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Background: Cervical cancer is a prevalent malignancy that is a major health problem for women worldwide. The cancer-preventive properties of metformin are well-known, but insufficient data have been reported regarding its relationship to cervical cancer. Therefore, in a nationwide population-based study, we investigated the association between metformin use and cervical cancer incidence in patients with newly diagnosed type 2 diabetes.Methods: This retrospective cohort study used the Korean National Health Insurance claims database. Individuals newly diagnosed with type 2 diabetes between January 2005 and December 2009 were included. The occurrence of cervical cancer was explored by matching for age, economic status, region of residence, and use of anti-diabetic medication.Results: In total, 66,013 metformin users and 64,756 non-users were analyzed. Cervical cancer occurred in 219 metformin users (0.33%) and 274 metformin non-users (0.42%) (hazard ratio [HR], 0.783; 95% confidence interval [CI], 0.655 to 0.036; P=0.007). Moreover, cervical cancer risk was considerably reduced in those treated with a high dose (>1,200,000 mg) or for an extended period (≥2,000 days) compared to non-users (HR, 0.151; 95% CI, 0.093 to 0.243; PPP

Purpose: The incidence of early-onset CRC is increasing. However, the effect of age of onset on the long-term outcome of colorectal cancer liver metastasis (CRLM) remains unclear. This study aimed to evaluate the association between the age of onset and the oncological outcome of CRLM patients and to investigate whether the prognostic role of RAS mutation is altered with age. Methods: We retrospectively investigated consecutive patients at our institution who underwent initial liver resection between 2006 and 2020. The inverse probability of treatment weighting (IPTW) method was used to balance the confounders among early- (≤45 years; EOCRLM), intermediate- (46–70 years; IOCRLM), and late-onset (>70 years; LOCRLM) groups. The prognostic role of RAS was assessed based on age group. Results: A total of 1189 patients were enrolled: 162 in the EOCRLM group, 930 in the IOCRLM group, and 97 in the LOCRLM group. No difference in disease-free survival (DFS) was found between the three groups. However, EOCRLM were more likely to develop extrahepatic and extrapulmonary metastasis and had significantly lower five-year OS rates than IOCRLM. After IPTW, EOCRLM remained a negative prognostic predictor. RAS mutations were significantly associated with worse survival than wild-type RAS in EOCRLM and IOCRLM. However, RAS mutation did not predict the prognosis of patients with LOCRLM. Conclusions: Patients with EOCRLM had a significantly lower OS than IOCRLM patients and age influences the prognostic power of RAS status. These findings may be helpful for doctors to guide the clinical treatments and develop follow-up strategies.

Background: The present study investigated the role of synergistic interaction between hyperuricemia and abdominal obesity as a risk factor for the components of metabolic syndrome.Methods: We performed a cross-sectional study using the data of 16,094 individuals from the seventh Korean National Health and Nutrition Examination Survey (2016 to 2018). The adjusted odds ratios of metabolic syndrome and its components were analyzed by multivariate logistic regression analysis. The presence of synergistic interaction between hyperuricemia and abdominal obesity was evaluated by calculating the additive scales—the relative excess risk due to interaction, attributable proportion due to interaction, and synergy index (SI).Results: There was a synergistic interaction between hyperuricemia and abdominal obesity in hypertriglyceridemia (men: SI, 1.39; 95% confidence interval [CI], 1.01 to 1.98; women: SI, 1.61; 95% CI, 1.02 to 2.69), and low high-density lipoprotein cholesterol (HDL-C) (men: SI, 2.03; 95% CI, 1.41 to 2.91; women: SI, 1.70; 95% CI, 1.05 to 2.95). There was no significant synergistic interaction between hyperuricemia and abdominal obesity for the risk of high blood pressure (men: SI, 1.22; 95% CI, 0.85 to 1.77; women: SI, 1.53; 95% CI, 0.79 to 2.97), and hyperglycemia (men: SI, 1.03; 95% CI, 0.72 to 1.47; women: SI, 1.39; 95% CI, 0.75 to 2.57).Conclusion: Hyperuricemia and abdominal obesity synergistically increased the risk of hypertriglyceridemia and low HDL-C in both sexes.

The aim was to identify the optimal criteria of postoperative complications (POCs) for predicting oncological outcomes after hepatectomy for colorectal liver metastases (CRLMs) and to investigate the variable prognostic implications of POCs according to the modified clinical score (M-CS). We identified 751 patients who underwent curative hepatic resection for CRLM between 2007 and 2018. Patients were categorized based on the M-CS. The impact of the severity [≥ Clavien–Dindo grade (C–D) III or comprehensive complication index (CCI) ≥ 26.2] or type [any infectious complications of POC (Inf-poc)] of POC on overall survival (OS) and recurrence-free survival (RFS) was assessed by univariate and multivariable analyses in different groups. Patients with a major or infectious complication were not associated with either RFS or OS in multivariable analysis of the whole cohort. However, patients with a high CCI had a worse OS (HR 1.51, P = 0.004). Among patients with low M-CS, patients with high CCI had worse OS (HR 1.49, P = 0.035) and RFS (HR 1.32, P = 0.048) than those without high CCI. In contrast, the survival disadvantage of a high CCI was not present in patients with a high M-CS. Compared to Inf-poc or major complications, a high CCI decreased long-term OS in patients treated with hepatectomy for CRLM. High CCI has a variable prognostic impact after hepatic resection for CRLM depending on the M-CS. POC is not a decisive factor to justify the use of hepatectomy for CRLM in patients with high M-CS.

