The Roles of Circular RNAs in Ischemic Stroke through Modulating Neuroinflammation.

Ischemic stroke (IS) remains a serious threat to human health. Neuroinflammatory response is an important pathophysiological process after IS. Circular RNAs (circRNAs), a member of the non-coding RNA family, are highly expressed in the central nervous system and widely involved in regulating physiological and pathophysiological processes. This study reviews the current evidence on neuroinflammatory responses, the role of circRNAs in IS and their potential mechanisms in regulating inflammatory cells, and inflammatory factors affecting IS damage. This review lays a foundation for future clinical application of circRNAs as novel biomarkers and therapeutic targets.

[Evidence map of clinical research on Chinese patent medicines for post-acute myocardial infarction heart failure].

An evidence map was established to comprehensively sort out the clinical research in the treatment of post-acute myocardial infarction heart failure(P-AMI-HF) with Chinese patent medicines, so as to reveal the distribution of evidence in this field. CNKI, Wanfang, VIP, SinoMed, PubMed, Cochrane Library, and EMbase were searched for the randomized controlled trial(RCT), systematic reviews/Meta-analysis, and guidelines/consensus in this field. The evidence was analyzed and displayed in the form of a combination of text, charts, bubble charts, and bar charts, and the quality of RCT, systematic reviews/Meta-analysis, and guidelines/consensus were evaluated by RoB 1.0, AMSTAR2, and AGREE Ⅱ, respectively. A total of 163 RCTs, 4 systematic reviews/Meta-analysis, 1 network Meta-analysis, 2 observational studies, and 5 guidelines/consensus were included. In recent years, the total number of publications in this field has shown an upward trend. There were a variety of Chinese patent medicines in the treatment of P-AMI-HF, among which Shenfu Injection received the most attention. The clinical RCT and systematic reviews/Meta-analysis generally had poor quality, and the RCT mostly had a small size, a single center, and a short cycle. The outcome indicators mainly included cardiac function indicators, myocardial injury markers, total response rate, hemodynamic indicators, and safety indicators, while the characteristic efficacy indicators of TCM received insufficient attention. The development processes of some guidelines/consensus lack standardization, which compromised their authority and rationality. Chinese patent medicines have advantages in the treatment of P-AMI-HF, while there are also problems, which remain to be solved by more high-quality evidence. That is, more large-sample and multi-center clinical studies should be carried out in the future, and the formulation process of relevant systematic reviews/Meta-analysis and guideline/consensus should be standardized and the quality of evidence should be improved. In this way, the effectiveness and safety of Chinese patent medicines in the treatment of P-AMI-HF can be explored.

Bipolar disorder and the gut microbiota: a bibliometric analysis.

Background: Previous studies have explored the relationship between bipolar disorder and gut microbiota. However, there has been no bibliometric analysis to summarize and analyze these publications. Our objective was to perform a bibliometric analysis to investigate the current status and frontiers of the publications in the field of the association between bipolar disorder and the gut microbiota. Methods: We retrieved publications concerning the interplay between the gut microbiota and bipolar disorder from the Web of Science Core Collection (WoSCC). The analysis was executed using WoSCC's literature analysis tool and VOSviewer 1.6.16. Results: In total, we identified 177 publications originating from 362 institutions across 39 countries/regions, and these articles were disseminated in 104 different journals. The most productive institutions, authors, countries/regions, and journals were Zhejiang University contributing 18 publications, Shaohua Hu authoring 12 publications, China with 53 publications, and Frontiers in Psychiatry with 11 publications. The first high-cited document was published in the Journal of Psychiatric Research in 2017, and authored by Evans. In this article, they found gut microbiome composition was associated with BD and its illness severity, and they concluded that targeting the gut microbiota may be helpful to develop the effective treatment for bipolar disorder. The top 5 keywords with the highest frequency except for bipolar disorder and gut microbiota were as follows: depression, inflammation, probiotic, gut-brain axis, and anxiety. Conclusion: In conclusion, this is the first bibliometric analysis to explore the publications in the field of the association between bipolar disorder and the gut microbiota. The main research hotspots regarding this field were the characteristics, abundance, and diversity of gut microbiome in bipolar disorder, the role of treatment and gut microbiome in bipolar disorder, microbiome-brain connections in bipolar disorder, and interventions for bipolar disorder based on microbiota composition modification. The number of studies about the association between gut microbiota and bipolar disorder is relatively small, and more studies are needed to expand our understanding the association between gut microbiota and bipolar disorder.

Identification critical host factors for Japanese encephalitis virus replication via CRISPR screening of human sgRNA library.

