Clinical efficacy and immune response of neoadjuvant camrelizumab plus chemotherapy in resectable locally advanced oesophageal squamous cell carcinoma: a phase 2 trial.

BACKGROUND: Neoadjuvant immunotherapy is under intensive investigation for esophageal squamous cell carcinoma (ESCC). This study assesses the efficacy and immune response of neoadjuvant immunochemotherapy (nICT) in ESCC. METHODS: In this phase II trial (ChiCTR2100045722), locally advanced ESCC patients receiving nICT were enrolled. The primary endpoint was the pathological complete response (pCR) rate. Multiplexed immunofluorescence, RNA-seq and TCR-seq were conducted to explore the immune response underlying nICT. RESULTS: Totally 42 patients were enrolled, achieving a 27.0% pCR rate. The 1-year, 2-year DFS and OS rates were 89.2%, 64.4% and 97.3%, 89.2%, respectively. RNA-seq analysis highlighted T-cell activation as the most significantly enriched pathway. The tumour immune microenvironment (TIME) was characterised by high CD4, CD8, Foxp3, and PD-L1 levels, associating with better pathological regression (TRS0/1). TIME was categorised into immune-infiltrating, immune-tolerant, and immune-desert types. Notably, the immune-infiltrating type and tertiary lymphoid structures correlated with improved outcomes. In the context of nICT, TIM-3 negatively influenced treatment efficacy, while elevated TIGIT/PD-1 expression post-nICT correlated positively with CD8+ T cell levels. TCR-seq identified three TCR rearrangements, underscoring the specificity of T-cell responses. CONCLUSIONS: Neoadjuvant camrelizumab plus chemotherapy is effective for locally advanced, resectable ESCC, eliciting profound immune response that closely associated with clinical outcomes.

Association between gut microbiota and seven gastrointestinal diseases: A Mendelian randomized study.

BACKGROUND: Observational research has shed light on the ability of gut microbes to influence the onset and progression of gastrointestinal diseases. The causal relationships between specific gut microbiomes and various gastrointestinal conditions, however, remain unknown. METHODS: We investigated the relationship between gut microbiota and seven specific gastrointestinal disorders using a robust two-sample Mendelian randomization (MR) approach. The inverse variance-weighted (IVW) method was used as the primary analysis tool in our study. Furthermore, we conducted multiple sensitivity analyses to strengthen the robustness of our findings and ensure the reliability of the IVW method. RESULTS: Our research has discovered significant links between the composition of gut microbiota and a variety of gastrointestinal ailments. We found compelling links between 13 gut microbiota and fatty liver, four gut microbiota and cirrhosis, eight gut microbiota and hepatocellular carcinoma, four gut microbiota and cholelithiasis, 12 gut microbiota and acute pancreatitis, eight gut microbiota and chronic pancreatitis, and 11 gut microbiota and pancreatic cancer. These findings shed light on the intricate relationship between gut microbes and the emergence of these specific gastrointestinal conditions. CONCLUSIONS: The findings of this extensive study not only validate the potential role of specific gut microbiota in gastrointestinal diseases, but also fill a critical gap in previous research. The discovery of these specific gut microbiota is a significant step forward because they may serve as novel and promising biomarkers for both the prevention and treatment of gastrointestinal conditions.

Renal Clearable Nanodots-Engineered Erythrocytes with Enhanced Circulation and Tumor Accumulation for Photothermal Therapy of Hepatocellular Carcinoma.

Living cell-mediated nanodelivery system is considered a promising candidate for targeted antitumor therapy; however, their use is restricted by the adverse interactions between carrier cells and nanocargos. Herein, a novel erythrocyte-based nanodelivery system is developed by assembling renal-clearable copper sulfide (CuS) nanodots on the outer membranes of erythrocytes via a lipid fusion approach, and demonstrate that it is an efficient photothermal platform against hepatocellular carcinoma. After intravenous injection of the nanodelivery system, CuS nanodots assembled on erythrocytes can be released from the system, accumulate in tumors in response to the high shear stress of bloodstream, and show excellent photothermal antitumor effect under the near infrared laser irradiation. Therefore, the erythrocyte-mediated nanodelivery system holds many advantages including prolonged blood circulation duration and enhanced tumor accumulation. Significantly, the elimination half-life of the nanodelivery system is 74.75 ± 8.77 h, which is much longer than that of nanodots (33.56 ± 2.36 h). Moreover, the other two kinds of nanodots can be well assembled onto erythrocytes to produce other erythrocyte-based hitchhiking platforms. Together, the findings promote not only the development of novel erythrocyte-based nanodelivery systems as potential platforms for tumor treatment but also their further clinical translation toward personalized healthcare.

