Altered gut microbiota and systemic immunity in Chinese patients with schizophrenia comorbid with metabolic syndrome.

BACKGROUND: Metabolic syndrome (MetS) is highly prevalent in individuals with schizophrenia (SZ), leading to negative consequences like premature mortality. Gut dysbiosis, which refers to an imbalance of the microbiota, and chronic inflammation are associated with both SZ and MetS. However, the relationship between gut dysbiosis, host immunological dysfunction, and SZ comorbid with MetS (SZ-MetS) remains unclear. This study aims to explore alterations in gut microbiota and their correlation with immune dysfunction in SZ-MetS, offering new insights into its pathogenesis. METHODS AND RESULTS: We enrolled 114 Chinese patients with SZ-MetS and 111 age-matched healthy controls from Zhejiang, China, to investigate fecal microbiota using Illumina MiSeq sequencing targeting 16 S rRNA gene V3-V4 hypervariable regions. Host immune responses were assessed using the Bio-Plex Pro Human Cytokine 27-Plex Assay to examine cytokine profiles. In SZ-MetS, we observed decreased bacterial α-diversity and significant differences in ß-diversity. LEfSe analysis identified enriched acetate-producing genera (Megamonas and Lactobacillus), and decreased butyrate-producing bacteria (Subdoligranulum, and Faecalibacterium) in SZ-MetS. These altered genera correlated with body mass index, the severity of symptoms (as measured by the Scale for Assessment of Positive Symptoms and Scale for Assessment of Negative Symptoms), and triglyceride levels. Altered bacterial metabolic pathways related to lipopolysaccharide biosynthesis, lipid metabolism, and various amino acid metabolism were also found. Additionally, SZ-MetS exhibited immunological dysfunction with increased pro-inflammatory cytokines, which correlated with the differential genera. CONCLUSION: These findings suggested that gut microbiota dysbiosis and immune dysfunction play a vital role in SZ-MetS development, highlighting potential therapeutic approaches targeting the gut microbiota. While these therapies show promise, further mechanistic studies are needed to fully understand their efficacy and safety before clinical implementation.

Diagnostic possibility of the combination of exhaled nitric oxide and blood eosinophil count for eosinophilic asthma.

BACKGROUND: Tests to identify reversible airflow limitation are important in asthma diagnosis, but they are time-consuming and it may be difficult for patients to cooperate. We aimed to evaluate whether the combination of fractional exhaled nitric oxide (FeNO) and blood eosinophil (B-Eos) can be used to distinguish some asthma patients who could avoid objective tests. METHODS: We conducted a retrospective cohort study on 7463 suspected asthma cases between January 2014 and December 2019 in Chongqing, China, and identified 2349 patients with complete FeNO, B-Eos count, and spirometry data. Asthma was diagnosed by clinicians by the criteria of recurrent respiratory symptoms and a positive bronchial-provocation or bronchodilation test (BPT, BPD). We evaluated the diagnostic accuracy of FeNO or B-Eos alone or both in combination for asthma using receiver operating characteristic (ROC) curve analysis. RESULTS: In this study, 824 patients were diagnosed with asthma. When FeNO and B-Eos counts were used in combination, the area under the ROC curve (AUC) for diagnosing asthma increased slightly (0.768 vs. 0.745 [FeNO] or 0.728 [B-Eos]; both P < 0.001). The odds ratio for having asthma increased progressively with a gradual increase in FeNO or B-Eos count (both P < 0.001; assessed using the Cochran-Armitage trend test). Further analysis of in-series combinations of different threshold values for these biomarkers indicated that moderately elevated biomarker levels (FeNO > 40 ppb and B-Eos > 300 cells/µl) support a diagnosis of asthma because diagnostic specificity was > 95% and the positive likelihood ratio (PLR) was > 10. This conclusion was verified when selecting the 2017-2019 data as the internal validation dataset. CONCLUSION: FeNO or B-Eos count alone is insufficient to accurately diagnose asthma. Patients with moderately elevated biomarkers (FeNO > 40 ppb and B-Eos > 300 cells/µl) could be diagnosed with asthma and avoid objective tests when such tests are not feasible.

