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The Bivalent Fear of Evaluation (BFEO) model posits that the fear of positive evaluation (FPE) is a core feature of social anxiety. As such, high socially anxious individuals may show attention bias when faced with positive stimuli. However, most of the previous studies focused on the negative attention bias of social anxiety, and less on the attention bias of positive stimuli. Meanwhile, the effect of stimulus presentation time on the attention bias pattern was unclear. In order to investigate this question, we used a dot-probe paradigm with facial expressions (happy, fearful, angry, neutral) presented for 100 ms and 500 ms. The ERP results showed: (1) For high socially anxious group, happy faces elicited a larger N1 for valid than for invalid cued probes, whereas for healthy control group, angry faces elicited a larger N1 for valid than for invalid cued probes. (2) When valid cues following happy faces presented for 500 ms, the N1 amplitude was larger than that of invalid cues. However, when valid cues following angry and fear faces presented for 100 ms, the N1 amplitude was larger than that of invalid cues. The results showed difficulty in attention disengagement of high socially anxious individuals from positive stimuli, as reflected by N1, illustrating the positive attention bias in social anxiety. These results prove that FPE may contribute to maintaining social anxiety.

The phenotypic transformation of vascular smooth muscle cells (VSMCs) plays a key role in the pathological process of atherosclerosis (AS), and TRPM7 is involved in this process. In this study, we verified whether circRNAs participate in the phenotypic transformation of VSMCs by regulating TRPM7 in AS. The RNA-sequencing data of atherosclerosis were downloaded and analysed from the GEO database. Only hsa_circ_0021155 related to TRPM7 was differentially expressed in AS. circRNA distribution and expression were observed via FISH and PCR. CCK8, scratch test and Transwell assay were used to observe the proliferation and migration of cells. Western blot was performed to examine changes in α-actin, calponin, SMMHC and TRPM7 proteins. The expression of hsa_circ_0021155 against has-miR-4459/miR-3689c was verified via PCR. The ceRNA relationship of TPRM7-miR4459-circ0021155 was verified via dual luciferase assay, and the effects of miR4459 mimic/inhibitor on the proliferation of cells were further observed. The expression of hsa_circ_0021155 and OX-LDL was increased in VSMCs. hsa_circ_0021155 promoted the expression of TRPM7 and inhibited the protein expression of α-actin, calponin and SMMHC. In addition, it promoted the proliferation and migration of cells and inhibited the expression of miR-3689c and miR-4459 but did not affect miR-4756-5p. The dual luciferase assay showed that circ0021155-miR4459-TRPM7 mRNA was highly compatible and could be mutually regulated by a ceRNA network. In conclusion, hsa_circ_0021155 regulates the proliferation, migration and phenotype transformation of VSMCs induced by OX-LDL via the miR-4459/TRPM7 axis. hsa_circ_0021155 and TRPM7 may offer novel therapeutic targets for atherosclerosis.

To determine the effectiveness of booster vaccinations on the risk of hospitalization with coronavirus disease 2019 (COVID-19) and how it varies by enrollee characteristics and interval from the initial vaccination to receipt of a booster.This cohort study used 100% Medicare claims from January 1, 2020, through December 31, 2021, and matched 3,940,475 individuals who received boosters to 3,940,475 controls based on week and type of original COVID-19 vaccine and demographic and clinical characteristics. We compared the association of booster vs no booster with COVID-19 hospitalization using Cox proportional hazards regression models controlling for patient characteristics. We also determined the association of time from original vaccine to booster with COVID-19 hospitalization.Over a maximum of 130 days of follow-up, boosted enrollees had 8.20 (95% CI, 7.81 to 8.60) COVID-19 hospitalizations per million days vs 43.70 (95% CI, 42.79 to 44.64) for controls (81% effectiveness). Effectiveness varied by race, prior hospitalizations, and certain comorbidities, for example, leukemia/lymphoma (53% effectiveness), autoimmune disease (73%), and dementia (73%). Boosters received between 6 and 9 months after original vaccination varied between 81% and 85% effectiveness, while boosters received at 5 to 6 months (62%) or less than 5 months (58%) were less effective.Boosters are highly effective in the Medicare population. Approximately 69,225 hospitalizations would be prevented by boosters in the 15 million individuals aged 65 years or older currently not boosted in a period similar to the September 2020 through January 2021 period studied. Boosters provided the greatest benefits if they were received between 6 and 9 months following original vaccinations. However, boosters were associated with substantial decreases in COVID-19 hospitalizations in all categories of enrollees.

Coronavirus disease 2019 (COVID-19) is a rapidly spreading disease that has caused an extensive burden to the world. Consequently, a large number of clinical trials have examined the efficacy of traditional Chinese medicine (TCM) for treating and preventing COVID-19, with coinciding proliferation of reviews summarizing these studies.This study aimed to evaluate the methodological quality and evidence quality of systematic reviews and meta-analyses on the efficacy of TCM.Seven electronic databases, including PubMed, Cochrane Library, Web of Science, China National Knowledge Infrastructure, Chongqing VIP, Wanfang Data and SinoMed, were searched for systematic reviews and meta-analyses in October 2021. Search terms such as "Chinese medicine," "Lianhua Qingwen" and "COVID-19" were used.Systematic reviews and meta-analyses of randomized controlled trials that evaluated the efficacy of TCM treatment of COVID-19 were included.A Measurement Tool to Assess Systematic Reviews Version 2.0 (AMSTAR 2) was used to evaluate the methodological quality. The quality of evidence was graded using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system. Data extraction and analysis were performed by two reviewers independently.There were 17 meta-analyses included in our overview. The intervention group was defined as TCM combined with Western medicine, while the control group was Western medicine alone. The methodological quality of all the included studies was moderate to poor. A total of 89 outcome indicators were evaluated, of which, 8 were rated as moderate quality, 39 as low quality, and 41 as very low quality. Only one outcome measure was graded as being of high quality. The moderate quality of evidence indicated that, for the treatment of COVID-19, the clinical efficacy of TCM in combination with Western medicine was better, in terms of lung recovery, rate of conversion to severe/critical cases, symptom scores, duration of symptoms, mortality, and length of hospital stay.Evidence from the included studies shows that, compared with conventional Western medical therapy alone, the addition of TCM to COVID-19 treatment may improve clinical outcomes. Overall, the quality of evidence of TCM for COVID-19 was moderate to poor. Meta-analyses of the use of TCM in the treatment of COVID-19 can be used for clinical decision making by accounting for the experiences of clinical experts, medical policies, and other factors.

ImportancePatients with ST-segment elevation myocardial infarction (STEMI) living in rural settings often have worse clinical outcomes compared with their urban counterparts. Whether this discrepancy is due to clinical characteristics or delays in timely reperfusion with primary percutaneous coronary intervention (PPCI) or fibrinolysis is unclear.ObjectiveTo assess process metrics and outcomes among patients with STEMI in rural and urban settings across the US.Design, Setting, and ParticipantsThis cross-sectional multicenter study analyzed data for 70 424 adult patients with STEMI from the National Cardiovascular Data Registry Chest Pain–MI Registry in 686 participating US hospitals between January 1, 2019, and June 30, 2020. Patients without a valid zip code were excluded, and those transferred to a different hospital during the course of the study were excluded from outcome analysis.Main Outcomes and MeasuresIn-hospital mortality and time-to-reperfusion metrics.ResultsThis study included 70 424 patients with STEMI (median [IQR] age, 63 [54-73] years; 49 850 [70.8%] male and 20 574 [29.2%] female; patient self-reported race: 6753 [9.6%] Black, 60 114 [85.4%] White, and 2096 [3.0%] of another race [including American Indian, Alaskan Native, Native Hawaiian, and Pacific Islander]; 5281 [7.5%] individuals of Hispanic or Latino ethnicity) in 686 hospitals (50 702 [72.0%] living in urban zip codes and 19 722 [28.0%] in rural zip codes). Patients from rural settings were less likely to undergo PPCI compared with patients from urban settings (14 443 [73.2%] vs 43 142 [85.1%], respectively; P P P P P P P P P Conclusions and RelevanceIn this large cohort of patients with STEMI from US hospitals participating in the National Cardiovascular Data Registry Chest Pain–MI Registry, patients living in rural settings had longer times to reperfusion, were less likely to receive PPCI or meet guideline-recommended time to reperfusion, and more frequently received fibrinolytics than patients living in urban settings. However, there was no difference in adjusted in-hospital mortality between patients with STEMI from urban and rural settings.