Japanese encephalitis virus (JEV) is a pathogen with a substantial impact on both livestock and human health. However, the critical host factors in the virus life cycle remain poorly understood. Using a library comprising 123411 small guide RNAs (sgRNAs) targeting 19050 human genes, we conducted a genome-wide clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9-based screen to identify essential genes for JEV replication. By employing knockout or knockdown techniques on genes, we identified eleven human genes crucial for JEV replication, such as prolactin releasing hormone receptor (PRLHR), activating signal cointegrator 1 complex subunit 3 (ASCC3), acyl-CoA synthetase long chain family member 3 (ACSL3), and others. Notably, we found that PRLHR knockdown blocked the autophagic flux, thereby inhibiting JEV infection. Taken together, these findings provide effective data for studying important host factors of JEV replication and scientific data for selecting antiviral drug targets.

Effects of microencapsulated essential oils and organic acids preparation on growth performance, slaughter characteristics, nutrient digestibility and intestinal microenvironment of broiler chickens.

To develop effective antibiotics alternatives is getting more and more important to poultry healthy production. The study investigated the effects of a microencapsulated essential oils and organic acids preparation (EOA) on growth performance, slaughter performance, nutrient digestibility and intestinal microenvironment of broilers. A total of 624 1-day-old male Arbor Acres broilers were randomly divided into 6 groups including the control group (T1) fed with basal diet, the antibiotic group (T2) supplemented with basal diet with 45 mg/kg bacitracin methylene disalicylate (BMD), and 4 inclusion levels of EOA-treated groups (T3, T4, T5, T6 groups) chickens given basal diet with 200, 400, 600, and 800 mg EOA/kg of diet, respectively. Results showed that compared with the control, the 200 mg/kg EOA group increased average daily gain (ADG) and average body weight (ABW) during the early stage (P < 0.05). EOA addition decreased crypt depth of the ileum (P < 0.05), but villus height to crypt depth ratio was increased by EOA addition at 200 and 400 mg/kg at d 21 (P < 0.05). Compared with the control, dietary addition EOA at 200, 400 and 600 mg/kg increased the lipase activity in the duodenum at d 21 (P < 0.05). Increased lactic acid bacteria population was found in cecal digesta of the 400 mg/kg EOA group at d 21 (P < 0.05), and higher concentration of butyric acid level was observed in cecal digesta at d 21 and d 42 in the 200 mg/kg EOA group compared with the control (P < 0.05). RT-PCR analysis found that dietary EOA addition decreased the gene expression of IL-1ß, COX-2 and TGF-ß4 in the ileum at d 21 (P < 0.05), while only the 200 mg/kg EOA increased the gene expression of IL-10, TGF-ß4, Claudin-1, ZO-1, CATH-1, CATH-3, AvBD-1, AvBD-9 and AvBD-12 in the ileum at d 42 (P < 0.05) compared with the control. In summary, adding 200 mg/kg and 400 mg/kg of the EOA to the diet could improve the growth performance and intestinal microenvironment through improving intestinal morphology, increasing digestive enzymes activity and cecal lactic acid bacteria abundance and butyric acid content, improving intestinal barrier function as well as maintaining intestinal immune homeostasis. The improving effect induced by EOA addition in the early growth stage was better than that in the later growth stage. Overall, the EOA product might be an effective antibiotic alternative for broiler industry.

Prognostic Implications of Quantitative Flow Ratio and Plaque Characteristics in Intravascular Ultrasound-Guided Treatment Strategy.

BACKGROUND: Quantitative flow ratio (QFR) is a method for evaluating fractional flow reserve without the use of an invasive coronary pressure wire or pharmacological hyperemic agent. OBJECTIVES: The aim of this study was to investigate the prognostic implications of QFR and plaque characteristics in patients who underwent intravascular ultrasound (IVUS)-guided treatment for intermediate lesions. METHODS: Among the IVUS-guided strategy group in the FLAVOUR (Fractional Flow Reserve and Intravascular Ultrasound for Clinical Outcomes in Patients with Intermediate Stenosis) trial, vessels suitable for QFR analysis were included in this study. High-risk features were defined as low QFR (≤0.90), quantitative high-risk plaque characteristics (qn-HRPCs) (minimal lumen area ≤3.5 mm2, or plaque burden ≥70%), and qualitative high-risk plaque characteristics (ql-HRPCs) (attenuated plaque, positive remodeling, or plaque rupture) assessed using IVUS. The primary clinical endpoint was target vessel failure (TVF), defined as a composite of cardiac death, target vessel myocardial infarction, and target vessel revascularization. RESULTS: A total of 415 (46.1%) vessels could be analyzable for QFR. The numbers of qn-HRPCs and ql-HRPCs increased with decreasing QFR. Among deferred vessels, those with 3 high-risk features exhibits a significantly higher risk of TVF compared with those with ≤2 high-risk features (12.0% vs 2.7%; HR: 4.54; 95% CI: 1.02-20.29). CONCLUSIONS: Among the IVUS-guided deferred group, vessels with qn-HRPC and ql-HRPC with low QFR (≤0.90) exhibited a significantly higher risk for TVF compared with those with ≤2 features. Integrative assessment of angiography-derived fractional flow reserve and anatomical and morphological plaque characteristics is recommended to improve clinical outcomes in patients undergoing IVUS-guided deferred treatment.