Exclusive and Switchable Superoxide Radical Generation by O2-Capture-Based Electron Transfer and Supramolecular Assembly.

Type-I photosensitizers (PSs) can generate free radical anions with a broad diffusion range and powerful damage effect, rendering them highly desirable in various areas. However, it still remains a recognized challenge to develop pure Type-I PSs due to the inefficiency in producing oxygen radical anions through the collision of PSs with nearby substrates. In addition, regulating the generation of oxygen radical anions is also of great importance toward the control of photosensitizer (PS) activities on demand. Herein, a piperazine-based cationic Type-I PS (PPE-DPI) that exhibits efficient intersystem crossing and subsequently captures oxygen molecules through binding O2 to the lone pair of nitrogen in piperazine is reported. The close spatial vicinity between O2 and PPE-DPI strongly promotes the electron transfer reaction, ensuring the exclusive superoxide radical (O2 •-) generation via Type-I process. Particularly, PPE-DPI with cationic pyridine groups is able to associate with cucurbit[7]uril (CB[7]) through host-guest interactions. Thus, supramolecular assembly and disassembly are easily utilized to realize switchable O2 •- generation. This switchable Type-I PS is successfully employed in photodynamic antibacterial control.

Phosphorylation of VP1 Mediated by CDK1-Cyclin B1 Facilitates Infectious Bursal Disease Virus Replication.

Infectious bursal disease virus (IBDV) is a double-stranded RNA (dsRNA) virus belonging to the genus Avibirnavirus in the family Birnaviridae. It can cause serious failure of vaccination in young poultry birds with impaired immune systems. Post-translational modifications of the VP1 protein are essential for viral RNA transcription, genome replication, and viral multiplication. Little information is available so far regarding the exact mechanism of phosphorylation of IBDV VP1 and its significance in the viral life cycle. Here, we provide several lines of evidence that the cyclin-dependent kinase 1 (CDK1)-cyclin B1 complex phosphorylates VP1, which facilitates viral replication. We show that the CDK1-cyclin B1 specifically interacts with VP1 and phosphorylates VP1 on the serine 7 residue, located in the N-terminal 7SPAQ10 region, which follows the optimal phosphorylation motif of CDK1, p-S/T-P. Additionally, IBDV infection drives the cytoplasmic accumulation of CDK1-cyclin B1, which co-localizes with VP1, supporting the kinase activity of CDK1-cyclin B1. Treatment with CDK1 inhibitor RO3306 and knockdown of CDK1-cyclin B1 severely disrupts the polymerase activity of VP1, resulting in diminished viral replication. Moreover, the replication of S7A mutant recombinant IBDV was significantly decreased compared to that of wild-type (WT) IBDV. Thus, CDK1-cyclin B1 is a crucial enzyme which phosphorylates IBDV VP1 on serine 7, which is necessary both for the polymerase activity of VP1 and for viral replication. IMPORTANCE Infectious bursal disease virus still poses a great economic threat to the global poultry farming industry. Detailed information on the steps of viral genome replication is essential for the development of antiviral therapeutics. Phosphorylation is a common post-translational modification in several viral proteins. There is a lack of information regarding the significance of VP1 phosphorylation and its role in modulating the viral life cycle. In this study, we found that CDK1-cyclin B1 accumulates in the cytoplasm and phosphorylates VP1 on serine 7. The presence of a CDK1 inhibitor and the silencing of CDK1-cyclin B1 decrease IBDV replication. The mutation of VP1 serine 7 to alanine reduces VP1 polymerase activity, disrupting the viral life cycle, which suggests that this residue serves an essential function. Our study offers novel insights into the regulatory mechanism of VP1 phosphorylation.

Preoperative short-course radiotherapy followed by chemotherapy and PD-1 inhibitor administration for locally advanced rectal cancer: A study protocol of a randomized phase II/III trial (STELLAR II study).