Background. Myasthenia gravis (MG) is an acquired autoimmune disease. The main clinical features of MG are skeletal muscle fatigue and pathological fatigue, which worsen at night or after fatigue, such as dyspnea, dysphagia, and systemic weakness. Plasma exchange (PE) is often used in patients with acute exacerbation of MG. Intravenous immunoglobulin (IVIG) is a collection of immunoglobulins from thousands of donors. IVIG can replace a variety of immunosuppressants or PE. However, the effect of PE or IVIG on patients’ consciousness, immune function, and prognosis is not clear. Objective. A prospective randomized test of the effects of PE combined with immunoglobulin on consciousness, immune function, and prognosis in patients with myasthenia gravis crisis (MGC). Methods. Sixty patients with MGC treated from February 2019 to April 2021 were enrolled in our hospital. The cases who received PE were set as the PE group, and those who received PE combined with immunoglobulin were set as the PE+immunoglobulin group. The efficacy, clinical score, state of consciousness, immune function, acetylcholine receptor antibody (AChR-Ab), lymphocyte (LYM), albumin (ALB) levels, and the incidence of adverse reactions were compared. Results. The improvement rate was 100.005% in the treatment group and 83.33% in the PE group. After treatment, the clinical score of the PE+immunoglobulin group was lower than that of the PE group, and the clinical relative score of the PE+immunoglobulin group was higher than that of the PE group ( P < 0.05 ). The number of conscious people in the PE+immunoglobulin group was more than that in the PE group ( P < 0.05 ). Immunoglobulin A, immunoglobulin M, immunoglobulin G, and immunoglobulin G in the PE+immunoglobulin group were higher than those in the PE group ( P < 0.05 ). The levels of AChR-Ab and ALB in the PE+immunoglobulin group were higher than those in the PE group, while the level of LYM in the PE+immunoglobulin group was lower than that in the PE group. The incidence of skin system, gastrointestinal system, nervous system, and systemic damage in the PE+immunoglobulin group was lower than that in the PE group ( P < 0.05 ). Conclusion. The treatment of MGC with PE combined with immunoglobulin can not only effectively enhance the consciousness and immune function of patients but also effectively promote the prognosis, and the safety of treatment can be guaranteed.

The oblique lateral locking plate system (OLLPS) is a novel internal fixation with a locking and reverse pedicle track screw configuration designed for oblique lumbar interbody fusion (OLIF). The OLLPS is placed in a single position through the oblique lateral surgical corridor to reduce operative time and complications associated with prolonged anesthesia and prone positioning. The purpose of this study was to verify the biomechanical effect of the OLLPS.An intact finite element model of L1-S1 (intact) was established based on computed tomography images of a healthy male volunteer. The L4-L5 intervertebral space was selected as the surgical segment. The surgical models were established separately based on OLIF surgical procedures and different internal fixations: 1) stand-alone OLIF (SA); 2) OLIF with a 2-screw lateral plate; 3) OLIF with a 4-screw lateral plate; 4) OLIF with OLLPS; and 5) OLIF with bilateral pedicle screw fixation (BPS). After validation of the intact model, physiologic loads were applied to the superior surface of L1 to simulate motions such as flexion, extension, left bending, right bending, left rotation, and right rotation. The evaluation indices included the L4/5 range of motion, the L4 maximum displacement, and the maximum stresses of the superior and inferior end plates, the cage, and the supplemental fixation.During OLIF surgery, the OLLPS provided multiplanar stability similar to that provided by BPS. Compared with 2-screw lateral plate and 4-screw lateral plate, OLLPS had better biomechanical properties in terms of enhancing the instant stability of the surgical segment, reducing the stress on the superior and inferior end plates of the surgical segment, and decreasing the risk of cage subsidence.With a minimally invasive background, the OLLPS can be used as an alternative to BPS in OLIF and it has better prospects for clinical promotions and applications.

Aims: Given the reversibility of methylation, biomarkers with discriminating ability are of great interest for targeted therapeutic sites. Materials & methods: Methylation array data of 461 lung adenocarcinoma (LUAD) patients comprising of 458 tumor and 32 LUAD paracancerous samples were compared using partial least squares discrimination analysis and receiver operating characteristics analysis. Results: A six-DNA methylation signature (corresponding to five genes) was found to significantly discriminate normal and LUAD samples. Kyoto Encyclopedia of Genes and Genomes analysis indicated enrichment of methylation sites in the Wnt pathway in LUAD compared with controls. Conclusion: This six-DNA methylation signature demonstrated potential as a novel biomarker for diagnosis and therapeutic targets. Further, inhibition of Wnt signaling pathway may be an important step in LUAD progression.

Biodegradable Zn-Li alloys exhibit superior mechanical performance and favorable osteogenic capability for load-bearing bone devices. Additive manufacturing (AM) endows freedom for the fabrication of bone implants of personalized structure to satisfy patient-specific needs. In this paper, AM of Zn-Li alloys was attempted for the first-time using laser powder bed fusion (LPBF), and the fabricated samples exhibited good fusion quality and high dimensional accuracy. The processing optimization, mechanical properties, in vitro corrosion behavior and cytocompatibility were investigated by using Zn-0.7Li bulk and porous samples. The ultimate tensile strength and elastic modulus of bulk samples respectively reached 416.5 MPa and 83.3 GPa, and both were the highest among various additively manufactured Zn alloys reported so far. Porous samples achieved compressive strength (18.2 MPa) and elastic modulus (298.0 MPa), which were comparable to those of cancellous bone. Porous samples exhibited a higher corrosion rate and alleviated the problem of slow degradation of Zn-Li alloys. Nevertheless, osteoblastic cells showed a more spreading and healthier morphology when adhering to the porous samples compared to the bulk samples, thus a better cytocompatibility was confirmed. This work shows tremendous potential to precisely design and modulate biodegradable Zn alloys to fulfill clinical needs by using AM technology. STATEMENT OF SIGNIFICANCE: This paper firstly studied processing optimization during laser powder bed fusion of Zn-Li alloy. Bulk and porous Zn-0.7Li samples in customized design were obtained with high formation quality. The tensile strength of bulk samples reached 416.5 MPa, while the compressive strength and modulus of porous samples reduced to 18.2 MPa and 298.0 MPa, comparable to those of bone. The weight loss of porous samples was roughly 5 times that of bulk samples; osteoblastic cells showed a more spreading and healthier morphology at porous samples, indicating improved biodegradation rate and cytocompatibility. This work shows tremendous potential to precisely design and modulate biodegradable Zn alloy porous scaffolds to fulfill clinical needs by using additive manufacturing technology.

Several studies have suggested that patients with epidermal growth factor receptor (EGFR)-mutated non-small-cell lung cancer (NSCLC) might benefit from the use of tyrosine kinase inhibitors (TKIs) in combination with antiangiogenic agents. This study aimed to comprehensively review the available evidence regarding the efficacy and safety of first-line TKI plus antiangiogenic agents versus TKIs alone in EGFR-mutated advanced NSCLC.A literature search was performed using PubMed to identify studies published up to Feb. 2020. Abstracts from major international conferences reported over the last 5 years were searched. The primary outcome was progression-free survival (PFS), and the secondary outcomes included overall survival (OS), the objective response rate (ORR), and toxicity.In total, 7 relevant trials comprising 1612 patients were identified. TKIs plus antiangiogenic agents led to significant improvements in PFS regardless of the EGFR mutation subtype and presence of brain metastasis. In particular, in the subgroup with the L858R mutation, the hazard ratio (HR) of PFS was 0.58 (95% confidence interval [CI], 0.48-0.71, P.001). The OS following combined treatment was similar to that following TKI monotherapy. The ORR was increased with the use of TKIs plus antiangiogenic agents (HR 1.10, 95% CI, 1.01-1.20, P = .029). In the safety analyses, TKIs plus antiangiogenic agents exhibited a significantly increased incidence of adverse events of grade 3 or higher.The use of TKIs plus antiangiogenic agents is associated with significantly improved PFS and ORR compared with TKIs alone in untreated EGFR-mutated NSCLC. The toxicities of combination therapy should be considered when making treatment choices.

