OBJECTIVES:Difficult-to-treat Crohn's disease (DTT-CD) represents a critical unmet need in inflammatory bowel disease (IBD) management. However, its genetic architectures remain poorly understood. We aimed to evaluate the genetic characteristics and clinical manifestations of DTT-CD cases through integrated trio-based whole exome sequencing (WES) and longitudinal phenotyping. METHODS:In this cross-sectional cohort study, DTT-CD patients who met the International Organization for the Study of Inflammatory Bowel Disease (IOIBD) criteria and their first-degree relatives underwent trio-WES analysis. Treatment persistence and remission rates were analyzed. Genetic variants were prioritized via cosegregation analysis, the American College of Medical Genetics and Genomics (ACMG) guidelines, and functional prediction algorithms. RESULTS:Among the 24 patients with DTT-CD, 87.5% failed at least two biologics, 33.3% required dual targeted therapy, and drug persistence declined across treatment lines (p = 0.0193). Remission rates were suboptimal (clinical: 41.7%; endoscopic: 50.0%). Trio-WES analysis identified 15 likely pathogenic candidate variants across 12 genes, including the established monogenic IBD gene XIAP (two novel variants: p.Asp247Glufs*19, p.Ser43X; two known variants: p.Arg381X, p.Arg238X), genome-wide association studies-implicated IBD risk genes (MAML2 and PLA2R1), and novel candidate variants (KIZ, LAMA5, SAMD9, etc.) that were potentially linked to epithelial-immune dysregulation. CONCLUSIONS:This is the first trio-WES study of DTT-CD that reveals a high prevalence of monogenic XIAP deficiency (16.7%), advocating for genetic screening in refractory cases. Novel candidate genes implicate polygenic mechanisms of therapeutic resistance. Family-based sequencing may be used to elucidate the genetic background of DTT-CD cases to guide molecular diagnosis and personalized therapy.

Background Metabolomics studies have identified various metabolic markers associated with stroke risk, yet much uncertainty persists regarding heterogeneity in these associations between different stroke subtypes. We aimed to examine metabolic profiles associated with incident stroke and its subtypes in Chinese adults. Methods and Results We performed a nested case–control study within the Dongfeng‐Tongji cohort, including 1029 and 266 incident cases of ischemic stroke (IS) and hemorrhagic stroke (HS), respectively, with a mean follow‐up period of 6.1±2.3 years. Fifty‐five metabolites in fasting plasma were measured by ultra‐high‐performance liquid chromatography–mass spectrometry. We examined the associations of metabolites with the risks of total stroke, IS, and HS, with a focus on the comparison of associations of plasma metabolite with IS and HS, using conditional logistic regression. We found that increased levels of asymmetrical/symmetrical dimethylarginine and glutamate were significantly associated with elevated risk of total stroke (odds ratios and 95%, 1.20 [1.08–1.34] and 1.22 [1.09–1.36], respectively; both Benjamini‐Hochberg‐adjusted P <0.05). When examining stroke subtypes, asymmetrical/symmetrical dimethylarginine was nominally associated with both IS and HS (odds ratios [95% CIs]: 1.16 [1.03–1.31] and 1.39 [1.07–1.81], respectively), while glutamate was associated with only IS (odds ratios [95% CI]: 1.26 [1.11–1.43]). The associations of glutamate with IS risk were significantly stronger among participants with hypertension and diabetes than among those without these diseases (both P for interaction <0.05). Conclusions This study validated the positive associations of asymmetrical/symmetrical dimethylarginine and glutamate with stroke risk, mainly that of IS, in a Chinese population, and revealed a novel unanimous association of with both IS and HS. Our findings provided potential intervention targets for stroke prevention.

Large Multimodal Models (LMMs) have achieved impressive success in visual understanding and reasoning, remarkably improving the performance of mathematical reasoning in a visual context. Yet, a challenging type of visual math lies in the multimodal graph theory problem, which demands that LMMs understand the graphical structures accurately and perform multi-step reasoning on the visual graph. Additionally, exploring multimodal graph theory problems will lead to more effective strategies in fields like biology, transportation, and robotics planning. To step forward in this direction, we are the first to design a benchmark named VisionGraph, used to explore the capabilities of advanced LMMs in solving multimodal graph theory problems. It encompasses eight complex graph problem tasks, from connectivity to shortest path problems. Subsequently, we present a Description-Program-Reasoning (DPR) chain to enhance the logical accuracy of reasoning processes through graphical structure description generation and algorithm-aware multi-step reasoning. Our extensive study shows that 1) GPT-4V outperforms Gemini Pro in multi-step graph reasoning; 2) All LMMs exhibit inferior perception accuracy for graphical structures, whether in zero/few-shot settings or with supervised fine-tuning (SFT), which further affects problem-solving performance; 3) DPR significantly improves the multi-step graph reasoning capabilities of LMMs and the GPT-4V (DPR) agent achieves SOTA performance.

