FFMAVP: a new classifier based on feature fusion and multitask learning for identifying antiviral peptides and their subclasses.

Antiviral peptides (AVPs) are widely found in animals and plants, with high specificity and strong sensitivity to drug-resistant viruses. However, due to the great heterogeneity of different viruses, most of the AVPs have specific antiviral activities. Therefore, it is necessary to identify the specific activities of AVPs on virus types. Most existing studies only identify AVPs, with only a few studies identifying subclasses by training multiple binary classifiers. We develop a two-stage prediction tool named FFMAVP that can simultaneously predict AVPs and their subclasses. In the first stage, we identify whether a peptide is AVP or not. In the second stage, we predict the six virus families and eight species specifically targeted by AVPs based on two multiclass tasks. Specifically, the feature extraction module in the two-stage task of FFMAVP adopts the same neural network structure, in which one branch extracts features based on amino acid feature descriptors and the other branch extracts sequence features. Then, the two types of features are fused for the following task. Considering the correlation between the two tasks of the second stage, a multitask learning model is constructed to improve the effectiveness of the two multiclass tasks. In addition, to improve the effectiveness of the second stage, the network parameters trained through the first-stage data are used to initialize the network parameters in the second stage. As a demonstration, the cross-validation results, independent test results and visualization results show that FFMAVP achieves great advantages in both stages.

Effect of Premedication With Pronase Before Upper Gastrointestinal Endoscopy: A Multicenter Prospective Randomized Controlled Study.

OBJECTIVES: This study aimed to confirm whether premedication with pronase before endoscopy improves mucosal visualization and increases precancerous lesion and cancer lesion detection rates. MATERIALS AND METHODS: From June 2018 to April 2019, out-patients scheduled for endoscopy from 13 hospitals were screened to be randomly allocated in a 2:1 ratio to premedication with pronase (group A) and water (group B). The primary endpoint was mucosal visibility scores, and the secondary endpoint was precancerous and cancer lesion detection rates. This trial was registered at Chinese Clinical Trial Registry, and the registration number was ChiCTR1800016853. RESULTS: Group A showed significantly lower mucosal visibility scores (better mucosal visibility) of esophagus, stomach, and duodenum than group B, with all P -values <0.001. The overall cancer detection rates between group A and group B were 0.83 and 1.08%, and overall detection rates of precancerous and cancer lesion were 4.4 and 4.9%, both without significant difference ( P =1.000 and 0.824). In addition, the flushing volume (milliliter) of group A (10.52±23.41) was less than group B (36.30±52.11) ( P <0.001), and the flushing frequency of group A (0.46±1.01) was fewer than group B (1.62±2.12) ( P <0.001). CONCLUSIONS: Premedication with pronase could achieve better mucosal visibility and decrease flushing frequency and volume, but may not increase lesion detection rates.

Effectiveness and safety of vonoprazan-based regimens compared with those of proton pump inhibitor (PPI)-based regimens as first-line agents for Helicobacter pylori: a meta-analysis of randomized clinical trials.

PURPOSE: Vonoprazan (VPZ), a reversible H+-K+ ATPase inhibitor, has a relatively fast and sustained acid-suppression action that is unaffected by diet or gene polymorphisms. Several randomized controlled trials have evaluated the difference in the eradication rate of Helicobacter pylori (HP) between VPZ-based and proton pump inhibitor (PPI)-based regimens. The present review aimed to (1) evaluate the efficacy, safety, and compliance of VPZ-based regimens compared with those of PPI-based regimens as first-line treatments for HP infection and (2) perform a subgroup analysis to examine the influence of differences in clarithromycin-resistance status, treatment duration, treatment regimens, and research region on treatment outcomes. METHODS: We conducted a systematic literature search on PubMed, Embase, Cochrane Library, Web of Science, and ChiCTR Register. Systematic searches, study selection, data extraction, risk of bias assessment, and statistical analysis were performed according to pre-registered protocol on the PROSPERO (CRD42022336608). RESULTS: Eight studies and 2956 HP-infected patients were enrolled. Only first-line therapy and RCT study were considered. VPZ-based group had a superior eradication efficacy compared to PPI-based group by intention-to-treat (ITT) (pooled risk ratio (RR): 1.14, 95% CI: 1.08-1.21, p < 0.00001) and per-protocol analysis (pooled RR: 1.13, 95% CI: 1.07-1.20, p < 0.00001). This finding was further validated by subgroup analysis depending on treatment regimens, duration, region, and clarithromycin resistance. In addition, there was no significant difference in adverse events (p = 0.33) and compliances (p = 0.30) between the regimens. CONCLUSION: The VPZ-based regimens showed a superior eradication efficacy compared to the already frequently used PPI-based regimens. Furthermore, VPZ-based therapy showed comparable tolerability and incidence of adverse events.