Vitamin K epoxide reductases (VKORs) are a large family of integral membrane enzymes found from bacteria to humans. Human VKOR, specific target of warfarin, has both the epoxide and quinone reductase activity to maintain the vitamin K cycle. Bacterial VKOR homologs, however, are insensitive to warfarin inhibition and are quinone reductases incapable of epoxide reduction. What affords the epoxide reductase activity in human VKOR remains unknown. Here, we show that a representative bacterial VKOR homolog can be converted to an epoxide reductase that is also inhibitable by warfarin. To generate this new activity, we first substituted several regions surrounding the active site of bacterial VKOR by those from human VKOR based on comparison of their crystal structures. Subsequent systematic substitutions narrowed down to merely eight residues, with the addition of a membrane anchor domain, that are responsible for the epoxide reductase activity. Substitutions corresponding to N80 and Y139 in human VKOR provide strong hydrogen bonding interactions to facilitate the epoxide reduction. The rest of six substitutions increase the size and change the shape of the substrate-binding pocket, and the membrane anchor domain stabilizes this pocket while allowing certain flexibility for optimal binding of the epoxide substrate. Overall, our study reveals the structural features of the epoxide reductase activity carried out by a subset of VKOR family in the membrane environment.

After the emergence of COVID-19 in 2019, it has now become a pandemic. COVID-19 has brought painful disasters to people all over the world. It not only threatens lives and health but also induces economic crises. At present, promising methods to eradicate COVID-19 mainly include drugs and vaccines. Enzyme inhibitors have always been a reliable strategy for the treatment of related diseases. Scientists worldwide have worked together to study COVID-19, obtained the structure of key SARS-CoV-2 associated enzymes, and reported the research of inhibitors of these enzymes. This article summarizes COVID-19-related enzyme inhibitors' recent development, mainly including 3CLpro, PLpro, TMPRSS2, and RdRp inhibitors, hoping to provide valuable weapons in the ensuing battle against COVID-19.

Contains fulltext : 221354.pdf (Publisher’s version ) (Closed access) Although self-persuasion was shown to be more effective than direct persuasion in changing attitudes and intentions, its effectiveness in different cultures remains unclear. Furthermore, research suggests that Eastern individuals tend to incorporate close others in the self to a larger extent than Western individuals. Combining both lines of research, the current studies examined whether thinking of a close other would influence the effectiveness of (self)-persuasion across cultures. Two parallel studies were conducted. U.S. participants (n study 1 = 195; n study 2 = 292) and Chinese participants (n study 1 = 187; n study 2 = 313) reported their initial attitudes and intentions toward five target behaviors prior to either think of a specific close other or not. Subsequently, they were randomly assigned to receive either a self-persuasion or a direct persuasion task. Specifically, the self-persuasion task led participants to generate own arguments or arguments that they think the close other would give; the direct persuasion task led participants to read given arguments or imagine that the arguments were from the close other. In the end, all participants reported their attitudes and intentions again after doing the persuasion tasks. The moderation effect of culture was only found in Study 1, such that direct persuasion worked more effectively in Chinese participants than self-persuasion, whereas the effectiveness of the two persuasive techniques did not differ in U.S. participants. In both studies, thinking of a close other was not found to influence the effectiveness of (self-)persuasion across cultures. Possible explanations and future research directions were discussed. 30 p.

Accurate and rapid diagnosis of malignant pleural and peritoneal effusions is critical due to potential association with advanced disease stages or progression. Traditional cytodiagnosis suffers from low efficiency and has difficulties in finding malignant tumor cells (MTCs) from a mass of exfoliated cells. Hence, a polymer microfluidic chip with a slanted spiral channel was employed for high-throughput and label-free enrichment of MTCs and MTC clusters from clinical malignant pleural and peritoneal effusions. The slanted spiral channel with trapezoidal cross-sections was fabricated by assembling two patterned polymer films of different thicknesses within one flow channel layer. After systematically exploring the effects of the particle size, effusion concentration, and flow rate on separation performance of the device, we realized the enrichment of MTCs from abundant blood cells in 2-fold diluted effusions. The results indicated that approximately 85% of the spiked tumor cells (A549 and MCF-7 cell lines) were recovered with high purities of over 37% at a high throughput of 2000 μL min

Internet gaming disorder (IGD) has become an increasing mental health issue worldwide. Previous studies indicated that IGD was related to maladaptive risk-taking behavior. However, the relationship among risk-taking behavior, reflection level, and resting-state functional connectivity (rsFC) between brain regions in IGD individuals remains unclear. The current study combined resting-state fMRI and the Devil task to investigate this issue. The behavioral results suggested that IGD participants exhibited increased risk-taking behavior in the Devil task than healthy controls. Moreover, IGD participants' risk-taking behavior was positively correlated with their reflection level. As for fMRI results, IGD participants showed stronger rsFC between orbitofrontal cortex (OFC) and inferior frontal gyrus (IFG) than healthy controls. Additionally, the mediation analyses revealed that, among IGD participants, the rsFC between OFC and IFG fully mediated the relationship between reflection level and risk-taking behavior. Together, the current study highlighted that the altered rsFC between OFC and IFG in IGD individuals modified the relationship between their reflection level and risk-taking behavior, which might contribute to the understanding of neural mechanisms underlying risk-taking behavior in IGD individuals.

Most of the existing stretchable strain sensors are based on the contact-resistance mechanism, where the stretchability and resistance variation depend on the change of the contact relationship of the conductive microstructures. These sensors usually exhibit large sensing ranges and gauge factors but unsatisfactory repeatability and linearity of the electrical responses because the contact is unstable. Here, we report a completely different design for stretchable strain sensors based on a contact-resistance-free structure, i.e., the off-axis serpentine sandwich structure (OASSS), with the mechanism of the stretch-bending-stretch transformation (SBST). Neither unstable contact resistance nor nonlinear constitutive and geometric behaviors occur for the OASSS while the sensor undergoes a large applied strain (50%), which guarantees high repeatability (repeatability error = 1.58%) and linearity (goodness-of-fitgt;0.999). Owing to such performances, the present sensors are not only applied to monitoring human activities and medical surgery but also to the ground tests of Tianwen-1, China's first Mars exploration mission.

Selenium (Se) plays an important role in human health. Approximately 80% of the world’s population does not consume enough Se which recommended by WHO (World Health Organization). Wheat is an important staple food and Se source for most people in the world. This article summarizes literatures about Se from 1936 to 2020 to investigate Se in wheat farming soil, wheat, and its derived foods. Se fortification and the recommended Se level in wheat were also discussed. Results showed that Se contents in wheat farming soil, grain, and its derived foods around the world were 3.8–552 (mean, 220.99), 0–8,270 (mean, 347.30), and 15–2,372 (mean, 211.86) μg·kg−1, respectively. Adopting suitable agronomic measures could effectively realize Se fortification in wheat. The contents in grain, flour, and its derived foods could be improved from 93.94 to 1,181.92, 73.06 to 1,007.75, and 86.90 to 587.61 μg·kg−1 in average after leaf Se fertilizer application in the field. There was a significant positive correlation between Se content in farming soil and grain, and it was extremely the same between foliar Se fertilizer concentration rate and grain Se increased rate. The recommended Se fortification level in cultivation of wheat in China, India, and Spain was 18.53–23.96, 2.65–3.37, and 3.93–9.88 g·hm−2 respectively. Milling processing and food type could greatly affect Se content of wheat derived food and should be considered seriously to meet people’s Se requirement by wheat.TOC graphic

BACKGROUND: Assessment of subclinical myocardial dysfunction by using feature tracking has shown promise in prognosis evaluation of heart failure with preserved ejection fraction (HFpEF). Global early diastolic longitudinal strain rate (eGLSR) can identify earlier diastolic dysfunction; however, limited data are available on its prognostic value in HFpEF. PURPOSE: To evaluate the association between left ventricular (LV) eGLSR and primary composite outcomes (all-cause death or heart failure hospitalization) in patients with HFpEF. MATERIALS AND METHODS: In this retrospective study, consecutive patients with HFpEF (included from January 2010 to March 2013) underwent cardiovascular MRI. The correlation between eGLSR and variables was assessed by using linear regression. The association between eGLSR (obtained with use of feature tracking) and outcomes was analyzed by using Cox proportional regression. RESULTS: A total of 186 patients with HFpEF (mean age ± standard deviation, 59 years ± 12; 77 women) were included. The eGLSR was weakly correlated with LV end-diastole volume index (Pearson correlation coefficient [r] = –0.35; P < .001), heart rate (r = 0.35; P < .001), and LV ejection fraction (r = 0.30; P < .001) and moderately correlated with LV end-systole volume index (r = –0.41; P < .001). At a median follow-up of 9.2 years (interquartile range, 8.7–10.0 years), 72 patients experienced primary composite outcomes. Impaired eGLSR, defined as an eGLSR of less than 0.57 per second, was associated with a greater rate of heart failure hospitalization or all-cause death (hazard ratio, 2.0 [95% CI: 1.1, 3.7]; P = .02) after adjusting for multiple clinical and imaging-based variables. CONCLUSION: Left ventricular global early diastolic longitudinal strain rate obtained from cardiovascular MRI feature tracking was independently associated with adverse outcomes in patients with heart failure with preserved ejection fraction. © RSNA, 2021 Online supplemental material is available for this article. An earlier incorrect version appeared online. This article was corrected on October 22, 2021.

