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In brief Various etiologies can cause uterine myometrium contraction, which leads to preterm birth. This study demonstrates a new functional relationship between the Ras-related C3 botulinum toxin substrate 1 (RAC1) and uterine myometrium contraction in preterm birth. Abstract Preterm birth (PTB) is a public health issue. The World Health Organization has recommended the use of tocolytic treatment to inhibit preterm labour and improve pregnancy outcomes. Intrauterine inflammation is associated with preterm birth. RAC1 can modulate inflammation in different experimental settings. In the current study, we explored whether RAC1 can modulate spontaneous uterine myometrium contraction in a mouse model of lipopolysaccharide (LPS)-induced intrauterine inflammation. Subsequently, we recorded uterine myometrium contraction and examined uterine Rac1 expression in a mouse model of preterm birth and a case in pregnant women by Western blotting analysis. We also measured progesterone levels in the blood serum of mice. Murine myometrium was obtained 12 h post LPS treatment. Human myometrium was obtained at the time of caesarean section. We found that in the LPS-treated group of mice, uterine myometrium contraction was enhanced, protein levels and activation of RAC1 were increased and serum progesterone levels were decreased. The protein levels of RAC1 were also increased in preterm birth and in pregnant women. NSC23766, a RAC1 inhibitor, attenuated uterine myometrium contraction and diminished RAC1 activation and COX-2 expression. Furthermore, silencing of RAC1 suppressed cell contraction and COX-2 expression in vitro. In conclusion, our results suggested that RAC1 may play an important role in modulating uterine myometrium contraction. Consequently, intervening with RAC1 represents a novel strategy for the treatment of preterm birth.

Gene fusions can drive tumor development for multiple types of cancer. Currently, many drugs targeting gene fusions are being approved for clinical application. At present, tyrosine receptor kinase (TRK) inhibitors targeting neurotrophic tyrosine receptor kinase (NTRK) gene fusions are among the first "tumor agnostic" drugs approved for pan-cancer use. Representative TRK inhibitors, including larotrectinib and entrectinib, have shown high efficacy for many types of cancer. At the same time, several second-generation drugs designed to overcome first-generation drug resistance are undergoing clinical development. Due to the rarity of NTRK gene fusions in common cancer types and technical issues regarding the complexity of fusion patterns, effectively screening patients for TRK inhibitor treatment in routine clinical practice is challenging. Different detection methods including immunohistochemistry, fluorescence in situ hybridization, reverse transcription-polymerase chain reaction, and (DNA and/or RNA-based) next-generation sequencing have pros and cons. As such, recommending suitable tests for individual patients and ensuring the quality of tests is essential. Moreover, at present, there is a lack of systematic review for the clinical efficacy and development status of first- and second-generation TRK inhibitors. To resolve the above issues, our expert group has reached a consensus regarding the diagnosis and treatment of NTRK gene fusion solid tumors, aiming to standardize clinical practice with the goal of benefiting patients with NTRK gene fusions treated with TRK inhibitors.

Disturbances or defects in the process of wound repair can disrupt the delicate balance of cells and molecules necessary for complete wound healing, thus leading to chronic wounds or fibrotic scars. Myofibroblasts are one of the most important cells involved in fibrotic scars, and reprogramming provides a potential avenue to increase myofibroblast clearance. Although myofibroblasts have long been recognized as terminally differentiated cells, recent studies have shown that myofibroblasts have the capacity to be reprogrammed into adipocytes. This review intends to summarize the potential of reprogramming myofibroblasts into adipocytes. We will discuss myofibroblast lineage tracing, as well as the known mechanisms underlying adipocyte regeneration from myofibroblasts. In addition, we investigated different changes in myofibroblast gene expression, transcriptional regulators, signalling pathways and epigenetic regulators during skin wound healing. In the future, myofibroblast reprogramming in wound healing will be better understood and appreciated, which may provide new ideas for the treatment of scarless wound healing.

To detect the expression of inflammatory factors such as interleukin-1β (IL-1β), interleukin-6 (IL-6), transforming growth factor (TGF-β), and tumor necrosis factor (TNF-α) in the tumor tissue of ventricular septal defect (VSD) in congenital heart disease and to explore the role of inflammatory response in the formation of aneurysmal perimembranous VSD(APVSD). Children with APVSD of congenital heart disease treated by surgery were selected and divided into true aneurysmal perimembranous group (TAP group) and pseudoaneurysmal perimembranous group (PAP group) according to echocardiography and surgical findings. There were 15 children in the TAP group and 31 in the PAP group. The aneurysmal perimembranous tissue of the two groups of children was collected during the operation. IL-1β, IL-6, TGF-β, and TNF-α were positively expressed in the aneurysmal perimembranous tissue of the two groups, and the expression levels of all inflammatory factors in the PAP group were higher than those in the TAP group, and the difference was statistically significant ( P < 0.05 ). The expression levels of IL-1β, IL-6, TGF-β, and TNF-α in the aneurysmal perimembranous tissue of the two groups were negatively correlated with the width of the APVSD breach. IL-1β, IL-6, TGF-β, and TNF-α may be involved in the occurrence and development of APVSD through inflammatory mechanism.

Background. This study aims at exploring the effect of obstructive sleep apnea–hypopnea syndrome (OSAHS) on the liver and kidney function indexes of patients and analyze the changes in these indexes after minimally invasive surgery. Method. Patients with OSAHS (n = 51) who were diagnosed via polysomnography (PSG) and received minimally invasive surgery in the sleep disorders diagnosis and treatment center of the West China Fourth Hospital of Sichuan University from January 2017 to January 2019 were selected as test subjects and placed in the OSAHS group. At the same time, 79 healthy people with no snoring or breathing difficulties were selected from the medical examination center of the hospital as the control group (tested as normal by PSG). These two groups were used to compare the differences in the related indexes of serum liver and kidney function and evaluate the changes in sleep monitoring and related liver and kidney function indexes in patients with OSAHS after minimally invasive surgery. Results. The alanine aminotransferase (ALT), aspartate aminotransferase (AST), and uric acid (UA) levels were higher in the OSAHS group (48.98 ± 36.34, 28.88 ± 14.80, and 422.30 ± 98.65, respectively) than in the control group (21.91 ± 11.61, 22.18 ± 6.19, and 330.49 ± 64.45 and t = 6.514, 3.549, and 6.373, respectively; p < 0.05 ). Of the patients with OSAHS, 17 were followed up for one year. After minimally invasive surgery, ALT decreased from 44.29 ± 20.61 to 26.47 ± 9.91 (t = 4.395), AST decreased from 27.71 ± 8.32 to 21.82 ± 4.81 (t = 3.673), and UA decreased from 397.35 ± 92.14 umol/L to 362.94 ± 106.76 umol/L (t = 2.580), and these differences were statistically significant ( p < 0.05 ).The changes in ALT (r = −0.635) and AST (r = −0.504) were related to the difference in the lowest blood oxygen saturation ( p < 0.05 ), and the change in UA was related to the difference in the apnea–hypopnea index (r = −0.532, p < 0.05 ). Conclusion. There are some abnormalities in liver- and kidney-function-related indexes in patients with OSAHS, and minimally invasive surgery can help to improve liver and kidney function in these patients.

Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and ultrasound (US), which are two common modalities for clinical breast tumor diagnosis besides Mammograms, can provide different and complementary information for the same tumor regions. Although many machine learning methods have been proposed for breast tumor classification based on either single modality, it remains unclear how to further boost the classification performance by utilizing paired multi-modality information with different dimensions. In this paper, we propose MRI-US multi-modality network (MUM-Net) to classify breast tumor into different subtypes based on 3D MR and 2D US images. The key insight of MUM-Net is that we explicitly distill modality-agnostic features for tumor classification. Specifically, we first adopt a discrimination-adaption module to decompose features into modality-agnostic and modality-specific ones with min-max training strategies. Then, we propose a feature fusion module to increase the compactness of the modality-agnostic features by utilizing an affinity matrix with nearest neighbour selection. We build a paired MRI-US breast tumor classification dataset containing 502 cases with three clinical indicators to validate the proposed method. In three tasks including lymph node metastasis, histological grade and Ki-67 level, MUM-Net achieves AUC scores of 0.8581, 0.8965 and 0.8577, outperforming other counterparts which are based on single task or single modality by a wide margin. In addition, we find that the extracted modality-agnostic features can help the network focus on the tumor regions in both modalities.

Prediction of cardiovascular disease (CVD) is important in clinical practice. Machine learning (ML) may offer an improved alternative to current CVD risk stratification in individual patients. We aim to identify important predictors and compare ML models with traditional models according to their prediction performance in a large long-term follow-up cohort.The Atherosclerosis Risk in Communities (ARIC) study was designed to study the progression of subclinical disease to cardiovascular events over a 25-year follow-up period. All phenotypic variables at visit 1 were obtained. All-cause death, CVD, and coronary heart disease were the outcomes for analysis. The ML framework involved variable selection using the random survival forest (RSF) method, model building, and 5-fold cross-validation. Model performance was evaluated by discrimination using the Harrell concordance index (C-index), accuracy using the Brier score (BS), and interpretability using the number of variables in the model.Of the 14,842 participants in ARIC, the average age was 54.2 years, with 45.2% male and 26.2% Black participants. Thirty-eight unique variables were selected in the RSF top 20 importance ranking of all 6 outcomes. Aging, hypertension, glucose metabolism, renal function, coagulation, adiposity, and sodium retention dominated the predictions of all outcomes. The ML models outperformed the regression models and established risk scores with a higher C-index, lower BS, and varied interpretability.The ML framework is useful for identifying important predictors of CVD and for developing models with robust performance compared with existing risk models.

Background and AimsCardiometabolic disorders (CMD) arise from a constellation of features such as increased adiposity, hyperlipidemia, hypertension and compromised glucose control. Many genetic loci have shown associations with individual CMD-related traits, but no investigations have focused on simultaneously identifying loci showing associations across all domains. We therefore sought to identify loci associated with risk across seven continuous CMD-related traits.Methods and ResultsWe conducted separate genome-wide association studies (GWAS) for systolic and diastolic blood pressure (SBP/DBP), hemoglobin A1c (HbA1c), low- and high-density lipoprotein cholesterol (LDL-C/HDL-C), waist-to-hip-ratio (WHR), and triglycerides (TGs) in the UK Biobank (N=356,574–456,823). Multiple loci reached genome-wide levels of significance (N=145-333) for each trait, but only four loci (in/nearVEGFA, GRB14-COBLL1, KLF14, andRGS19-OPRL1)were associated with risk across all seven traits (P−8). We sought replication of these four loci in an independent set of seven trait-specific GWAS meta-analyses.GRB14-COBLL1showed the most consistent replication, revealing nominally significant associations (PConclusionsOur analyses suggest that very few loci are associated in the same direction of risk with traits representing the full spectrum of CMD features. We identified four such loci, and an understanding of the pathways between these loci and CMD risk may eventually identify factors that can be used to identify pathologic disturbances that represent broadly beneficial therapeutic targets.

Summary Background The quadrivalent human papillomavirus (HPV) vaccine was shown to prevent infections and lesions related to HPV6, 11, 16, and 18 in a randomised, placebo-controlled study in men aged 16–26 years. We assessed the incidences of external genital warts related to HPV6 or 11, and external genital lesions and anal dysplasia related to HPV6, 11, 16, or 18, over 10 years of follow-up. Methods The 3-year base study was an international, multicentre, double-blind, randomised, placebo-controlled trial done at 71 sites in 18 countries. Eligible participants were heterosexual men (aged 16–23 years) or men who have sex with men (MSM; aged 16–26 years). Men who had clinically detectable anogenital warts or genital lesions at screening that were suggestive of infection with non-HPV sexually transmitted diseases, or who had a history of such findings, were excluded. Eligible participants were randomly assigned (1:1) to receive three doses of either quadrivalent HPV vaccine or placebo on day 1, month 2, and month 6, administered as a 0·5-mL injection into the deltoid muscle. The 7-year, open-label, long-term follow-up extension study was done at 46 centres in 16 countries. Participants who received one or more doses of the quadrivalent HPV vaccine in the base study were eligible for enrolment into the long-term follow-up study (early vaccination group). Placebo recipients were offered the three-dose quadrivalent HPV vaccine at the end of the base study; those who received one or more quadrivalent HPV vaccine doses were eligible for enrolment into the long-term follow-up study (catch-up vaccination group). The primary efficacy endpoints were the incidence of external genital warts related to HPV6 or 11 and the incidence of external genital lesions related to HPV6, 11, 16, or 18 in all participants and the incidence of anal intraepithelial neoplasia (including anal warts and flat lesions) or anal cancer related to HPV6, 11, 16, or 18 in MSM only. The primary efficacy analysis was done in the per-protocol population for the early vaccination group, which included participants who received all three vaccine doses, were seronegative at day 1 and PCR-negative from day 1 through month 7 of the base study for the HPV type being analysed, had no protocol violations that could affect evaluation of vaccine efficacy, and had attended at least one visit during the long-term follow-up study. For the catch-up vaccination group, efficacy was assessed in the modified intention-to-treat population, which included participants who had received at least one vaccine dose, were seronegative and PCR-negative for HPV types analysed from day 1 of the base study to the final follow-up visit before receiving the quadrivalent HPV vaccine, and had at least one long-term follow-up visit. Safety was assessed in all randomised participants who received at least one vaccine dose. This study is registered with ClinicalTrials.gov , NCT00090285 . Findings Between Aug 10, 2010, and April 3, 2017, 1803 participants were enrolled in the long-term follow-up study, of whom 936 (827 heterosexual men and 109 MSM) were included in the early vaccination group and 867 (739 heterosexual men and 128 MSM) were included in the catch-up vaccination group. Participants in the early vaccination group were followed up for a median of 9·5 years (range 0·1–11·5) after receiving the third dose of the quadrivalent HPV vaccine, and participants in the catch-up vaccination group were followed up for a median of 4·7 years (0·0–6·6) after receiving the third dose. In early vaccine group participants during long-term follow-up compared with the placebo group in the base study, the incidence per 10 000 person-years of external genital warts related to HPV6 or 11 was 0·0 (95% CI 0·0–8·7) versus 137·3 (83·9–212·1), of external genital lesions related to HPV6, 11, 16, or 18 was 0·0 (0·0–7·7) versus 140·4 (89·0–210·7), and of anal intraepithelial neoplasia or anal cancer related to HPV6, 11, 16, or 18 in MSM only was 20·5 (0·5–114·4) versus 906·2 (553·5–1399·5). Compared with during the base study (ie, before quadrivalent HPV vaccine administration), during the long-term follow-up period, participants in the catch-up vaccination group had no new reported cases of external genital warts related to HPV6 or 11 (149·6 cases per 10 000 person-years [95% CI 101·6–212·3] vs 0 cases per 10 000 person-years [0·0–13·5]) or external genital lesions related to HPV6, 11, 16, or 18 (155·1 cases per 10 000 person-years [108·0–215·7] vs 0 cases per 10 000 person-years [0·0–10·2]), and a lower incidence of anal intraepithelial neoplasia or anal cancer related to HPV6, 11, 16, or 18 (886·0 cases per 10 000 person-years [583·9–1289·1] vs 101·3 cases per 10 000 person-years [32·9–236·3]). No vaccine-related serious adverse events were reported. Interpretation The quadrivalent HPV vaccine provides durable protection against anogenital disease related to HPV6, 11, 16, and 18. The results support quadrivalent HPV vaccination in men, including catch-up vaccination. Funding Merck Sharp & Dohme.