Although many studies revealed transcriptomic subtypes of HCC, concordance of the subtypes are not fully examined. We aim to examine a consensus of transcriptomic subtypes and correlate them with clinical outcomes.By integrating 16 previously established genomic signatures for HCC subtypes, we identified five clinically and molecularly distinct consensus subtypes. STM (STeM) is characterized by high stem cell features, vascular invasion, and poor prognosis. CIN (Chromosomal INstability) has moderate stem cell features, but high genomic instability and low immune activity. IMH (IMmune High) is characterized by high immune activity. BCM (Beta-Catenin with high Male predominance) is characterized by prominent β-catenin activation, low miRNA expression, hypomethylation, and high sensitivity to sorafenib. DLP (Differentiated and Low Proliferation) is differentiated with high hepatocyte nuclear factor 4A activity. We also developed and validated a robust predictor of consensus subtype with 100 genes and demonstrated that five subtypes were well conserved in patient-derived xenograft models and cell lines. By analyzing serum proteomic data from the same patients, we further identified potential serum biomarkers that can stratify patients into subtypes.Five HCC subtypes are correlated with genomic phenotypes and clinical outcomes and highly conserved in preclinical models, providing a framework for selecting the most appropriate models for preclinical studies.

Background The effectiveness of operative treatments other than neurectomy for Morton’s neuroma remains debatable despite several reported studies. This review aimed to evaluate the effects of operative treatments for Morton’s neuroma other than neurectomy using an algorithmic approach and a structured critical framework to assess the methodological quality of reported studies. Methods Several electronic databases were searched for articles published until August 2021 that evaluated the outcomes of operative treatments other than neurectomy in patients diagnosed with Morton’s neuroma. Data searches, extraction, analysis, and quality assessments were performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, and the clinical outcomes were evaluated using objective, subjective, and negative outcomes; complications; and reoperation rate and type. Results After reviewing 11,213 studies, 22 studies were finally included. Although a number of studies with high level of evidence are limited, we divided them according to four categories: (1) neurolysis with or without nerve transposition, (2) minimally invasive nerve decompression, (3) metatarsal osteotomy, and (4) additional procedures after nerve transection or neurectomy. All categories showed reliable outcomes except minimally invasive nerve decompression. The proportion of postoperative neurogenic symptoms was lower with neurolysis than with neurectomy. Conclusion Whether the alternative procedures were superior to neurectomy remains unclear as the number of good quality studies was limited. The proportion of postoperative neurogenic symptoms was lower with neurolysis than with neurectomy. Furthermore, performing simultaneous dorsal transposition of the nerve along with neurolysis is more recommended than neurolysis alone. Surgeons should be more careful with minimally invasive deep transverse intermetatarsal ligament release and metatarsal shortening osteotomy as their effectiveness remains inconclusive. Finally, we strongly recommend performing intramuscular embedding or intermuscular transposition of the nerve cutting end if neurectomy or nerve transection is inevitable. Level of Evidence Level III, systematic review

The World Health Organization recently highlighted the serious worldwide problem of the emergence of antibiotic-resistant or antibiotic multidrug-resistant bacteria. Carbapenem-resistant Enterobacterales, including carbapenemase-producing Enterobacterales (CPE), are major antibiotic-resistant bacteria that can be identified by various methods, including antibiotic susceptibility testing, PCR, and immunologic assays. However, there is a need for a faster, more accurate, low-cost, and easy method to detect CPE strains. We previously developed an osmotic shock matrix-assisted laser desorption/ionization mass spectrometry (OS-MALDI MS) method for directly detecting intact Klebsiella pneumoniae carbapenemase (KPC) using osmotic shock cell lysis. In this study, we evaluated the OS-MALDI MS method and compared it with two other methods (octyl-glucoside-aided direct KPC detection method [OG-MALDI MS] and Bruker's MBT subtyping module indirect method [MBT-SM MALDI MS]). We first completed an analytical performance evaluation of the OS-MALDI MS method according to Clinical and Laboratory Standards Institute guidelines. Clinical testing was performed with 437 clinical isolates, including 292 KPC-producing bacteria and 145 non-KPC-producing bacteria. The OS-MALDI MS method exhibited 95.9% sensitivity, 100.0% specificity, and 100.0% precision for detecting KPC. Accuracy of the OS-MALDI MS, OG-MALDI MS, and MBT-SM MALDI MS methods was 97.3%, 55.9%, and 50.2%, respectively. In conclusion, the OS-MALDI MS method clearly outperformed the other methods, exhibiting the highest accuracy and sensitivity of the three methods. We propose the OS-MALDI MS method as a practical, useful method for clinic environments, which may help guide appropriate antibiotic treatment and contribute to the prevention of the spread of CPE.

Hyaluronan is a structural component of the expanded cumulus matrix, and hyaluronan synthase 2 is the major enzyme for the synthesis of hyaluronan in humans. Versican cross-links the hyaluronan-rich matrix to cumulus cells and is critical for successful ovulation. Activin A is a critical intrafollicular regulator of ovarian function. Although activin A has been shown to promote cumulus matrix expansion in mice, the functional role of activin A in the regulation of cumulus expansion in the human ovary remains to be elucidated. Using primary and immortalized human granulosa-lutein cells as study models, we provide the first data showing that activin A increased the production of hyaluronan by upregulating the expression of hyaluronan synthase 2 in these cells. Additionally, activin A also promoted the expression of the hyaluronan-binding protein versican. Moreover, using inhibitor- and small interfering RNA-mediated inhibition approaches, we found that these stimulatory effects of activin A are most likely mediated through the type I receptor activin receptor-like kinase (ALK4)-mediated Sma- and Mad-related protein (SMAD2)/SMAD3-SMAD4 signaling pathway. Notably, the chromatin immunoprecipitation analyses demonstrated that SMAD4 could bind to human hyaluronan synthase 2 and VERSICAN promoters. The results obtained from this in vitro study suggest that locally produced activin A plays a functional role in the regulation of hyaluronan production and stabilization in human granulosa-lutein cells.