Successful management of fatal cardiac tamponade resulting from intravascular intervention for central vein occlusion in hemodialysis patients: A case report.

This case report highlights the successful management of fatal cardiac tamponade caused by intravascular intervention for central vein occlusion in hemodialysis patients. Prompt diagnosis and treatment are essential for patient prognosis in such cases. We present a case involving a challenging surgical procedure to address multiple complications, emphasizing the importance of early detection and appropriate interventions. The patient, who had a history of long-term central venous catheter use for hemodialysis, was diagnosed with central vein stenosis in addition to superior vena cava occlusion, hemodialysis catheter rupture, hypertension, and end-stage renal disease. Urgent ultrasound examination during surgery revealed pericardial effusion, prompting immediate pericardial drainage for stabilization. To overcome the complex challenges, we successfully performed an innominate vein-right atrial appendage bypass to restore vascular access and salvage the patient's life. The timely use of echocardiography for diagnosis and pericardial drainage contributed to stabilizing the patient's vital signs, providing an opportunity for subsequent surgical intervention. The innominate vein-right atrial appendage bypass procedure successfully relieved central vein stenosis and saved the patient's life. Although this surgical technique is not widely documented in hemodialysis patients with central venous involvement, it show cases the potential benefits for clinicians managing vascular access in this patient population. This case report underscores the need for awareness among clinicians regarding the risk of cardiac tamponade associated with intravascular intervention for central vein stenosis in hemodialysis patients. Minimizing central venous catheterization and prioritizing autogenous arteriovenous fistulas are crucial principles in preparing vascular access for hemodialysis patients. Early detection, timely interventions, and consideration of alternative surgical techniques can improve outcomes and prevent life-threatening complications.

Prosthetic brachial artery-external jugular vein arteriovenous grafts as a novel option for hemodialysis access: A case report.

Following the exhaustion of all conventional hemodialysis access options in the upper extremities, a prosthetic arteriovenous loop was performed between the brachial artery (BA) and the external jugular vein (EJV) as a novel access option for hemodialysis in the present case report. During the procedure, a polytetrafluoroethylene graft was anastomosed to the BA and the EJV, and looped on the upper limb. The safety and reliability of BA-EJV access was evaluated by determining the complications, patency and intervention rates. The patient was then followed up for 20 months. The graft became thrombosed 20 months after the placement. There were no complications, such as infection, bleeding or aneurysmal lesions. Overall, the present study demonstrates that hemodialysis via BA-EJV access represents an unusual, yet effective and safe procedure, which may be conducted with acceptable complications and patency rates.

Upadacitinib sustained-release tablets for the treatment of chronic refractory gouty arthritis: a case report and literature review.

Background: Gouty arthritis (GA) is a crystal-related joint disease caused by the deposition of monosodium urate (MSU) crystals, directly associated with hyperuricemia resulting from purine metabolism disorder and/or reduced uric acid excretion. Acute attacks of typical gouty arthritis are generally relieved through the clinical use of NSAIDs, colchicine, or glucocorticoids. However, managing patients with chronic refractory gout poses challenges due to complications such as multiple tophi, gouty nephropathy, diabetes, and gastrointestinal bleeding. While there have been numerous studies on gout in recent years, research specifically regarding chronic refractory gout remains limited. The management of such cases still faces several unresolved issues, including recurrent disease flare-ups and poor patient compliance leading to inadequate drug utilization and increased risk of side effects. In this report, we present a case of successful improvement in chronic refractory gouty arthritis using the biologic agent upadacitinib sustained-release tablets. Case presentation: Our case report involves a 53 years-old Asian patient with recurrent gouty arthritis who had a history of over 20 years without regular treatment, presenting with tophi and an increasing number of painful episodes. During hospitalization, various analgesics and anti-inflammatory drugs provided inadequate relief, requiring the use of steroids to alleviate symptoms. However, tapering off steroids proved challenging. We decided to add upadacitinib sustained-release tablets to the treatment regimen, which ultimately improved the patient's condition. After 6 months of follow-up, the patient has not experienced any further acute pain episodes. Conclusion: This case highlights the potential therapeutic effect of upadacitinib sustained-release tablets during the acute phase of chronic refractory gouty arthritis.