The prognosis of bladder cancer patients is strongly related to both the immune-infiltrating cells and the expression of lncRNAs. In this study, we analyzed the infiltration of immune cells in 403 bladder cancer samples obtained from TCGA by applying the ssGSEA to these samples, then dividing them into high/low immune cell infiltration groups. Based on these groupings, we found 404 differentially expressed immune infiltration-related lncRNAs, which were successively analyzed by univariate Cox regression, then Least Absolute Shrinkage and Selection Operator (LASSO), and finally stepwise multiple Cox regression. Then 12 differentially expressed immune infiltration-related lncRNAs were identified and used to construct a prognostic signature for bladder cancer. Subsequently, Kaplan-Meier analysis, univariate Cox regression, multivariate Cox regression, and multivariate time-dependent ROC analyses (for 1, 3, 5 years) all revealed that this signature performed well in predicting overall survival and served as an independent prognostic factor for patients with bladder cancer. Finally, both TIMER and CIBESORT showed that this 12-lncRNA prognostic signature for bladder cancer was associated with the infiltration of immune cell subtypes. Besides, nomogram considered risk score and clinical characteristics was assembled and showed great performance. More importantly, we found our signature could well distinguish the drug response of patients with bladder cancer. High risk patients showed a better response to cisplatin, doxorubicin, and anti- CTLA4 immunotherapy, low risk patients showed a better response to methotrexate and anti-PD1 immunotherapy compared with each other.

Killer cell immunoglobulin-like receptors (KIRs) are important receptors for regulating the killing of virus-infected or cancer cells of natural killer (NK) cells. KIR2DS2 can recognize peptides derived from hepatitis C virus (HCV) or global flaviviruses (such as dengue and Zika) presented by HLA-C*0102 to activate NK cells, and has shown promising results when used for cancer immunotherapy. Here, we present the complex structure of KIR2DS2 with HLA-C*0102 at a resolution of 2·5Å. Our structure reveals that KIR2DS2 can bind with HLA-C*0102 and HLA-A*1101 in two different directions. Moreover, Tyr45 (in activating receptor KIR2DS2) and Phe45 (in inhibitory KIRs) distinguish the two different binding models and binding affinity between activating KIRs and inhibitory KIRs. The conserved 'AT' motif of the peptide mediates recognition and determines the peptide specificity of recognition. These structural characteristics shed light on how KIRs activate NK cells and can provide a molecular basis for immunotherapy by NK cells.

Purpose. Recent researches showed the vital role of BACH1 in promoting the metastasis of lung cancer. We aimed to explore the value of BACH1 in predicting the overall survival (OS) of early-stage (stages I-II) lung adenocarcinoma. Patients and Methods. Lung adenocarcinoma cases were screened from the Cancer Genome Atlas (TCGA) database. Functional enrichment analysis was performed to obtain the biological mechanisms of BACH1. Gene set enrichment analysis (GSEA) was performed to identify the difference of biological pathways between high- and low-BACH1 groups. Univariate and multivariate COX regression analysis had been used to screen prognostic factors, which were used to establish the BACH1 expression-based prognostic model in the TCGA dataset. The C-index and time-dependent AUC curve were used to evaluate predictive power of the model. External validation of prognostic value was performed in two independent datasets from Gene Expression Omnibus (GEO). Decision analysis curve was finally used to evaluate clinical usefulness of the BACH1-based model beyond pathologic stage alone. Results. BACH1 was an independent prognostic factor for lung adenocarcinoma. High-expression BACH1 cases had worse OS. BACH1-based prognostic model showed an ideal C-index and t -AUC and validated by two GEO datasets, independently. More importantly, the BACH1-based model indicated positive clinical applicability by DCA curves. Conclusion. Our research confirmed that BACH1 was an important predictor of prognosis in early-stage lung adenocarcinoma. The higher the expression of BACH1, the worse OS of the patients.

Caffeine is among the most highly consumed substances worldwide, and it has been associated with decreased cardiovascular risk. Although caffeine has been shown to inhibit the proliferation of vascular smooth muscle cells (VSMCs), the mechanism underlying this effect is unknown. Here, we demonstrated that caffeine decreased VSMC proliferation and induced macroautophagy/autophagy in an in vivo vascular injury model of restenosis. Furthermore, we studied the effects of caffeine in primary human and mouse aortic VSMCs and immortalized mouse aortic VSMCs. Caffeine decreased cell proliferation, and induced autophagy flux via inhibition of MTOR signaling in these cells. Genetic deletion of the key autophagy gene Atg5, and the Sqstm1/p62 gene encoding a receptor protein, showed that the anti-proliferative effect by caffeine was dependent upon autophagy. Interestingly, caffeine also decreased WNT-signaling and the expression of two WNT target genes, Axin2 and Ccnd1 (cyclin D1). This effect was mediated by autophagic degradation of a key member of the WNT signaling cascade, DVL2, by caffeine to decrease WNT signaling and cell proliferation. SQSTM1/p62, MAP1LC3B-II and DVL2 were also shown to interact with each other, and the overexpression of DVL2 counteracted the inhibition of cell proliferation by caffeine. Taken together, our in vivo and in vitro findings demonstrated that caffeine reduced VSMC proliferation by inhibiting WNT signaling via stimulation of autophagy, thus reducing the vascular restenosis. Our findings suggest that caffeine and other autophagy-inducing drugs may represent novel cardiovascular therapeutic tools to protect against restenosis after angioplasty and/or stent placement.

