Epithelial-mesenchymal plasticity in cancer: signaling pathways and therapeutic targets.

Currently, cancer is still a leading cause of human death globally. Tumor deterioration comprises multiple events including metastasis, therapeutic resistance and immune evasion, all of which are tightly related to the phenotypic plasticity especially epithelial-mesenchymal plasticity (EMP). Tumor cells with EMP are manifest in three states as epithelial-mesenchymal transition (EMT), partial EMT, and mesenchymal-epithelial transition, which orchestrate the phenotypic switch and heterogeneity of tumor cells via transcriptional regulation and a series of signaling pathways, including transforming growth factor-ß, Wnt/ß-catenin, and Notch. However, due to the complicated nature of EMP, the diverse process of EMP is still not fully understood. In this review, we systematically conclude the biological background, regulating mechanisms of EMP as well as the role of EMP in therapy response. We also summarize a range of small molecule inhibitors, immune-related therapeutic approaches, and combination therapies that have been developed to target EMP for the outstanding role of EMP-driven tumor deterioration. Additionally, we explore the potential technique for EMP-based tumor mechanistic investigation and therapeutic research, which may burst vigorous prospects. Overall, we elucidate the multifaceted aspects of EMP in tumor progression and suggest a promising direction of cancer treatment based on targeting EMP.

A promising anti-tumor targeting on ERMMDs mediated abnormal lipid metabolism in tumor cells.

The investigation of aberrations in lipid metabolism within tumor has become a burgeoning field of study that has garnered significant attention in recent years. Lipids can serve as a potent source of highly energetic fuel to support the rapid growth of neoplasia, in where the ER-mitochondrial membrane domains (ERMMDs) provide an interactive network for facilitating communication between ER and mitochondria as well as their intermembrane space and adjunctive proteins. In this review, we discuss fatty acids (FAs) anabolic and catabolic metabolism, as well as how CPT1A-VDAC-ACSL clusters on ERMMDs participate in FAs transport, with a major focus on ERMMDs mediated collaborative loop of FAO, Ca2+ transmission in TCA cycle and OXPHOS process. Here, we present a comprehensive perspective on the regulation of aberrant lipid metabolism through ERMMDs conducted tumor physiology might be a promising and potential target for tumor starvation therapy.

Protecting Prostate Cancer Classification From Rectal Artifacts via Targeted Adversarial Training.

Magnetic resonance imaging (MRI)-based deep neural networks (DNN) have been widely developed to perform prostate cancer (PCa) classification. However, in real-world clinical situations, prostate MRIs can be easily impacted by rectal artifacts, which have been found to lead to incorrect PCa classification. Existing DNN-based methods typically do not consider the interference of rectal artifacts on PCa classification, and do not design specific strategy to address this problem. In this study, we proposed a novel Targeted adversarial training with Proprietary Adversarial Samples (TPAS) strategy to defend the PCa classification model against the influence of rectal artifacts. Specifically, based on clinical prior knowledge, we generated proprietary adversarial samples with rectal artifact-pattern adversarial noise, which can severely mislead PCa classification models optimized by the ordinary training strategy. We then jointly exploited the generated proprietary adversarial samples and original samples to train the models. To demonstrate the effectiveness of our strategy, we conducted analytical experiments on multiple PCa classification models. Compared with ordinary training strategy, TPAS can effectively improve the single- and multi-parametric PCa classification at patient, slice and lesion level, and bring substantial gains to recent advanced models. In conclusion, TPAS strategy can be identified as a valuable way to mitigate the influence of rectal artifacts on deep learning models for PCa classification.

Misdiagnosed as Fungal Keratitis: Herpes Simplex Virus-1 Keratitis Confirmed by Next-Generation Sequencing.