Challenges and strategies associated with CAR-T cell therapy in blood malignancies.

Cellular immunotherapy, particularly CAR-T cells, has shown potential in the improvement of outcomes in patients with refractory and recurrent malignancies of the blood. However, achieving sustainable long-term complete remission for blood cancer remains a challenge, with resistance and relapse being expected outcomes for many patients. Although many studies have attempted to clarify the mechanisms of CAR-T cell therapy failure, the mechanism remains unclear. In this article, we discuss and describe the current state of knowledge regarding these factors, which include elements that influence the CAR-T cell, cancer cells as a whole, and the microenvironment surrounding the tumor. In addition, we propose prospective approaches to overcome these obstacles in an effort to decrease recurrence rates and extend patient survival subsequent to CAR-T cell therapy.

One-Shot Weakly-Supervised Segmentation in 3D Medical Images.

Deep neural networks typically require accurate and a large number of annotations to achieve outstanding performance in medical image segmentation. One-shot and weakly-supervised learning are promising research directions that reduce labeling effort by learning a new class from only one annotated image and using coarse labels instead, respectively. In this work, we present an innovative framework for 3D medical image segmentation with one-shot and weakly-supervised settings. Firstly a propagation-reconstruction network is proposed to propagate scribbles from one annotated volume to unlabeled 3D images based on the assumption that anatomical patterns in different human bodies are similar. Then a multi-level similarity denoising module is designed to refine the scribbles based on embeddings from anatomical- to pixel-level. After expanding the scribbles to pseudo masks, we observe the miss-classified voxels mainly occur at the border region and propose to extract self-support prototypes for the specific refinement. Based on these weakly-supervised segmentation results, we further train a segmentation model for the new class with the noisy label training strategy. Experiments on three CT and one MRI datasets show the proposed method obtains significant improvement over the state-of-the-art methods and performs robustly even under severe class imbalance and low contrast. Code is publicly available at https://github.com/LWHYC/OneShot_WeaklySeg.

Contrastive Semi-Supervised Learning for Domain Adaptive Segmentation Across Similar Anatomical Structures.

Convolutional Neural Networks (CNNs) have achieved state-of-the-art performance for medical image segmentation, yet need plenty of manual annotations for training. Semi-Supervised Learning (SSL) methods are promising to reduce the requirement of annotations, but their performance is still limited when the dataset size and the number of annotated images are small. Leveraging existing annotated datasets with similar anatomical structures to assist training has a potential for improving the model's performance. However, it is further challenged by the cross-anatomy domain shift due to the image modalities and even different organs in the target domain. To solve this problem, we propose Contrastive Semi-supervised learning for Cross Anatomy Domain Adaptation (CS-CADA) that adapts a model to segment similar structures in a target domain, which requires only limited annotations in the target domain by leveraging a set of existing annotated images of similar structures in a source domain. We use Domain-Specific Batch Normalization (DSBN) to individually normalize feature maps for the two anatomical domains, and propose a cross-domain contrastive learning strategy to encourage extracting domain invariant features. They are integrated into a Self-Ensembling Mean-Teacher (SE-MT) framework to exploit unlabeled target domain images with a prediction consistency constraint. Extensive experiments show that our CS-CADA is able to solve the challenging cross-anatomy domain shift problem, achieving accurate segmentation of coronary arteries in X-ray images with the help of retinal vessel images and cardiac MR images with the help of fundus images, respectively, given only a small number of annotations in the target domain. Our code is available at https://github.com/HiLab-git/DAG4MIA.