Cyclin-dependent-kinase-4/6 inhibitor (CDK4/6i) plus endocrine therapy (ET) is standard of care for patients with advanced hormone receptor (HR)-positive, HER2-negative breast cancer (BC). The Breast Medical Oncology database at MD Anderson Cancer Center (MDACC) was analyzed to assess effectiveness of the CDK4/6i palbociclib plus ET compared to ET alone. From a total of 5402 advanced HR+ HER2- BC patients referred to MDACC between 1997 and 2020, we identified eligible patients who received palbociclib in combination with first-line (n = 778) and second-line (n = 410) ET. We further identified "control" patients who received ET alone in the first-line (n = 2452) and second-line (n = 1183) settings. Propensity score matching analysis was conducted to balance baseline demographic and clinical characteristics between palbociclib and control cohorts to assess the effect of palbociclib treatment on progression-free survival (PFS) and overall survival (OS). For propensity-matched-cohort in the first-line setting (n = 708), palbociclib group had significantly longer median PFS (17.4 vs 11.1 months; P .0001) compared to controls. Median OS (44.3 vs 40.2 months) did not show a statistically significant benefit in the first line setting. However, in the second-line setting, with 380 propensity-matched-cohort, the palbociclib group had significantly longer PFS (10 vs 5 months, P .0001) as well as OS (33 vs 24 months; P .022), compared to controls. We conclude that in this single center analysis of a large cohort of metastatic HR+ HER2- BC patients, palbociclib in combination with ET was associated with improved PFS in both first-line and second-line settings and OS in the second-line setting compared to ET alone cohort.

To assess prognostic influences of RAS mutational status and primary tumor site on cases with colorectal liver metastasis (CRLM) who underwent hepatectomy.Clinicopathological data of 762 patients with CRLM who underwent hepatectomy between January 2000 and November 2018 were retrospectively analyzed. The left-sided tumors (LST) included tumors located in the splenic flexure, descending colon, sigmoid colon, and rectum; while right-sided tumors (RST) included those located in the cecum, ascending colon, and transverse colon. RAS mutational status was determined using Sanger sequencing or next-generation sequencing, including KRAS (Codons 12, 13, and 61) and NRAS (Codons 12, 13, and 61), which were defined as wild-type (RASwt) and mutant-type (RASmut), respectively. Survival curves were plotted using the Kaplan-Meier plotter and compared by the log rank test. The clinicopathological data were analyzed using univariate and multivariate analyses.The 5-year overall survival (OS) in the LST group was longer than that in the RST group (OS: 47.1% vs. 31.0%, p = 0.000, respectively), and the OS in the RASwt group was longer compared with that in the RASmut group (OS: 53.6% vs. 24.0%, p = 0.000). Besides, overall survival of the patients after hepatectomy was alternative, which was stratified by primary tumor site, with the 1-, 3-, and 5-year survival rates of 93.1%, 62.1%, and 47.1% for patients with LST, and 91.1%, 42.8%, and 31.0% for patients with RST, respectively. OS and disease-free survival (DFS) were significantly different stratified by RAS mutational status, with the 1-, 3-, and 5-year rates of 96.9%, 67.9%, and 53.6% for patients with RASwt tumors, and 85.7%, 41.5%, and 24.0% for patients with RASmut tumors, respectively. The 1-, 3-, and 5-year DFS rates were 51.9%, 30.0%, and 26.7% for patients with RASwt tumors, and 35.8%, 18.2%, and 14.9% for patients with RASmut tumors, respectively. The results of multivariate analysis showed that RAS mutational status and primary tumor site were both independent influencing factors of OS.RAS mutational status and primary tumor site affect OS independently in CRLM patients undergoing hepatectomy. The worse prognosis of RST cannot be simply attributed to the imbalance of RAS mutational status in different primary tumor sites.

Investigating cellular and vesicular heterogeneity in breast cancer remains a challenge, which encourages the development of controllable in vitro systems that mimic the tumor microenvironment. Although three-dimensional cell culture better recapitulates the heterogeneity observed in tumor growth and extracellular vesicle (EV) biogenesis, the physiological relevance is often contrasted with the control offered by two-dimensional cell culture. Therefore, to challenge this misconception we developed a novel microfluidic system harboring highly tunable three-dimensional EV microbioreactors ((EV)μBRs) to model micrometastatic EV release in breast cancer while capitalizing on the convenient, low-volume, and sterile interface provided by microfluidics. The diameter and cellular occupancy of the (EV)μBRs could be precisely tailored to various configurations, supporting the formation of breast cancer tumor spheroids. To immobilize the (EV)μBRs within a microchannel and facilitate EV extraction, oxygen inhibition in free-radical polymerization was repurposed to rapidly generate two-layer hydrodynamic traps in situ using a digital-micromirror device (DMD)-based ultraviolet (UV) projection system. Breast cancer tumor spheroid-derived EVs were harvested with as little as 20 μL from the microfluidic system and quantified by single-EV immunofluorescence for CD63 and CD81. Despite the low-volume extraction, differences in biomarker expression and coexpression of the tetraspanins on single EVs were observed. Furthermore, the (EV)μBRs were capable of recapitulating heterogeneity at a cellular and vesicular degree, indicating the utility and robustness of the microfluidic system to investigate physiologically relevant EVs in breast cancer and other disease models.

(.) is known to be a major risk factor for the development of gastric cancer. In recent years, increasing attention is being paid to the role of non-. (NHPHs) in this disease and the role of microorganisms in local tumor microenvironment. In this study, we aimed to compare the microbial community composition and the predicted functional profile in paired cancer and adjacent normal tissues of gastric cancer patients. Cancer tissues and adjacent normal tissues were collected from 10 patients with gastric cancer under endoscopy, and genomic DNA was extracted. The V3-V4 region of the 16S rRNA gene was amplified by PCR and paired-end sequencing was performed on the Illumina MiSeq System. The data was analyzed using QIIME 2 software. The results showed that microbial richness and diversity as well as genetic diversity are significantly lower in cancer tissues compared with adjacent normal tissues. At the phylum level, the dominant taxa are , , , and in both groups. At the genus level, some taxa, such as and, are significantly enriched in cancer tissues, while other taxa, such as , are enriched in adjacent normal tissues. Moreover, those taxa enriched in cancer tissues are associated with the synthesis and degradation of ketone bodies. In conclusion, there is a significant difference in the composition of the mucosa-related microbial communities between cancer tissues and adjacent normal tissues in patients with gastric cancer.