Mental Health Among University Students, Using the 12-item General Health Questionnaire.

Context: To date, researchers have found that poor mental health was common during the COVID-19 epidemic. Even if they had been relatively resistant to suicidal ideation during the first three waves of the pandemic, university students may experience a delayed impact on their mental health. Objective: The study intended to measure mental health among university students in Wuhu City, China and to identify an effective approach to universities can use to prevent mental-health issues. Design: The research team performed a cross-sectional study. Setting: The study took place at Anhui polytechnic university, Wuhu, China. Participants: Participants were 2371 students at Anhui polytechnic university in Wuhu city, China. Outcome Measures: The research team used the two-item General Health Questionnaire-12 (GHQ-12) to measure participants' mental health. Results: Among the 2371 participants, 1727 had poor mental health (72.84%), including 843 males (48.81%) and 884 females (51.19%). Poor mental health was significantly associated with an urban residential location (P > .01), the female gender (p>0.01), the second school year (P > .01), and the parents' education level of junior high school or below (both P > .01). Conclusions: The current study suggests that poor mental health among university students is common. Being female, from an urban area, and in the second year of school and having parents with an education of junior high school or below had poorer mental health than those who were male, from the countryside, and in the first year of school and who had parents with a higher level of education.

Identification of critical quality factors and critical satisfaction gaps in emergency training courses for new nurses by the multi-criteria network structure model.

OBJECTIVE: To identify critical quality factors and critical satisfaction gaps in emergency training courses for new nurses through a systematic decision-making model. METHODS: Firstly, the service quality (SERVQUAL) was used in the evaluation index system of this study. Then, the decision-making trial and evaluation laboratory (DEMATEL) method was used to analyze the relationship structure and the corresponding weights between the indicators. Finally, the importance-performance analysis (IPA) method was used to identify the categories of all indicators and the corresponding strategic directions. Fifteen new nurses in Taizhou Hospital of Zhejiang Province were selected as participants in this study. RESULTS: The IPA results showed that "(C13)," "(C22)," "(C52)," "(C53)," "(C54)," "(C55)," "(C56),"and "(C57)" are critical satisfaction gaps. From the results of influence network and weight, empathy (C5) was the critical quality factor of the entire training course. The influence network relationship structure and weight had a 98.1% significant confidence level, indicating good stability. CONCLUSION: Teachers' empathy is key to the learning outcomes of new nurses in emergency nursing training courses. Hence, teachers should be attentive to the empathetic quality of their teaching methods to help new nurses gain knowledge and experience in emergency care, especially when they come from different professions and departments.

Development and validation of a radiomics signature as a non-invasive complementary predictor of gastroesophageal varices and high-risk varices in compensated advanced chronic liver disease: A multicenter study.