Segmentation of multiple Organs-at-Risk associated with brain tumors based on coarse-to-fine stratified networks.

BACKGROUND: Delineation of Organs-at-Risks (OARs) is an important step in radiotherapy treatment planning. As manual delineation is time-consuming, labor-intensive and affected by inter- and intra-observer variability, a robust and efficient automatic segmentation algorithm is highly desirable for improving the efficiency and repeatability of OAR delineation. PURPOSE: Automatic segmentation of OARs in medical images is challenged by low contrast, various shapes and imbalanced sizes of different organs. We aim to overcome these challenges and develop a high-performance method for automatic segmentation of 10 OARs required in radiotherapy planning for brain tumors. METHODS: A novel two-stage segmentation framework is proposed, where a coarse and simultaneous localization of all the target organs is obtained in the first stage, and a fine segmentation is achieved for each organ, respectively, in the second stage. To deal with organs with various sizes and shapes, a stratified segmentation strategy is proposed, where a High- and Low-Resolution Residual Network (HLRNet) that consists of a multiresolution branch and a high-resolution branch is introduced to segment medium-sized organs, and a High-Resolution Residual Network (HRRNet) is used to segment small organs. In addition, a label fusion strategy is proposed to better deal with symmetric pairs of organs like the left and right cochleas and lacrimal glands. RESULTS: Our method was validated on the dataset of MICCAI ABCs 2020 challenge for OAR segmentation. It obtained an average Dice of 75.8% for 10 OARs, and significantly outperformed several state-of-the-art models including nnU-Net (71.6%) and FocusNet (72.4%). Our proposed HLRNet and HRRNet improved the segmentation accuracy for medium-sized and small organs, respectively. The label fusion strategy led to higher accuracy for symmetric pairs of organs. CONCLUSIONS: Our proposed method is effective for the segmentation of OARs of brain tumors, with a better performance than existing methods, especially on medium-sized and small organs. It has a potential for improving the efficiency of radiotherapy planning with high segmentation accuracy.

Akkermansia muciniphila in neuropsychiatric disorders: friend or foe?

An accumulating body of evidence suggests that the bacterium Akkermansia muciniphila exhibits positive systemic effects on host health, mainly by improving immunological and metabolic functions, and it is therefore regarded as a promising potential probiotic. Recent clinical and preclinical studies have shown that A. muciniphila plays a vital role in a variety of neuropsychiatric disorders by influencing the host brain through the microbiota-gut-brain axis (MGBA). Numerous studies observed that A. muciniphila and its metabolic substances can effectively improve the symptoms of neuropsychiatric disorders by restoring the gut microbiota, reestablishing the integrity of the gut mucosal barrier, regulating host immunity, and modulating gut and neuroinflammation. However, A. muciniphila was also reported to participate in the development of neuropsychiatric disorders by aggravating inflammation and influencing mucus production. Therefore, the exact mechanism of action of A. muciniphila remains much controversial. This review summarizes the proposed roles and mechanisms of A. muciniphila in various neurological and psychiatric disorders such as depression, anxiety, Parkinson's disease, Alzheimer's disease, multiple sclerosis, strokes, and autism spectrum disorders, and provides insights into the potential therapeutic application of A. muciniphila for the treatment of these conditions.

CDDSA: Contrastive domain disentanglement and style augmentation for generalizable medical image segmentation.

