115 enrolled patients, 67 were classified in the earlier use group, and 48 were classified in the later use group. Mean period of HFrEF diagnosis to Sac/Val use was 52.1 ± 14.3 days in the earlier use group, and 201.8 ± 127.3 days in the later use group. During the median follow-up of 721 days, primary outcome occurred in 21 patients (18.3%). The earlier use group experienced significantly fewer primary outcome than the later use group (10.4% vs. 29.2%, P = 0.010). The Kaplan-Meier survival curve showed better event-free survival in the earlier use group than in the later use group (log rank = 0.017). There were no significant differences in cardiac death, all-cause death, and ventricular arrhythmia between two groups (1.5% vs. 2.1%, P = 0.811; 1.5% vs. 4.2%, P = 0.375; 3.0% vs. 0%, P = 0.227, respectively). Despite a significantly lower baseline LVEF in the earlier use group (21.3 ± 6.4% vs. 24.8 ± 7.9%, P = 0.012), an early prominent increase of LVEF was noted before 6 months (35.2 ± 11.9% vs. 27.8 ± 8.8%, P = 0.007). A delayed improvement of LVEF in the later use group resulted in similar LVEF at last follow-up in both groups (40.7 ± 13.4% vs. 39.4 ± 10.9%, P = 0.686). Although the trajectory of left ventricular remodelling showed similar pattern in two groups, left atrial (LA) reverse remodelling was less prominent in the later use group during the follow-up period (final LA volume index: 43.6 ± 14.3 mL/m2 vs. 55.2 ± 17.1 mL/m2 , P = 0.011). CONCLUSIONS: Earlier use of Sac/Val was related with better clinical outcome and earlier left ventricular reverse remodelling. Remodelling of LA was less prominent in the later use group implying delayed response in diastolic function.

Decreased Health-Seeking Behaviors in People With Depressive Symptoms: The Korea National Health and Nutrition Examination Survey 2014, 2016, and 2018.

OBJECTIVE: The purpose of this study was to investigate the effects of depressive symptoms on health-seeking behaviors using the large epidemiological study data of the Korea National Health and Nutrition Examination (KNHANES). METHODS: Data from the Korea National Health and Nutrition Examination Survey (KNHANES), which is a large-scale national survey, were used in this study. The Patient Health Questionnaire-9 (PHQ-9) was used to assess the depressive state of the participants. Specialized self-reported questionnaires that included questions about health-seeking behaviors were also performed. To examine the relationships between depression and health-seeking behaviors, complex sample logistic regression models with control for covariates were used. RESULTS: There was a significant association between decreased health-seeking behaviors and depressive symptoms in adults (odds ratio [OR]: 3.11, 95% confidence interval [CI]: 2.44-3.96). The association was found to be especially strong in males (OR: 2.63, 95% CI: 1.69-4.10) versus in females (OR: 2.49, 95% CI: 1.90-3.27). With regard to age group, younger adults (19-44 years of age) showed the highest OR (OR: 3.07, 95% CI: 2.12-4.45). CONCLUSION: Our findings support the idea that there is a significant association between health-seeking behaviors and depressive symptoms in the Korean population. These results suggest that individuals with decreased health-seeking behaviors could be evaluated for depressive symptoms.

PET-Based Radiogenomics Supports mTOR Pathway Targeting for Hepatocellular Carcinoma.

PURPOSE: This work aimed to explore in depth the genomic and molecular underpinnings of hepatocellular carcinoma (HCC) with increased 2[18F]fluoro-2-deoxy-d-glucose (FDG) uptake in PET and to identify therapeutic targets based on this imaging-genomic surrogate. EXPERIMENTAL DESIGN: We used RNA sequencing and whole-exome sequencing data obtained from 117 patients with HCC who underwent hepatic resection with preoperative FDG-PET/CT imaging as a discovery cohort. The primary radiogenomic results were validated with transcriptomes from a second cohort of 81 patients with more advanced tumors. All patients were allocated to an FDG-avid or FDG-non-avid group according to the PET findings. We also screened potential drug candidates targeting FDG-avid HCCs in vitro and in vivo. RESULTS: High FDG avidity conferred worse recurrence-free survival after HCC resection. Whole transcriptome analysis revealed upregulation of mTOR pathway signals in the FDG-avid tumors, together with higher abundance of associated mutations. These clinical and genomic findings were replicated in the validation set. A molecular signature of FDG-avid HCCs identified in the discovery set consistently predicted poor prognoses in the public-access datasets of two cohorts. Treatment with an mTOR inhibitor resulted in decreased FDG uptake followed by effective tumor control in both the hyperglycolytic HCC cell lines and xenograft mouse models. CONCLUSIONS: Our PET-based radiogenomic analysis indicates that mTOR pathway genes are markedly activated and altered in HCCs with high FDG retention. This nuclear imaging biomarker may stimulate umbrella trials and tailored treatments in precision care of patients with HCC.