Background:The genetic variant of tumor necrosis factor superfamily member 15 (TNFSF15) is associated with Crohn's disease (CD) and the development of intestinal fibrosis and stricturing. We aimed to investigate its predictive role in disease progression and the impact of ileal fibrosis-associated protein expression in Chinese patients with CD. Methods:We genotyped the single nucleotide polymorphism rs6478109 within the TNFSF15 gene in 428 CD patients and 450 health controls to assess its association with CD. Genotype-phenotype correlation analyses were performed. Mucosal samples from non-diseased terminal ileum were analyzed for TL1A and fibrosis-associated protein expression using western blot and immunohistochemistry. Results:The G allele frequency of rs6478109 was significantly higher among CD patients compared with health controls (63.3% vs. 46.7%, P < 0.001). Patients with GG genotype were more predisposed to develop the stricturing phenotype, compared with those with AA + AG genotypes with a hazard ratio of 1.426 (95% confidence interval: 1.029-1.977, P = 0.033). This trend was similarly observed in patients utilizing biological agents, with a hazard ratio of 4.396 (95% confidence interval: 1.780-10.854, P = 0.001). Furthermore, increased TL1A, pro-fibrotic proteins, and TGFβ1/Smad3 pathway activation were observed in non-diseased ileal mucosa of patients with GG genotype compared with those with AA genotype. Conclusions:The TNFSF15 risk genotype GG could promote the expression of pro-fibrotic proteins and may serve as a predictor for stricturing CD.

The emergence of multimodal large models (MLMs) has significantly advanced the field of visual understanding, offering remarkable capabilities in the realm of visual question answering (VQA). Yet, the true challenge lies in the domain of knowledge-intensive VQA tasks, which necessitate not just recognition of visual elements, but also a deep comprehension of the visual information in conjunction with a vast repository of learned knowledge. To uncover such capabilities of MLMs, particularly the newly introduced GPT-4V and Gemini, we provide an in-depth evaluation from three perspectives: 1) Commonsense Knowledge, which assesses how well models can understand visual cues and connect to general knowledge; 2) Fine-grained World Knowledge, which tests the model's skill in reasoning out specific knowledge from images, showcasing their proficiency across various specialized fields; 3) Comprehensive Knowledge with Decision-making Rationales, which examines model's capability to provide logical explanations for its inference, facilitating a deeper analysis from the interpretability perspective. Additionally, we utilize a visual knowledge-enhanced training strategy and multimodal retrieval-augmented generation approach to enhance MLMs, highlighting the future need for advancements in this research direction. Extensive experiments indicate that: a) GPT-4V demonstrates enhanced explanation generation when using composite images as few-shots; b) GPT-4V and other MLMs produce severe hallucinations when dealing with world knowledge; c) Visual knowledge enhanced training and prompting technicals present potential to improve performance. Codes: https://github.com/HITsz-TMG/Cognitive-Visual-Language-Mapper

Background: Metals in the human body represent both environmental exposure and nutritional status. Little is known about the miRNA signature in relation to circulating metals in humans. Objectives: To characterize metal-associated miRNAs in leukocytes, individually and collectively as networks.Methods: In a panel of 160 Chinese adults, we measured 23 metals/metalloids in plasma, and sequenced miRNAs and mRNAs in leukocytes. We used linear regression to model the associations between ln-transformed metal concentrations and normalized miRNA levels adjusting for potential confounders. We inferred the enriched leukocyte subtypes for the identified miRNAs using an association approach. We utilized mRNA sequencing data to explore miRNA functions. We also constructed modules to identify metal-associated miRNA networks.Results: We identified 55 metal-associated miRNAs at false discovery rate-adjusted P < 0.05. In particular, we found that lead, nickel, and vanadium were positively associated with potentially lymphocyte-enriched miR-142-3p, miR-150-3p, miR-28-5p, miR-361-3p, and miR-769-5p, and were inversely associated with potentially granulocyte-enriched let-7a/c/d-5p and miR-1294. Interestingly, the five lymphocyte-enriched miRNAs inhibi-ted, whereas miR-1294 activated, ROS and DNA repair pathways. We further confirmed the findings using oxidative damage biomarkers. Next, we clustered co-expressed miRNAs into modules, and identified four miRNA modules that were associated with different metals. The identified modules represented miRNAs enriched in different leukocyte subtypes, and were involved in biological processes including hematopoiesis and immune response, mitochondrial functions, and response to the stimulus.Conclusions: At commonly exposed low levels, circulating metals were associated with distinct miRNA signatures in leukocytes. The identified miRNAs, individually or as regulatory networks, may provide a mechanistic link between metal exposure and pathophysiological changes in the immune system.