Generalization to previously unseen images with potential domain shifts is essential for clinically applicable medical image segmentation. Disentangling domain-specific and domain-invariant features is key for Domain Generalization (DG). However, existing DG methods struggle to achieve effective disentanglement. To address this problem, we propose an efficient framework called Contrastive Domain Disentanglement and Style Augmentation (CDDSA) for generalizable medical image segmentation. First, a disentangle network decomposes the image into domain-invariant anatomical representation and domain-specific style code, where the former is sent for further segmentation that is not affected by domain shift, and the disentanglement is regularized by a decoder that combines the anatomical representation and style code to reconstruct the original image. Second, to achieve better disentanglement, a contrastive loss is proposed to encourage the style codes from the same domain and different domains to be compact and divergent, respectively. Finally, to further improve generalizability, we propose a style augmentation strategy to synthesize images with various unseen styles in real time while maintaining anatomical information. Comprehensive experiments on a public multi-site fundus image dataset and an in-house multi-site Nasopharyngeal Carcinoma Magnetic Resonance Image (NPC-MRI) dataset show that the proposed CDDSA achieved remarkable generalizability across different domains, and it outperformed several state-of-the-art methods in generalizable segmentation. Code is available at https://github.com/HiLab-git/DAG4MIA.

Altered oral microbiota and immune dysfunction in Chinese elderly patients with schizophrenia: a cross-sectional study.

Schizophrenia (SZ) is a complex psychiatric neurodevelopmental disorder with uncertain etiology and pathogenesis. Increasing evidence has recognized the key role of the gut microbiota in SZ. However, few studies have investigated the potential link between oral microbiota and SZ. We studied the tongue coating microbiota and inflammatory profiles of 118 elderly SZ patients and 97 age-matched healthy controls using Illumina MiSeq sequencing and multiplex immunoassays, respectively. Reduced α-diversity, along with a significant difference in ß-diversity, were observed in patients with SZ. We have identified SZ-associated oral dysbiosis, characterized by increased Streptococcus and Fusobacterium, as well as decreased Prevotella and Veillonella. These differential genera could potentially serve as biomarkers for SZ, either alone or in combination. Additionally, an elevated Streptococcus/Prevotella ratio could indicate oral dysbiosis. These differential genera formed two distinct clusters: Streptococcus-dominated and Prevotella-dominated, which exhibited different correlations with the altered immunological profiles. Furthermore, we also observed disruptions in the inferred microbiota functions in SZ-associated microbiota, particularly in lipid and amino acid metabolism. Our study provides novel insights into the characteristics of tongue coating microbiota and its associations with immunological disturbances in elderly SZ patients, which offer new targets for the diagnosis and treatment of SZ in the elderly.

Probiotics for the treatment of depression and its comorbidities: A systemic review.

Depression is one of the most common psychiatric conditions, characterized by significant and persistent depressed mood and diminished interest, and often coexists with various comorbidities. The underlying mechanism of depression remain elusive, evidenced by the lack of an appreciate therapy. Recent abundant clinical trials and animal studies support the new notion that the gut microbiota has emerged as a novel actor in the pathophysiology of depression, which partakes in bidirectional communication between the gut and the brain through the neuroendocrine, nervous, and immune signaling pathways, collectively known as the microbiota-gut-brain (MGB) axis. Alterations in the gut microbiota can trigger the changes in neurotransmitters, neuroinflammation, and behaviors. With the transition of human microbiome research from studying associations to investigating mechanistic causality, the MGB axis has emerged as a novel therapeutic target in depression and its comorbidities. These novel insights have fueled idea that targeting on the gut microbiota may open new windows for efficient treatment of depression and its comorbidities. Probiotics, live beneficial microorganisms, can be used to modulate gut dysbiosis into a new eubiosis and modify the occurrence and development of depression and its comorbidities. In present review, we summarize recent findings regarding the MGB axis in depression and discuss the potential therapeutic effects of probiotics on depression and its comorbidities.

Alterations of the fecal and vaginal microbiomes in patients with systemic lupus erythematosus and their associations with immunological profiles.