Objective: The purpose of this study was to report a case of herpes simplex virus-1 (HSV-1) keratitis misdiagnosed as fungal keratitis due to its clinical presentation being similar to that of fungal keratitis, ultimately diagnosed by NGS. Patients and Methods: A 59-year-old male presented with reduced vision in the right eye, combined with a history of trauma with vegetative matter. The corneal ulcer was accompanied with feathery infiltration, satellite lesion, and endothelial plaques. In vivo confocal microscopy (IVCM) showed hyper-reflective linear, thin, and branching interlocking structures. Fungal keratitis was diagnosed. Voriconazole 100 mg orally daily, topical tobramycin and 1% voriconazole were initiated empirically right away. The condition was aggravated and penetrating keratoplasty was performed. Anterior segment optical coherence tomography (AS-OCT) demonstrated the presence of plaques with a clear boundary between plaques and endothelium, resembling the AS-OCT images observed in cases of viral keratitis. Next-generation sequencing (NGS) further detected HSV-1 deoxyribonucleic acid, and no fungal component was found. Antifungal agents were discontinued and antiviral treatments were added. Results: We successfully treated a patient with HSV-1 keratitis who was misdiagnosed due to clinical features and IVCM findings similar to fungal keratitis. The patient's infection was controlled. At 2 years after surgery, the cornea recovered well. Conclusions: HSV-1 keratitis with atypical clinical presentation can be easily misdiagnosed. This case report emphasizes the importance of NGS in diagnosing the pathogens of keratitis.

Characteristics of Neonatal Sepsis and Predictive Values of Polyfunctional Assessment of Umbilical Cord Neutrophils Based on Single Cell Proteomic Secretion.

The early diagnosis of neonatal sepsis is crucial as it remains a prevalent cause of neonatal mortality. In this study, we conducted an analysis on the clinical data and detection indicators of 22 cases with sepsis and 62 cases without sepsis among neonates. Our findings indicate that the clinical signs observed in neonates with sepsis lack specificity. In addition, the commonly used clinical inflammatory indicators (such as leukocyte count, neutrophil-to-lymphocyte ratio [NLR], C-reactive protein [CRP], procalcitonin) exhibit limited sensitivity and specificity. Furthermore, the current clinical measures lack the assessment of inflammatory factors. Therefore, in order to enhance the accuracy of early sepsis diagnosis in neonates, we have employed a novel microfluidic-based single-cell technology platform for the analysis of 32 cytokines secreted by neutrophils at the individual cell level under various toxin stimulation conditions. We have further investigated and compared the disparities in single-cell protein secretomics between umbilical cord blood neutrophils and healthy adult peripheral neutrophils within an in vitro sepsis model. Our findings indicate that in a resting state UCB neutrophils exhibited lower polyfunctionality compared with healthy adult blood neutrophils, and notable variations in cytokine secretion profiles were detected between the two groups. However, the polyfunctionality of UCB neutrophils significantly increased and surpassed that of healthy adult neutrophils when exposed to alpha-hemolysin or lipopolysaccharide. UCB neutrophils secreted a wide range of chemokines and inflammatory factors, among which GM-CSF and IL-18 were the most significant. Furthermore, we initially categorized the functional subgroups of neutrophils by considering the secretion of five primary cytokines by neutrophils (GM-CSF, IL-18, IL-8, MIP-1ß, and MIF). The current study, for the first time, examined in detail the heterogeneity of protein secretion and the functional diversity of UCB neutrophils stimulated by different antigens. Moreover, new insight into neonatal sepsis, early diagnosis, and wider clinical applications of UCB neutrophils are provided by these data.

Epithelial Membrane Protein 2 (EMP2) Blockade Attenuates Pathological Neovascularization in Murine Oxygen-Induced Retinopathy.