Fulminant hepatic failure (FHF) is a potentially fatal liver disease that is associated with intrahepatic infiltration of inflammatory cells. As the receptor of polyunsaturated long chain fatty acids, GPR120 can regulate cell differentiation, proliferation, metabolism, and immune response. However, whether GPR120 is involved in FHF remains unknown. Using Propionibacterium acnes (P. acnes)-primed, LPS-induced FHF in mice, we found that interference with GPR120 activity using pharmacological agonist attenuated the severity of the liver injury and mortality of FHF in mice, while a lack of GPR120 exacerbated the disease. GPR120 activation potently alleviated FHF and led to decreased T helper (Th) 1 cell response and expansion of regulatory T cells (Tregs). Interestingly, GPR120 agonist didn’t directly target T cells, but dramatically induced a distinct population of CD11c+MHC IIlowCD80lowCD86low regulatory DCs in the livers of FHF mice. GPR120 was found to restrict HIF-1α-dependent glycolysis. The augmented HIF-1α stabilization caused by GPR120 antagonism or deletion could be attenuated by the inhibition of ERK or by the activation of AMPK. Through the analysis of the clinical FHF, we further confirmed the activation of GPR120 was negatively associated with the severity in patients. Our findings indicated that GPR120 activation has therapeutic potential in FHF. Strategies to target GPR120 using agonists or free fatty acids (FFAs) may represent a novel approach to FHF treatment.

Dysregulation of the gut microbiota by environmental factors is associated with a variety of autoimmune and immune-mediated diseases. In addition, naturally-occurring extracellular antibiotic resistance genes (eARGs) might directly enter the gut via the food chain. However, following gut microbiota exposure to eARGs, the ecological processes shaping the microbiota community assembly, as well as the interplay between the microbiota composition, metabolic function, and the immune responses, are not well understood. Increasing focus on the One Health approach has led to an urgent need to investigate the direct health damage caused by eARGs. Herein, we reveal the significant influence of eARGs on microbiota communities, strongly driven by stochastic processes. How eARGs-stimulate variations in the composition and metabolomic function of the gut microbiota led to cytokine responses in mice of different age and sex were investigated. The results revealed that cytokines were significantly associated with immunomodulatory microbes, metabolites, and ARGs biomarkers. Cytokine production was associated with specific metabolic pathways (arachidonic acid and tryptophan metabolic pathways), as confirmed by

The basilar artery has the most perioperative complications in stenting compared to the other intracranial arteries. We aim to study whether the procedural safety in stenting for basilar stenosis has improved. This study was a single-arm, non-randomized trial that included historically controlled patients for comparison. Between January 2012 and March 2019, 147 consecutive patients with symptomatic basilar stenoses receiving elective stenting treatment were included in current basilar artery stenting (BAS) group. The prospectively collected and registered 120 patients by the same interventional team from September 2001 to November 2011 were set as historical BAS group for control. A total of 267 individuals were included in this study, with a mean age of 59.5 ± 8.1 years. The proportion of patients with lesion length15 mm was 26.5% (39/147) in the current BAS group versus 4.2% (5/120) in the historical BAS group. We found significant differences between these 2 groups in Mori A (17.7% vs 42.5%) and Mori C patients (42.9% vs 13.3%). The proportion of patients receiving preoperative high-resolution magnetic resonance (HRMRI) evaluation was 83.0% (122/147) in the current BAS group versus 20.8% (25/120) in the historical group (P .05). Balloon-expendable stent (BES) (n = 1), Wingspan (n = 34), and Enterprise (n = 112) stents were placed in the current BAS group. In contrast, only balloon-expendable stent (BES) (n = 48) and Wingspan (n = 72) were deployed in the historical BAS group. The incidence of the safety endpoint (SE) was 4.1% (involving 6 patients) in the current BAS group versus 11.7% (involving 14 patients) in the historical BAS group (P .05). In multivariate analysis, no risk factor was associated with the occurrence of the safety endpoint (SE). When BAS cases operated by the surgical team accumulated to 120 to 150, the incidence of complications decreased significantly. This is the largest sample size study to discuss the safety of BAS. The significantly decreased incidence of complications indicates that the improving technical measures and the accumulation of operation experience are necessary.

Diet can not only provide nutrition for intestinal microbiota, it can also remodel them. However, is unclear whether and how diet affects the spread of antibiotic resistance genes (ARGs) in the intestinal microbiota. Therefore, we employed selected high-sugar, high-fat, high-protein, and normal diets to explore the effect. The results showed that high-sugar, high-fat, and high-protein diets promoted the amplification and transfer of exogenous ARGs among intestinal microbiota, and up-regulated the expression of trfAp and trbBp while significantly altered the intestinal microbiota and its metabolites. Inflammation-related products were strongly correlated with the spread of ARGs, suggesting the intestinal microenvironment after diet remodeling might be conducive to the spreading of ARGs. This may be attributed to changes in bacterial membrane permeability, the SOS response, and bacterial composition and diversity caused by diet-induced inflammation. In addition, acceptor bacteria (zygotes) screened by flow cytometry were mostly Proteobacteria, Firmicutes and Actinobacteria, and most were derived from dominant intestinal bacteria remodeled by diet, indicating that the transfer of ARGs was closely linked to diet, and had some selectivity. Metagenomic results showed that the gut resistance genome could be affected not only by diet, but by exogenous antibiotic resistant bacteria (ARB). Many ARG markers coincided with bacterial markers in diet groups. Therefore, dominant bacteria in different diets are important hosts of ARGs in specific dietary environments, but the many pathogenic bacteria present may cause serious harm to human health.