Community-Based Multi-Site Randomized Controlled Trial of Behavioral Activation for Patients with Depressive Disorders.

Behavioral activation (BA) is a beneficial and relatively cost-effective treatment option for depression. This study utilized a pragmatic randomized controlled research design to investigate whether BA, as compared with treatment as usual (TAU), led to superior treatment effects, when delivered in community mental health settings by retrained community mental health professionals. Patients with depressive disorders (n = 64) were randomly assigned to a 10-session BA (n = 31) or TAU (n = 33) group. The depressive symptoms and behavioral engagement were assessed at the baseline, post-treatment, and a six-month follow-up. Results showed that, as compared to the TAU group, the BA group had: (1) a reduction in depression severity, as evidenced by large effect sizes and greater response rates, and (2) an increase in behavioral engagement. However, the post-treatment gains were not maintained at the six-month follow-up. The implications and limitations of the study are also discussed (KCT0004098, June 27, 2019, retrospectively registered).

Comprehensive characterization of viral integrations and genomic aberrations in HBV-infected intrahepatic cholangiocarcinomas.

BACKGROUND AND AIMS: Despite the epidemiological association between intrahepatic cholangiocarcinoma (iCCA) and HBV infection, little is known about the relevant oncogenic effects. We sought to identify the landscape and mechanism of HBV integration, along with the genomic architecture of HBV-infected iCCA (HBV-iCCA) tumors. APPROACH AND RESULTS: We profiled a cohort of 108 HBV-iCCAs using whole-genome sequencing, deep sequencing, and RNA sequencing, together with preconstructed data sets of HBV-infected HCC (HBV-HCC; n = 167) and combined hepatocellular cholangiocarcinoma (HBV-cHCC/CCA; n = 59), and conventional (n = 154) and fluke-related iCCAs (n = 16). Platforms based on primary iCCA cell lines to evaluate the functional effects of chimeric transcripts were also used. We found that HBV had inserted at multiple sites in the iCCA genomes in 45 (41.7%) of the tumors. Recurrent viral integration breakpoints were found at nine different sites. The most common insertional hotspot (7 tumors) was in the TERT (telomerase reverse transcriptase) promoter, where insertions and mutations (11 tumors) were mutually exclusive, and were accompanied by promoter hyperactivity. Recurrent HBV integration events (5 tumors) were also detected in FAT2 (FAT atypical cadherin 2), and were associated with enrichment of epithelial-mesenchymal transition-related genes. A distinctive intergenic insertion (chr9p21.3), between DMRTA1 (DMRT like family A1) and LINC01239 (long intergenic non-protein coding RNA 1239), had oncogenic effects through activation of the mammalian target of rapamycin (mTOR)/4EBP/S6K pathway. Regarding the mutational profiles of primary liver cancers, the overall landscape of HBV-iCCA was closer to that of nonviral conventional iCCA, than to HBV-HCC and HBV-cHCC/CCA. CONCLUSIONS: Our findings provide insight into the behavior of iCCAs driven by various pathogenic mechanisms involving HBV integration events and associated genomic aberrations. This knowledge should be of use in managing HBV carriers.

Differential characteristics of repeated polysomnography and multiple sleep latency test parameters in narcolepsy type 1 and type 2 patients: a longitudinal retrospective study.

PURPOSE: Narcolepsy is a chronic disorder and its phenotype is dichotomized into narcolepsy type 1 (NT1) and narcolepsy type 2 (NT2). The clinical course and pathophysiological mechanisms of these two clinical entities and their differences are not adequately defined. This study aimed to explore the differential longitudinal patterns of polysomnography (PSG) and multiple sleep latency test (MSLT) in NT1 and NT2. METHODS: In this retrospective study demographic characteristics, PSG, and MSLT parameters at baseline and follow-up were compared between NT1 and NT2 patients. Patients with both follow-up MSLT and PSG were selected for sub-group analysis. Baseline and follow-up MSLT and PSG parameters were compared. RESULTS: Of 55 patients with narcolepsy, mean follow-up periods were 7.4 ± 3.5 years for NT1 and 5.5 ± 2.9 for NT2. Demographic data showed increased body mass index and prevalence of sleep paralysis in NT1. Baseline PSG characteristics between NT1 and NT2 showed decreased sleep latency (p = 0.016) and REM latency (p = 0.046) in NT1 group when compared with NT2. Nocturnal SOREMP on PSG was more prevalent in NT1 (p = 0.017), and half of NT2 patients with nocturnal SOREMP on PSG changed their diagnoses to NT1. On follow-up PSG, NT1 displayed reductions in sleep stage N2 (p = 0.006) and N3 (p = 0.048), while wake after sleep onset (WASO) (p = 0.023) and apnea-hypopnea index (AHI) (p = 0.007) were significantly increased. CONCLUSION: Differential MSLT and PSG characteristics of NT1 and NT2 in at baseline and follow-up indicate that NT1 and NT2 are distinct disease phenotypes, and that they present with a contrasting course of disease.