BACKGROUND AND AIM: Gastroesophageal varices (GEV) present in compensated advanced chronic liver disease (cACLD) and can develop into high-risk varices (HRV). The gold standard for diagnosing GEV is esophagogastroduodenoscopy (EGD). However, EGD is invasive and less tolerant. This study aimed to develop and validate radiomics signatures based on noncontrast-enhanced computed tomography (CT) images for non-invasive diagnosis of GEV and HRV in patients with cACLD. METHODS: The multicenter trial enrolled 161 patients with cACLD from six university hospitals in China between January 2015 and September 2019, who underwent both EGD and noncontrast-enhanced CT examination within 14 days prior to the endoscopy. Two radiomics signatures, termed rGEV and rHRV, respectively, were built based on CT images in a training cohort of 129 patients and validated in a prospective validation cohort of 32 patients (ClinicalTrials. gov identifier: NCT03749954). RESULTS: In the training cohort, both rGEV and rHRV exhibited high discriminative abilities on determining the existence of GEV and HRV with the area under receiver operating characteristic curve (AUC) of 0.941 (95% confidence interval [CI] 0.904-0.978) and 0.836 (95% CI 0.766-0.905), respectively. In validation cohort, rGEV and rHRV showed high discriminative abilities with AUCs of 0.871 (95% CI 0.739-1.000) and 0.831 (95% CI 0.685-0.978), respectively. CONCLUSIONS: This study demonstrated that rGEV and rHRV could serve as the satisfying auxiliary parameters for detection of GEV and HRV with good diagnostic performance.

Deoxycholic Acid-Induced Gut Dysbiosis Disrupts Bile Acid Enterohepatic Circulation and Promotes Intestinal Inflammation.

BACKGROUND: A Western diet is a risk factor for the development of inflammatory bowel disease (IBD). High levels of fecal deoxycholic acid (DCA) in response to a Western diet contribute to bowel inflammatory injury. However, the mechanism of DCA in the natural course of IBD development remains unanswered. AIMS: The aim of this study is to investigate the effect of DCA on the induction of gut dysbiosis and its roles in the development of intestinal inflammation. METHODS: Wild-type C57BL/6J mice were fed an AIN-93G diet, either supplemented with or without 0.2% DCA, and killed at 24 weeks. Distal ileum and colon tissues were assessed by histopathological analysis. Hepatic and ileal gene expression was examined by qPCR, and the gut microbiota was analyzed by high-throughput 16S rRNA gene sequencing. HPLC-MS was used for fecal bile acid quantification. RESULTS: Mice fed the DCA-supplemented diet developed focal areas of ileal and colonic inflammation, accompanied by alteration of the composition of the intestinal microbiota and accumulation of fecal bile acids. DCA-induced dysbiosis decreased the deconjugation of bile acids, and this regulation was associated with the repressed expression of target genes in the enterohepatic farnesoid X receptor-fibroblast growth factor (FXR-FGF15) axis, leading to upregulation of hepatic de novo bile acid synthesis. CONCLUSIONS: These results suggest that DCA-induced gut dysbiosis may act as a key etiologic factor in intestinal inflammation, associated with bile acid metabolic disturbance and downregulation of the FXR-FGF15 axis.

Accuracy of ASGE high-risk criteria in evaluation of patients with suspected common bile duct stones.