Background Human epidermal growth factor receptor2+ subtype breast cancer has a high degree of malignancy and a poor prognosis. The aim of this study is to develop a prediction model for the human epidermal growth factor receptor2+ subtype (non-luminal) of breast cancer based on the clinical and ultrasound features related with estrogen receptor, progesterone receptor, and human epidermal growth factor receptor2. Methods We collected clinical data and reviewed preoperative ultrasound images of enrolled breast cancers from September 2017 to August 2020. We divided the data into in three groups as follows. Group I: estrogen receptor ± , Group II: progesterone receptor ± and Group III: human epidermal growth factor receptor2 ± . Univariate and multivariate logistic regression analyses were used to analyze the clinical and ultrasound features related with biomarkers among these groups. A model to predict human epidermal growth factor receptor2+ subtype was then developed based on the results of multivariate regression analyses, and the efficacy was evaluated using the area under receiver operating characteristic curve, accuracy, sensitivity, specificity. Results The human epidermal growth factor receptor2+ subtype accounted for 138 cases (11.8%) in the training set and 51 cases (10.1%) in the test set. In the multivariate regression analysis, age ≤ 50 years was an independent predictor of progesterone receptor + (p = 0.007), and posterior enhancement was a negative predictor of progesterone receptor + (p = 0.013) in Group II; palpable axillary lymph node, round, irregular shape and calcifications were independent predictors of the positivity for human epidermal growth factor receptor-2 in Group III (p = 0.001, p = 0.007, p = 0.010, p Conclusions Our study established a model to predict the human epidermal growth factor receptor2-positive subtype with moderate performance. And the results demonstrated that clinical and ultrasound features were significantly associated with biomarkers.

Summary Background & aims Epidemiologic studies are inconsistent regarding the association of dietary omega-3 polyunsaturated fatty acids (PUFA) and/or fish intake with risk of age-related macular degeneration (AMD) incidence and progression. The objective was to determine these associations by conducting a meta-analysis of available studies. Methods Three electronic databases were searched for studies that quantified dietary omega-3 PUFA and/or fish intake from inception to December 2020 without language restriction. Three investigators independently assessed for inclusion and extracted data. Study-specific risk estimates were combined using random-effects model. Potential dose–response associations were explored with the use of generalized least-squares trend estimation. Results 21 studies were included in the meta-analysis. Higher dietary intakes of omega-3 PUFA was significantly associated with 14% (relative risk [RR]: 0.86, 95% confidence interval [CI]: 0.77, 0.96) and 29% (RR: 0.71, 95% CI: 0.55, 0.91) lower risk of early and late AMD, respectively. The dose–response analysis showed a 6% and 22% decrease in the risk of early and late AMD for each additional 1 g/d omega-3 PUFA intake. For individual omega-3 PUFA, the intake of eicosapentaenoic acid and docosahexaenoic acid was inversely associated with lower AMD risk, whereas no association was found for the alpha-linolenic acid. Consistent inverse associations were also found between fish intake and AMD. The pooled RRs comparing extreme categories of fish intake were 0.79 (95% CI: 0.70, 0.90) and 0.71 (95% CI: 0.60, 0.85) for early and late AMD risk, respectively. Every 15 g/d of fish consumption was associated with 13% and 14% lower early and late AMD. In addition, fish intake was associated with a significantly reduced risk of AMD progression (RR: 0.73, 95% CI: 0.53, 1.00). Conclusions A high intake of dietary omega-3 PUFA or fish was associated with a reduced risk of developing of AMD, which further supports that consumption of omega-3 PUFA-rich foods may be a new avenue nutritional approach to preventing AMD.

Amplification and overexpression of the SOX2 oncogene represent a hallmark of squamous cancers originating from diverse tissue types. Here, we find that squamous cancers selectively amplify a 3’ noncoding region together with SOX2, which harbors squamous cancer-specific chromatin accessible regions. We identify a single enhancer e1 that predominantly drives SOX2 expression. Repression of e1 in SOX2-high cells causes collapse of the surrounding enhancers, remarkable reduction in SOX2 expression, and a global transcriptional change reminiscent of SOX2 knockout. The e1 enhancer is driven by a combination of transcription factors including SOX2 itself and the AP-1 complex, which facilitates recruitment of the co-activator BRD4. CRISPR-mediated activation of e1 in SOX2-low cells is sufficient to rebuild the e1-SOX2 loop and activate SOX2 expression. Our study shows that squamous cancers selectively amplify a predominant enhancer to drive SOX2 overexpression, uncovering functional links among enhancer activation, chromatin looping, and lineage-specific copy number amplifications of oncogenes., SOX2 amplification and overexpression represents a hallmark of squamous cancers with distinct distribution of chromatin accessible regions depending on cancer type. Here, the authors identify a single enhancer e1 that predominantly drives SOX2 expression in squamous cancer.

Background Continuous relative phase (CRP) has gained popularity to assess movement performances in recent decades. Research question The application and interpretation of CRP in common movements such as running and jumping are still unclear. Methods This systematic review summarized the current applications, methodology, parameters of interest, and interpretations of CRP variables in running and jumping. Reviewed articles were found in five databases from January 1999 to December 2020, and 1613 records were obtained. After applying selection criteria and analysis of study quality to titles, abstracts, and full texts, 38 articles were identified for subsequent review. Results Twenty-eight reviewed articles relating to running were found to compare the coordination among pathological gait, footwear designs, running speed, gender, age, running level, fatigue state, and treadmill effect. In addition, ten reviewed articles relating to jumping were found to compare the coordination among different types of jump (e.g., squat jump coordination, countermovement jump, single leg jump) and insole effect. Significance The CRP and its variability (CRPv) are two common variables to describe the changes and differences of coordination patterns, respectively. These reviewed articles suggest that CRP tools are effective to assess the coordination and performances in running and jumping, as these values are related to external (environment/equipment) and internal (self-biological) changes. In the future, studying higher-order analysis of movement patterns using CRP tools can provide meaningful interpretation of movement behavior.

Background. Renal cell carcinoma (RCC) is one of the most common aggressive malignant tumors in the urinary system, among which the clear cell renal cell carcinoma (ccRCC) is the most common subtype. The immune-related long noncoding ribonucleic acids (irlncRNAs) which are abundant in immune cells and immune microenvironment (IME) have potential significance in evaluating the prognosis and effects of immunotherapy. The signature based on irlncRNA pairs and independent of the exact expression level seems to have a latent predictive significance for the prognosis of patients with malignant tumors but has not been applied in ccRCC yet. Method. In this article, we retrieved The Cancer Genome Atlas (TCGA) database for the transcriptome profiling data of the ccRCC and performed coexpression analysis between known immune-related genes (ir-genes) and lncRNAs to find differently expressed irlncRNA (DEirlncRNA). Then, we adopted a single-factor test and a modified LASSO regression analysis to screen out ideal DEirlncRNAs and constructed a Cox proportional hazard model. We have sifted 28 DEirlncRNA pairs, 12 of which were included in this model. Next, we compared the area under the curve (AUC), found the cutoff point by using the Akaike information criterion (AIC) value, and distinguished the patients with ccRCC into a high-risk group and a low-risk group using this value. Finally, we tested this model by investigating the relationship between risk score and survival, clinical pathological characteristics, cells in tumor immune microenvironment, chemotherapy, and targeted checkpoint biomarkers. Results. A novel immune-related lncRNA pair signature consisting of 12 DEirlncRNA pairs was successfully constructed and tightly associated with overall survival, clinical pathological characteristics, cells in tumor immune microenvironment, and reactiveness to immunotherapy and chemotherapy in patients with ccRCC. Besides, the efficacy of this signature was verified in some commonly used clinicopathological subgroups and could serve as an independent prognostic factor in patients with ccRCC. Conclusions. This signature was proven to have a potential predictive significance for the prognosis of patients with ccRCC and the efficacy of immunotherapy.