Background Mounting experimental evidence has shown that the gut microbiota plays a significant role in the pathogenesis of mastitis, and clinical investigations have found that the occurrence of mastitis is correlated with ruminal dysbiosis. However, the underlying mechanism by which the ruminal microbiota participates in the development of mastitis remains unknown. Results In the present study, we found that cows with clinical mastitis had marked systemic inflammation, which was associated with significant ruminal dysbiosis, especially enriched Proteobacteria in the rumen. Ruminal microbiota transplantation from mastitis cows (M-RMT) to mice induced mastitis symptoms in recipient mice along with increased mammary proinflammatory signature activation of the TLR4-cGAS-STING-NF-κB/NLRP3 pathways. M-RMT also induced mucosal inflammation and impaired intestinal barrier integrity, leading to increased endotoxemia and systemic inflammation. Moreover, we showed that M-RMT mirrored ruminal microbiota disruption in the gut of recipient mice, as evidenced by enriched Proteobacteria and similar bacterial functions, which were correlated with most proinflammatory parameters and serum lipopolysaccharide (LPS) levels in mice. Recurrent low-grade LPS treatment mirrored gut dysbiosis-induced endotoxemia and caused severe mastitis in mice. Furthermore, we found that gut dysbiosis-derived LPS reduced host alkaline phosphatase activity by activating neuraminidase (Neu), which facilitates low-grade LPS exposure and E. coli-induced mastitis in mice. Conversely, treatment with calf intestinal alkaline phosphatase or the Neu inhibitor zanamivir alleviated low-grade LPS exposure and E. coli-induced mastitis in mice. Conclusions Our results suggest that ruminal dysbiosis-derived low-grade endotoxemia can cause mastitis and aggravate pathogen-induced mastitis by impairing host anti-inflammatory enzymes, which implies that regulating the ruminal or gut microbiota to prevent low-grade systemic inflammation is a potential strategy for mastitis intervention.

BackgroundThe human leukocyte antigen class I (HLA-I) genotype has been linked with differential immune responses to infectious disease and cancer. However, the clinical relevance of germline HLA-mediated immunity in gastrointestinal (GI) cancer remains elusive.MethodsThis study retrospectively analyzed the genomic profiling data from 84 metastatic GI cancer patients treated with immune checkpoint blockade (ICB) recruited from Peking University Cancer Hospital (PUCH). A publicly available dataset from the Memorial Sloan Kettering (MSK) Cancer Center (MSK GI cohort) was employed as the validation cohort. For the PUCH cohort, we performed HLA genotyping by whole exome sequencing (WES) analysis on the peripheral blood samples from all patients. Tumor tissues from 76 patients were subjected to WES analysis and immune oncology-related RNA profiling. We studied the associations of two parameters of germline HLA as heterozygosity and evolutionary divergence (HED, a quantifiable measure of HLA-I evolution) with the clinical outcomes of patients in both cohorts.ResultsOur data showed that neither HLA heterozygosity nor HED at the HLA-A/HLA-C locus correlated with the overall survival (OS) in the PUCH cohort. Interestingly, in both the PUCH and MSK GI cohorts, patients with high HLA-B HED showed a better OS compared with low HLA-B HED subgroup. Of note, a combinatorial biomarker of HLA-B HED and tumor mutational burden (TMB) may better stratify potential responders. Furthermore, patients with high HLA-B HED were characterized with a decreased prevalence of multiple driver gene mutations and an immune-inflamed phenotype.ConclusionsOur results unveil how HLA-B evolutionary divergence influences the ICB response in patients with GI cancers, supporting its potential utility as a combinatorial biomarker together with TMB for patient stratification in the future.

A massive depletion of CD4+ T lymphocytes has been described in early and acute human immunodeficiency virus (HIV) infection, leading to an imbalance between the human microbiome and immune responses. In recent years, a growing interest in the alterations in gut microbiota in HIV infection has led to many studies; however, only few studies have been conducted to explore the importance of oral microbiome in HIV-infected individuals. Evidence has indicated the dysbiosis of oral microbiota in people living with HIV (PLWH). Potential mechanisms might be related to the immunodeficiency in the oral cavity of HIV-infected individuals, including changes in secretory components such as reduced levels of enzymes and proteins in saliva and altered cellular components involved in the reduction and dysfunction of innate and adaptive immune cells. As a result, disrupted oral immunity in HIV-infected individuals leads to an imbalance between the oral microbiome and local immune responses, which may contribute to the development of HIV-related diseases and HIV-associated non-acquired immunodeficiency syndrome comorbidities. Although the introduction of antiretroviral therapy (ART) has led to a significant decrease in occurrence of the opportunistic oral infections in HIV-infected individuals, the dysbiosis in oral microbiome persists. Furthermore, several studies with the aim to investigate the ability of probiotics to regulate the dysbiosis of oral microbiota in HIV-infected individuals are ongoing. However, the effects of ART and probiotics on oral microbiome in HIV-infected individuals remain unclear. In this article, we review the composition of the oral microbiome in healthy and HIV-infected individuals and the possible effect of oral microbiome on HIV-associated oral diseases. We also discuss how ART and probiotics influence the oral microbiome in HIV infection. We believe that a deeper understanding of composition and function of the oral microbiome is critical for the development of effective preventive and therapeutic strategies for HIV infection.

Broadly neutralizing antibodies (bNAbs) possess favorable safety, and passive immunization using these can prevent or control human immunodeficiency virus type 1 (HIV-1) infection. However, bNAbs generally used for monotherapy (IC80 > 5 μg/mL) have limited breadth and potency and neutralize only 70–90% of all HIV-1 strains. To address the need for broader coverage of the HIV-1 epidemic and enhance the ability of bNAbs to target HIV-1, we fused the single-chain variable antibody fragment (scFv) of bNAbs (PG9, PGT123, or NIH45–46) with full-length ibalizumab (iMab) in an scFv-monoclonal antibody tandem format to construct bispecific bNAbs (BibNAbs). Additionally, we described the feasibility of BibNAb gene delivery mediated by recombinant adeno-associated virus 8 (rAAV8) for generating long-term expression with a single injection as opposed to short-term passive immunization requiring continuous injections. Our results showed that the expressed BibNAbs targeting two distinct epitopes exhibited neutralizing activity against 20 HIV-1 pseudoviruses in vitro. After injecting a single rAAV8 vector, the expression and neutralizing activity of the BibNAbs in serum were sustained for 24 weeks. To the best of our knowledge, very few studies have been published on BibNAb gene delivery using rAAV8 vectors against HIV-1. BibNAb gene delivery using rAAV8 vectors may be promising for passive immunization against HIV-1 infection.

Acute kidney injury (AKI) is mainly characterized by rapid decline of renal function. Currently, the strategy of stem cells might be a therapy to treat AKI. The objective of this study was to obtain human urine-derived cells (HUCs) from patients with AKI, followed by establishing induced pluripotent stem (iPS) cell line. We isolated urine cells from patients with AKI and found that the cells could survive long term with epithelioid morphology and maintain a normal karyotype. The cell line had expression of renal-specific markers and renal development-related genes. After induction, the urine cells cotransfecting with TET-ON vectors were converted into iPS cells. The HUC-derived iPS (HUC-iPS) was positive for alkaline phosphatase staining, and had expression of pluripotency markers, consistent with human embryonic fibroblast-derived iPS cell. Notably, HUC-iPS could be induced to undergo directional kidney precursor cells (KPCs) differentiation under defined conditions, and transplantation of KPCs resulted in reducing kidney damage from ischemia-reperfusion injury in mice. Therefore, we successfully established HUC-iPS cell from patients with AKI and provided a novel stem cell resource for cell therapy in AKI.

The paper aimed to explore the mechanism of miR-137 in modulating glioma.qRT-PCR detected miR-137 and E2F7 mRNA expression in cells. The protein expression of E2F7 was measured using Western blot assay. Cell proliferation, scratch healing, transwell and programmed cell death assays were conducted to examine the influences of the genes on the biological function of glioma cells. The dual-luciferase assay verified the interaction between miR-137 and E2F7.MiR-137 was lowly expressed in glioma cells, and E2F7 was highly expressed. MiR-137 suppressed progression and promoted programmed cell death of glioma cells. MiR-137 could target and negatively regulate E2F7 expression to further accelerate programmed cell death of glioma cells.It was found that miR-137 could target E2F7 to restrain cell progression and accelerate programmed cell death of glioma cells, which is helpful to search for new molecular therapeutic targets for glioma.