BACKGROUND AND AIMS: ERCP is recommended for patients considered high risk for choledocholithiasis after biochemical testing and abdominal US. Our aim was to determine whether the American Society for Gastrointestinal Endoscopy (ASGE) guidelines accurately select patients for whom the risk of ERCP is justified. METHODS: Consecutive patients hospitalized with suspected choledocholithiasis at Sir Run Run Shaw Hospital who received biochemical testing, abdominal US, and definitive testing for choledocholithiasis (MRCP, EUS, ERCP, intraoperative cholangiogram, and/or common bile duct [CBD] exploration) were identified. Patients with choledocholithiasis on abdominal US, with bilirubin levels >4 mg/dL (normal values <1.2 mg/dL), bilirubin levels ≥1.8 mg/dL plus a dilated CBD and/or clinical cholangitis were considered high risk per ASGE guidelines. RESULTS: Of 2724 patients with suspected choledocholithiasis, 1171 (43%) met high-risk criteria. Definitive testing (MRCP in 2442 [90%], EUS in 67 [2%], ERCP in 659 [24%], intraoperative cholangiogram in 229 [8%], and CBD exploration in 447 [16%]) revealed choledocholithiasis in 1076 [40%] patients. The specificity of the ASGE high-risk criteria was 74% (95% confidence interval [CI], 72%-77%) and positive predictive value was 64% (95% CI, 61%-67%). Using a more restrictive criteria (choledocholithiasis on abdominal US, bilirubin >4 mg/dL plus dilated CBD) improved the specificity to 94% (95% CI, 93%-95%) and positive predictive value to 85% (95% CI, 82%-88%). Doubling or more of bilirubin to >4 mg/dL and ≥1.8 mg/dL at second testing had specificities of 98% (95% CI, 96%-99%) and 95% (95% CI, 93%-96%), with positive predictive values of 62% (95% CI, 48%-76%) and 54% (95% CI, 44%-65%), respectively. CONCLUSIONS: Although ASGE high-risk criteria demonstrated >50% probability of the patient having choledocholithiasis, more than a third of the patients would receive diagnostic ERCPs. Criteria with choledocholithiasis on abdominal US and/or bilirubin levels >4 mg/dL plus a dilated CBD showed higher specificity and positive predictive value.

The tumor promoting roles of erythropoietin/erythropoietin receptor signaling pathway in gastric cancer.

Erythropoietin (EPO), binding with its receptor (EPOR), plays an important role in erythropoiesis. EPOR is reported to be expressed in various non-hematopoietic cancers, including gastric cancer. Although recombinant human EPO (rhEPO) has been widely used clinically in anemia patients, it remains controversial whether it would promote tumor progression. In this study, we used siRNA interference method to downregulate EPOR expression to investigate the function of EPO/EPOR pathway in human gastric cancer cells. We found EPOR expressed significantly higher in gastric cancer tissues, and also in most gastric cancer cell lines. RhEPO promoted gastric cancer cell proliferation, migration in AGS cells, and promoted cells from G0/G1 stage to G2/M stage, but had no regulation on AGS cell apoptosis. Downregulation of EPOR expression by siRNA interference in AGS cells resulted in no significant effects on proliferation and invasiveness of the cells, but induced apoptosis (p < 0.05). Xenografted gastric tumor model was used to explore the effect of EPOR-overexpression on gastric cancer cells in vivo. Our result showed that overexpression of EPOR enhanced tumor formation in nude mice (p < 0.01). Our results suggest that EPO/EPOR pathway promotes gastric cancer formation, proliferation, migration, and decreases apoptosis.

Risk factors for colorectal neoplasms based on colonoscopy and pathological diagnoses of Chinese citizens: a multicenter, case-control study.

PURPOSE: Since observational data in the urban residents are required to better assess the risk factors of colorectal neoplasm occurrence and the effectiveness of colonoscopy screening and surveillance, we conducted a case-control study at multicenters in China to identify patient characteristics and neoplasm features of colorectal adenoma (CRA) and colorectal carcinoma (CRC). METHODS: A total of 4089 patients who had undergone a colonoscopy from 19 hospitals were enrolled, of which 1106 had CRA and 466 had CRC. They were compared with controls. The analysis provides features and risk factors of colorectal neoplasm using multivariate logistic regression. RESULTS: Increasing age, a family history of colorectal cancer or previous cases of colorectal adenoma or hypertension disease, gastrointestinal surgery, regular intake of pickled food (adjusted odds ratio [aOR] 1.42, 95 % confidence interval [CI], 1.048-1.924), consumption of alcohol, and a positive result of fecal occult blood testing (FOBT; aOR 2.509, 95 % CI 1.485-4.237) were associated with an increased risk of CRA. In the CRC group, increasing age, regular intake of pickled foods, and a positive FOBT result were risk factors. In addition, a positive abdominal computed tomography (CT) before a colonoscopy and physical signs of emaciation were also significantly associated with an increasing risk of colorectal carcinoma. Regular intake of vegetables decreased the risk of both CRA and CRC. CONCLUSIONS: Age, pickled foods, and a positive FOBT are risk factors for colorectal neoplasm. Vegetable intake was associated with a decreased risk of CRA and CRC.