Over the past 30 years, treatments from different disciplines have been applied to spastic cerebral palsy (SCP). However, few bibliometric studies have been conducted to date. This study explored the knowledge base, emerging hotspots, and future trends related to SCP treatment research using bibliometric analysis.Publications on SCP treatment included in the Web of Science Core Collection database between 1990 and 2020 were retrieved, and Medical Subject Headings terms were extracted from PubMed. Online bibliometric analysis website (http://bibliometric.com/), 2 pieces of software called "CiteSpace" and "VOSViewer" were used for quantitative analysis and knowledge map establishment.A total of 1668 papers were retrieved from 1990 to 2020. The number of publications has increased annually. Developmental Medicine and Child Neurology is the most productive and the highest co-cited journal. The United States has been the largest contributor. Vrije Universiteit Amsterdam ranked first in the number of papers published among institutions that have conducted correlational research. Becher JG and Graham HK should be considered scholars who have made outstanding contributions. The knowledge base of the SCP treatment research field is thoughtfully constructed to promote understanding of the field.This bibliometric study identified global achievements, research hotspots, and trends of SCP treatment. They provide insights into the research field and valuable information for future scientific research and clinical treatment.

PurposeNeoadjuvant chemoradiotherapy (nCRT) is a standard treatment option for patients with stage III oesophageal cancer. Approximately 30% of oesophageal cancer patients will have a pathological complete response (pCR) after nCRT. However, available clinical methods cannot accurately predict pCR for patients. We aimed to find more indicators that could be used to predict the pathological response to nCRT.MethodA total of 84 patients with stage III oesophageal squamous cell cancer were enrolled in this study. Ten patients failed to have surgery as a result of progressive disease (PD). Among the patients who underwent surgery, 32 patients had a pathologic complete response (pCR), whereas 42 patients showed no or partial response (npCR) after nCRT. Routine blood test results and lymphocyte subset assessments before and after nCRT were retrospectively analysed. Univariate and multivariate analyses were used to identify independent predictors of the clinical curative effect of nCRT. Eventually, nomograms were established for predicting the PD and pCR rates.ResultsThe numbers of lymphocytes, B lymphocytes, T lymphocytes, Th lymphocytes, Ts lymphocytes, and NK cells and the percentages of B lymphocytes and NK cells were decreased significantly after nCRT (P < 0.0001), whereas the percentages of T lymphocytes and Ts lymphocytes increased (P < 0.0001). Univariate analysis showed that age, the length of the lesion, the level of haemoglobin before nCRT, and the amount of change in haemoglobin were related to PD, and the percentage of NK cells after nCRT was related to pCR. Multivariate logistic analysis demonstrated that the length of the lesion, the neutrophil-to-lymphocyte ratio (NLR) before nCRT, and the amount of change in haemoglobin were independent predictors of PD, whereas the percentage of NK cells after nCRT was an independent predictor of pCR.ConclusionLymphocyte subsets changed dramatically during nCRT, and these changes together with baseline and posttreatment lymphocyte subsets have predictive value in determining the response to nCRT for oesophageal cancer.

Background and objective The Cortical Bone Trajectory (CBT) technique provides an alternative method for fixation in the lumbar spine in patients with osteoporosis. An accuracy CBT screw placement could improve mechanical stability and reduce complication rates. Purpose The purpose of this study is to explore the accuracy of cortical screw placement with the application of implanted spinous process clip (SPC) guide. Methods and materials Four lumbar specimens with T12-S1 were used to access the accuracy of the cortical screw. The SPC-guided planning screws were compared to the actual inserted screws by superimposing the vertebrae and screws preoperative and postoperative CT scans. According to preoperative planning, the SPC guide was adjusted to the appropriate posture to allow the K-wire drilling along the planned trajectory. Pre and postoperative 3D-CT reconstructions was used to evaluate the screw accuracy according to Gertzbein and Robbins classification. Intraclass correlation coefficients (ICCs) and Bland–Altman plots were used to examine SPC-guided agreements for CBT screw placement. Results A total of 48 screws were documented in the study. Clinically acceptable trajectory (grades A and B) was accessed in 100% of 48 screws in the planning screws group, and 93.8% of 48 screws in the inserted screws group (p = 0.242). The incidence of proximal facet joint violation (FJV) in the planning screws group (2.1%) was comparable to the inserted screws group (6.3%) (p = 0.617). The lateral angle and cranial angle of the planned screws (9.2 ± 1.8° and 22.8 ± 5.6°) were similar to inserted screws (9.1 ± 1.7° and 23.0 ± 5.1°, p = 0.662 and p = 0.760). Reliability evaluated by intraclass correlation coefficients and Bland–Altman showed good consistency in cranial angle and excellent results in lateral angle and distance of screw tip. Conclusions Compared with preoperative planning screws and the actually inserted screws, the SPC guide could achieve reliable execution for cortical screw placement.

BackgroundTertiary lymphoid structures (TLSs) are emerging as a potential predictor of prognosis and response to immunotherapy in some solid tumors. However, the comprehensive role of TLSs in bladder cancer remains unclear.MethodsEighteen bladder cancer (BCa) datasets were downloaded from The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), ArratyExpress and IMvigor210. Based on 39 validated TLS signature genes (TSGs), we evaluated the TLS patterns in all patients, and correlated the TLS patterns with prognosis and tumor microenvironment (TME) cell-infiltrating characteristics. The cox regression model and principal component analysis (PCA) algorithms were used to construct the TLS score, which helps to quantify the TLS pattern in individuals.ResultsThe landscape of 39 validated TSGs in BCa was assessed first. Five distinct TLS patterns and four gene clusters were determined. TLS cluster C2 and gene cluster A were thought to be characterized by mature TLSs and showed better prognosis and higher immune cells infiltration than other clusters. The TLS score was discovered to be tightly correlated with the infiltration level of immune cells, and could predict the maturation status of TLSs to some extent. We found TLS score was an excellent predictor for prognosis in patients with BCa independent of tumor mutation burden (TMB), and low TLS score was related to better prognosis than high TLS score. Besides, low TLS score was correlated with a better response to immune checkpoint blockade (ICB) immunotherapy and commonly used chemotherapy drugs.ConclusionsOur work demonstrated the characteristics of TLSs in BCa. By using the TLS score, we could evaluate the TLS pattern in individuals. Better understanding of TLS pattern and the usage of TLS score could help instruct clinical strategy and precision medicine for BCa.