The gut microbiota represents an important reservoir of antibiotic-resistant bacteria (ARB), which poses a significant threat to public health. However, little is known about the emergence of ARB in the gut after the combined exposure to antibiotics and non-antibiotic pharmaceutics. Here, Escherichia coli, a common opportunistic pathogen in the gut microbiota, was exposed to the antidepressant duloxetine (2.5 µg/L–25 mg/L) and/or chloramphenicol (6 µg/L–4 mg/L). The resistant strains were isolated to determine the minimum inhibition concentration (MIC) of 29 antibiotics. Then, genome-wide DNA sequencing, global transcriptomic sequencing, and real-time quantitative polymerase chain reaction were performed to quantify the synergy between duloxetine and chloramphenicol. Combined exposure synergistically increased the mutation frequency of chloramphenicol resistance by 2.45–9.01 fold compared with the independent exposure. A combination index reaching 187.7 indicated strong duloxetine and chloramphenicol synergy. The resultant mutants presented heritable enhanced resistance to 12 antibiotics and became ARB to eight antibiotics. Furthermore, combined exposure significantly increased the transcriptomic expression of acrA, acrB, and marA in E. coli, and generated a more robust oxidative stress response. Together with the occurrence of DNA mutations in marR in the mutants, stronger triggers to the AcrAB-TolC transport system and the MlaFEDB ABC transporter via reactive oxygen species (ROS)-induced mutagenesis, verified by gene knockout, contributed to the synergistic enhancement of antibiotic resistance in the combined exposure group. Regardless of whether their formation was induced by duloxetine, chloramphenicol, or their combination, the E. coli mutants showed 1.1–1.7-fold increases in the expression levels of acrA, acrB, acrZ, mdtE, and mdtF. This pattern indicated that the mutants shared the same resistance mechanisms against chloramphenicol, involving the improved efflux pumps AcrAB-TolC and mdtEF. Our findings demonstrated that antibiotics and non-antibiotic pharmaceutics synergistically accelerate the evolution of ARB and may enhance their spread.

Background Diagnostic criteria for sarcopenia have not been established in Chinese. This study established criteria based on the L3‐skeletal muscle index (L3‐SMI) and assessed its value for outcomes predicting in cirrhotic Chinese patients. Methods Totally 911 subjects who underwent a CT scan at two centres were enrolled in Cohort 1 (394 male and 417 female subjects, aged 20–80 years). The data of those subjects younger than 60 years (365 male and 296 female subjects) were used to determine the reference intervals of the L3‐SMI and its influencing factors. Cohort 2 consisted of 480 patients (286 male and 184 female patients) from three centres, and their data were used to investigate the prevalence of sarcopenia and evaluate the value of L3‐SMI for predicting the prognosis and complications of cirrhosis. Results Age and sex had the greatest effects on the L3‐SMI (P 14 (RR = 4.310, 95% CI 2.091–8.882, P

IntroductionNeoadjuvant chemoradiotherapy (nCRT) is the foundation treatment for locally advanced rectal cancer (LARC). The nCRT can improve the efficacy of immunotherapy because of its in situ vaccine effect.ObjectiveThe aim is to identify stable and reliable transcriptome signatures to predict the efficacy of immune checkpoint blockade (ICB) in patients with LARC.MethodsImmunophenotyping was established using xCell immune cell infiltration abundance and consistent clustering in GSE39582 and verified in several data sets. The effects of immunophenotyping, follicular regulatory T cells, tumor-associated fibroblasts (CAFs), and tertiary lymphoid structure (TLS) signatures on the efficacy of ICB were analyzed using IMvigor210, GSE91061, and an independent Daping Hospital (DPH) cohort.ResultsThere are four stable and repeatable immune subtypes in rectal cancer, among which C1 is a low immune infiltration type, C2 is a high interstitial infiltration type, C3 is a high immune infiltration type, and C4 is an ion channel type. C2 is mainly characterized by high infiltration of CAF. C3 is characterized by high infiltration of cytotoxic T lymphocytes, high expression of PD-L1 and TLS. In rectal cancer patients receiving nCRT, immunophenotyping was not significantly associated with pathological remission rate, but immunophenotyping was an independent prognostic factor of RFS. In IMvigor210 patients treated with atezolizumab, the pathological remission rates of C1, C2, C3, and C4 were 23.86%, 10.94%, 33.33%, and 23.08% respectively (χ2 = 8.981, P = 0.029), which were 11.76%, 50.00%, 42.86%, and 0.0% respectively in the GSE91061 patient treatment with nivolumab (Fisher’s exact probability, P = 0.018). Both follicular regulatory T cells and CAF showed a further impact on the ICB therapeutic efficacy of C2 and C3 subtypes. Additionally, both the GSE91404 and DPH cohorts showed that nCRT treatment induced a significant increase in the expression of TNFRSF9 and the abundance of macrophages in the C3 subtype.ConclusionOur data suggest that there are four immune types of rectal cancer, which are related to the prognosis of patients. Among them, C3 and some C2 subtypes represent the patients who may benefit from ICB after nCRT treatment.

Eighteen scalarane sesterterpenoids (

Sports-related traumatic brain injuries are the most common injury in adolescents and young adults due to recurrent concussion experiences and head shock. Therefore, this study was designed to describe player characteristics and situational factors associated with concussions in the World Taekwondo Championships using systematic video analysis. Athlete injury data were collected using a web-based injury surveillance system at the World Taekwondo Championships organized by World Taekwondo from 2017 to 2019. Seven video footage were independently analyzed by four analysts using a modified Heads-Up Checklist. Descriptive statistical analysis was used. The incidence of concussion was 3.21 per 1000 games. Most players with concussions were shorter than their opponents, and most concussions were caused by a roundhouse kick on the front of the face. Regarding the acceleration direction of the head after the impact, transverse and multiplane directions were the most common. Most players with a concussion have used a closed stance and did not use blocking techniques during the defense. The rate of concussions caused by penalties was 42.9%. Based on our findings, no other injury mechanisms, except for direct blows to the head, were observed. Therefore, education on the risk and symptoms of concussion, the appropriate management and blocking techniques should be emphasized in TKD-S to reduce incidence of concussion.

The impact of serum thyroid hormone levels on thyroid cancer risk is unclear. Some studies reported that elevated thyroid-stimulating hormone (TSH) is associated with higher risk for incidence of thyroid cancer, but other studies reported no relationship. We conducted a large cohort study in 164,596 South Korean men and women who were free of thyroid cancer at baseline and underwent health examination with hormone levels of thyroid function. A parametric proportional hazard model was used to evaluate the adjusted hazard ratio (HR) and 95% CI. During 2,277,749.78 person-years of follow-up, 1280 incident thyroid cancers were identified (men = 593, women = 687). Among men, the multivariable-adjusted HR (95% CI) for thyroid cancer comparing low levels of TSH with normal levels of TSH was 2.95 (1.67–5.23), whereas the corresponding HR (95% CI) in women was 1.5 (0.88–2.55). High levels of free T4 and free T3 were also associated with incident thyroid cancer in both men and women. In clinical implication, overt hyperthyroidism is associated with thyroid cancer in both men and women. Within the euthyroid range, the highest tertile of TSH was associated with a lower risk of thyroid cancer than the lowest TSH tertile and the highest FT4 tertile was associated with a higher risk of thyroid cancer than the lowest FT4 tertile in both men and women. Our finding indicates that low levels of TSH and high levels of FT4, even within the normal range, were associated with an increased risk of incident thyroid cancer.