Emergence of a clinical Salmonella enterica serovar 1,4,[5], 12: i:-isolate, ST3606, in China with susceptibility decrease to ceftazidime-avibactam carrying a novel blaCTX-M-261 variant and a blaNDM-5.

PURPOSE: The detection rate of Salmonella enterica serovar 1,4,[5], 12: i: - (S. 1,4,[5], 12: i: -) has increased as the most common serotype globally. A S. 1,4,[5], 12: i: - strain named ST3606 (sequence type 34), isolated from a fecal specimen of a child with acute diarrhea hospitalized in a tertiary hospital in China, was firstly reported to be resistant to carbapenem and ceftazidime-avibactam. The aim of this study was to characterize the whole-genome sequence of S. 1,4,[5], 12: i: - isolate, ST3606, and explore its antibiotic resistance genes and their genetic environments. METHODS: The genomic DNA of S. 1,4,[5], 12: i: - ST3606 was extracted and performed with single-molecule real-time sequencing. Resistance genes, plasmid replicon type, mobile elements, and multilocus sequence types (STs) of ST3606 were identified by ResFinder 3.2, PlasmidFinder, OriTfinder database, ISfinder database, and MLST 2.0, respectively. The conjugation experiment was utilized to evaluate the conjugation frequency of pST3606-2. Protein expression and enzyme kinetics experiments of CTX-M were performed to analyze hydrolytic activity of a novel CTX-M-261 enzyme toward several antibiotics. RESULTS: Single-molecule real-time sequencing revealed the coexistence of a 109-kb IncI1-Iα plasmid pST3606-1 and a 70.5-kb IncFII plasmid pST3606-2. The isolate carried resistance genes, including blaNDM-5, sul1, qacE, aadA2, and dfrA12 in pST3606-1, blaTEM-1B, aac(3)-lld, and blaCTX-M-261, a novel blaCTX-M-1 family member, in pST3606-2, and aac(6')-Iaa in chromosome. The blaCTX-M-261 was derived from blaCTX-M-55 by a single-nucleotide mutation 751G>A leading to amino acid substitution of Val for Met at position 251 (Val251Met), which conferred CTX-M increasing resistance to ceftazidime verified by antibiotics susceptibility testing of transconjugants carrying pST3606-2 and steady-state kinetic parameters of CTX-M-261. pST3606-1 is an IncI1-α incompatibility type that shares homology with plasmids of pC-F-164_A-OXA140, pE-T654-NDM-5, p_dm760b_NDM-5, and p_dmcr749c_NDM-5. The conjugation experiment demonstrated that pST3606-2 was successfully transferred to the Escherichia coli recipient C600 with four modules of OriTfinder. CONCLUSION: Plasmid-mediated horizontal transfer plays an important role in blaNDM-5 and blaCTX-M-261 dissemination, which increases the threat to public health due to the resistance to most ß-lactam antibiotics. This is the first report of blaCTX-M-261 and blaNDM-5 in S. 1,4,[5], 12: i: -. The work provides insights into the enzymatic function and demonstrates the ongoing evolution of CTX-M enzymes and confirms urgency to control resistance of S. 1,4,[5], 12: i: -.

Physiology- or Imaging-Guided Strategies for Intermediate Coronary Stenosis.