The process of urban development in China is that cities retain independent administrative divisions, realize inter-regional urban integration, and then establish metropolitan areas; this process has high requirements for the coordinated development of cities. China’s cities still need to receive approximately 300 million people in the future, and these urban populations are mainly planned in the emerging metropolitan area. In order to clarify the problems and development of the direction of China’s emerging megalopolis in the process of building a framework for carrying urban population, and to provide reference for China’s urbanization process, the entropy weight method–coupling coordination degree model–panel vector autoregression model (EWM-CCDM-PVAR) is constructed to measure the development level, coupling coordination degree and dynamic response relationship of NTU-UI-UE in the Jiaodong Economic Circle. First, the development level of new-type urbanization and urban infrastructure in the Jiaodong Economic Circle has been steadily improved, but regional differences have been expanding year by year. The urban environment of most cities in the Jiaodong Economic Circle is deteriorating. Second, the CCD level of NTU-UI-UE in the Jiaodong Economic Circle is on the rise, but the CCD level of NTU-UI-UE in Weifang and Yantai is only a Moderate-coupling coordination type, and the development within the region is uneven. Third, both NTU-UI and UI-UE in the Jiaodong Economic Circle have established a dynamic response relationship of mutual promotion, but NTU-UE has a dynamic response relationship of mutual inhibition. Fourth, despite different problems, the Jiaodong Economic Circle has made certain achievements in the process of regional integration and has initially formed a metropolitan circle pattern with Qingdao as its core, Weifang as its west center, Yantai and Weihai as its north center and Rizhao as its south center.

Human immunodeficiency virus (HIV) infection might have effects on both the human bacteriome and mycobiome. Although many studies have focused on alteration of the bacteriome in HIV infection, only a handful of studies have also characterized the composition of the mycobiome in HIV-infected individuals. Studies have shown that compromised immunity in HIV infection might contribute to the development of opportunistic fungal infections. Despite effective antiretroviral therapy (ART), opportunistic fungal infections continue to be a major cause of HIV-related mortality. Human immune responses are known to play a critical role in controlling fungal infections. However, the effect of HIV infection on innate and adaptive antifungal immunity remains unclear. Here, we review recent advances in understanding of the fungal microbiota composition and common fungal diseases in the setting of HIV. Moreover, we discuss innate and adaptive antifungal immunity in HIV infection.

Fungicides can lead to soil and plant diseases after long-term enrichment in the environment; they can also penetrate deeper into the soil and groundwater by rainwater or irrigation, threatening the water environment and human health. Therefore, it is crucial to develop a simple, rapid, efficient, and sensitive analytical method for the detection of fungicides in the water environment. Sample pretreatment is important for the extraction and enrichment of pollutants from environmental water. Magnetic solid phase extraction (MSPE) is a new sample pretreatment method, which uses magnetic materials as adsorbents dispersed in solution, and rapid separation can be achieved by the aid of external magnets. Because of its advantages of short analytical time, less organic solvent consumption, and easy separation of adsorbents, MSPE has attracted much attention. The key to MSPE is the preparation of highly selective magnetic adsorbents. Covalent organic frameworks have the advantages of large surface area, good chemical and thermal stability, tunable porous structure, low density, and easy functionalization, all of which are ideal for adsorbing fungicides. The concentration of fungicides in environmental water is low. Ultrahigh performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) has high sensitivity and high selectivity, which is suitable for the analysis of fungicides. In this work, a magnetic covalent organic framework Fe

Several antihypertensive drugs have been used for the treatment of glaucoma. However, the effect of hypertension and antihypertensive drugs on glaucoma is still unclear.Leveraging large-scale genome-wide association study summary statistics for glaucoma (Ncase = 4737, Ncontrol = 458,196), blood pressure (BP) (N = 422,771), and intraocular pressure (IOP) (N = 31,269), the genetic correlation and causal relationship of genetically assessed IOP, systolic blood pressure (SBP), diastolic blood pressure (DBP), and 12 types of antihypertensive drugs with glaucoma were evaluated using linkage disequilibrium score (LDSC) regression, univariate mendelian randomization (MR), and multivariable MR.LDSC results showed a suggestive association of glaucoma with SBP (Rg = 0.12, P = 0.0076) and DBP (Rg = 0.17, P = 0.02). In univariate MR, genetically elevated BP in participants was not identified to lead to an increased glaucoma risk (SBP: odds ratio [OR], 1.05 [95% confidence interval {CI}, 0.91-1.21]; P = 0.52; DBP: OR, 1.07 [95% CI, 0.93-1.23]; P = 0.34). The results of univariate MR were replicated in multivariable MR (SBP: OR, 0.95 [95% CI, 0.71-1.29]; P = 0.75; DBP: OR, 1.13 [95% CI, 0.85-1.51]; P = 0.41). Furthermore, there was insufficient evidence to suggest that antihypertensive drugs were associated with glaucoma.Together, controlling BP may not help prevent and treat glaucoma, and antihypertensive drugs may neither treat nor worsen glaucoma.Treating with antihypertensive drugs should not be used as an intervention for patients with glaucoma.

BackgroundStudies have shown that hepatocellular carcinoma (HCC) heterogeneity is a main cause leading to failure of treatment. Technology of single-cell sequencing (scRNA) could more accurately reveal the essential characteristics of tumor genetics.MethodsFrom the Gene Expression Omnibus (GEO) database, HCC scRNA-seq data were extracted. The FindCluster function was applied to analyze cell clusters. Autophagy-related genes were acquired from the MSigDB database. The ConsensusClusterPlus package was used to identify molecular subtypes. A prognostic risk model was built with the Least Absolute Shrinkage and Selection Operator (LASSO)–Cox algorithm. A nomogram including a prognostic risk model and multiple clinicopathological factors was constructed.ResultsEleven cell clusters labeled as various cell types by immune cell markers were obtained from the combined scRNA-seq GSE149614 dataset. ssGSEA revealed that autophagy-related pathways were more enriched in malignant tumors. Two autophagy-related clusters (C1 and C2) were identified, in which C1 predicted a better survival, enhanced immune infiltration, and a higher immunotherapy response. LASSO–Cox regression established an eight-gene signature. Next, the HCCDB18, GSA14520, and GSE76427 datasets confirmed a strong risk prediction ability of the signature. Moreover, the low-risk group had enhanced immune infiltration and higher immunotherapy response. A nomogram which consisted of RiskScore and clinical features had better prediction ability.ConclusionTo precisely assess the prognostic risk, an eight-gene prognostic stratification signature was developed based on the heterogeneity of HCC immune cells.

We identified relapsing fever (RF)

Aims: To identify a novel subtype with DNA driver methylation-transcriptomic multiomics and predict prognosis and therapy response in serous ovarian cancer (SOC). Methods: SOC cohorts with both mRNA and methylation were collected, and DNA driver methylation (DNAme) was identified with the MithSig method. A novel prognostic subtype was developed by integrating the information on DNAme and prognosis-regulated DNAme-associated mRNA by similarity network fusion. Results: 43 overlapped DNAme were identified in three independent cohorts. SOC patients were categorized into three distinct subtypes by integrated multiomics. There were differences in prognosis, tumor microenvironment and response to therapy among the subtypes. Conclusion: This study identified 43 DNAmes and proposes a novel subtype toward personalized chemotherapy and immunotherapy for SOC patients based on multiomics.