Purpose: Retinopathy of prematurity (ROP) results from postnatal hyperoxia exposure in premature infants and is characterized by aberrant neovascularization of retinal blood vessels. Epithelial membrane protein-2 (EMP2) regulates hypoxia-inducible factor (HIF)-induced vascular endothelial growth factor (VEGF) production in the ARPE-19 cell line and genetic knock-out of Emp2 in a murine oxygen-induced retinopathy (OIR) model attenuates neovascularization. We hypothesize that EMP2 blockade via intravitreal injection protects against neovascularization. Methods: Ex vivo choroid sprouting assay was performed, comparing media and human IgG controls versus anti-EMP2 antibody (Ab) treatment. In vivo, eyes from wild-type (WT) mice exposed to hyperoxia from postnatal (P) days 7 to 12 were treated with P12 intravitreal injections of control IgG or anti-EMP2 Abs. Neovascularization was assessed at P17 by flat mount imaging. Local and systemic effects of anti-EMP2 Ab treatment were assessed. Results: Choroid sprouts treated with 30 µg/mL of anti-EMP2 Ab demonstrated a 48% reduction in vessel growth compared to control IgG-treated sprouts. Compared to IgG-treated controls, WT OIR mice treated with 4 µg/g of intravitreal anti-EMP2 Ab demonstrated a 42% reduction in neovascularization. They demonstrated down-regulation of retinal gene expression in pathways related to vasculature development and up-regulation in genes related to fatty acid oxidation and tricarboxylic acid cycle respiratory electron transport, compared to controls. Anti-EMP2 Ab-treated OIR mice did not exhibit gross retinal histologic abnormalities, vision transduction abnormalities, or weight loss. Conclusions: Our results suggest that EMP2 blockade could be a local and specific treatment modality for retinal neovascularization in oxygen-induced retinopathies, without systemic adverse effects.

High-Tcsuperconductivity in doped molecular superconductors ofK4B8-xMxH32(M = C, N) under high pressure.

Stabilized and metallic light elements hydrides have provided a potential route to achieve the goal of room-temperature superconductors at moderate or ambient pressures. Here, we have performed systematic DFT theoretical calculations to examine the effects of different light elements C and N atoms doped in cubic K4B8H32hydrides on the superconductivity at low pressures. As a result of various atoms substituting, we have found that metallic K4B_{8-x}MxH32(M = C, N) hydrides are dynamically stable at 50 GPa, band structures and density of states (DOS) indicate that sizeableTccorrelates with a high B-H DOS at the Fermi level. With the increasing of B atoms in K4B_{8-x}MxH32hydrides, the DOS values at Fermi level have been improved due to the delocalized electrons in B-H bonds, which result in strong electron-phonon coupling (EPC) interaction and increase theTcfrom 19.04 to 77.07 K for KC2H8and KB2H8at 50 GPa. The NH4unit in stable K4B7NH32hydrides has weakened the EPC and led to lowTcvalue of 21.47 K. Our results suggest the light elements hydrides KB2H8and K4B7CH32could estimate highTcvalues at 50 GPa, and the boron hydrides would be potential candidates to design or modulate hydrides superconductors with highTcat moderate or ambient pressures.

Insights gained into the injury mechanism of drug and herb induced liver injury in the hepatic microenvironment.

Drug-Induced Liver Injury (DILI) and herb Induced Liver Injury (HILI) continues to pose a substantial challenge in both clinical practice and drug development, representing a grave threat to patient well-being. This comprehensive review introduces a novel perspective on DILI and HILI by thoroughly exploring the intricate microenvironment of the liver. The dynamic interplay among hepatocytes, sinusoidal endothelial cells, Kupffer cells, hepatic stellate cells, cholangiocytes, and the intricate vascular network assumes a central role in drug metabolism and detoxification. Significantly, this microenvironment is emerging as a critical determinant of susceptibility to DILI and HILI. The review delves into the multifaceted interactions within the liver microenvironment, providing valuable insights into the complex mechanisms that underlie DILI and HILI. Furthermore, we discuss potential strategies for mitigating drug-induced liver injury by targeting these influential factors, emphasizing their clinical relevance. By highlighting recent advances and future prospects, our aim is to shed light on the promising avenue of leveraging the liver microenvironment for the prevention and mitigation of DILI and HILI. This deeper understanding is crucial for advancing clinical practices and ensuring patient safety in the realm of DILI and HILI.

The impact of renaming schizophrenia on destigmatization: The Asian experience.