Assessing evidence-based practice competencies of undergraduate nursing students using a developed multi-criteria decision-analysis model.

AIM: The developed multi-criteria decision analysis model was used to identify the inter-influence relationships and key factors affecting the EBP competencies of UNSs, to assess the EBP competencies of UNSs and based on these results, to formulate an improvement strategy to enhance the EBP competencies of UNSs. BACKGROUND: EBP is considered a core competency in international nursing practice. However, few studies have developed EBP evaluation models and applied them to assessing and improving the EBP competencies of UNSs. DESIGN: This is a quantitative study with multi-criteria decision-analysis model. METHODS: Firstly, the questionnaire was designed based on the characteristics of the DEMATEL and VIKOR-AS methods, which was completed by 17 nursing experts from a case hospital in Zhejiang Province, China. Subsequently, the DEMATEL method was used to analyze the inter-influence relationships among various criteria to determine their respective weights. Finally, the VIKOR method is utilized to integrate multiple criteria and their relative weights to assign comprehensive scores to each UNSs. RESULTS: The use of the DEMATEL method reveals that "Knowledge (C1)", "Mastering the basic scientific research methods during the study of the undergraduate courses (C11)", "Being able to consult clinical experts appropriately when encountering problems in clinical practice (C23)" and "Understanding the importance of reading journals related to the nursing profession regularly (C34)" were critical influencing factors. "Skill (C2)," "Being able to explain the essential roles of the best research evidence in determining clinical practice (C15)," "Being able to apply the collected research evidence to the individual case in nursing care (C25)" and "Paying attention to using the evidence-based nursing practice concept to determine the best clinical practice (C35)" were the most influential factors. According to the VIKOR method, the performance of the UNSs in the case hospitals in terms of EBP competencies from highest to lowest was Student C, Student B and Student A. However, all of these students suffered from deficiencies at the knowledge level. CONCLUSIONS: The application of the DEMATEL and VIKOR methods provides a systematic and comprehensive approach to the assessment of EBP competencies of UNSs. The lack of EBP competencies of UNSs in case hospitals is mainly reflected in knowledge level. To improve UNSs' EBP competencies, medical schools and hospital educators should propose short- and long-term strategies to improve knowledge.

Cost-effectiveness and cost-utility of a digital technology-driven hierarchical healthcare screening pattern in China.

Utilization of digital technologies for cataract screening in primary care is a potential solution for addressing the dilemma between the growing aging population and unequally distributed resources. Here, we propose a digital technology-driven hierarchical screening (DH screening) pattern implemented in China to promote the equity and accessibility of healthcare. It consists of home-based mobile artificial intelligence (AI) screening, community-based AI diagnosis, and referral to hospitals. We utilize decision-analytic Markov models to evaluate the cost-effectiveness and cost-utility of different cataract screening strategies (no screening, telescreening, AI screening and DH screening). A simulated cohort of 100,000 individuals from age 50 is built through a total of 30 1-year Markov cycles. The primary outcomes are incremental cost-effectiveness ratio and incremental cost-utility ratio. The results show that DH screening dominates no screening, telescreening and AI screening in urban and rural China. Annual DH screening emerges as the most economically effective strategy with 341 (338 to 344) and 1326 (1312 to 1340) years of blindness avoided compared with telescreening, and 37 (35 to 39) and 140 (131 to 148) years compared with AI screening in urban and rural settings, respectively. The findings remain robust across all sensitivity analyses conducted. Here, we report that DH screening is cost-effective in urban and rural China, and the annual screening proves to be the most cost-effective option, providing an economic rationale for policymakers promoting public eye health in low- and middle-income countries.