To investigate the association between adherence to healthy dietary patterns, such as Mediterranean dietary pattern(MED), dietary approaches to stop hypertension(DASH), Mediterranean-DASH intervention for neurodegenerative delay with cognitive disorders(MIND), and the incidence of cognitive disorders.Prospective studies on the association of MED, DASH and MIND with cognitive disorders in Chinese and English literatures were retrieved from PubMed, Wanfang, CNKI and VIP databases by title/abstract retrieval strategy from database establishment to February 28, 2022. Relative risk and its 95% confidence intervals were extracted to calculated the pooled effect and dose-response relationship. Heterogeneity was calculated by using Q test and I~2, and publication bias were analyzed by funnel plot, Beggapos;s test and Eggerapos;s test.Totally, 124 977 participants and 15 studies about the relationship between healthy dietary patterns and cognitive impairment diseases were included in this study. Compared with the lower adherence group, the relative risks of cognitive disorders were 0.84(95%CI 0.84-0.97) for participants with higher adherence to MED, 0.79(95%CI 0.79-1.00) for participants with higher adherence to DASH, 0.48(95%CI 0.32-0.71) for participants with higher adherence to MIND, respectively. Subgroup analysis showed that the risk of mild cognitive impairment was 0.76(95%CI 0.65-0.90) for participants with higher adherence to MED, and 0.63(95%CI 0.48-0.82) for DASH. No significant association were observed in the relationship of MED, DASH with dementia. Different scoring method for dietary patterns, dietary survey method, study area, follow-up time and sample size might be the main sources of heterogeneity.Higher adherence to MED, DASH and MIND were associated with lower risk of cognitive disorders. MED and DASH were associated with a reduced risk of mild cognitive impairment rather than dementia.

Cadmium (Cd) is one of the toxic heavy metals found widely in the environment. Skin is an important target organ of Cd exposure. However, the adverse effects of Cd on human skin are still not well known. In this study, normal human skin keratinocytes (HaCaT cells) were studied for changes in cell viability, morphology, DNA damage, cycle, apoptosis, and the expression of endoplasmic reticulum (ER) stress-related genes (XBP-1, BiP, ATF-4, and CHOP) after exposure to Cd for 24 h. We found that Cd decreased cell viability in a concentration-dependent manner, with a median lethal concentration (LC50) of 11 µM. DNA damage induction was evidenced by upregulation of the level of γ-H2AX. Furthermore, Cd induced G0/G1 phase cell cycle arrest and apoptosis in a dose-dependent manner and upregulated the mRNA levels of ER stress biomarker genes (XBP-1, BiP, ATF4, and CHOP). Taken together, our results showed that Cd induced cytotoxicity and DNA damage in HaCaT cells, eventually resulting in cell cycle arrest in the G0/G1 phase and apoptosis. In addition, ER stress may be involved in Cd-induced HaCaT apoptosis. Our data imply the importance of reducing Cd pollution in the environment to reduce its adverse impacts on human skin.

Tris (1-chloro-2-propyl) phosphate (TCPP) is one of the most frequently detected organophosphorus flames in the environment. Continuous daily exposure to TCPP may harm human skin. However, little is known about the adverse effects of TCPP on human skin. In this study, we first evaluated the detrimental effects and tried to uncover the underlying mechanisms of TCPP on human skin keratinocytes (HaCaT) after 24 h exposure. We found that TCPP caused a concentration-dependent decrease in HaCaT cell viability after exposure to 1.56–400 μg/mL for 24 h, with an IC50 of 275 μg/mL. TCPP also promoted the generation of intracellular reactive oxygen species (ROS) and triggered DNA damage, evidenced by an increase of phosphorylated histone H2A.X (γH2A.X) in the nucleus. Furthermore, the cell cycle was arrested at the G1 phase at 100 μg/mL by upregulation of the mRNA expression of p53 and p21 and downregulation of cyclin D1 and CDK4 expression. Additionally, both the senescence-associated-β-galactosidase activity and related proinflammatory cytokine IL-1β and IL-6 were elevated, indicating that TCPP exposure caused cellular senescence may be through the p53-dependent DNA damage signal pathway in HaCaT cells. Taken together, our data suggest that flame-retardant exposure may be a key precipitating factor for human skin aging.

Background The pathogenesis of kidney stone disease (KSD) is not fully understood, and potential contributing factors remain to be explored. Several studies have revealed that the urinary microbiome (urobiome) of stone formers was distinct from that of healthy individuals using 16S rRNA gene sequencing, most of which only provided microbial identification at the genus level. 2bRAD sequencing for Microbiome (2bRAD-M) is a novel sequencing technique that enables accurate characterization of the low-biomass microbiome at the species resolution. We aimed to apply 2bRAD-M to profile the renal pelvis urobiome of unilateral kidney stone patients and compared the urobiome with and without stone(s). Method A total of 30 patients with unilateral stones were recruited, and their renal pelvis urine from both sides was collected. A ureteroscope was inserted into the renal pelvis with stone(s) and a ureteral catheter was placed into the ureteroscope to collect renal pelvis urine. This procedure was repeated again with new devices to collect the urine of the other side. 2bRAD-M was performed to characterize the renal pelvis urobiome of unilateral stone formers to explore whether microbial differences existed between the stone side and the non-stone side. Results The microbial community composition of the stone side was similar to that of the non-stone side. Paired comparison showed that Corynebacterium was increased and Prevotella and Lactobacillus were decreased in the stone side. Four species (Prevotella bivia, Lactobacillus iners, Corynebacterium aurimucosum, and Pseudomonas sp_286) were overrepresented in the non-stone side. 24 differential taxa were also identified between two groups by linear discriminant analysis effect size (LEfSe). Extensive and close connections among genera and species were observed in the correlation analysis. Moreover, a random forest classifier was constructed using specific enriched species, which can distinguish the stone side from the non-stone side with an accuracy of 71.2%. Conclusion This first 2bRAD-M microbiome survey gave an important hint towards the potential role of urinary dysbiosis in KSD and provided a better understanding of mechanism of stone formation.

Background Hepatitis B virus (HBV) remains a major global public health problem worldwide; in endemic areas, mother-to-child transmission (MTCT) of HBV is the most common transmission route. Previous studies have shown that amniocentesis for prenatal diagnosis increases the risk of MTCT of HBV among highly viraemic mothers. However, no data is available on MTCT related fetal blood sampling (FBS) because of the paucity of cases or lack of attention. We present a case series of HBV-infected women who underwent FBS with or without antiviral therapy during pregnancy and discuss the risk of MTCT after FBS. Case presentation Six hepatitis B surface antigen (HBsAg)-positive pregnant women who underwent FBS for prenatal diagnosis were retrospectively reviewed. Their infants were followed up with HBV serology parameters until at least 12 months of age. Among 6 cases, two hepatitis B e-antigen (HBeAg)-positive mothers had high viral loads > 7.0 log10 IU/mL, and one of them received antiviral therapy at 26+ 3 gestational weeks and achieved an anticipated level of 4.52 log10 IU/mL before FBS, while the other one did not receive any antiviral treatment. The other 4 cases were HBeAg-negative with low viral loads. Only a child born to the HBeAg-positive mother, who had no antiviral therapy with a viral load of 7.48 log10 IU/mL before FBS, was found to have MTCT with HBsAg persistently positive from birth to 12 months of age. The other 5 children were both HBsAg-negative and HBsAb-positive at the end of follow-up. Conclusions FBS may increase the risk of MTCT of HBV in women with HBeAg-positive and high viral loads; therefore, FBS should be avoided in this high-risk population. Maternal HBV serologic testing and awareness of the potential risk of MTCT should be recommended before FBS. Antiviral therapy may be effective to decrease the risk of MTCT after FBS in highly viraemic women.