The term "schizophrenia" can indeed carry stigmatizing connotations. Proposals to rename schizophrenia have emerged as a potential strategy to alleviate this stigma, but the impact of such a change is not yet fully understood. In several Asian countries that have adopted a new name for schizophrenia, there is evidence that renaming is associated with improved attitudes towards individuals with schizophrenia and an increased willingness to disclose diagnoses. However, the portrayal of schizophrenia in the media seems unaffected by these name changes. In other countries where "schizophrenia" is still the standard term, alternative names have been suggested, but research on their effectiveness in reducing stigma shows mixed results. Mental health professionals frequently support a name change, recognizing the term's negative implications. However, it is crucial to recognize that a mere semantic revision, devoid of substantial conceptual alterations, may only offer a temporary decrease in stigma. Thus, renaming schizophrenia, coupled with a re-conceptualization of the disorder, may be a constructive step toward reducing its stigmatization.

Exploring the role of anticipatory postural adjustment duration within APA2 subphase as a potential mediator between clinical disease severity and fall risk in Parkinson's disease.

Introduction: People with Parkinson's Disease (PD) often show reduced anticipatory postural adjustments (APAs) before voluntary steps, impacting their stability. The specific subphase within the APA stage contributing significantly to fall risk remains unclear. Methods: We analyzed center of pressure (CoP) trajectory parameters, including duration, length, and velocity, throughout gait initiation. This examination encompassed both the postural phase, referred to as anticipatory postural adjustment (APA) (APA1, APA2a, APA2b), and the subsequent locomotor phases (LOC). Participants were instructed to initiate a step and then stop (initiating a single step). Furthermore, we conducted assessments of clinical disease severity using the Unified Parkinson's Disease Rating Scale (UPDRS) and evaluated fall risk using Tinetti gait and balance scores during off-medication periods. Results: Freezing of gait (FOG) was observed in 18 out of 110 participants during the measurement of CoP trajectories. The Ramer-Douglas-Peucker algorithm successfully identified CoP displacement trajectories in 105 participants (95.5%), while the remaining 5 cases could not be identified due to FOG. Tinetti balance and gait score showed significant associations with levodopa equivalent daily dose, UPDRS total score, disease duration, duration (s) in APA2a (s) and LOC (s), length in APA1 (cm) and APA2b (cm), mediolateral velocity in APA1 (X) (cm/s), APA2a (X) (cm/s), APA2b (X) (cm/s) and LOC (X) (cm/s), and anterior-posterior velocity in APA2a (Z) (cm/s) and APA2b (Z) (cm/s). Multiple linear regression revealed that only duration (s) in APA2a and UPDRS total score was independently associated with Tinetti gait and balance score. Further mediation analysis showed that the duration (s) in APA2a served as a mediator between UPDRS total score and Tinetti balance and gait score (Sobel test, p = 0.047). Conclusion: APA2 subphase duration mediates the link between disease severity and fall risk in PD, suggesting that longer APA2a duration may indicate reduced control during gait initiation, thereby increasing fall risk.

Primary thyroid nuclear protein in testis carcinoma: a case report and literature review.

Background: Nuclear protein in testis (NUT) carcinoma (NC) is a rare, highly aggressive neoplasm, usually accompanying with NUTM1 (NUT midline carcinoma family member 1) gene fusions. Primary thyroid NC is clinically rare and to date there is no established treatment guideline available for NC. We report a case of histopathologically confirmed thyroid NC and provide reference for diagnosis and treatment. Case Description: We presented a 32-year-old female admitted to hospital with "painful neck swelling and progressive dysphagia". Preoperative ultrasound-guided core needle aspiration biopsy suggested a poorly differentiated tumor. Considering the tumor was totally unresected on computed tomography (CT) scan, a partial thyroidectomy was performed to obtain sufficient tissue for a clear diagnosis. Histopathological specimens showed features of sudden keratosis. Strong immunoreactivity with NUT was detected by immunohistochemistry (IHC) and thus confirmed the diagnosis of NC. CK5/6, P40 and P63 were partially positive exclusively in keratosis area. Next-generation sequencing (NGS) and RNA sequencing results revealed a NSD3-NUTM1 fusion. The patient was treated with a combined regimen of radiotherapy of 70 Gy, chemotherapy with paclitaxel (albumin-bound), immunotherapy with nivolumab, targeted therapy with anlotinib and BET inhibitor NHWD-870, but the patient died 7 months after diagnosis. Conclusions: Thyroid NC is a rare and distinct pathological subset of NUT carcinoma with a higher rate of NSD3-NUTM1 fusion. In the clinical diagnosis process, we recommended performing NUT IHC for poorly differentiated thyroid tumors. Gene rearrangement detection is also helpful for diagnosis and treatment. At present, surgery and radiation are still first choices for NC, and advances in targeted immunotherapy such as bromodomain and end motif inhibitors (BETi) may bring better treatment options to patients.