Digital ray: enhancing cataractous fundus images using style transfer generative adversarial networks to improve retinopathy detection.

BACKGROUND/AIMS: The aim of this study was to develop and evaluate digital ray, based on preoperative and postoperative image pairs using style transfer generative adversarial networks (GANs), to enhance cataractous fundus images for improved retinopathy detection. METHODS: For eligible cataract patients, preoperative and postoperative colour fundus photographs (CFP) and ultra-wide field (UWF) images were captured. Then, both the original CycleGAN and a modified CycleGAN (C2ycleGAN) framework were adopted for image generation and quantitatively compared using Frechet Inception Distance (FID) and Kernel Inception Distance (KID). Additionally, CFP and UWF images from another cataract cohort were used to test model performances. Different panels of ophthalmologists evaluated the quality, authenticity and diagnostic efficacy of the generated images. RESULTS: A total of 959 CFP and 1009 UWF image pairs were included in model development. FID and KID indicated that images generated by C2ycleGAN presented significantly improved quality. Based on ophthalmologists' average ratings, the percentages of inadequate-quality images decreased from 32% to 18.8% for CFP, and from 18.7% to 14.7% for UWF. Only 24.8% and 13.8% of generated CFP and UWF images could be recognised as synthetic. The accuracy of retinopathy detection significantly increased from 78% to 91% for CFP and from 91% to 93% for UWF. For retinopathy subtype diagnosis, the accuracies also increased from 87%-94% to 91%-100% for CFP and from 87%-95% to 93%-97% for UWF. CONCLUSION: Digital ray could generate realistic postoperative CFP and UWF images with enhanced quality and accuracy for overall detection and subtype diagnosis of retinopathies, especially for CFP.\ TRIAL REGISTRATION NUMBER: This study was registered with ClinicalTrials.gov (NCT05491798).

Phospho-SXXE/D motif mediated TNF receptor 1-TRADD death domain complex formation for T cell activation and migration.

In TNF-treated cells, TNFR1, TNFR-associated death domain protein (TRADD), Fas-associated death domain protein, and receptor-interacting protein kinase proteins form the signaling complex via modular interaction within their C-terminal death domains. In this paper, we report that the death domain SXXE/D motifs (i.e., S381DHE motif of TNFR1-death domain as well as S215LKD and S296LAE motifs of TRADD-death domain) are phosphorylated, and this is required for stable TNFR1-TRADD complex formation and subsequent activation of NF-κB. Phospho-S215LKD and phospho-S296LAE motifs are also critical to TRADD for recruiting Fas-associated death domain protein and receptor-interacting protein kinase. IκB kinase ß plays a critical role in TNFR1 phosphorylation of S381, which leads to subsequent T cell migration and accumulation. Consistently, we observed in inflammatory bowel disease specimens that TNFR1 was constitutively phosphorylated on S381 in those inflammatory T cells, which had accumulated in high numbers in the inflamed mucosa. Therefore, SXXE/D motifs found in the cytoplasmic domains of many TNFR family members and their adaptor proteins may serve to function as a specific interaction module for the α-helical death domain signal transduction.

Advances of endoscopic and surgical management in gastrointestinal stromal tumors.

As one of the most common mesenchymal malignancies in the digestive system, gastrointestinal stromal tumors (GISTs) occur throughout the alimentary tract with diversified oncological characteristics. With the advent of the tyrosine kinase inhibitor era, the treatment regimens of patients with GISTs have been revolutionized and GISTs have become the paradigm of multidisciplinary therapy. However, surgery resection remains recognized as the potentially curative management for the radical resection and provided with favorable oncological outcomes. The existing available surgery algorithms in clinical practice primarily incorporate open procedure, and endoscopic and laparoscopic surgery together with combined operation techniques. The performance of various surgery methods often refers to the consideration of risk evaluation of recurrence and metastases; the degree of disease progression; size, location, and growth pattern of tumor; general conditions of selected patients; and indications and safety profile of various techniques. In the present review, we summarize the fundamental principle of surgery of GISTs based on risk assessment as well as tumor size, location, and degree of progress with an emphasis on the indications, strengths, and limitations of current surgery techniques.