The purpose of this study was to develop and validate the Intention for Warm-up among Children and Adolescents Scale (IWCAS). There were four phases and four sets of participants in the development of the IWCAS. In the first phase, the domains of intention were defined, and related components were developed, organized, and validated. In the second phase, 446 elementary and middle school students participated in a pilot study for the first version of the scale, which was revised based on the information obtained. In the third phase, 12 graduates in sports pedagogy served on an expert panel and organized the items into domain areas and developed a second version of the IWCAS. In the final phase, 1322 elementary and middle school students from three k-12 schools completed the revised version of the IWCAS, and exploratory and confirmatory factor analyses were conducted. Based on the results, the IWCAS was shortened by deleting some items in two domains; this resulted in 11 items of the final version with 3 domains: (1) attitude toward warm-up, (2) subjective norm, and (3) perceived behavioral control that, according to the indices, generate reliable and structurally valid scores. The composite internal consistency for the three domains ranged from 0.74 to 0.85. The researchers hypothesized the IWCAS is a valid and reliable scale, which can be used by P.E. teachers or coaches to evaluate the intention of primary and secondary school students to perform warm-ups.

MotivationAnticancer combination therapy has been developed to increase efficacy by enhancing synergy. Patient-derived xenografts (PDXs) have emerged as reliable preclinical models to develop effective treatments in translational cancer research. However, in most PDX combination experiments, PDXs are tested on single dose levels and dose-response surface methods are not applicable for testing synergism.ResultsWe propose a comprehensive statistical framework to assess joint action of drug combinations from PDX tumor growth curve data. We provide various metrics and robust statistical inference procedures that locally (at a fixed time) and globally (across time) access combination effects under classical drug interaction models. Integrating genomic and pharmacological profiles in non-small-cell lung cancer (NSCLC), we have shown the utilities of combPDX in discovering effective therapeutic combinations and relevant biological mechanisms.AvailabilityWe provide an interactive web server, combPDX (https://licaih.shinyapps.io/CombPDX/), to analyze PDX tumor growth curve data and perform power analyses.ContactMJHa@mdanderson.orgSupplementary informationSupplementary data are available at Bioinformatics online.

Rehabilitation of the hand motor function is essential for stroke patients to resume activities of daily living. Recent studies have shown that wearable robot systems, like a multi degree-of-freedom soft glove, have the potential to improve hand motor impairment. The rehabilitation system, which is intuitively controlled according to the user's intention, is expected to induce active participation of the user and further promote brain plasticity. However, due to the patient-specific nature of stroke patients, extracting the intention from stroke patients is still challenging. In this study, we implemented a classifier that combines EEG and EMG to detect chronic stroke patients' four types of intention: rest, grasp, hold, and release. Three chronic stroke patients participated in the experiment and performed rest, grasp, hold, and release actions. The rest vs. grasp binary classifier and release vs. hold binary classifier showed 76.9% and 86.6% classification accuracy in real-time, respectively. In addition, patient-specific accuracy comparisons showed that the hybrid approach was robust to upper limb impairment level compared to other approaches. We believe that these results could pave the way for the development of BCI-based robotic hand rehabilitation therapy.

The frequent incidents of password leakage have increased people’s attention and research on password security. Password guessing is an essential part of password cracking and password security research. The progression of deep learning technology provides a promising way to improve the efficiency of password guessing. However, the mainstream models proposed for password guessing, such as RNN (or other variants, such as LSTM, GRU), GAN and VAE still face some problems, such as the low efficiency and high repetition rate of the generated passwords. In this paper, we propose a password-guessing model based on the temporal convolutional neural network (PassTCN). To further improve the performance of the generated passwords, we propose a novel password probability label-learning method, which reconstructs labels based on the password probability distribution of the training set and deduplicates the training set when training. Experiments on the RockYou dataset showed that, when generating 108 passwords, the coverage rate of PassTCN with password probability label learning (PassTCN-PPLL) reached 12.6%, which is 87.2%, 72.6% and 42.9% higher than PassGAN (a password-guessing model based on GAN), VAEPass (a password-guessing model based on VAE) and FLA (a password-guessing model based on LSTM), respectively. The repetition rate of our model is 25.9%, which is 45.1%, 31.7% and 17.4% lower than that of PassGAN, VAEPass and FLA, respectively. The results confirm that our approach not only improves the coverage rate but also reduces the repetition rate.

Background Somnipathy and diabetes are independently associated with an increased risk of cardiovascular disease (CVD). However, whether a combination of both conditions is associated with a higher risk of CVD events remains uncertain. Therefore, the aim of this meta‐analysis was to clarify this association. Methods and Results We searched MEDLINE, Web of Science, EMBASE, ClinicalTrials.gov , and the Cochrane Central Register for Controlled Trials. We included randomized controlled trials, nonrandomized trials, and prospective observational cohort studies that assessed the combined effect of diabetes and comorbid somnipathy on CVD risk and mortality for at least 1 year. Outcomes included CVD, coronary heart disease, stroke, and all‐cause mortality. Twelve studies involving 582 267 participants were included in the meta‐analysis. Patients with somnipathy and comorbid diabetes exhibited increased risks of CVD, coronary heart disease, stroke, and all‐cause mortality (risk ratio [RR], 1.27 [95% CI, 1.12–1.45], P P P =0.004, and RR, 1.56 [95% CI, 1.26–1.94], P Conclusions The coexistence of somnipathy and diabetes is associated with higher risks of CVD, coronary heart disease, stroke, and mortality than somnipathy or diabetes alone. Resolving sleep problems in patients with diabetes may reduce the risks of CVD, stroke, and mortality. Registration Information https://www.crd.york.ac.uk/prospero/ . Identifier: PROSPERO CRD42021274566.