Importance: Treatment strategies for intermediate coronary lesions guided by fractional flow reserve (FFR) and intravascular ultrasonography (IVUS) have shown comparable outcomes. Identifying low-risk deferred vessels to ensure the safe deferral of percutaneous coronary intervention (PCI) and high-risk revascularized vessels that necessitate thorough follow-up can help determine optimal treatment strategies. Objectives: To investigate outcomes according to treatment types and FFR and IVUS parameters after FFR- or IVUS-guided treatment. Design, Setting, and Participants: This cohort study included patients with intermediate coronary stenosis from the Fractional Flow Reserve and Intravascular Ultrasound-Guided Intervention Strategy for Clinical Outcomes in Patients With Intermediate Stenosis (FLAVOUR) trial, an investigator-initiated, prospective, open-label, multicenter randomized clinical trial that assigned patients into an IVUS-guided strategy (which recommended PCI for minimum lumen area [MLA] ≤3 mm2 or 3 mm2 to 4 mm2 with plaque burden [PB] ≥70%) or an FFR-guided strategy (which recommended PCI for FFR ≤0.80). Data were analyzed from November to December 2022. Exposures: FFR or IVUS parameters within the deferred and revascularized vessels. Main Outcomes and Measures: The primary outcome was target vessel failure (TVF), a composite of cardiac death, target vessel myocardial infarction, and revascularization at 2 years. Results: A total of 1619 patients (mean [SD] age, 65.1 [9.6] years; 1137 [70.2%] male) with 1753 vessels were included in analysis. In 950 vessels for which revascularization was deferred, incidence of TVF was comparable between IVUS and FFR groups (3.8% vs 4.1%; P = .72). Vessels with FFR greater than 0.92 in the FFR group and MLA greater than 4.5 mm2 or PB of 58% or less in the IVUS group were identified as low-risk deferred vessels, with a decreased risk of TVF (hazard ratio [HR], 0.25 [95% CI, 0.09-0.71]; P = .009). In 803 revascularized vessels, the incidence of TVF was comparable between IVUS and FFR groups (3.6% vs 3.7%; P = .95), which was similar in the revascularized vessels undergoing PCI optimization (4.2% vs 2.5%; P = .31). Vessels with post-PCI FFR of 0.80 or less in the FFR group or minimum stent area of 6.0 mm2 or less or with PB at stent edge greater than 58% in the IVUS group had an increased risk for TVF (HR, 7.20 [95% CI, 3.20-16.21]; P < .001). Conclusions and Relevance: In this cohort study of patients with intermediate coronary stenosis, FFR- and IVUS-guided strategies showed comparable outcomes in both deferred and revascularized vessels. Binary FFR and IVUS parameters could further define low-risk deferred vessels and high-risk revascularized vessels.

Quantitative Flow Ratio-Derived Index of Microcirculatory Resistance as a Novel Tool to Identify Microcirculatory Function in Patients with Ischemia and No Obstructive Coronary Artery Disease.

BACKGROUND: Coronary microvascular disease (CMVD) is associated with adverse cardiovascular outcomes. However, there is no reliable and noninvasive quantitative diagnostic method available for CMVD. The use of a pressure wire to measure the index of microcirculatory resistance (IMR) is possible, but it has inevitable practical restrictions. We hypothesized that computation of the quantitative flow ratio could be used to predict CMVD with symptoms of ischemia and no obstructive coronary artery disease (INOCA). METHODS: We retrospectively assessed the diagnostic efficiency of the quantitative flow ratio-derived index of microcirculatory resistance (QMR) in 103 vessels from 66 patients and compared it with invasive IMR using the thermodilution technique. RESULTS: Patients were divided into the CMVD group (41/66, 62.1%) and non-CMVD group (25/66, 37.9%). Pressure wire IMR measurements were made in 103 coronary vessels, including 44 left descending arteries, 18 left circumflex arteries, and 41 right coronary arteries. ROC curve analysis showed a good diagnostic performance of QMR for all arteries (area under the curve = 0.820, 95% confidence interval 0.736-0.904, p < 0.001) in predicting microcirculatory function. The optimal cut-off for QMR to predict microcirculatory function was 266 (sensitivity: 82.9%, specificity: 72.6%, and diagnostic accuracy: 76.7%). CONCLUSION: QMR is a promising tool for the assessment of coronary microcirculation. The assessment of the IMR without the use of a pressure wire may enable more rapid, convenient, and cost-effective assessment of coronary microvascular function.

The prevalence of coronary microvascular dysfunction (CMD) in heart failure with preserved ejection fraction (HFpEF): a systematic review and meta-analysis.