AIM: For patients with locally advanced rectal cancer, previous STELLAR studies have shown that a new adjuvant treatment paradigm of short-course radiotherapy followed by neoadjuvant chemotherapy can achieve pathological complete response rates superior to those of standard care; however, the 3-year DFS is inferior to neoadjuvant concurrent radiotherapy. Recent studies have shown that immune checkpoint inhibitors may improve the prognosis of rectal cancer and have good synergy with radiotherapy. Therefore, neoadjuvant chemotherapy combined with immune checkpoint inhibitors after a short course of radiotherapy has the potential to further improve complete response rates and prognosis. METHOD: The STELLAR II study is a multicentre, open label, two-arm randomized, phase II/III trial of short-course radiotherapy followed by neoadjuvant chemotherapy concurrent with immunotherapy for locally advanced rectal cancer. A total of 588 patients with locally advanced rectal cancer (LARC) will be randomly assigned to the experimental and control groups. The experimental group will receive short-course radiotherapy and neoadjuvant chemotherapy in combination with sindilizumab, while the control group will receive short-course radiotherapy and neoadjuvant chemotherapy. Both groups will subsequently receive either total rectal mesenteric resection or a watch & wait (W&W) strategy. The phase II primary endpoint is the complete remission rate, and the secondary endpoints include grade 3-4 adverse events, perioperative complications, R0 resection rate, overall survival, local recurrence rate, distant metastasis rate and quality of life score. A seamless phase II/III randomized controlled design will be used to investigate the effectiveness and safety of the TNT strategy with the addition of immunotherapy. The trial opened, and the first patient was recruited on 31 August 2022. Trial registration number and date of registration: ClinicalTrials.gov NCT05484024, 29 July 2022. DISCUSSION: The STELLAR II trial will prospectively evaluate the efficacy of TNT treatment strategies that incorporate immune checkpoint inhibitors. The trial will yield important information to guide routine management of patients with local advanced rectal cancer.

The changing health effects of air pollution exposure for respiratory diseases: a multicity study during 2017-2022.

BACKGROUND: Multifaceted SARS-CoV-2 interventions have modified exposure to air pollution and dynamics of respiratory diseases. Identifying the most vulnerable individuals requires effort to build a complete picture of the dynamic health effects of air pollution exposure, accounting for disparities across population subgroups. METHODS: We use generalized additive model to assess the likely changes in the hospitalisation and mortality rate as a result of exposure to PM2.5 and O3 over the course of COVID-19 pandemic. We further disaggregate the population into detailed age categories and illustrate a shifting age profile of high-risk population groups. Additionally, we apply multivariable logistic regression to integrate demographic, socioeconomic and climatic characteristics with the pollution-related excess risk. RESULTS: Overall, a total of 1,051,893 hospital admissions and 34,954 mortality for respiratory disease are recorded. The findings demonstrate a transition in the association between air pollutants and hospitalisation rates over time. For every 10 µg/m3 increase of PM2.5, the rate of hospital admission increased by 0.2% (95% CI: 0.1-0.7%) and 1.4% (1.0-1.7%) in the pre-pandemic and dynamic zero-COVID stage, respectively. Conversely, O3-related hospitalization rate would be increased by 0.7% (0.5-0.9%) in the pre-pandemic stage but lowered to 1.7% (1.5-1.9%) in the dynamic zero-COVID stage. Further assessment indicates a shift of high-risk people from children and young adolescents to the old, primarily the elevated hospitalization rates among the old people in Lianyungang (RR: 1.53, 95%CI: 1.46, 1.60) and Nantong (RR: 1.65, 95%CI: 1.57, 1.72) relative to those for children and young adolescents. Over the course of our study period, people with underlying diseases would have 26.5% (22.8-30.3%) and 12.7% (10.8-14.6%) higher odds of having longer hospitalisation and over 6 times higher odds of deaths after hospitalisation. CONCLUSIONS: Our estimates provide the first comprehensive evidence on the dynamic pollution-health associations throughout the pandemic. The results suggest that age and underlying diseases collectively determines the disparities of pollution-related health effect across population subgroups, underscoring the urgency to identifying the most vulnerable individuals to air pollution.