Disease Burden of Total and Early-Onset Colorectal Cancer in China from 1990 to 2019 and Predictions of Cancer Incidence and Mortality.

Background: Understanding the temporal trends in the epidemiology of colorectal cancer (CRC) and early-onset CRC (EOCRC) in China is essential for policymakers to develop appropriate strategies to reduce the CRC burden. Methods: The prevalence, incidence, mortality, years of life lived with disability (YLDs), years of life lost (YLLs), and disability-adjusted life years (DALYs) of CRC were obtained from the Global Burden of Disease (GBD) Study 2019. The incidence and mortality of CRC over the next 25 years were predicted. Results: From 1990 to 2019, the prevalence, incidence, and mortality of total CRC and EOCRC significantly increased in males, with milder trends in females. In 2019, the number of people living with CRC (or EOCRC) in China was approximately 3.4 (0.59) million, which was over seven (five) times higher than that in 1990. The DALYs, YLDs, and YLLs moderately increased from 1990 to 2019 in both sexes. The age-standardized mortality rate (ASMR) for females has shown a stable trend in total CRC, and a downward trend in EOCRC since 2000. While the ASMR for males showed increasing trends in total CRC and EOCRC. In 2019, the highest incidence, prevalence, YLDs, YLLs, and DALYs were all observed in the 65 to 69 age group, while the highest mortality was in the 70 to 74. By 2044, the incidence and deaths of CRC are expected to reach 1310 thousand and 484 thousand, respectively. For EOCRC, the incidence will peak at about 101 thousand around 2034, and the mortality will continuously decrease to a nadir at about 18 thousand around 2044. Conclusion: Although the age-standardized incidence and mortality of total CRC and EOCRC in China will reach a plateau, the number of incident cases and deaths of CRC have been increasing in the last three decades and will continue to increase in the next 25 years.

Efficacy and safety of modified tetracycline dosing in a quadruple therapy for Helicobacter pylori: A retrospective single center study.

BACKGROUND: Although highly effective as a component of Helicobacter pylori (H. pylori) treatment regimen, tetracycline is associated with a high incidence of medication-related adverse events. Modified dosing of tetracycline as part of quadruple therapy may improve safety while providing comparable eradication rates. AIM: To evaluate the efficacy and safety of modified dosing of tetracycline in patients receiving tetracycline and furazolidone-containing quadruple therapy in patients with H. pylori infection. METHODS: Consecutive patients (10/2020-12/2021) who received tetracycline and furazolidone quadruple therapy for H. pylori infection at Sir Run Run Shaw Hospital were identified. All patients received tetracycline, furazolidone, proton pump inhibitor, and bismuth for 14 d as primary or rescue therapy. Modified tetracycline dose group received tetracycline 500 mg twice daily while standard group received 750 mg twice daily or 500 mg three times daily. RESULTS: Three hundred and ninety-four patients [mean age = 46.3 ± 13.9, male = 137 (34.8%), and 309 (78.4%) primary therapy] completed tetracycline and furazolidone quadruple therapy for H. pylori infection including those who received modified tetracycline dose in 157 and standard doses in 118 (750 mg twice daily) and 119 (500 mg three times daily). Eradication rates in the modified tetracycline dose group were 92.40% and in the standard groups, eradication rates were 93.20% for 750 mg twice daily group and 92.43% for 500 mg three times daily group, respectively, without statistical difference (P = 0.959). The incidence of adverse events was lower in the modified tetracycline dose (15.3% vs 32.3% and 29.4%; P = 0.002) compared to the standard dose group. CONCLUSION: In a real-world experience, modified tetracycline dosing as part of tetracycline and furazolidone quadruple therapy for 14 d demonstrated high efficacy, comparable to standard tetracycline dose regimens, with a favorable safety profile.