To date, studies on the prevalence of coronary microvascular dysfunction (CMD) in heart failure with preserved ejection fraction (HFpEF) have not been summarized and analyzed as a whole. We conducted this systematic review and meta-analysis to assess the prevalence of CMD in patients with HFpEF. The PubMed, Cochrane, and Embase databases were searched from dates of inception until May 1, 2023. The primary outcome was the prevalence of CMD in patients with HFpEF, and values of CMD prevalence were pooled using a random-effects model. In total, 10 studies involving 1267 patients, including 822 with HFpEF and 445 without HFpEF, were included. The pooled prevalence of CMD in patients with HFpEF was 71% (95% CI, 0.63-0.79). In the subgroup analysis, the prevalence of CMD was 79% (95% CI, 0.71-0.87) by invasive measurement and 66% (95% CI, 0.54-0.77) by noninvasive measurement and 67% (95% CI, 0.52-0.82) with CFR < 2.0 and 75.0% (95% CI, 0.71-0.79) with CFR < 2.5. The prevalence of endothelium-independent CMD and endothelium-dependent CMD was 62% (95% CI, 0.53-0.72) and 50% (95% CI, 0.19-0.81), respectively. The prevalence of CMD was 74% (95% CI = 0.69-0.79) and 66% (95% CI = 0.41-0.90) in prospective and retrospective studies, respectively. Compared with the control group, patients with HFpEF had a significantly lower CFR (MD = - 1.28, 95% CI = - 1.82 to - 0.74, P < 0.01) and a higher prevalence of CMD (RR = 2.21, 95% CI = 1.52 to 3.20, P < 0.01). Qualitative analysis demonstrated that CMD might be associated with poor clinical outcomes in patients with HFpEF. In conclusion, this is the first systematic review and meta-analysis of all studies reporting the prevalence of CMD in patients with HFpEF. Our study demonstrates that CMD is common in patients with HFpEF and might be associated with poor clinical outcomes in these patients. Clinicians should attach importance to CMD in the diagnosis and treatment of HFpEF. The number of studies in this field is relatively small. Therefore, more high-quality studies are needed to explore the diagnostic and prognostic value of CMD and the potential role of CMD as a therapeutic target in patients with HFpEF.

Rationale and design of a comparison of angiography-derived fractional flow reserve-guided and intravascular ultrasound-guided intervention strategy for clinical outcomes in patients with coronary artery disease: a randomised controlled trial (FLAVOUR II).

INTRODUCTION: Percutaneous coronary intervention (PCI) guided by coronary angiography-derived fractional flow reserve (FFR) or intravascular ultrasound (IVUS) has shown improved clinical outcomes compared with angiography-only-guided PCI. In patients with intermediate stenoses, FFR resulted in fewer coronary interventions and was non-inferior to IVUS with respect to clinical outcomes. However, whether this finding can be applied to angiography-derived FFR in significant coronary artery disease (CAD) remains unclear. METHOD AND ANALYSIS: The comparison of angiography-derived FFR-guided and IVUS-guided intervention strategies for clinical outcomes in patients with coronary artery disease (FLAVOUR II) trial is a multicentre, prospective, randomised controlled trial. A total of 1872 patients with angiographically significant CAD (stenoses of at least 50% as estimated visually through angiography) in a major epicardial coronary artery will be randomised 1:1 to receive either angiography-derived FFR-guided or IVUS-guided PCI. Patients will be treated with second-generation drug-eluting stent according to the predefined criteria for revascularisation: angiography-derived FFR≤0.8 and minimal lumen area (MLA)≤3 mm2 or 3 mm270%. The primary endpoint is a composite of all-cause death, myocardial infarction and revascularisation at 12 months after randomisation. We will test the non-inferiority of the angiography-derived FFR-guided strategy compared with the IVUS-guided decision for PCI and the stent optimisation strategy.The FLAVOUR II trial will provide new insights into optimal evaluation and treatment strategies for patients with CAD. ETHICS AND DISSEMINATION: FLAVOUR II was approved by the institutional review board at each participating site (The Second Affiliated Hospital of Zhejiang University School of Medicine Approval No: 2020LSYD410) and will be conducted in line with the Declaration of Helsinki. Informed consent would be obtained from each patient before their participation. The study results will be submitted to a scientific journal. TRIAL REGISTRATION NUMBER: NCT04397211.

Bibliometric and visual analysis of doxorubicin-induced cardiotoxicity.