Kindlin-2 controls angiogenesis through modulating Notch1 signaling.

Kindlin-2 is critical for development and homeostasis of key organs, including skeleton, liver, islet, etc., yet its role in modulating angiogenesis is unknown. Here, we report that sufficient KINDLIN-2 is extremely important for NOTCH-mediated physiological angiogenesis. The expression of KINDLIN-2 in HUVECs is significantly modulated by angiogenic factors such as vascular endothelial growth factor A or tumor necrosis factor α. A strong co-localization of CD31 and Kindlin-2 in tissue sections is demonstrated by immunofluorescence staining. Endothelial-cell-specific Kindlin-2 deletion embryos die on E10.5 due to hemorrhage caused by the impaired physiological angiogenesis. Experiments in vitro show that vascular endothelial growth factor A-induced multiple functions of endothelial cells, including migration, matrix proteolysis, morphogenesis and sprouting, are all strengthened by KINDLIN-2 overexpression and severely impaired in the absence of KINDLIN-2. Mechanistically, we demonstrate that KINDLIN-2 inhibits the release of Notch intracellular domain through binding to and maintaining the integrity of NOTCH1. The impaired angiogenesis and avascular retinas caused by KINDLIN-2 deficiency can be rescued by DAPT, an inhibitor of γ-secretase which releases the intracellular domain from NOTCH1. Moreover, we demonstrate that high glucose stimulated hyperactive angiogenesis by increasing KINDLIN-2 expression could be prevented by KINDLIN-2 knockdown, indicating Kindlin-2 as a potential therapeutic target in treatment of diabetic retinopathy. Our study for the first time demonstrates the significance of Kindlin-2 in determining Notch-mediated angiogenesis during development and highlights Kindlin-2 as the potential therapeutic target in angiogenic diseases, such as diabetic retinopathy.

A Novel Active Learning Framework for Cross-Subject Human Activity Recognition from Surface Electromyography.

Wearable sensor-based human activity recognition (HAR) methods hold considerable promise for upper-level control in exoskeleton systems. However, such methods tend to overlook the critical role of data quality and still encounter challenges in cross-subject adaptation. To address this, we propose an active learning framework that integrates the relation network architecture with data sampling techniques. Initially, target data are used to fine tune two auxiliary classifiers of the pre-trained model, thereby establishing subject-specific classification boundaries. Subsequently, we assess the significance of the target data based on classifier discrepancy and partition the data into sample and template sets. Finally, the sampled data and a category clustering algorithm are employed to tune model parameters and optimize template data distribution, respectively. This approach facilitates the adaptation of the model to the target subject, enhancing both accuracy and generalizability. To evaluate the effectiveness of the proposed adaptation framework, we conducted evaluation experiments on a public dataset and a self-constructed electromyography (EMG) dataset. Experimental results demonstrate that our method outperforms the compared methods across all three statistical metrics. Furthermore, ablation experiments highlight the necessity of data screening. Our work underscores the practical feasibility of implementing user-independent HAR methods in exoskeleton control systems.

Differences in networks of alexithymia and cognitive emotion regulation strategies among older adults with different health statuses in eastern China-A network analysis and network comparison.

To identify core and bridge nodes in the network structure of alexithymia and cognitive emotion regulation strategies in community-dwelling older adults, and compare network differences among older adults with different health statuses, we recruited 677 participants and network analysis was performed in R 4.2.0. After including the covariates, the nodes Catastrophizing, Difficulty Identifying feelings, and Refocusing on Planning ranked as the top three. The nodes Externally Oriented Thoughts and Difficulty Identifying Feelings were identified as bridge nodes based on bridge strength values. Significant differences were observed between the healthy and comorbidity groups, and also between the single chronic disease and comorbidity groups (p < 0.05). Catastrophizing, Difficulty Identifying Feelings, and Refocusing on Planning were the core nodes, and Externally Oriented Thoughts and Difficulty Identifying Feelings were the key bridge nodes. The network structure of comorbidity in older adults was characterized by stronger ties to non-adaptive cognitive emotion regulation strategies.

Evaluation of malnutrition by objective nutritional indexes and predictors in hospitalized patients with COVID-19.