SHP2 inhibition mitigates adaptive resistance to MEK inhibitors in KRAS-mutant gastric cancer through the suppression of KSR1 activity.

Despite the promising antitumor activity of RAF/MEK inhibitors for RAS-driven cancers, not all patients respond to these therapies. Adaptive resistance has been reported as a major culprit in non-responders, which can be reversed by SHP2 inhibitors (SHP2is) in multiple cancer cells; however, the underlying mechanisms remain unknown. In this study, we found that KRAS-mutant gastric cancer cells respond to MEK inhibitors (MEKis) with adaptive resistance. Markedly, SHP2 activation accompanied by ERK signaling restoration in MEKi-treated cells, and a MEKi and SHP2i combination had a synergistic effect on downstream signaling blockade. In vivo, SHP099 combined with AZD6244 (selumetinib) was highly efficacious for the treatment of xenografts. Mechanistically, SHP2 was found to interact with the scaffold protein KSR1 through its protein tyrosine phosphatase domain. KSR1 knockdown sensitized cells to AZD6244, whereas a KSR1 activating mutation (S269A) diminished the synergistic anti-proliferative effect of SHP2i and MEKi. Interestingly, activated SHP2, during adaptive resistance to MEKis, impaired the interaction with KSR1, activating KSR1 to promote MAPK signaling. In conclusion, SHP2 promotes adaptive resistance to MEKis by activating KSR1; selumetinib combined with SHP099 might be an available therapeutic strategy for KRAS-mutant gastric cancers.

Real-Time Evaluation of Helicobacter pylori Infection by Convolution Neural Network During White-Light Endoscopy: A Prospective, Multicenter Study (With Video).

INTRODUCTION: Convolutional neural network during endoscopy may facilitate evaluation of Helicobacter pylori infection without obtaining gastric biopsies. The aim of the study was to evaluate the diagnosis accuracy of a computer-aided decision support system for H. pylori infection (CADSS-HP) based on convolutional neural network under white-light endoscopy. METHODS: Archived video recordings of upper endoscopy with white-light examinations performed at Sir Run Run Shaw Hospital (January 2019-September 2020) were used to develop CADSS-HP. Patients receiving endoscopy were prospectively enrolled (August 2021-August 2022) from 3 centers to calculate the diagnostic property. Accuracy of CADSS-HP for H. pylori infection was also compared with endoscopic impression, urea breath test (URT), and histopathology. H. pylori infection was defined by positive test on histopathology and/or URT. RESULTS: Video recordings of 599 patients who received endoscopy were used to develop CADSS-HP. Subsequently, 456 patients participated in the prospective evaluation including 189 (41.4%) with H. pylori infection. With a threshold of 0.5, CADSS-HP achieved an area under the curve of 0.95 (95% confidence interval [CI], 0.93-0.97) with sensitivity and specificity of 91.5% (95% CI 86.4%-94.9%) and 88.8% (95% CI 84.2%-92.2%), respectively. CADSS-HP demonstrated higher sensitivity (91.5% vs 78.3%; mean difference = 13.2%, 95% CI 5.7%-20.7%) and accuracy (89.9% vs 83.8%, mean difference = 6.1%, 95% CI 1.6%-10.7%) compared with endoscopic diagnosis by endoscopists. Sensitivity of CADSS-HP in diagnosing H. pylori was comparable with URT (91.5% vs 95.2%; mean difference = 3.7%, 95% CI -1.8% to 9.4%), better than histopathology (91.5% vs 82.0%; mean difference = 9.5%, 95% CI 2.3%-16.8%). DISCUSSION: CADSS-HP achieved high sensitivity in the diagnosis of H. pylori infection in the real-time test, outperforming endoscopic diagnosis by endoscopists and comparable with URT. Clinicaltrials.gov ; ChiCTR2000030724.