Background Primary gastric lymphoma (PGL) is the most common extranodal non-Hodgkin lymphoma (NHL). Due to the rarity of the disease, it is important to create a predictive model that provides treatment and prognosis for patients with PGL and physicians. Methods A total of 8898 and 127 patients diagnosed with PGL were obtained from the SEER database and from our Cancer Center as training and validation cohorts, respectively. Univariate and multivariate Cox proportional hazards models were used to investigate independent risk factors for the construction of predictive survival nomograms, and a web nomogram was developed for the dynamic prediction of survival of patients with PGL. The concordance index (C-index), calibration plot, and receiver operating characteristics (ROC) curve were used to evaluate and validate the nomogram models. Results There were 8898 PGL patients in the SEER cohort, most of whom were married men over the age of 60, 16.1% of the primary tumors were localized in the antrum and pylori of the stomach, which was similar to the composition of 127 patients in the Chinese cohort, making both groups comparable. The Nomogram of overall survival (OS) was compiled based on eight variables, including age at diagnosis, sex, race, marital status, histology, stage, radiotherapy and chemotherapy. Cancer-specific survival (CSS) nomogram was developed with eight variables, including age at diagnosis, sex, marital status, primary tumor site, histology, stage, radiotherapy and chemotherapy. The C-index of OS prediction nomogram was 0.948 (95% CI: 0.901–0.995) in the validation cohort, the calibration plots showed an optimal match and a high area below the ROC curve (AUC) was observed in both training and validation sets. Also, we established the first web-based PGL survival rate calculator (https://yangjinru.shinyapps.io/DynNomapp/). Conclusion The web dynamic nomogram provided an insightful and applicable tool for evaluating PGL prognosis in OS and CSS, and can effectively guide individual treatment and monitoring.

Lumbar transforaminal epidural steroid injections are used widely to alleviate low back radicular pain, but it requires real-time fluoroscopy, which can increase the risk of radiation exposure. Anteroposterior or lateral real-time fluoroscopy can be used during lumbar transforaminal epidural steroid injections, but there have been no comparative studies on the exposure of physicians to radiation from anteroposterior or lateral real-time fluoroscopy. The aim of this study was to compare the cumulative radiation exposure to each body part of the physician according to the method of real-time fluoroscopy when performing lumbar transforaminal epidural steroid injections.A single physician performed lumbar transforaminal epidural steroid injections, and 2 groups of patients were formed based on the method used: group A (anteroposterior real-time fluoroscopy) and group L (lateral real-time fluoroscopy). Dosimeters were placed outside the chest, inside the chest, outside the thyroid collar, inside the thyroid collar, outside the groin, inside the groin, outside the lead gloves, and left rim of the glasses.A total of 200 lumbar transforaminal epidural steroid injections were analyzed, and the radiation exposure was measured by cumulative dose equivalents in mSv. The dose equivalents were lower at every level in group A compared with group L except for outside the groin.The cumulative radiation exposure at all the measurement sites was lower for anteroposterior real-time fluoroscopy compared with lateral real-time fluoroscopy when performing lumbar transforaminal epidural steroid injections, except for outside the groin.

Conventional PD-L1 immunohistochemical tissue biopsies only predict 20%-40% of non-small cell lung cancer (NSCLC) patients that will respond positively to anti-PD-1/PD-L1 immunotherapy. Herein, we present an immunogold biochip to quantify single extracellular vesicular RNA and protein (

Objective The study aims to address whether serum anti-müllerian hormone (AMH) levels fluctuate in the short term after medication application, including oral contraceptives (OCs), metformin (MET), Gonadotropin-releasing hormone agonist (GnRH-a), dehydroepiandrosterone (DHEA), vitamin D (VD), clomiphene citrate (CC), and letrozole (LET). Methods Published literature from PubMed, Embase, and Cochrane central was retrieved up until 19 September 2021. A total of 51 self-control studies with an average Newcastle–Ottawa quality assessment scale (NOS) score of 6.90 were analyzed. The extracted data were entered into Stata software, and the weighted mean difference/standardized mean difference (WMD/SMD) and 95% confidence interval (CI) were used for data analysis. Results After OCs treatment the AMH level showed a significant decline in women with normal ovarian function, which was significant within 3 months (WMD = -1.43, 95% CI: -2.05 to -0.80, P P P = 0.05), and descent at 3 months (P = 0.02). After DHEA treatment the serum AMH increased in diminished ovarian reserve (DOR) / poor ovarian response (POR) patients (WMD = 0.18, 95% CI: 0.09 to 0.27, P P = 0.0004). After CC treatment the serum AMH decreased significantly in PCOS patients, specifically in non-obese patients (WMD = -1.24, 95% CI: -1.87 to -0.61, P = 0.0001). Conclusions Serum AMH levels may be affected in the short term after drug application. Specifically, OC, MET and CC lead to decreased AMH level, DHEA and VD lead to increased AMH level, and GnRH-a leads to dynamic variation, which is correlated with PCOS, obesity, age, and duration of medication. The impacts of these medications should be taken into consideration when AMH is used as a marker of ovarian reserve.

Background The increasing occurrence of multidrug-resistant organisms (MDROs) infections has posed major challenge to solid organ transplantation (SOT). For SOT recipients, high-dose immunosuppressants and broad-spectrum antibiotics can markedly increase the risk of early postoperative MDRO infections and thus have adverse effects on the outcomes of SOT. Here, we analyzed the incidence and clinical features of early MDRO infections after SOT, in an attempt to provide new evidence for the control and treatment of early MDROs. Methods The clinical data of 133 patients with MDRO infections after SOT in our department from 2017 to 2020 were retrospectively collected, and clinical features including incidence, etiologies, infection sites, and complications, were analyzed. Results The incidence of MDRO infections after SOT was 9.9%. Simultaneous liver and kidney transplantation patients had the highest incidence of MDRO infections, followed by the recipients of liver transplantation and simultaneous pancreas-kidney transplantation; patients undergoing renal transplantation had the lowest incidence of MDRO infections. The most common pathogen was extended spectrum beta-lactamase (ESBL)-producing organisms (n=88, 66.2%), the most common infection site was the urinary system (n=58, 43.6%), and the main postoperative complications were urinary tract infections (n=44, 33.1%) and lung infections (n=41, 30.8%). MDRO infections were cured in most cases. Conclusions A sound knowledge of the clinical features of MDRO infection after SOT is important for the successful prevention and treatment of these infections.