Nutritional information on hospitalized patients with COVID-19 is limited. We aimed to (1) investigate the prevalence of nutrition risk defined by the Scored Nutritional Risk Screening (NRS 2002) and malnutrition assessed by prognostic nutritional index (PNI) and controlling nutritional status score (CONUT), (2) observe the nutritional intervention, and (3) explore the predictors of critical condition and mortality. Nutritional risk was 53.00% and the prevalence of malnutrition was 79.09% and 88.79% among 464 patients based on PNI and CONUT, respectively. The area under the receiver operating characteristic curve for hypersensitivity C-reactive protein (hs-CRP), platelet-to-lymphocyte ratio (PLR), PNI, neutrophil/lymphocyte ratio (NLR), systemic immune-inflammation index (SII), and CONUT were 0.714, 0.677, 0.243, 0.778, 0.742, and 0.743, respectively, in discerning critical patients. The mortality-related area under the curve of hs-CRP, PLR, PNI, NLR, SII, and CONUT were 0.740, 0.647, 0.247, 0.814, 0.758, and 0.767, respectively. The results showed that CONUT and NLR were significantly correlated with the critical conditions. Our study revealed a high prevalence of nutritional risk and malnutrition among hospitalized patients with COVID-19. NLR, PLR, hs-CRP, SII, and CONUT are independent predictors of critical conditions and mortality. CONUT and NLR could assist clinicians in discerning critical cases.

Nutritional status and body composition of patients with head and neck cancer treated with perioperative evidence-based nutritional management.

We aimed to describe nutritional status and body composition profiles perioperative head and neck cancer (HNC) patients managed with whole-course nutritional support. Scored Nutritional Risk Screening (NRS 2002), Patient-Generated Subjective Global Assessment (PG-SGA), and body composition were conducted. The factors related to weight loss and skeletal muscle mass (SMM) were identified. Lower weight and body composition levels in low skeletal muscle index (SMI≤9.90 kg/m2) group were observed. Levels of albumin, prealbumin, prognostic nutritional index (PNI), and lymphocyte-to-monocyte ratio (LMR) were lower than pre-operative, but the values after 2 weeks were higher than 1 week post-operatively (all p<0.01). The neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) were increased at 1 and 2 weeks post-operative compared to pre-operative (both p<0.01). Post-operatively, NLR at 2 weeks was lowed than 1 week (p = 0.02). A negative correlation was observed between SMM loss and serum prealbumin (r = -0.255, p = 0.029). Pre-operative BMI (p<0.01), tumor differentiation (p = 0.003), and nutritional risk (p = 0.049) were risk factors for weight loss. In conclusions, for perioperative HNC patients, loss of adipose tissue occurred earlier than muscle. Prealbumin should be considered as an indicator for monitoring of recovery in clinical practice.

Porcine Epidemic Diarrhea Virus nsp7 Inhibits Interferon-Induced JAK-STAT Signaling through Sequestering the Interaction between KPNA1 and STAT1.

Porcine epidemic diarrhea virus (PEDV) is a highly pathogenic enteric coronavirus that causes high mortality in piglets. Interferon (IFN) responses are the primary defense mechanism against viral infection; however, viruses always evolve elaborate strategies to antagonize the antiviral action of IFN. Previous study showed that PEDV nonstructural protein 7 (nsp7), a component of the viral replicase polyprotein, can antagonize ploy(I:C)-induced type I IFN production. Here, we found that PEDV nsp7 also antagonized IFN-α-induced JAK-STAT signaling and the production of IFN-stimulated genes. PEDV nsp7 did not affect the protein and phosphorylation levels of JAK1, Tyk2, STAT1, and STAT2 or the formation of the interferon-stimulated gene factor 3 (ISGF3) complex. However, PEDV nsp7 prevented the nuclear translocation of STAT1 and STAT2. Mechanistically, PEDV nsp7 interacted with the DNA binding domain of STAT1/STAT2, which sequestered the interaction between karyopherin α1 (KPNA1) and STAT1, thereby blocking the nuclear transport of ISGF3. Collectively, these data reveal a new mechanism developed by PEDV to inhibit type I IFN signaling pathway. IMPORTANCE In recent years, an emerging porcine epidemic diarrhea virus (PEDV) variant has gained attention because of serious outbreaks of piglet diarrhea in China and the United States. Coronavirus nonstructural protein 7 (nsp7) has been proposed to act with nsp8 as part of an RNA primase to generate RNA primers for viral RNA synthesis. However, accumulating evidence indicates that coronavirus nsp7 can also antagonize type I IFN production. Our present study extends previous findings and demonstrates that PEDV nsp7 also antagonizes IFN-α-induced IFN signaling by competing with KPNA1 for binding to STAT1, thereby enriching the immune regulation function of coronavirus nsp7.