Background: Doxorubicin-induced cardiotoxicity represents a prevalent adverse effect encountered in patients undergoing treatment with doxorubicin. To date, there has been no bibliometric study to summarize the field of doxorubicin-induced cardiotoxicity. In our study, we aim to determine the current status and frontiers of doxorubicin-induced cardiotoxicity by bibliometric analysis. Methods: The documents concerning doxorubicin-induced cardiotoxicity are obtained from the Web of Science Core Collection database (WOSCC), and VOSviewer 1.6.16, CiteSpace 5.1.3 and the WOSCC's literature analysis wire were used to conduct the bibliometric analysis. Results: In total, 7,021 publications were encompassed, which are produced by 37,152 authors and 6,659 organizations, 1,323 journals, and 101 countries/regions. The most productive author, institution, country and journal were Bonnie Ky with 35 publications, University of Texas with 190 documents, the United States with 1,912 publications, and PLOS ONE with 120 documents. The first high-cited article was published in the NEJM with 8,134 citations authored by DJ Slamon et al., in 2001. For keyword analysis, there are four clusters depicted in distinct directions. The keywords in the red cluster are oxidative stress, apoptosis, and cardiomyopathy. The keywords in the green cluster are cardiotoxicity, heart failure, and anthracycline. The keywords in the blue cluster are chemotherapy, trastuzumab, and paclitaxel. The keywords in the purple cluster are doxorubicin, adriamycin, and cancer. Most of the documents were derived from the United States, China and Italy (4,080/7,021, 58.1%). The number of studies from other countries should be increased. Conclusion: In conclusion, the main research hotspots and frontiers in the field of doxorubicin-induced cardiotoxicity include the role of doxorubicin in cardiotoxicity, the mechanisms underlying doxorubicin-induced cardiotoxicity, and the development of treatment strategies for doxorubicin-induced cardiotoxicity. More studies are needed to explore the mechanisms and treatment of doxorubicin-induced cardiotoxicity.

Clinical Outcomes of Deferred Lesions by IVUS Versus FFR-Guided Treatment Decision.

BACKGROUND: There are limited data regarding the safety of deferral of percutaneous coronary intervention based on intravascular ultrasound (IVUS) findings. The current study sought to compare the prognosis between deferred lesions based on IVUS and fractional flow reserve (FFR)-guided treatment decision. METHODS: This study is a post hoc analysis of the FLAVOUR randomized trial (Fractional Flow Reserve and Intravascular Ultrasound for Clinical Outcomes in Patients With Intermediate Stenosis) that compared 2-year clinical outcomes between IVUS- and FFR-guided treatment decision on intermediate coronary artery lesions using predefined criteria. In both IVUS and FFR groups, vessels were classified into deferred or revascularized vessels, and patients were classified as those with or without deferred lesions. Vessel-oriented composite outcomes (cardiac death, target vessel myocardial infarction, or target vessel revascularization) in deferred vessels and patient-oriented composite outcomes (death, myocardial infarction, or any revascularization) in patients with deferred lesions were compared between the IVUS and FFR groups. RESULTS: A total of 1682 patients and 1820 vessels were analyzed, of which 922 patients and 989 vessels were deferred. At 2 years, there was no difference in the cumulative incidence of vessel-oriented composite outcomes in deferred vessels between IVUS (n=375) and FFR (n=614) groups (3.8% versus 4.1%; hazard ratio, 0.91 [95% CI, 0.47-1.75]; P=0.77). The risk of vessel-oriented composite outcomes was comparable between deferred and revascularized vessels following treatment decision by IVUS (3.8% versus 3.5%; hazard ratio, 1.09 [95% CI, 0.54-2.19]; P=0.81) and FFR (4.1% versus 3.6%; hazard ratio, 1.14 [95% CI, 0.56-2.32]; P=0.72). In comparison of patient-oriented composite outcomes in patients with deferred lesions, there was no significant difference between the IVUS (n=357) and FFR (n=565) groups (6.2% versus 5.9%; hazard ratio, 1.05 [95% CI, 0.61-1.80]; P=0.86). CONCLUSIONS: In patients with intermediate coronary artery stenosis, deferral of percutaneous coronary intervention based on IVUS-guided treatment decision showed comparable risk of clinical events with FFR-guided treatment decision. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02673424.

The Association between the EAT-Lancet Diet and Diabetes: A Systematic Review.

Several studies have explored the association between diabetes and the EAT-Lancet diet. Thus, the objective of our study was to conduct a systematic review to analyze and summarize all clinical studies concerning the association between diabetes and the EAT-Lancet diet. We undertook a comprehensive search of the Embase, Cochrane, and PubMed databases up to 15 August 2023. All clinical studies concerning the association between diabetes and the EAT-Lancet diet were summarized and analyzed. In total, our systematic review included five studies of four prospective studies and one cross-sectional study, encompassing 259,315 participants. All the included studies were evaluated as high quality. The outcomes from all studies indicated that adherence to the EAT-Lancet diet was correlated with a reduced risk of diabetes. In conclusion, the EAT-Lancet diet may be an effective dietary intervention for diabetes. Nevertheless, the number of studies examining the association between diabetes and the EAT-Lancet diet is limited. Further high-quality studies are required to expand our understanding of the benefits of the EAT-Lancet diet for patients with diabetes.