Background: Exploring the human microbiome in multiple body niches is beneficial for clinicians to determine which microbial dysbiosis should be targeted first. We aimed to study whether both the fecal and vaginal microbiomes are disrupted in SLE patients and whether they are correlated, as well as their associations with immunological features. Methods: A group of 30 SLE patients and 30 BMI-age-matched healthy controls were recruited. Fecal and vaginal samples were collected, the 16S rRNA gene was sequenced to profile microbiomes, and immunological features were examined. Results: Distinct fecal and vaginal bacterial communities and decreased microbial diversity in feces compared with the vagina were found in SLE patients and controls. Altered bacterial communities were found in the feces and vaginas of patients. Compared with the controls, the SLE group had slightly lower gut bacterial diversity, which was accompanied by significantly higher bacterial diversity in their vaginas. The most predominant bacteria differed between feces and the vagina in all groups. Eleven genera differed in patients' feces; for example, Gardnerella and Lactobacillus increased, whereas Faecalibacterium decreased. Almost all the 13 genera differed in SLE patients' vaginas, showing higher abundances except for Lactobacillus. Three genera in feces and 11 genera in the vagina were biomarkers for SLE patients. The distinct immunological features were only associated with patients' vaginal microbiomes; for example, Escherichia-Shigella was negatively associated with serum C4. Conclusions: Although SLE patients had fecal and vaginal dysbiosis, dysbiosis in the vagina was more obvious than that in feces. Additionally, only the vaginal microbiome interacted with patients' immunological features.

Exploring the gut mycobiome: differential composition and clinical associations in hypertension, chronic kidney disease, and their comorbidity.

Background: Hypertension (HTN) and chronic kidney disease (CKD) pose significant global health challenges and often coexist, amplifying cardiovascular risks. Recent attention has turned to the gut mycobiome as a potential factor in their pathophysiology. Our study sought to examine the gut fungal profile in individuals with HTN, CKD, and the concurrent HTN+CKD condition, investigating its connections with serum cytokines, renal function, and blood pressure. Methods and materials: We investigated three distinct participant groups: a cohort of 50 healthy controls (HC), 50 individuals diagnosed with HTN-only, and 50 participants suffering from both HTN and CKD (HTN+CKD). To facilitate our research, we gathered fecal and blood samples and conducted a comprehensive analysis of serum cytokines. Moreover, fungal DNA extraction was conducted with meticulous care, followed by sequencing of the Internal Transcribed Spacer (ITS) region. Results: HTN+CKD patients displayed distinctive fungal composition with increased richness and diversity compared to controls. In contrast, HTN-only patients exhibited minimal fungal differences. Specific fungal genera were notably altered in HTN+CKD patients, characterized by increased Apiotrichum and Saccharomyces levels and reduced Candida abundance. Our correlation analyses revealed significant associations between fungal genera and serum cytokines. Moreover, certain fungal taxa, such as Apiotrichum and Saccharomyces, exhibited positive correlations with renal function, while others, including Septoria, Nakaseomyces, and Saccharomyces, were linked to blood pressure, particularly diastolic pressure. Conclusion: Gut mycobiome dysbiosis in individuals with comorbid HTN and CKD differs significantly from that observed in HTN-only and healthy controls. The interactions between serum cytokines, renal function, and blood pressure emphasize the potential impact of the fungal microbiome on these conditions. Additional research is required to clarify the underlying mechanisms and identify therapeutic opportunities associated with mycobiome dysbiosis in HTN and CKD.

Elevated Levels of Serum Alkaline Phosphatase are Associated with Increased Risk of Cardiovascular Disease: A Prospective Cohort Study.