BACKGROUND: Older adults have many comorbidities contributing to mortality. OBJECTIVE: To develop a summary Elixhauser (S-Elixhauser) comorbidity score to predict 30-day, in-hospital, and 1-year mortality in older adults using the 38 comorbidities operationalized by the Agency for Healthcare Research and Quality (AHRQ). DESIGN: Retrospective cohort study. SETTING: Medicare beneficiaries from 2017 to 2019. PATIENTS: Persons hospitalized in 2018 (n = 899 844) and 3 disease-specific hospitalized cohorts. MEASUREMENTS: Weights were derived for 38 comorbidities to predict 30-day, in-hospital, and 1-year mortality. The S-Elixhauser score was internally validated and calibrated. Individual Elixhauser comorbidity indicators (38 comorbidities), the modified application of the AHRQ-derived Elixhauser summary score, the Charlson comorbidity indicators (17 comorbidities), and the Charlson summary score were externally validated. The c-statistic was used to evaluate discrimination of a comorbidity score model. RESULTS: The S-Elixhauser score was well calibrated and internally validated, with a c-statistic of 0.705 (95% CI, 0.703 to 0.707) in predicting 30-day mortality, 0.654 (CI, 0.651 to 0.657) for in-hospital mortality, and 0.743 (CI, 0.741 to 0.744) for 1-year mortality. In external validation of other comorbidity indices for 30-day mortality, the c-statistic was 0.711 (CI, 0.709 to 0.713) for the individual Elixhauser comorbidity indicators, 0.688 (CI, 0.686 to 0.690) for the AHRQ Elixhauser score, 0.696 (CI, 0.694 to 0.698) for the Charlson comorbidity indicators, and 0.690 (CI, 0.688 to 0.693) for the Charlson summary score. In 3 disease-specific populations, the discrimination of the S-Elixhauser score in predicting 30-day mortality ranged from 0.657 to 0.732. LIMITATIONS: Validation of the S-Elixhauser comorbidity score and head-to-head comparison with other comorbidity scores in an external population are needed to evaluate comparative performance. CONCLUSION: The S-Elixhauser comorbidity score is well calibrated and internally validated but its advantage over the AHRQ Elixhauser and Charlson summary scores is unclear. PRIMARY FUNDING SOURCE: National Institute on Aging.

Wild yak (Bos mutus) and domestic yak (Bos grunniens) are adapted to high altitude environment and have ecological, economic, and cultural significances on the Qinghai-Tibetan Plateau (QTP). Currently, the genetic and cellular bases underlying adaptations of yak to extreme conditions remains elusive. In the present study, we assembled two chromosome-level genomes, one each for wild yak and domestic yak, and screened structural variants (SVs) through the long-read data of yak and taurine cattle. The results revealed that 6733 genes contained high-FST SVs. 127 genes carrying special type of SVs were differentially expressed in lungs of the taurine cattle and yak. We then constructed the first single-cell gene expression atlas of yak and taurine cattle lung tissues and identified a yak-specific endothelial cell subtype. By integrating SVs and single-cell transcriptome data, we revealed that the endothelial cells expressed the highest proportion of marker genes carrying high-FST SVs in taurine cattle lungs. Furthermore, we identified pathways which were related to the medial thickness and formation of elastic fibers in yak lungs. These findings provide new insights into the high-altitude adaptation of yak and have important implications for understanding the physiological and pathological responses of large mammals and humans to hypoxia.

Ubiquitin-specific peptidase 9X (USP9X) has been reported to be closely associated with the formation and progression of a variety of malignant tumors. However, the mechanism by which USP9X is involved in osteosarcoma and development has not been clearly studied. This work aimed to probe the influence of USP9X on osteosarcoma cell proliferation, migration and invasion. This study recruited sixty-seven patients with histologically definited osteosarcoma. Osteosarcoma samples and cell-line were used to reflect the expression level of USP9X. Analysis of cell proliferation by thiazolium blue (MTT) assays. Transwell experiments and wound healing were used to verify cell migration and invasion capabilities. The effect of USP9X was investigated through in vivo experiments. USP9X-related pathway proteins were detected by Western blot and quantitative real-time PCR (qRT-PCR). The expression of USP9X in osteosarcoma was higher than that in adjacent tissues. The overall survival of patients with USP9X-negative patients was better than that of patients with USP9X-positive. The growth of osteosarcoma cells in vivo and in vitro was inhibited by USP9X inhibitor. Cell migration and invasion were significantly inhibited by down-regulation of USP9X. USP9X was involved in extracellular signal-regulated kinase 1/2 (ERK1/2) and phosphatidylinositol-3-kinases/protein-serine-threonine kinase (PI3K/Akt) pathway in osteosarcoma cells. Proliferation, migration and invasion of osteosarcoma cells were inhibited by down-regulation of USP9X, and were related to the ERK1/2 and PI3K/Akt signaling pathways, therefore, it might probably become a new target for the prevention and treatment of osteosarcoma.

Deep learning (DL) has been applied for automatic left ventricle (LV) ejection fraction (EF) measurement, but the diagnostic performance was rarely evaluated for various phenotypes of heart disease. This study aims to evaluate a new DL algorithm for automated LVEF measurement using two-dimensional echocardiography (2DE) images collected from three centers. The impact of three ultrasound machines and three phenotypes of heart diseases on the automatic LVEF measurement was evaluated. Using 36890 frames of 2DE from 340 patients, we developed a DL algorithm based on U-Net (DPS-Net) and the biplane Simpson's method was applied for LVEF calculation. Results showed a high performance in LV segmentation and LVEF measurement across phenotypes and echo systems by using DPS-Net. Good performance was obtained for LV segmentation when DPS-Net was tested on the CAMUS data set (Dice coefficient of 0.932 and 0.928 for ED and ES). Better performance of LV segmentation in study-wise evaluation was observed by comparing the DPS-Net v2 to the EchoNet-dynamic algorithm (

Metal-organic frameworks (MOFs) are composed of metal ions/clusters and organic ligands, showing accessible functional sites, ultra-high porosity, and large specific surface area. Tricopper benzene-1,3,5-tricarboxylate (CuBTC), as a three-dimensional MOF architecture with an open and robust micro-/nanoconfiguration, possesses excellent catalytic performance and superior electric conductivity as compared to bulk MOF. In this study, CuBTC was used as a substrate on which molybdenum disulfide (MoS

Many kinds of cancer cells are intrinsically sensitive to ferroptosis, and research interest regarding ferroptosis has been sparked by its significant role in many detrimental diseases. Ferroptosis is a novel type of iron-dependent cell death mediated by accumulation of reactive oxygen species and lipid peroxidation. Furthermore, a large number of small agents can induce ferroptosis in numerous kinds of cancer cells, including prostate cancer, pancreatic cancer, breast cancer, lymphomas, and renal cancer. These insights may help discover novel approaches for cancer therapeutic strategies; however, there is considerable uncertainty regarding ferroptosis in head and neck cancer (HNC). So far, no review of the current studies on this topic has been published. Therefore, we here elaborate the mechanisms of ferroptosis and summarize the latest findings regarding its role in HNC according to current literature. The respective findings shed light on the role of ferroptosis in HNC treatment with a number of important implications for future practice in HNC management, as outlined in this review.

Background Although Mex3 RNA‐binding family member A (Mex3a) has demonstrated an important role in multiple cancers, its role and regulatory mechanism in CRC is unclear. In this study, we aimed to investigate the role and clinical significance of Mex3a in CRC and to explore its underlying mechanism. Methods Western blotting and quantitative real‐time polymerase chain reaction (qRT‐PCR) were performed to detect the expression levels of genes. 5‐Ethynyl‐2'‐deoxyuridine (EDU) and transwell assays were utilized to examine CRC cell proliferation and metastatic ability. The R software was used to do hierarchical clustering analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. Overexpression and rescue experiments which included U0126, a specific mitogen activated protein kinase kinase/extracellular regulated protein kinase (MEK/ERK) inhibitor, and PX‐478, a hypoxia‐inducible factor 1 subunit alpha (HIF‐1α) inhibitor, were used to study the molecular mechanisms of Mex3a in CRC cells. Co‐immunoprecipitation (Co‐IP) assay was performed to detect the interaction between two proteins. Bioinformatics analysis including available public database and Starbase software (starbase.sysu.edu.cn) were used to evaluate the expression and prognostic significance of genes. TargetScan (www.targetscan.org) and the miRDB (mirdb.org) website were used to predict the combination site between microRNA and target mRNA. BALB/c nude mice were used to study the function of Mex3a and hsa‐miR‐6887‐3p in vivo. Results Clinicopathological and immunohistochemical (IHC) studies of 101 CRC tissues and 79 normal tissues demonstrated that Mex3a was a significant prognostic factor for overall survival (OS) in CRC patients. Mex3a knockdown substantially inhibited the migration, invasion, and proliferation of CRC cells. Transcriptome analysis and mechanism verification showed that Mex3a regulated the RAP1 GTPase activating protein (RAP1GAP)/MEK/ERK/HIF‐1α pathway. Furthermore, RAP1GAP was identified to interact with Mex3a in Co‐IP experiments. Bioinformatics and dual‐luciferase reporter experiments revealed that hsa‐miR‐6887‐3p could bind to the 3'‐untranslated regions (3'‐UTR) of the Mex3a mRNA. hsa‐miR‐6887‐3p downregulated Mex3a expression and inhibited the tumorigenesis of CRC both in vitro and in vivo. Conclusions Our study demonstrated that the hsa‐miR‐6887‐3p/Mex3a/RAP1GAP signaling axis was a key regulator of CRC and Mex3a has the potential to be a new diagnostic marker and treatment target for CRC.