Effects of Lianhuaqingwen Capsules in adults with mild-to-moderate coronavirus disease 2019: an international, multicenter, double-blind, randomized controlled trial.

BACKGROUND: In a randomized trial, Lianhuaqingwen (LHQW) capsule was effective for accelerating symptom recovery among patients with coronavirus disease 2019 (COVID-19). However, the lack of blinding and limited sample sizes decreased the level of clinical evidence. OBJECTIVES: To evaluate the efficacy and safety of LHQW capsule in adults with mild-to-moderate COVID-19. METHODS: We conducted a double-blind randomized controlled trial in adults with mild-to-moderate COVID-19 (17 sites from China, Thailand, Philippine and Vietnam). Patients received standard-of-care alone or plus LHQW capsules (4 capsules, thrice daily) for 14 days. The primary endpoint was the median time to sustained clinical improvement or resolution of nine major symptoms. RESULTS: The full-analysis set consisted of 410 patients in LHQW capsules and 405 in placebo group. LHQW significantly shortened the primary endpoint in the full-analysis set (4.0 vs. 6.7 days, hazards ratio: 1.63, 95% confidence interval: 1.39-1.90). LHQW capsules shortened the median time to sustained clinical improvement or resolution of stuffy or runny nose (2.8 vs. 3.7 days), sore throat (2.0 vs. 2.6 days), cough (3.2 vs. 4.9 days), feeling hot or feverish (1.0 vs. 1.3 days), low energy or tiredness (1.3 vs. 1.9 days), and myalgia (1.5 vs. 2.0 days). The duration to sustained clinical improvement or resolution of shortness of breath, headache, and chills or shivering did not differ significantly between the two groups. Safety was comparable between the two groups. No serious adverse events were reported. INTERPRETATION: LHQW capsules promote recovery of mild-to-moderate COVID-19 via accelerating symptom resolution and were well tolerated. Trial registration ChiCTR2200056727 .

The E3 ubiquitin ligase TRIM31 attenuates NLRP3 inflammasome activation in Helicobacter pylori-associated gastritis by regulating ROS and autophagy.

BACKGROUND: The NLRP3 inflammasome activation is the molecular basis of Helicobacter pylori (Hp)-associated gastritis. Tripartite motif (TRIM) 31 is involved in diverse pathological events. However, whether TRIM31 plays a role in the activation of NLRP3 inflammasome in Hp infection is not clarified. METHODS: A mouse model of chronic Hp infection was established, and the gastric tissues were subjected to the polymerase chain reaction, western blotting, histopathological analysis, and RNA sequencing. The mitochondrial membrane potential and ROS in the human gastric epithelium GES-1 cells with or without Hp infection were measured by flow cytometry. GES-1 cells with or without TRIM31 knockdown were transfected with mCherry-EGFP-LC3 adenovirus. After rapamycin and bafilomycin A1 stimulation, autophagy flux in the above primed GES-1 cells was assessed by laser confocal microscope. Lysosomal acidification and expression levels of cathepsin B and cathepsin D in GES-1 cells with Hp infection were measured. RESULTS: NLRP3 inflammasome was activated in the gastric tissues of mice with chronic Hp infection in vivo and the GES-1 cells with Hp infection in vitro. TRIM31 was downregulated in Hp infection. TRIM31 negatively regulated the NLRP3 inflammasome activation. Enhanced ROS, impaired autophagy flux, and decreased expression of lysosomal cathepsin B and cathepsin D were observed in TRIM31-deficient GES-1 cells with Hp infection. In turn, inhibition of ROS led to the decreased expression of NLRP3 inflammasome. CONCLUSIONS: Together, our data identified that TRIM31 negatively regulated the activation of NLRP3 inflammasome in Hp-associated gastritis by affecting ROS and autophagy of gastric epithelial cells. Video abstract.