CroMAM: A Cross-Magnification Attention Feature Fusion Model for Predicting Genetic Status and Survival of Gliomas using Histological Images.

Predicting the gene mutation status in whole slide images (WSI) is crucial for the clinical treatment, cancer management, and research of gliomas. With advancements in CNN and Transformer algorithms, several promising models have been proposed. However, existing studies have paid little attention on fusing multi-magnification information, and the model requires processing all patches from a whole slide image. In this paper, we propose a cross-magnification attention model called CroMAM for predicting the genetic status and survival of gliomas. The CroMAM first utilizes a systematic patch extraction module to sample a subset of representative patches for downstream analysis. Next, the CroMAM applies Swin Transformer to extract local and global features from patches at different magnifications, followed by acquiring high-level features and dependencies among single-magnification patches through the application of a Vision Transformer. Subsequently, the CroMAM exchanges the integrated feature representations of different magnifications and encourage the integrated feature representations to learn the discriminative information from other magnification. Additionally, we design a cross-magnification attention analysis method to examine the effect of cross-magnification attention quantitatively and qualitatively which increases the model's explainability. To validate the performance of the model, we compare the proposed model with other multi-magnification feature fusion models on three tasks in two datasets. Extensive experiments demonstrate that the proposed model achieves state-of-the-art performance in predicting the genetic status and survival of gliomas. The implementation of the CroMAM will be publicly available upon the acceptance of this manuscript at https://github.com/GuoJisen/CroMAM.

Intracapsular Enucleation of Cervical Sympathetic Chain Schwannoma: Improved Strategy of Intraoperative Hemostasis and Better Outcome.

Objective: Intracapsular enucleation (ICE) of cervical sympathetic chain schwannoma (CSCS) is associated with technical difficulties, with diffuse hemorrhage being the main challenge in our previous attempts. This article presents our new strategy for achieving better hemostasis during ICE procedures in CSCS cases. Methods: A retrospective review of CSCS cases treated at our tertiary medical institution was undertaken between April 2018 and February 2024. Only cases with successful ICE were included. Results: A total of 8 cases were included, with 4 male and 4 female patients and an age range of 23 to 77 (average and median ages were 48.5 and 49.5 years, respectively). The presenting symptom was a neck mass for all the patients, with 4 masses on the left and 4 on the right sides. Enucleation was first undertaken for the first 3 cases (before March 2022), followed by hemostasis; this strategy was quite difficult and time-consuming. For the remaining 5 cases, a new strategy was developed to preemptively manage any potential nourishing vessel between the capsule and tumor parenchyma, which significantly decreased operation time (P = .0155) and facilitated hemorrhage control. First bite syndrome (FBS) was avoided in all cases. Postoperative Horner's syndrome (HS) was avoided in 1 patient (Case 6, new strategy) but occurred in 7 patients, taking 8 days to 1 month to recover with the new strategy (4 patients), significantly shorter (P = .0364) than before (3 patients, 1-3 months). The median duration of follow-up was 20 months. No recurrence was documented. Conclusions: ICE was achieved for CSCS cases, especially with our newly developed strategy, by preemptively and securely managing potential nourishing vessels. Operation time and duration of recovery of postoperative HS could both be shortened. Moreover, FBS could be avoided.

Investigating spatiotemporal and kinematic gait parameters in individuals with Parkinson's disease with a history of freezing of gait and exploring the effects of dopaminergic therapy on freezing of gait subtypes.