Background Little is known about how continuity of care for hospitalized patients varies among hospitals. We describe the number of different general internal medicine physicians seeing hospitalized patients during a medical admission and how that varies by hospital. Methods We conducted a retrospective study of a national 20% sample of Medicare inpatients from 01/01/16 to 12/31/18. In patients with routine medical admissions (length of stay of 3–6 days, no Intensive Care Unit stay, and seen by only one generalist per day), we assessed odds of receiving all generalist care from one generalist. We calculated rates for each hospital, adjusting for patient and hospital characteristics in a multi-level logistic regression model. Results Among routine medical admissions with 3- to 6-day stays, only 43.1% received all their generalist care from the same physician. In those with a 3-day stay, 50.1% had one generalist providing care vs. 30.8% in those with a 6-day stay. In a two-level (admission and hospital) logistic regression model controlling for patient characteristics and length of stay, the odds of seeing just one generalist did not vary greatly by patient characteristics such as age, race/ethnicity, comorbidity or reason for admission. There were large variations in continuity of care among different hospitals and geographic areas. In the highest decile of hospitals, the adjusted mean percentage of patients receiving all generalist care from one physician was > 84.1%, vs. Conclusions Continuity of care provided by generalist physicians to medical inpatients varies widely among hospitals. The impact of this variation on quality of care is unknown.

Aflatioxin B

The intestinal compensatory proliferative potential is a key influencing factor for susceptibility to radiation-induced intestinal injury. Studies indicated that the carnitine palmitoyltransferase 1 (CPT1) mediated fatty acid β-oxidation (FAO) plays a crucial role in promoting the survival and proliferation of tumor cells. Here, we aimed to explore the effect of 60Co gamma rays on CPT1 mediated FAO in the radiation-induced intestinal injury models, and investigate the role of CPT1 mediated FAO in the survival and proliferation of intestinal cells after irradiation. We detected the changed of FAO in the plasma and small intestine of Sprague Dawley (SD) rats at 24 h after 60Co gamma irradiation (0, 5 and 10 Gy), using target metabolomics, qRT-PCR, immunohistochemistry (IHC), western blot (WB) and related enzymatic activity kits. We then analyzed the FAO changes in radiation-induced intestinal injury models regardless of ex vivo (mice enteroids), or in vitro (normal human intestinal epithelial cell lines, HIEC-6). HIEC-6 cells were transduced with lentivirus vector GV392 and treated with puromycin for obtaining CPT1 stable knockout cell lines, named CPT1 KO. CPT1 enzymatic activities of HIEC-6 cells and mice enteroids were also inhibited by pharmaceutical inhibitor ST1326 and Etomoxir (ETO), to study the function of CPT1 in the survival and proliferation of HIEC-6 cells after 60Co gamma irradiation. We found that CPT1 mediated FAO was altered in the small intestine of the SD rats after irradiation, especially, the expression level and enzymatic activity of CPT1 were significantly increased. Similarly, the expression levels of CPT1 were also remarkably enhanced in mice enteroids and HIEC-6 cells after irradiation. CPT1 inhibition decreased the proliferation of the HIEC-6 cells and mice enteroids after irradiation partially by reducing the extracellular signal-regulated kinase (ERK1/2) and c-Jun N-terminal kinase (JNK) pathways activation, CPT1 inhibition also reduced the proliferation of mice enteroids after irradiation partially by down-regulating the Wnt/β-catenin signaling activity. In conclusion, our study indicated that CPT1 plays a crucial role in promoting intestinal epithelial cell proliferation after irradiation.

The tumor immune microenvironment could provide prognostic and predictive information. It is necessary to develop a noninvasive radiomics-based biomarker of a previously validated tumor immune microenvironment signature of gastric cancer (GC) with immunohistochemistry staining.A total of 230 patients (training (n = 153) or validation (n = 77) cohort) with gastric cancer were subjected to (Positron Emission Tomography-Computed Tomography) radiomics feature extraction (80 features). A radiomics tumor immune microenvironment score (RTIMS) was developed to predict the tumor immune microenvironment signature with LASSO logistic regression. Furthermore, we evaluated its relation with prognosis and chemotherapy benefits.A 8-feature radiomics signature was established and validated (area under the curve=0.692 and 0.713). The RTIMS signature was significantly associated with disease-free survival and overall survival both in the training and validation cohort (allThis PET/CT radiomics model provided a promising way to assess the tumor immune microenvironment and to predict clinical outcomes and chemotherapy response. The RTIMS signature could be useful in estimating tumor immune microenvironment and predicting survival and chemotherapy benefit for patients with gastric cancer, when validated by further prospective randomized trials.

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging tick-borne disease with a high case fatality rate. Few studies have been performed on bacterial or fungal coinfections or the effect of antibiotic therapy. A retrospective, observational study was performed to assess the prevalence of bacterial and fungal coinfections in patients hospitalized for SFTSV infection. The most commonly involved microorganisms and the effect of antimicrobial therapy were determined by the site and source of infection. A total of 1201 patients hospitalized with SFTSV infection were included; 359 (29.9%) had microbiologically confirmed infections, comprised of 292 with community-acquired infections (CAIs) and 67 with healthcare-associated infections (HAIs). Death was independently associated with HAIs, with a more significant effect than that observed for CAIs. For bacterial infections, only those acquired in hospitals were associated with fatal outcomes, while fungal infection, whether acquired in hospital or community, was related to an increased risk of fatal outcomes. The infections in the respiratory tract and bloodstream were associated with a higher risk of death than that in the urinary tract. Both antibiotic and antifungal treatments were associated with improved survival for CAIs, while for HAIs, only antibiotic therapy was related to improved survival, and no effect from antifungal therapy was observed. Early administration of glucocorticoids was associated with an increased risk of HAIs. The study provided novel clinical and epidemiological data and revealed risk factors, such as bacterial coinfections, fungal coinfections, infection sources, and treatment strategies associated with SFTS deaths/survival. This report might be helpful in curing SFTS and reducing fatal SFTS.

Ovarian cancer (OC) is a highly malignant cancer with great metastatic potential. Here we aimed to investigate the role of Piezo1, a gene related to the mechanical environment of the tumor, in promoting the metastasis of OC. We performed Piezo1 knockdown in A-1847 cells using small hairpin RNAs, and the cells were inoculated subcutaneously in nude mice. Piezo1 knockdown decreased the tumor growth rate of OC tumor xenografts in mice and reduced cell migration in vitro. Metastasis in the lung was also attenuated after Piezo1 knockdown as revealed by HE staining of the lung tissues, which was concomitant with downregulation of E-Cadherin and vimentin and upregulation of N-Cadherin analyzed using western blot analysis, suggesting suppressed epithelial-to-mesenchymal transition. Migration of Piezo1-knockdown cells was also analyzed for their migratory capabilities using the scratch assay. We also analyzed the key proteins in the Hippo/YAP signaling pathway using western blot after treating A-1847 and 3AO cells with a Piezo1 inducer, Yoda1. Piezo1 inducer Yoda1 activated Hippo/YAP signal in OC cells. In conclusion, Piezo1 is overexpressed in OC tissues and contributes to OC tumor growth and metastasis. Suppression of Piezo1 is a potential therapeutic strategy for OC.

BackgroundCurrently available prognostic tools and focused therapeutic methods result in unsatisfactory treatment of gastric cancer (GC). A deeper understanding of human epidermal growth factor receptor 2 (HER2)-coexpressed metabolic pathways may offer novel insights into tumour-intrinsic precision medicine.MethodsThe integrated multi-omics strategies (including transcriptomics, proteomics and metabolomics) were applied to develop a novel metabolic classifier for gastric cancer. We integrated TCGA-STAD cohort (375 GC samples and 56753 genes) and TCPA-STAD cohort (392 GC samples and 218 proteins), and rated them as transcriptomics and proteomics data, resepectively. 224 matched blood samples of GC patients and healthy individuals were collected to carry out untargeted metabolomics analysis.ResultsIn this study, pan-cancer analysis highlighted the crucial role of ERBB2 in the immune microenvironment and metabolic remodelling. In addition, the metabolic landscape of GC indicated that alanine, aspartate and glutamate (AAG) metabolism was significantly associated with the prevalence and progression of GC. Weighted metabolite correlation network analysis revealed that glycolysis/gluconeogenesis (GG) and AAG metabolism served as HER2-coexpressed metabolic pathways. Consensus clustering was used to stratify patients with GC into four subtypes with different metabolic characteristics (i.e. quiescent, GG, AAG and mixed subtypes). The GG subtype was characterised by a lower level of ERBB2 expression, a higher proportion of the inflammatory phenotype and the worst prognosis. However, contradictory features were found in the mixed subtype with the best prognosis. The GG and mixed subtypes were found to be highly sensitive to chemotherapy, whereas the quiescent and AAG subtypes were more likely to benefit from immunotherapy.ConclusionsTranscriptomic and proteomic analyses highlighted the close association of HER-2 level with the immune status and metabolic features of patients with GC. Metabolomics analysis highlighted the co-expressed relationship between alanine, aspartate and glutamate and glycolysis/gluconeogenesis metabolisms and HER2 level in GC. The novel integrated multi-omics strategy used in this study may facilitate the development of a more tailored approach to GC therapy.