Artificial intelligence-based diagnosis of abnormalities in small-bowel capsule endoscopy.

BACKGROUND : Further development of deep learning-based artificial intelligence (AI) technology to automatically diagnose multiple abnormalities in small-bowel capsule endoscopy (SBCE) videos is necessary. We aimed to develop an AI model, to compare its diagnostic performance with doctors of different experience levels, and to further evaluate its auxiliary role for doctors in diagnosing multiple abnormalities in SBCE videos. METHODS : The AI model was trained using 280 426 images from 2565 patients, and the diagnostic performance was validated in 240 videos. RESULTS : The sensitivity of the AI model for red spots, inflammation, blood content, vascular lesions, protruding lesions, parasites, diverticulum, and normal variants was 97.8 %, 96.1 %, 96.1 %, 94.7 %, 95.6 %, 100 %, 100 %, and 96.4 %, respectively. The specificity was 86.0 %, 75.3 %, 87.3 %, 77.8 %, 67.7 %, 97.5 %, 91.2 %, and 81.3 %, respectively. The accuracy was 95.0 %, 88.8 %, 89.2 %, 79.2 %, 80.8 %, 97.5 %, 91.3 %, and 93.3 %, respectively. For junior doctors, the assistance of the AI model increased the overall accuracy from 85.5 % to 97.9 % (P  < 0.001, Bonferroni corrected), comparable to that of experts (96.6 %, P > 0.0125, Bonferroni corrected). CONCLUSIONS : This well-trained AI diagnostic model automatically diagnosed multiple small-bowel abnormalities simultaneously based on video-level recognition, with potential as an excellent auxiliary system for less-experienced endoscopists.

Application of artificial intelligence to digital-rapid on-site cytopathology evaluation during endoscopic ultrasound-guided fine needle aspiration: A proof-of-concept study.

BACKGROUND: During endoscopic ultrasound-guided fine needle aspiration (EUS-FNA), cytopathology with rapid on-site evaluation (ROSE) can improve diagnostic yield and accuracy. However, ROSE is unavailable in most Asian and European institutions because of the shortage of cytopathologists. Therefore, developing computer-assisted diagnostic tools to replace manual ROSE is crucial. Herein, we reported the validation of an artificial intelligence (AI)-based model (ROSE-AI model) to substitute manual ROSE during EUS-FNA. METHODS: A total of 467 digitized images from Diff-Quik (D&F)-stained EUS-FNA slides were divided into training (3642 tiles from 367 images) and internal validation (916 tiles from 100 images) datasets. The ROSE-AI model was trained and validated using training and internal validation datasets, respectively. The specificity was emphasized while developing the model. Then, we evaluated the AI model on a 693-image external dataset. We assessed the performance of the AI model to detect cancer cells (CCs) regarding the accuracy, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). RESULTS: The ROSE-AI model achieved an accuracy of 83.4% in the internal validation dataset and 88.7% in the external test dataset. The sensitivity and PPV were 79.1% and 71.7% in internal validation dataset and 78.0% and 60.7% in external test dataset, respectively. CONCLUSION: We provided a proof of concept that AI can be used to replace manual ROSE during EUS-FNA. The ROSE-AI model can address the shortage of cytopathologists and make ROSE available in more institutes.

Proanthocyanidins suppress NLRP3 inflammasome and M1 macrophage polarization to alleviate severe acute pancreatitis in mice.

The role of reactive oxygen species (ROS) is crucial for the pathogenesis of acute pancreatitis (AP). Proanthocyanidins (PAs) have been confirmed to exert antioxidant activity. Our study aimed to determine whether PAs alleviated SAP via reducing ROS, suppressing NLRP3 inflammasome, and inhibiting M1 macrophage polarization. Our study investigated the protective effects of PAs on pancreatic histopathological injury using SAP mice. The effects of PAs on macrophages were investigated in inflammatory RAW 264.7 cells or mouse bone marrow-derived macrophages (BMDMs) induced by lipopolysaccharide (LPS). Immunofluorescence staining and/or western blot assay were employed to evaluate NLRP3 inflammasome in macrophages and pancreatic tissue. Cell counting kit-8 (CCK-8) was used to access effects of PAs on cell viability and cytometry flow was used to determine the effects of the PAs on the ROS levels of the RAW 264.7 cells. Then, we evaluated M1 macrophage polarization using flow cytometry or real-time quantitative polymerase chain reaction (RT-qPCR). PAs administration alleviated pancreatic inflammation in SAP mice. The PAs depressed NLRP3 inflammasome and inhibited M1 macrophage polarization in pancreatic tissue. We also found that the PAs showed no cellular toxicity but decreased ROS levels in RAW 264.7 cells, downregulated the NLRP3 inflammasome in the macrophages, and inhibited cell M1 macrophage polarization. Our study indicates the anti-inflammatory properties of the PAs on SAP mice by decreasing ROS levels, suppressing NLRP3 inflammasome, and M1 macrophage polarization.