Background Pain is one of the most common concomitant symptoms among cancer patients. Pharmacologic agents are regarded as a cornerstone of cancer pain management. ‘Dose titration’ with short-acting morphine is widely accepted. Such a titration method is very complicated. The analgesic background establishment is often delayed. Titration based on sustained-release opioids is also recommended, but the onset of analgesic effect requires hours, whereas the rescue analgesia is always needed. This study evaluated the optimized morphine titration scheme with a simultaneous combination of sustained-release morphine and subcutaneous morphine. Methods In a multicenter, 7-day, randomized controlled study, patients with moderate to severe cancer pain were assigned to receive either sustained-release morphine and subcutaneous morphine simultaneously (rapid titration) or only subcutaneous morphine to dose titration. The primary outcome was the safety and the number of times of rescue therapy as needed in the first 24 h. Results A total of 108 patients with moderate to severe cancer pain were included in the study. The number of times of rescue analgesics in the first 24 h significantly reduced in the rapid titration group (0.4 ± 0.48 vs. 2.3 ± 0.78, P = 0.000). No differences in the intensity of opioid-related symptoms were found between the two groups. Conclusions Rapid titration is safe and efficient, which could significantly decrease rescue analgesics in the first 24 h and achieve better analgesic efficacy for cancer pain patients.

Due to the body’s systemic distribution of photothermal agents (PTAs), and to the imprecise exposure of lasers, photothermal therapy (PTT) is challenging to use in treating tumor sites selectively. Striving for PTT with high selectivity and precise treatment is nevertheless important, in order to raise the survival rate of cancer patients and lower the likelihood of adverse effects on other body sections. Here, we studied cold atmospheric plasma (CAP) as a supplementary procedure to enhance selectivity of PTT for cancer, using the classical photothermic agent’s gold nanostars (AuNSs). In in vitro experiments, CAP decreases the effective power of PTT: the combination of PTT with CAP at lower power has similar cytotoxicity to that using higher power irradiation alone. In in vivo experiments, combination therapy can achieve rapid tumor suppression in the early stages of treatment and reduce side effects to surrounding normal tissues, compared to applying PTT alone. This research provides a strategy for the use of selective PTT for cancer, and promotes the clinical transformation of CAP.

Background. Thoracolumbar spinal fracture associated with severe spinal cord injury (sSCI) is a kind of severe traumatic spine injury. Although various approaches are currently used to treat sSCI-related thoracolumbar fractures, the neurological function of patients has not been significantly improved by surgery. Objective. To evaluate the therapeutic effects of the new procedure of posterior injured vertebra column resection (PIVCR) and spinal shortening for the treatment of thoracolumbar fracture associated with sSCI. Methods. In this retrospective case-control observational study, we included 66 patients with thoracolumbar fractures associated with sSCI in our institution from January 2015 to December 2017. According to the different surgical approaches, the patients were allocated to group A (n = 32, received simple posterior decompression and fixation) and group B (n = 34, received PIVCR and spinal shortening). All patients’ clinical and radiologic outcomes were collected to evaluate retrospectively. The clinical outcomes were gathered, including the intraoperative blood loss, operative time, visual analog scale (VAS) score, and American Spinal Injury Association (ASIA) impairment scale. The radiologic outcomes were collected involving the range of spinal shortening, canal encroachment, heights of the anterior edge of the vertebral body, and the Cobb angle. Results. There was no significant difference in the two groups regarding preoperative demographic data, VAS scores, segmental kyphosis Cobb, canal encroachment, and neurological status. The range of spinal shortening in group B was an average 1.57 ± 0.40 cm and 36.45 ± 6.56% of the height of the single spinal motion segment. Due to the characteristics of the surgical procedure, group B got complete decompression of the spinal cord and better postoperative canal decompression than group A. Thus, better clinical outcomes, including neurological improvement, loss of corrective Cobb angle, and VAS improvement, were shown in group B at the follow-up investigation than those in group A ( P < 0.05 ). Conclusion. PIVCR and spinal shortening surgical procedure is a safe, reliable, and effective approach to treating thoracolumbar fracture associated with sSCI.

Among women aged 27-45 years, the quadrivalent human papillomavirus (qHPV; HPV6/11/16/18) vaccine was generally well tolerated, efficacious, and immunogenic in the placebo-controlled FUTURE III study (NCT00090220; n = 3253). The qHPV vaccine was also generally well tolerated and highly immunogenic in men aged 27-45 years who participated in the single-cohort mid-adult male (MAM) study (NCT01432574; n = 150). Here, we report results of a long-term follow up (LTFU) extension of FUTURE III with up to 10 years follow-up. To understand the relevance of the mid-adult women LTFU study in the context of mid-adult men vaccination, we report results from post-hoc, cross-study immunogenicity analyses conducted to compare immunogenicity (geometric mean titers; GMTs) at 1-month post-qHPV vaccine dose 3 in women and men aged 27-45 years versus women and men aged 16-26 years from prior efficacy studies. The qHPV vaccine demonstrated durable protection against the combined endpoint of HPV6/11/16/18-related high-grade cervical dysplasia and genital warts up to 10 years (median 8.9) post-dose 3 and sustained HPV6/11/16/18 antibody responses through approximately 10 years in women aged 27-45 years. Efficacy of qHPV vaccine in men aged 27-45 years was inferred based on the cross-study analysis of qHPV vaccine immunogenicity demonstrating non-inferior HPV6/11/16/18 antibody responses in men aged 27-45 years versus 16-26 years. In conclusion, durable effectiveness of the qHPV vaccine was demonstrated in women 27-45 years of age, and vaccine efficacy was inferred in men 27-45 years of age based on the serological results.

BackgroundPatients with relapsed or refractory (R/R) lymphomas have benefited from chimeric antigen receptor (CAR)-T-cell therapy. However, this treatment is linked to a high frequency of adverse events (AEs), such as cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and hematologic toxicity. There has been increasing interest in hematological toxicity in recent years, as it can result in additional complications, such as infection or hemorrhage, which remain intractable.MethodsWe conducted a retrospective, single-institution study to evaluate the patterns and outcomes of cytopenia following CAR-T-cell infusion and potential associated factors.ResultsOverall, 133 patients with R/R lymphoma who received CAR-T-cell therapy from June, 2017 to April, 2022 were included in this analysis. Severe neutropenia, anemia and thrombocytopenia occurred frequently (71, 30 and 41%, respectively) after CAR-T-cell infusion. A total of 98% of severe neutropenia and all severe thrombocytopenia cases occurred in the early phase. Early severe cytopenia was associated with CRS incidence and severity, as well as peak inflammatory factor (IL-6, C-reactive protein (CRP), and ferritin) levels. In multivariate analysis, prior hematopoietic stem cell transplantation (HSCT), baseline hemoglobin (HB), and lymphodepleting chemotherapy were independent adverse factors associated with early severe cytopenia. In addition, 18% and 35% of patients had late neutrophil- and platelet (PLT)-related toxicity, respectively. In multivariate analysis, lower baseline PLT count was an independent factor associated with late thrombocytopenia. More severe cytopenia was associated with higher infection rates and poorer survival.ConclusionsThis research indicates that improved selection of patients and management of CRS may help to decrease the severity of cytopenias and associated AEs and improve survival following CAR-T-cell therapy.Clinical Trial Registrationhttps://www.clinicaltrials.gov/ct2/show/NCT03196830, identifier NCT03196830.