Introduction: Freezing of Gait (FOG) is a prevalent and debilitating symptom in idiopathic Parkinson's disease (PD). This study evaluated spatiotemporal and kinematic gait parameters in individuals with PD with a history of FOG and explored the effects of dopaminergic therapy on FOG subtypes. Methods: One hundred and nine individuals with PD underwent clinical assessments and quantitative biomechanical measures during walking cycles before and after dopaminergic therapy. Individuals with FOG were classified into levodopa-responsive and levodopa-unresponsive groups. Results: Individuals with FOG displayed longer disease duration and higher Unified Parkinson's Disease Rating Scale (UPDRS) II, III, IV scores, and total scores and levodopa equivalent dose, than those without FOG (all p < 0.0001). Following propensity score matching of 15 pairs based on UPDRS total score and disease duration during the off-medication state, the analysis comparing the FOG and non-FOG groups revealed no significant differences in spatiotemporal and kinematic parameters. In 39 cases of FOG, dopaminergic therapy improved gait performance in individuals with PD, enhancing spatiotemporal parameters (speed, stride length, step length, step variability) and kinematic parameters (shoulder and elbow flexion/extension range of motion (ROM), pelvic rotation, and hip abduction/adduction ROM) regardless of FOG responsiveness to dopaminergic therapy. A significant difference in trunk sway ROM (p = 0.029) remained before and after dopaminergic therapy, even after adjusting for disease duration and clinical severity. Discussion: Dopaminergic therapy had varying effects on PD with FOG, improving several spatiotemporal and kinematic gait parameters but being less effective in levodopa-unresponsive cases. Quantitative biomechanical measures offer detailed insights into gait performance, aiding personalized fall risk assessment and guiding individualized rehabilitation programs.

An astroglial basis of major depressive disorder: Molecular, Cellular, and Circuit Features.

Major depressive disorder (MDD) is a common psychiatric disorder and has been a leading cause of disability worldwide. Astrocytes play a role in the maintenance of the function of the central nervous system (CNS), both physiologically and pathologically. Accumulated evidence indicates that the astrocyte is an important contributor to the pathophysiology of MDD including blood-brain barrier (BBB) integrity, gap junctions, gliotransmission, glutamate homeostasis, and energy metabolism. Here, we comprehensively summarize an astroglial basis for MDD based on molecular, cellular, and circuit properties, suggesting that astrocytes appear to be highly sensitive to stress and are likely to be uniquely positioned to integrate peripheral and central stress responses.

Co-immobilization of ß-agarase and α-agarase for degradation of agarose to prepare bioactive 3,6-anhydro-L-galactose.

Agarose from biomass can be used to synthesize the rare sugar 3,6-anhydro-L-galactose (L-AHG), and the new synthesis route and functional properties of L-AHG have always been the focus of research. Here we developed a novel method to co-immobilize Aga50D and BpGH117 onto streptavidin-coated magnetic nanoparticles and achieved the conversion of agarose to bioactive L-AHG in one pot. Results showed that enzymes were successfully immobilized on the carrier. The activity of co-immobilized enzymes was 2.5-fold higher than that of single immobilized enzymes. Compared with free enzymes, co-immobilized enzymes exhibited enhanced thermal stability. The co-immobilized enzymes retained 79.45 % relative activity at 40 °C for 3 h, while the free enzymes only possessed 21.40 % residual activity. After eight cycles, the co-immobilized enzymes still retained 73.47 % of the initial activity. After silica gel chromatography, the purity of L-AHG obtained by co-immobilized enzymes hydrolysis reached 83.02 %. Furthermore, bioactivity experiments demonstrated that L-AHG displayed better antioxidant and antibacterial effects than neoagarobiose. L-AHG had broad-spectrum antibacterial activity, while neoagarobiose and D-galactose did not show an obvious antibacterial effect. This study provides a feasible method for the production of L-AHG by a co-immobilized multi-enzyme system and confirms that L-AHG plays a key role in the bioactivity of neoagarobiose.