BACKGROUND: During the coronavirus disease 2019 (COVID-19) epidemic, tumor patients and their families might suffer from greater psychological stress as a result of anxiety or other psychological disorders. We conducted an online study during the epidemic to explore the mental state of tumor patients and their families during this extraordinary time. METHODS: A cross-sectional survey was carried out. Questionnaires were distributed through the WeChat "Questionnaire Star" network. The snowball sampling technique was adopted and further promoted by subjects who had completed the questionnaire. RESULTS: A total of 1,030 valid questionnaires were collected. There were 609 (59.13%) tumor patients and 421 (40.87%) family members. One hundred and fifty-six (15.15%) subjects had anxiety, among which 65 (6.31%) had moderate to severe anxiety. Single-factor analysis indicated that age (>60 years old), the farmer occupation, and a high sleep disorder assessment score were risk factors for anxiety, while the latter two might also be independent risk factors, as suggested by multi-factor analysis. Infrequent contact with doctors was an independent risk factor for cancer patients, while uninterrupted anti-tumor therapy was an independent protective factor. 40.19% of the subjects expressed a need for psychosocial support during the COVID-19 period. CONCLUSIONS: The COVID-19 outbreak resulted in tumor patients and their relatives experiencing greater psychological pressure than usual, and patients were more worried about anti-tumor treatment and disease progression impacted by the epidemic. Both groups had a significant need for psychosocial help.

Background/Aims: To prevent the perinatal transmission of hepatitis B virus (HBV) from mother to child, administration of an antiviral agent during preg nancy has been attempted in women who are either hepatitis B e antigen posi tive or have a high viral load. In this systematic review and meta-analysis with randomized controlled trials, we analyzed the efficacy and safety of tenofovir disoproxil fumarate (TDF) in preventing the perinatal transmission of HBV in pregnant women who have high HBV DNA titers. Methods: Multiple comprehensive databases (PubMed, EMBASE, and Cochrane databases) were searched for studies evaluating the efficacy of TDF for the pre vention of perinatal transmission of HBV. Results: Two studies (one open label study and one double blind study) were included and analyzed. Intention-to-treat analysis (527 pregnancies) showed that the preventive effect of TDF was not significant (odds ratio [OR], 0.53; 95% confidence interval [CI], 0.13 to 2.17; p = 0.38, I2 = 81%). However, the per-proto col analysis showed that TDF significantly reduced perinatal transmission (OR, 0.10; 95% CI, 0.01 to 0.77; p = 0.03, I2 = 0%). There was no significant difference between the TDF group and the control group with respect to maternal and fetal safety outcomes. Conclusions: In pregnant women who have high HBV DNA titers, TDF can re duce the perinatal transmission from mother to child without significant ad verse events.

To date, 5-fluorouracil-based chemotherapy is very important for locally advanced or metastatic colorectal cancer (CRC). However, chemotherapy resistance results in tumor recurrence and metastasis, which is a major obstacle for treatment of CRC.In the current research, we establish 5-fluorouracil resistant cell lines and explore the potential targets associated with 5-fluorouracil resistance in CRC. Moreover, we perform clinical specimen research, in vitro and in vivo experiments and molecular mechanism research, to reveal the biological effects and the mechanism of DCLK1 promoting 5-fluorouracil resistance, and to clarify the potential clinical value of DCLK1 as a target of 5-fluorouracil resistance in CRC.We discover that doublecortin-like kinase 1 (DCLK1), a cancer stem cell maker, is correlated with 5-fluorouracil resistance, and functionally promotes cancer stemness and 5-fluorouracil resistance in CRC. Mechanistically, we elucidate that DCLK1 interacts with cell cycle and apoptosis regulator 1 (CCAR1) through the C-terminal domain, and phosphorylates CCAR1 at the Ser343 site, which is essential for CCAR1 stabilisation. Moreover, we find that DCLK1 positively regulates β-catenin signalling via CCAR1, which is responsible for maintaining cancer stemness. Subsequently, we prove that blocking β-catenin inhibits DCLK1-mediated 5-fluorouracil resistance in CRC cells. Importantly, we demonstrate that DCLK1 inhibitor could block CCAR1/β-catenin pathway-mediated cancer stemness and consequently suppresses 5-fluorouracil resistant CRC cells in vitro and in vivo.Collectively, our findings reveal that DCLK1 promotes 5-fluorouracil resistance in CRC by CCAR1/β-catenin pathway-mediated cancer stemness, and suggest that targeting DCLK1 might be a promising method to eliminate cancer stem cells for overcoming 5-fluorouracil resistance in CRC.

Viral waterborne diseases are widespread in cities due largely to the occurrence of enteric viruses in urban rivers, which pose a significant concern to human health. Yet, the application of rapid detection technology for enteric viruses in environmental water remains undeveloped globally. Here, multiple linear regression (MLR) modeling and artificial neural network (ANN) modeling, which used frequently measured physicochemical parameters in river water, were constructed to predict the concentration of enteric viruses including human enteroviruses (EnVs), rotaviruses (HRVs), astroviruses (AstVs), noroviruses GⅡ (HuNoVs GⅡ), and adenoviruses (HAdVs) in rivers. After training, testing, and validating, ANN models showed better performance than any MLR model for predicting the viral concentration in Jinhe River. All determined R-values for ANN models exceeded 0.89, suggesting a strong correlation between the predicted and measured outputs for target enteric viruses. Furthermore, ANN models provided a better congruence between the observed and predicted concentrations of each virus than MLR models did. Together, these findings strongly suggest that ANN modeling can provide more accurate and timely predictions of viral concentrations based on frequent (or routine) measurements of physicochemical parameters in river water, which would improve assessments of waterborne disease prevalence in cities.