A Bibliometric Analysis of Alternate-Day Fasting from 2000 to 2023.

Alternate-day fasting (ADF) is becoming more popular since it may be a promising diet intervention for human health. Our study aimed to conduct a comprehensive bibliometric analysis to investigate current publication trends and hotspots in the field of ADF. Publications regarding ADF were identified from the Web of Science Core Collection (WOSCC) database. VOSviewer 1.6.16 and Online Analysis Platform were used to analyze current publication trends and hotspots. In total, there were 184 publications from 362 institutions and 39 countries/regions, which were published in 104 journals. The most productive countries/regions, institutions, authors, and journals were the USA, University of Illinois Chicago, Krista A. Varady, and Nutrients, respectively. The first high-cited publication was published in PNAS and authored by R. Michael Anson, and it was also the first article about ADF. The top five keywords with the highest frequency were as follows: calorie restriction, weight loss, intermittent fasting, obesity, and body weight. In conclusion, this is the first comprehensive bibliometric analysis related to ADF. The main research hotspots and frontiers are ADF for obesity and cardiometabolic risk, and ADF for several different population groups including healthy adults and patients with diabetes, nonalcoholic fatty liver disease (NAFLD), and cancer. The number of studies about ADF is relatively small, and more studies are needed to extend our knowledge about ADF, to improve human health.

Genome-wide enhancer-gene regulatory maps link causal variants to target genes underlying human cancer risk.

Genome-wide association studies have identified numerous variants associated with human complex traits, most of which reside in the non-coding regions, but biological mechanisms remain unclear. However, assigning function to the non-coding elements is still challenging. Here we apply Activity-by-Contact (ABC) model to evaluate enhancer-gene regulation effect by integrating multi-omics data and identified 544,849 connections across 20 cancer types. ABC model outperforms previous approaches in linking regulatory variants to target genes. Furthermore, we identify over 30,000 enhancer-gene connections in colorectal cancer (CRC) tissues. By integrating large-scale population cohorts (23,813 cases and 29,973 controls) and multipronged functional assays, we demonstrate an ABC regulatory variant rs4810856 associated with CRC risk (Odds Ratio = 1.11, 95%CI = 1.05-1.16, P = 4.02 × 10-5) by acting as an allele-specific enhancer to distally facilitate PREX1, CSE1L and STAU1 expression, which synergistically activate p-AKT signaling. Our study provides comprehensive regulation maps and illuminates a single variant regulating multiple genes, providing insights into cancer etiology.

Genetic Variants That Impact Alternative Polyadenylation in Cancer Represent Candidate Causal Risk Loci.

Alternative polyadenylation (APA) is emerging as a major mechanism of posttranscriptional regulation. APA can impact the development and progression of cancer, suggesting that the genetic determinants of APA might play an important role in regulating cancer risk. Here, we depicted a pan-cancer atlas of human APA quantitative trait loci (apaQTL), containing approximately 0.7 million apaQTLs across 32 cancer types. Systematic multiomics analyses indicated that cancer apaQTLs could contribute to APA regulation by altering poly(A) motifs, RNA-binding proteins (RBP), and chromatin regulatory elements and were preferentially enriched in genome-wide association studies (GWAS)-identified cancer susceptibility loci. Moreover, apaQTL-related genes (aGene) were broadly related to cancer signaling pathways, high mutational burden, immune infiltration, and drug response, implicating their potential as therapeutic targets. Furthermore, apaQTLs were mapped in Chinese colorectal cancer tumor tissues and then screened for functional apaQTLs associated with colorectal cancer risk in 17,789 cases and 19,951 controls using GWAS-ChIP data, with independent validation in a large-scale population consisting of 6,024 cases and 10,022 controls. A multi-ancestry-associated apaQTL variant rs1020670 with a C>G change in DNM1L was identified, and the G allele contributed to an increased risk of colorectal cancer. Mechanistically, the risk variant promoted aberrant APA and facilitated higher usage of DNM1L proximal poly(A) sites mediated by the RBP CSTF2T, which led to higher expression of DNM1L with a short 3'UTR. This stabilized DNM1L to upregulate its expression, provoking colorectal cancer cell proliferation. Collectively, these findings generate a resource for understanding APA regulation and the genetic basis of human cancers, providing insights into cancer etiology. SIGNIFICANCE: Cancer risk is mediated by alternative polyadenylation quantitative trait loci, including the rs1020670-G variant that promotes alternative polyadenylation of DNM1L and increases colorectal cancer risk.