Deep learning for colorectal cancer detection in contrast-enhanced CT without bowel preparation: a retrospective, multicentre study.

BACKGROUND: Contrast-enhanced CT scans provide a means to detect unsuspected colorectal cancer. However, colorectal cancers in contrast-enhanced CT without bowel preparation may elude detection by radiologists. We aimed to develop a deep learning (DL) model for accurate detection of colorectal cancer, and evaluate whether it could improve the detection performance of radiologists. METHODS: We developed a DL model using a manually annotated dataset (1196 cancer vs 1034 normal). The DL model was tested using an internal test set (98 vs 115), two external test sets (202 vs 265 in 1, and 252 vs 481 in 2), and a real-world test set (53 vs 1524). We compared the detection performance of the DL model with radiologists, and evaluated its capacity to enhance radiologists' detection performance. FINDINGS: In the four test sets, the DL model had the area under the receiver operating characteristic curves (AUCs) ranging between 0.957 and 0.994. In both the internal test set and external test set 1, the DL model yielded higher accuracy than that of radiologists (97.2% vs 86.0%, p < 0.0001; 94.9% vs 85.3%, p < 0.0001), and significantly improved the accuracy of radiologists (93.4% vs 86.0%, p < 0.0001; 93.6% vs 85.3%, p < 0.0001). In the real-world test set, the DL model delivered sensitivity comparable to that of radiologists who had been informed about clinical indications for most cancer cases (94.3% vs 96.2%, p > 0.99), and it detected 2 cases that had been missed by radiologists. INTERPRETATION: The developed DL model can accurately detect colorectal cancer and improve radiologists' detection performance, showing its potential as an effective computer-aided detection tool. FUNDING: This study was supported by National Science Fund for Distinguished Young Scholars of China (No. 81925023); Regional Innovation and Development Joint Fund of National Natural Science Foundation of China (No. U22A20345); National Natural Science Foundation of China (No. 82072090 and No. 82371954); Guangdong Provincial Key Laboratory of Artificial Intelligence in Medical Image Analysis and Application (No. 2022B1212010011); High-level Hospital Construction Project (No. DFJHBF202105).

Risk of rituximab-induced hepatitis B flare after antiviral discontinuation in rheumatic patients with chronic hepatitis B virus.

OBJECTVES: Among immunosuppressants, rituximab is most strongly associated with the risk of hepatitis B virus (HBV) reactivation in chronic HBV individuals. Current guidelines recommending antiviral prophylaxis for these patients on rituximab are predominantly based on studies in oncology. However, limited data existed for the precise risk of HBV flares, effectiveness and optimal duration of antiviral prophylaxis in rituximab-treated rheumatic patients, whose immune status and treatment regimen differ significantly from those of oncology patients. Therefore, we aimed to assess the incidence and clinical outcome of HBV reactivation in HBsAg-positive patients receiving rituximab for various autoimmune diseases who discontinue the antiviral agents. METHODS: A retrospective analysis was performed on 95 hepatitis B surface antigen (HBsAg)-positive patients treated with rituximab for autoimmune diseases in a single centre in Taiwan. HBV related hepatitis, defined as alanine aminotransferase (ALT) more than 3 times of baseline level and concurrent HBV reactivation, after anti-viral discontinuation, was the primary endpoint. Factors associated with HBV hepatitis flare and off-antiviral hepatitis flare were also analysed. RESULTS: With nucleos(t)ide analogues (NA) prophylaxis, no hepatitis flares occurred. However, without prophylaxis, 59% had flare (24.5 per 100 person-years) and 8% experienced liver decompensation. Concurrent steroid use was a dose-dependent risk factor for flare. After NA discontinuation, rituximab "retreatment" led to flares in 75% of cases and liver decompensation in 63% of patients. Stopping NAs within one-year post-rituximab, even without further rituximab treatment, resulted in a 38% flare rate. CONCLUSIONS: This study offers the direct evidence for the necessity of universal antiviral prophylaxis in rheumatic patients with chronic HBV receiving rituximab. After NA discontinuation, rituximab "retreatment" led to even higher flare rate and worse outcome. Patients who completed rituximab treatment should also keep antiviral agents for at least one more year to prevent hepatitis flare.