Optical Coherence Tomography Angiography (OCTA) is a non-invasive and non-contacting imaging technique, which can visualize the microvasculature of the retina and optic nerve head in human eyes in vivo. The adequate image quality of OCTA is a prerequisite for the downstream quantification of the retinal microvasculature. Conventionally, the image quality score is based on signal strength. Yet, it is insufficient for identifying artifacts such as motion and off-centration, which rely on specialized knowledge and relies on tediously time-consuming manual identification. The primary issue in OCTA analysis is to sort out the foveal avascular zone (FAZ) region in the retina, as it highly correlates with any visual acuity disease. However, the variations in OCTA visual quality affect the performance of deep learning in any downstream marginally. Moreover, filtering the low-quality OCTA images is both labor-intensive and time-consuming. To address these issues, we develop an automated computer-aided OCTA image processing system using deep neural networks as the classifier and segmentor to help ophthalmologists in clinical diagnosis and research. This system can be an assistive tool as it can process OCTA images of different formats to assess the quality and segment the FAZ area. Our code is freely available at https://github.com/shanzha09/COIPS.git. Another major contribution is the large-scale OCTA dataset, namely OCTA-25K-IQA-SEG we publicize for performance evaluation. It is comprised of four subsets, namely sOCTA-3x3-10k, sOCTA-6x6-14k, sOCTA-3x3-1.1k-seg, and dOCTA-6x6-1.1k-seg, which contains a total number of 25,665 images.

This dataset is publish by the research "A Deep Learning-based Quality Assessment and Segmentation System with a Large-scale Benchmark Dataset for Optical Coherence Tomographic Angiography Image" Detail: This dataset is the pixel-level mask annotation for FAZ segmentation. 1,101 3 × 3 mm2 sOCTA images chosen from gradable and best OCTA images randomly in subset sOCTA-3x3-10k, and 1,143 6 × 6 mm2dOCTA images were annotated by an experienced ophthalmologist. GitHub: https://github.com/shanzha09/COIPS These datasets are public available, if you use the dataset or our system in your research, please cite our paper: A Deep Learning-based Quality Assessment and Segmentation System with a Large-scale Benchmark Dataset for Optical Coherence Tomographic Angiography Image. arXiv:https://arxiv.org/abs/2107.10476v1

Voltage-dependent anion channels (VDACs) are situated in the outer membrane of the mitochondria and serve as gatekeepers that control metabolite and ion exchange between the cytosol and mitochondria. VDAC1 is one of the most studied members of the VDAC protein family and is overexpressed in multiple types of cancer. However, the specific biological function and regulatory mechanism of VDAC1 in breast cancer remains unclear. The present study investigated the biological role of VDAC1 in breast cancer cells using an MTS assay. The association of clinicopathological features with VDAC1 in breast cancer was analyzed by Gene Expression Profiling Interactive Analysis. The regulatory mechanism of VDAC1 was determined by cell transfection, western blot analysis, reverse transcription-quantitative (q)PCR analysis, chromatin immunoprecipitation (ChIP) and ChIP-qPCR analysis. The results of the present study demonstrated that VDAC1 promoted breast cancer proliferation and was associated with a poor prognosis in patients with breast cancer. Additionally, it was observed that the expression of VDAC1 could be decreased by the bromodomain inhibitor (JQ1), and bromodomain-containing protein 4 (BRD4) was indicated to be a regulator of VDAC1. Furthermore, results suggested that VDAC1 may be involved in the resistance of breast cancer to JQ1. Collectively, the present findings uncovered important aspects of the function of VDAC1 in the tumor progression of breast cancer, and may provide a basis for potential therapeutic strategies for the treatment of breast cancer.

Background: laparoscopic appendectomy(LA) has proved to be a safe alternative to open appendectomy( OA) in uncomplicated appendicitis; however, the feasibility of LA for complicated appendicitis(CA) has not been conclusively determined.Objectives: To assess the feasibility and safety of LA for CA through a systematic review and meta-analysis.Methods: A literature search in PubMed, Embase, Cochrane Library, and web of Science was performed for eligible studies published from the inception of the databases to January 2016. All studies comparing LA and OA for CA were reviewed. After literature selection, data extraction and quality assessment were performed by two reviewers independently, and meta-analysis was conducted using Revman software, vision 5.2.Results: Two randomized controlled trials (RCTs) and 14 retrospective cohort studies(RCSs) were finally identified. Our meta-analysis showed that LA for CA could reduce the rate of surgical site infections (SSIs) (OR = 0.28; 95% CI: 0.25 to 0.31, P < 0.00001), but LA did not increase the rate of postoperative intra-abdominal abscess(IAA) (OR = 0.79; 95% CI: 0.45 to 1.34, P = 0.40). The results showed that the operating time in the LA groups was much longer than that in the OA groups (WMD = 13.78, 95% CI: 8.99 to 18.57, P < 0.00001). However, the length of hospital stays in the LA groups were significantly shorter than those in the OA groups (WMD = -2.47, 95% CI: -3.75 to -1.19, P < 0.0002), and the time until oral intake(TTOI) was much earlier in the LA groups than in the OA groups (WMD = -0.88, 95% CI: -1.20 to -0.55, P < 0.00001). No significant difference was observed in the times of postoperative analgesia between the two groups(P > 0.05).Conclusion: LA was feasible and safe for complicated appendicitis, and it not only could shorten the hospital stays and the time until oral intake, but it could also reduce the risk of surgical site infection. (C) 2017 IJS Publishing Group Ltd. Published by Elsevier Ltd. All rights reserved.