Impact of plaque characteristics on percutaneous coronary intervention-related microvascular dysfunction: insights from angiographic microvascular resistance and intravascular ultrasound.

Background: The correlation between percutaneous coronary intervention (PCI)-related microvascular dysfunction (MVD) and plaque characteristics remains unclear. To investigate this correlation and its prognosis, we assessed changes in MVD by angiographic microvascular resistance (AMR) and intracoronary ultrasound scans after PCI. Methods: We conducted a retrospective study that enrolled 250 patients with coronary artery disease between July 2016 and December 2018. We collected demographic characteristics, laboratory tests, coronary angiography (CAG) and intracoronary ultrasound findings. We calculated quantitative flow ratio (QFR) and AMR by CAG. The endpoint was vessel-oriented composite outcomes (VOCOs). Results: After 47 exclusions, we divided 203 cases into a deteriorated group (n=139) and an improved group (n=64) based on AMR change after PCI. Compared with the improved group, the deteriorated group had smaller lumen area [3.03 (interquartile range, 2.20-3.91) vs. 3.55 mm2 (interquartile range, 2.45-4.57), P=0.033], higher plaque burden [78.92% (interquartile range, 73.95-82.61%) vs. 71.93% (interquartile range, 62.70-77.51%), P<0.001], and higher proportion of lipidic components (13.86%±4.67% vs. 11.78%±4.41%, P=0.024). Of 186 patients who completed 4.81±1.55 years follow-up, 56 developed VOCOs. Receiver-operating characteristic (ROC) curve analysis showed post-PCI AMR and VOCOs correlation (area under the curve: 0.729, P<0.001). Multivariate regression analysis showed post-PCI AMR >285 mmHg·s/m correlated with adverse outcome (hazard ratio =4.350; 95% confidence interval: 1.95-9.703; P<0.001). Conclusions: Intravascular ultrasound (IVUS) imaging and AMR revealed an association of post-PCI MVD with a smaller lumen area, more severe plaque burden, and a higher percentage of lipidic components. Post-PCI MVD was an independent risk factor for poor prognosis.

Genetic Control of Alternative Splicing and its Distinct Role in Colorectal Cancer Mechanisms.

BACKGROUND & AIMS: Dysregulation of alternative splicing is implicated in many human diseases, and understanding the genetic variation underlying transcript splicing is essential to dissect the molecular mechanisms of cancers. We aimed to provide a comprehensive functional dissection of splicing quantitative trait loci (sQTLs) in cancer and focus on elucidating its distinct role in colorectal cancer (CRC) mechanisms. METHODS: We performed a comprehensive sQTL analysis to identify genetic variants that control messenger RNA splicing across 33 cancer types from The Cancer Genome Atlas and independently validated in our 154 CRC tissues. Then, large-scale, multicenter, multi-ethnic case-control studies (34,585 cases and 76,023 controls) were conducted to examine the association of these sQTLs with CRC risk. A series of biological experiments in vitro and in vivo were performed to investigate the potential mechanisms of the candidate sQTLs and target genes. RESULTS: The molecular characterization of sQTL revealed its distinct role in cancer susceptibility. Tumor-specific sQTL further showed better response to cancer development. In addition, functionally informed polygenic risk score highlighted the potentiality of sQTLs in the CRC prediction. Complemented by large-scale population studies, we identified that the risk allele (T) of a multi-ancestry-associated sQTL rs61746794 significantly increased the risk of CRC in Chinese (odds ratio, 1.20; 95% CI, 1.12-1.29; P = 8.82 × 10-7) and European (odds ratio, 1.11; 95% CI, 1.07-1.16; P = 1.13 × 10-7) populations. rs61746794-T facilitated PRMT7 exon 16 splicing mediated by the RNA-binding protein PRPF8, thus increasing the level of canonical PRMT7 isoform (PRMT7-V2). Overexpression of PRMT7-V2 significantly enhanced the growth of CRC cells and xenograft tumors compared with PRMT7-V1. Mechanistically, PRMT7-V2 functions as an epigenetic writer that catalyzes the arginine methylation of H4R3 and H3R2, subsequently regulating diverse biological processes, including YAP, AKT, and KRAS pathway. A selective PRMT7 inhibitor, SGC3027, exhibited antitumor effects on human CRC cells. CONCLUSIONS: Our study provides an informative sQTLs resource and insights into the regulatory mechanisms linking splicing variants to cancer risk and serving as biomarkers and therapeutic targets.