Development and validation of a prognostic model for assessing long COVID risk following Omicron wave-a large population-based cohort study.

BACKGROUND: Long coronavirus disease (COVID) after COVID-19 infection is continuously threatening the health of people all over the world. Early prediction of the risk of Long COVID in hospitalized patients will help clinical management of COVID-19, but there is still no reliable and effective prediction model. METHODS: A total of 1905 hospitalized patients with COVID-19 infection were included in this study, and their Long COVID status was followed up 4-8 weeks after discharge. Univariable and multivariable logistic regression analysis were used to determine the risk factors for Long COVID. Patients were randomly divided into a training cohort (70%) and a validation cohort (30%), and factors for constructing the model were screened using Lasso regression in the training cohort. Visualize the Long COVID risk prediction model using nomogram. Evaluate the performance of the model in the training and validation cohort using the area under the curve (AUC), calibration curve, and decision curve analysis (DCA). RESULTS: A total of 657 patients (34.5%) reported that they had symptoms of long COVID. The most common symptoms were fatigue or muscle weakness (16.8%), followed by sleep difficulties (11.1%) and cough (9.5%). The risk prediction nomogram of age, diabetes, chronic kidney disease, vaccination status, procalcitonin, leukocytes, lymphocytes, interleukin-6 and D-dimer were included for early identification of high-risk patients with Long COVID. AUCs of the model in the training cohort and validation cohort are 0.762 and 0.713, respectively, demonstrating relatively high discrimination of the model. The calibration curve further substantiated the proximity of the nomogram's predicted outcomes to the ideal curve, the consistency between the predicted outcomes and the actual outcomes, and the potential benefits for all patients as indicated by DCA. This observation was further validated in the validation cohort. CONCLUSIONS: We established a nomogram model to predict the long COVID risk of hospitalized patients with COVID-19, and proved its relatively good predictive performance. This model is helpful for the clinical management of long COVID.

Phyllanthus emblica fruit extract alleviates halitosis and reduces the inflammatory response to oral bacteria.

OBJECTIVE: To assess the efficacy of Phyllanthus emblica extract in alleviating halitosis and reducing the inflammatory response to halitosis-related bacteria. METHODOLOGY: This investigation, using Phyllanthus emblica fruit extract (PE), involved four aspects. First, we evaluated the effect on growth and aggregation of halitosis-related bacteria, including Fusobacterium nucleatum, Porphyromonas gingivalis, and Solobacterium moorei, using a microdilution assay and scanning electron microscopy. Second, volatile sulfur compound (VSC) levels were measured on individuals with halitosis in randomized short-term (26 participants) and double-blind randomized long-term trials (18 participants in each group) after rinsing with PE for 3, 6, and 12 h, and 28 days. Third, we analyzed pro-inflammatory cytokine expression in TR146 cells using quantitative real-time PCR and enzyme-linked immunosorbent assays. Lastly, we assessed pro-inflammatory cytokine secretion and Toll-like receptor (TLR) 2 mRNA expression via the same experimental methods in a three-dimensional oral mucosal epithelial model (3D OMEM). RESULTS: PE extract dose-dependently inhibited the growth of F. nucleatum (50% inhibition concentration [IC50]=0.079%), P. gingivalis (IC50=0.65%), and S. moorei (IC50=0.07%) and effectively prevented bacterial aggregation. Furthermore, VSC contents decreased significantly at 3, 6, and 12 h after rinsing with 5% PE compared with those in the control. Long-term use of mouthwash containing 5% PE for 28 days led to a significant decrease in VSC contents. PE attenuated the F. nucleatum- or P. gingivalis-stimulated mRNA expression and protein release of interleukin (IL)-6 and IL-8 in TR146 cells. It also suppressed IL-8 and prostaglandin E2 secretion and TLR2 mRNA expression in F. nucleatum-induced OMEMs. CONCLUSION: Our findings support the use of PE in oral care products to alleviate halitosis and it may reduce inflammation.