Geographical variation in the effect of ambient temperature on infectious diarrhea among children under 5 years.

Understanding the geographical distribution in the association of temperature with childhood diarrhea can assist in formulating effective localized diarrhea prevention practices. This study aimed to identify the geographical variation in terms of temperature thresholds, lag effects, and attributable fraction (AF) in the effects of ambient temperature on Class C Other Infectious Diarrhea (OID) among children <5 years in Jiangsu Province, China. Daily data of OID cases and meteorological variables from 2015 to 2019 were collected. City-specific minimum morbidity temperature (MMT), increasing risk temperature (IRT), maximum risk temperature (MRT), maximum risk lag day (MRD), and lag day duration (LDD) were identified as risk indicators for the temperature-OID relationship using distributed lag non-linear models. The AF of OID incidence due to temperature was evaluated. Multivariable regression was also applied to explore the underlying modifiers of the AF. The geographical distributions of MMT, IRT, and MRT generally decreased with the latitude increment varying between 22.3-34.7 °C, -2.9-18.1 °C, and -6.8-23.2 °C. Considerable variation was shown in the AF ranging from 0.2 to 8.5%, and the AF significantly increased with latitude (95% confidence interval (CI): -3.458, -0.987) and economic status decrement (95% CI: -0.161, -0.019). Our study demonstrated between-city variations in the association of temperature with OID, which should be considered in the localized clinical and public health practices to decrease the incidence of childhood diarrhea.

Perioperative and oncologic outcomes of laparoscopic versus open liver resection for combined hepatocellular-cholangiocarcinoma: a propensity score matching analysis.

BACKGROUND: Laparoscopic liver resection (LLR) has now been established as a safe and minimally invasive technique that is deemed feasible for treating hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). However, the role of LLR in treating combined hepatocellular-cholangiocarcinoma (cHCC-CC) patients has been rarely reported. This study aimed to assess the efficacy of LLR when compared with open liver resection (OLR) procedure for patients with cHCC-CC. METHODS: A total of 229 cHCC-CC patients who underwent hepatic resection (34 LLR and 195 OLR patients) from January 2014 to December 2018 in Zhongshan Hospital, Fudan University were enrolled and underwent a 1:2 propensity score matching (PSM) analysis between the LLR and OLR groups to compare perioperative and oncologic outcomes. Overall survival (OS) and recurrence-free survival (RFS) parameters were assessed by the log-rank test and the sensitivity analysis. RESULTS: A total of 34 LLR and 68 OLR patients were included after PSM analysis. The LLR group displayed a shorter postoperative hospital stay (6.61 vs. 8.26 days; p value < 0.001) when compared with the OLR group. No significant differences were observed in the postoperative complications' incidence or a negative surgical margin rate between the two groups (p value = 0.409 and p value = 1.000, respectively). The aspartate aminotransferase (AST), alanine aminotransferase (ALT), and inflammatory indicators in the LLR group were significantly lower than those in the OLR group on the first and third postoperative days. Additionally, OS and RFS were comparable in both the LLR and OLR groups (p value = 0.700 and p value = 0.780, respectively), and similar results were obtained by conducting a sensitivity analysis. CONCLUSION: LLR can impart less liver function damage, better inflammatory response attenuation contributing to a faster recovery, and parallel oncologic outcomes when compared with OLR. Therefore, LLR can be recommended as a safe and effective therapeutic modality for treating selected cHCC-CC patients, especially for those with small tumors in favorable location.