AIM: We aimed to investigate the associations of serum alkaline phosphatase (ALP) levels with incident cardiovascular disease (CVD), coronary heart disease (CHD), and stroke, as well as their subtypes, among men and women in a prospective cohort study. METHODS: A total of 11,408 men and 14,981 women were included to evaluate the associations between ALP levels and incident CVD. Participants were divided into four groups according to the quartiles of serum ALP levels in men and women separately. Cox proportional hazard models were used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: During an average follow-up of 7.3 years, 7,015 incident CVDs (5,561 CHDs and 1,454 strokes) were documented. After adjustments for age, body mass index, smoking status, drinking status, diabetes, hyperlipidemia, hypertension, physical activity, aspirin usage, anticoagulants usage, menopausal status (women only), family history of CVD, estimated glomerular filtration rate, white blood cell counts, and admission batch and comparing the lowest quartile of ALP, the adjusted HRs (95% CIs) of participants in the highest quartile were 1.22 (1.11-1.34) for CVD, 1.14 (1.02-1.28) for CHD, 1.43 (1.18-1.73) for stroke, 1.31 (1.09-1.57) for acute coronary syndrome (ACS), 1.37 (1.11-1.70) for ischemic stroke, and 1.75 (1.10-2.79) for hemorrhagic stroke in men and 1.12 (1.01-1.23) for CVD, 1.10 (0.99-1.23) for CHD, 1.18 (0.92-1.51) for stroke, 1.23 (1.03-1.47) for ACS, 1.10 (0.83-1.45) for ischemic stroke, and 1.54 (0.90-2.65) for hemorrhagic stroke in women. The ALP-CVD associations remained significant even within the normal ranges of ALP levels (40-150 U/L). Moreover, linear dose-response relationships were found between ALP levels and incident CVD. CONCLUSIONS: Higher ALP levels, even within the normal range, were significantly associated with increased risks of CVD, in a dose-dependent manner. These findings suggested that regular monitoring of ALP levels may help in improving the early identification of the population at higher CVD risk.

Selection, identification and crystal structure of shark-derived single-domain antibodies against a green fluorescent protein.

Shark variable domain of new antigen receptors (VNARs) are the smallest naturally occurring binding domains with properties of low complexity, small size, cytoplasmic expression, and ease of engineering. Green fluorescent protein (GFP) molecules have been analyzed in conventional microscopy, but their spectral characteristics preclude their use in techniques offering substantially higher resolution. Besides, the GFP molecules can be quenched in acidic environment, which makes it necessary to develop anti-GFP antibody to solve these problems. In view of the diverse applications of GFP and unique physicochemical features of VNAR, the present study aims to generate VNARs against GFP. Here, we identified 36 VNARs targeting eCGP123, an extremely stable GFP, by phage display from three immunized sharks. These VNARs bound to eCGP123 with affinity constant KD values ranging from 6.76 to 605 nM. Among them, two lead VNARs named aGFP-14 and aGFP-15 with nanomolar eCGP123-binding affinity were selected for in-depth characterization. aGFP-14 and aGFP-15 recognized similar epitopes on eCGP123. X-ray crystallography studies clarified the mechanism by which aGFP14 interacts with eCGP123. aGFP-14 also showed cross-reaction with EGFP, with KD values of 47.2 nM. Finally, immunostaining analyses demonstrated that aGFP-14 was able to bind effectively to the EGFP expressed in both cultured cells and mouse brain tissues, and can be used as a fluorescence amplifier for EGFP. Our research demonstrates a feasible idea for the screening and production of shark-derived VNARs. The two high-affinity VNARs developed in the study contribute to the diversity of GFP sdAbs and may enhance the applications of GFP.

HMRNet: High and Multi-Resolution Network With Bidirectional Feature Calibration for Brain Structure Segmentation in Radiotherapy.

Accurate segmentation of Anatomical brain Barriers to Cancer spread (ABCs) plays an important role for automatic delineation of Clinical Target Volume (CTV) of brain tumors in radiotherapy. Despite that variants of U-Net are state-of-the-art segmentation models, they have limited performance when dealing with ABCs structures with various shapes and sizes, especially thin structures (e.g., the falx cerebri) that span only few slices. To deal with this problem, we propose a High and Multi-Resolution Network (HMRNet) that consists of a multi-scale feature learning branch and a high-resolution branch, which can maintain the high-resolution contextual information and extract more robust representations of anatomical structures with various scales. We further design a Bidirectional Feature Calibration (BFC) block to enable the two branches to generate spatial attention maps for mutual feature calibration. Considering the different sizes and positions of ABCs structures, our network was applied after a rough localization of each structure to obtain fine segmentation results. Experiments on the MICCAI 2020 ABCs challenge dataset showed that: 1) Our proposed two-stage segmentation strategy largely outperformed methods segmenting all the structures in just one stage; 2) The proposed HMRNet with two branches can maintain high-resolution representations and is effective to improve the performance on thin structures; 3) The proposed BFC block outperformed existing attention methods using monodirectional feature calibration. Our method won the second place of ABCs 2020 challenge and has a potential for more accurate and reasonable delineation of CTV of brain tumors.