This study was to examine the anti-inflammatory effect of sappanone A on interleukin- (IL-) 1Chondrocytes were pretreated with sappanone A for 2 h before subsequent IL-1Sappanone A inhibited the IL-1Sappanone A may be a potent therapeutic agent for OA.

The oral cavity is considered a potential reservoir of Helicobacter pylori (H. pylori), and the imbalance of oral microbiota directly reflects the health of the host. We aimed to explore the relationship among oral microbiota, H. pylori infection, and vonoprazan-amoxicillin (VA) dual therapy for H. pylori eradication.Helicobacter pylori-positive patients were randomized into low- or high-dose VA dual therapy (i.e., amoxicillin 1 g b.i.d. or t.i.d. and vonoprazan 20 mg b.i.d) for 7 or 10 days. H. pylori-negative patients served as normal controls. Saliva samples were collected from 41 H. pylori-positive patients and 13 H. pylori-negative patients. The oral microbiota was analyzed by 16S rRNA gene sequencing, followed by bioinformatics analysis.Helicobacter pylori-positive patients had higher richness and diversity and better evenness of oral microbiota than normal controls. Beta diversity analysis estimated by Bray-Curtis or weighted UniFrac showed distinct clustering between H. pylori-positive patients and normal controls. The number of bacterial interactions was reduced in H. pylori-positive patients compared with that in negative patients. Forty-one patients evaluated before and after successful H. pylori eradication were divided into low (L-VA) and high dose (H-VA) amoxicillin dose groups. The alpha and beta diversity of the oral microbiota between L-VA and H-VA patients exhibited no differences at the three time points (before eradication, after eradication, and at confirmation of H. pylori infection cure).Helicobacter pylori infection could alter the diversity, composition, and bacterial interactions of the oral microbiota. Both L-VA and H-VA dual therapy showed minimal influence on the oral microbiota.

Metastasis is a crucial reason for the poor prognosis of gastric cancer. Angiogenesis is closely associated with tumor invasion and metastasis. Cancer-derived exosomes play an important role in the establishment of the tumor microenvironment. In this study, exosomes were isolated by sequential differential centrifugation, and they were verified by transmission electron microscopy. Changes in the biological behavior of human umbilical vein endothelial cells were evaluated with downstream cellular functional experiments. The RNA and protein levels of the miRNA target gene were determined by real-time qPCR and western blotting. A mouse xenograft model was adopted to evaluate the correlation between exosome-derived miR-130a and tumor growth in vivo. We demonstrated that exosomes delivered miR-130a from gastric cancer cells into vascular cells to promote angiogenesis and tumor growth by targeting c-MYB both in vivo and in vitro. miR-130a packaged in exosomes secreted from cancer cells acts as a driver of angiogenesis. Therefore, miR-130a might be a potential biomarker for monitoring the activity of gastric cancer. In addition, suppressing the expression or blocking the transmission of these exosomes might be a novel antiangiogenic therapeutic strategy for gastric cancer.

The extracellular matrix (ECM) is a vital component of the tumor microenvironment, which interplays with stromal and tumor cells to stimulate the capacity of cancer cells to proliferate, migrate, invade, and undergo angiogenesis. Nevertheless, the crucial functions of ECM-related genes (ECMGs) in pancreatic adenocarcinoma (PAAD) have not been systematically evaluated. Hence, a comprehensive evaluation of the ECMGs is required in pan-cancer, especially in PAAD. First, a pan-cancer overview of ECMGs was explored through the integration of expression profiles, prognostic values, mutation information, methylation levels, and pathway-regulation relationships. Seven ECMGs (i.e. LAMB3, LAMA3, ITGB6, ITGB4, ITGA2, LAMC2, and COL11A1) were identified to be hub genes of PAAD, which were obviously up-regulated in PAAD and considerably linked to tumor stage as well as prognosis. Subsequently, patients with PAAD were divided into 3 clusters premised on ECMG expression and ECM scores. Cluster 2 was the subtype with the best prognosis accompanied by the lowest ECM scores, further verifying ECM's significant contribution to the pathophysiological processes of PAAD. Significant differences were observed for oncogene and tumor suppressor gene expression, immune microenvironment, and chemotherapy sensitivity across three ECM subtypes. After applying a variety of bioinformatics methods, a novel and robust ECM-associated mRNA-lncRNA-based prognostic panel (ECM-APP) was developed and validated for accurately predicting clinical outcomes of patients with PAAD. Patients with PAAD were randomly categorized into the train, internal validation, and external validation cohorts; meanwhile, each patient was allocated into high-risk (unfavorable prognosis) and low-risk (favorable prognosis) populations premised on the expression traits of ECM-related mRNAs and lncRNAs. The discrepancy in the tumor mutation burden and immune microenvironment might be responsible for the difference in prognoses across the high-risk and low-risk populations. Overall, our findings identified and validated seven ECMGs remarkably linked to the onset and progression of PAAD. ECM-based molecular classification and prognostic panel aid in the prognostic assessment and personalized intervention of patients with PAAD.

Cells of the aerobic metabolic organism are inevitably subjected to the damage from reactive oxygen species (ROS). ROS cause multiple forms of DNA damage, among which the oxidation product of guanine G 8-hydroxyguanine (8-oxoG) is the most frequent DNA oxidative damage, recognized by the specific glycosidase OGG1 that initiates the base excision repair pathway. If left unrepaired, 8-oxoG may pair with A instead of C, leading to a mutation of G: C to T: A during replication. Thus, the accumulation of 8-oxoG or the abnormal OGG1 repair is thought to affect gene function, which in turn leads to the development of tumor or aging-related diseases. However, a series of recent studies have shown that 8-oxoG tends to be produced in regulatory regions of the genome. 8-oxoG can be regarded as an epigenetic modification, while OGG1 is a specific reader of this information. Substrate recognition, binding or resection by OGG1 can cause DNA conformation changes or affect histone modifications, causing up-regulation or down-regulation of genes with different properties. Thus, in addition to the potential genotoxicity, the association of guanine oxidative damage with development of tumors is closely related to its aberrant initiation of gene expression through epigenetic mechanisms. In this review, we summarize the underlying mechanism of 8-oxoG and repair enzyme OGG1 in tumor development and progression, with aims to interpret the relationship between DNA oxidative damage and tumor from a new perspective, and provide new ideas and targets for tumor treatment.有氧代谢有机体细胞无法避免活性氧(reactive oxygen species, ROS)的伤害。ROS会造成多种形式的DNA损伤,其中鸟嘌呤G的氧化产物8-羟鸟嘌呤(8-oxoG)是频度最高的一种DNA氧化损伤,由特异性的糖苷酶OGG1识别并开启碱基切除修复通路完成修复。8-oxoG如果没有及时修复,可能会在复制的过程中引入G:C配对到T:A配对的碱基颠换突变。因此8-oxoG的积累或OGG1修复功能异常被认为会影响基因功能,进而导致肿瘤或衰老相关疾病的发生,然而直接实验证据却极为有限。近年来一系列研究表明,8-oxoG倾向于产生在基因的调控区,在这种情形下,8-oxoG可视为一种表观遗传学修饰,而OGG1则是这一信息的特异性读取者,OGG1对底物的识别、结合或切除会引发DNA构象或组蛋白修饰的改变,进而引起基因表达的上调或下调。因此,除了潜在的遗传毒性,鸟嘌呤氧化损伤与肿瘤的关联与其通过表观遗传学机制引发基因表达的异常密切相关。本文对8-oxoG及修复酶OGG1与肿瘤发生发展的关联机制进行了分析与总结,旨在提示研究人员从新的视角解读DNA氧化损伤与肿瘤的关系,并为肿瘤的治疗提供新的思路和靶点。.