Associations of Baseline and Changes in Leukocyte Counts with Incident Cardiovascular Events: The Dongfeng-Tongji Cohort Study.

AIM: The aim of the present study was to investigate the associations of baseline and longitudinal changes in leukocyte counts with incident cardiovascular disease (CVD). METHODS: We conducted a prospective study to investigate the associations of baseline and 5-year changes in leukocyte counts with incident CVD and its subtypes in middle-aged and elderly Chinese. We estimated the hazard ratios (HRs) and 95% confidence intervals (CIs) for CVD using the Cox proportional-hazards models. RESULTS: In the analyses of baseline total leukocyte count of 26,655 participants, compared with the lowest quartile (＜4.71×109/L), participants in the fourth quartile (＞6.70×109/L) had 11% higher risk for CVD. Consistent with total leukocyte count, neutrophil count also exhibited a significant positive association with the risk of CVD. In the analyses of 5-year changes in total leukocyte count of 11,594 participants, the changes in leukocyte count were categorized into three groups, i.e., the decreased group (＜25%), stable group (25%-75%), and increased group (＞75%). Compared with participants in the stable group (-1.18 to 0.44×109/L), participants in the increased group (＞0.44×109/L) had 14% higher risk for CVD. We also observed significant positive associations of the changes in neutrophil and monocyte counts with the risk of CVD. Furthermore, the total leukocyte count in the second or third tertile at the first follow-up with a 5-year increase was related to higher CVD risk. CONCLUSION: High baseline total leukocyte count and a 5-year increase in total leukocyte count were related to higher CVD risk.

Automatic segmentation of organs-at-risks of nasopharynx cancer and lung cancer by cross-layer attention fusion network with TELD-Loss.

PURPOSE: Radiotherapy is one of the main treatments of nasopharyngeal cancer (NPC) and lung cancer. Accurate segmentation of organs at risks (OARs) in CT images is a key step in radiotherapy planning for NPC and lung cancer. However, the segmentation of OARs is influenced by the highly imbalanced size of organs, which often results in very poor segmentation results for small and difficult-to-segment organs. In addition, the complex morphological changes and fuzzy boundaries of OARs also pose great challenges to the segmentation task. In this paper, we propose a cross-layer attention fusion network (CLAF-CNN) to solve the problem of accurately segmenting OARs. METHODS: In CLAF-CNN, we integrate the spatial attention maps of the adjacent spatial attention modules to make the segmentation targets more accurately focused, so that the network can capture more target-related features. In this way, the spatial attention modules in the network can be learned and optimized together. In addition, we introduce a new Top-K exponential logarithmic Dice loss (TELD-Loss) to solve the imbalance problem in OAR segmentation. The TELD-Loss further introduces a Top-K optimization mechanism based on Dice loss and exponential logarithmic loss, which makes the network pay more attention to small organs and difficult-to-segment organs, so as to enhance the overall performance of the segmentation model. RESULTS: We validated our framework on the OAR segmentation datasets of the head and neck and lung CT images in the StructSeg 2019 challenge. Experiments show that the CLAF-CNN outperforms the state-of-the-art attention-based segmentation methods in the OAR segmentation task with average Dice coefficient of 79.65% for head and neck OARs and 88.39% for lung OARs. CONCLUSIONS: This work provides a new network named CLAF-CNN which contains cross-layer spatial attention map fusion architecture and TELD-Loss for OAR segmentation. Results demonstrated that the proposed method could obtain accurate segmentation results for OARs, which has a potential of improving the efficiency of radiotherapy planning for nasopharynx cancer and lung cancer.