ObjectiveThe objective of this study was to explore and verify the subtypes in hepatocellular carcinoma based on the immune (lymphocyte and myeloid cells), stem, and stromal cells in the tumor microenvironment and analyze the biological characteristics and potential relevance of each cluster.MethodsWe used the xCell algorithm to calculate cell scores and got subtypes by k-means clustering. In the external validation sets, we verified the conclusion stability by a neural network model. Simultaneously, we speculated the inner connection between clusters by pseudotime trajectory analysis and confirmed it by pathway enrichment, TMB, CNV, etc., analysis.ResultAccording to the results of the consensus cluster, we chose k = 4 as the optimal value and got four different subtypes (C1, C2, C3, and C4) with different biological characteristics based on infiltrating levels of 48 cells in TME. In univariable Cox regression, the hazard ratio (HR) value of C3 versus C1 was 2.881 (95% CI: 1.572–5.279); in multivariable Cox regression, we corrected the age and TNM stage, and the HR value of C3 versus C1 was 2.510 (95% CI: 1.339–4.706). C1 and C2 belonged to the immune-active type, C3 and C4 related to the immune-insensitive type and the potential conversion relationships between clusters. We established a neural network model, and the area under the curves of the neural network model was 0.949 in the testing cohort; the same survival results were also observed in the external validation set. We compared the differences in cell infiltration, immune function, pathway enrichment, TMB, and CNV of four clusters and speculated that C1 and C2 were more likely to benefit from immunotherapy and C3 may benefit from FGF inhibitors.DiscussionOur analysis provides a new approach for the identification of four tumor microenvironment clusters in patients with liver cancer and identifies the biological differences and predicts the immunotherapy efficacy between the four subtypes.

Objective This paper aims to explore the diagnostic value of enhanced magnetic resonance imaging (MRI) combined with a carcinoembryonic antigen (CEA) and carbohydrate antigen in terms of the liver metastasis of colorectal cancer. Methods A total of 167 colorectal cancer patients with liver metastasis and 167 colorectal cancer patients without liver metastasis were selected as the subjects. An automatic electrochemiluminescence analyser was then used to detect the tumour markers CEA, CA19-9, CA125 and CA72-4. The consistency between the MRI examination and clinical pathological examination was also analysed, and the sensitivity, specificity and positive and negative predictive values of various combined detection methods were compared. Results The abnormal rates of CEA, CA19-9, CA125 and CA72-4 in the two groups were statistically significant (P < 0.05), while the results of the enhanced MRI and clinicopathological examination for liver metastasis in patients with colon cancer were largely consistent (Kappa coefficient = 0.788, P < 0.000). However, the two methods were inconsistent. The false positive rate of the enhanced MRI examination was 15.3%, while the false negative rate was 6.0%. The specificity (94.61%), positive predictive value (92.68%) and positive likelihood ratio (12.67%) were the highest for the MRI combined with serial CEA, while the sensitivity (98.80%) and negative predictive value (97.22%) were the highest with the MRI combined with parallel CEA, and this combination returned the lowest negative likelihood ratio (0.03). Conclusion The combination of MRI and CEA excludes non-metastatic patients and identifies colorectal liver metastasis cancer patients. Overall, it has a higher diagnostic value.

Multiple myeloma is the second most common hematological malignancy. Despite significant advances in treatment, relapse is common and carries a poor prognosis. Thus, it is critical to elucidate the genetic factors contributing to disease progression and drug resistance. Here, we carry out integrative clinical sequencing of 511 relapsed, refractory multiple myeloma (RRMM) patients to define the disease’s molecular alterations landscape. The NF-κB and RAS/MAPK pathways are more commonly altered than previously reported, with a prevalence of 45–65% each. In the RAS/MAPK pathway, there is a long tail of variants associated with the RASopathies. By comparing our RRMM cases with untreated patients, we identify a diverse set of alterations conferring resistance to three main classes of targeted therapy in 22% of our cohort. Activating mutations in IL6ST are also enriched in RRMM. Taken together, our study serves as a resource for future investigations of RRMM biology and potentially informs clinical management.

Costimulatory molecules are involved in initiation of anti-tumor immune responses while long non‐coding RNAs (lncRNAs) regulate the development of various cancers. However, the roles of lncRNA in hepatocellular carcinoma (HCC) have not been fully established. In this study, we aimed at identifying lncRNAs-related costimulatory molecules in HCC and to construct a prognostic signature for predicting the clinical outcomes for HCC patients. Data were downloaded from The Cancer Genome Atlas database for bioinformatics analyses. Costimulatory molecules were obtained from published literature. The R software, SPSS, and GraphPad Prism were used for statistical analyses. A risk model that is based on five costimulatory molecule-related lncRNAs was constructed using lasso and Cox regression analyses. Multivariate regression analysis revealed that the risk score could predict the prognostic outcomes for HCC. Samples in high- and low-risk groups exhibited significant differences in gene set enrichment and immune infiltration levels. Through colony formation and CCK8 assays, we found that AC099850.3 was strongly associated with HCC cell proliferation. We identified and validated a novel costimulatory molecule-related survival model. In addition, AC099850.3 was found to be closely associated with clinical stages and proliferation of HCC cells, making it a potential target for HCC treatment.

Urolithiasis is one of the most common diseases in urology, with a lifetime prevalence of 14% and is more prevalent in males compared to females. We designed to explore sex disparities in the Chinese population to provide evidence for prevention measures and mechanisms of stone formation.A total of 98232 Chinese individuals who had undergone a comprehensive examination in 2017 were included. Fully adjusted odds ratios for kidney stones were measured using restricted cubic splines. Multiple imputations was applied for missing values. Propensity score matching was utilised for sensitivity analysis.Among the 98232 included participants, 42762 participants (43.53%) were females and 55470 participants (56.47%) were males. Patients' factors might cast an influence on the development of kidney stone disease distinctly between the two genders. A risk factor for one gender might have no effect on the other gender. The risk for urolithiasis in females continuously rises as ageing, while for males the risk presents a trend to ascend until the age of around 53 and then descend.Patients' factors might influence the development of kidney stones distinctly between the two genders. As age grew, the risk to develop kidney stones in females continuously ascended, while the risk in males presented a trend to ascend and then descend, which was presumably related to the weakening of the androgen signals.Key messagesWe found that patients' factors might cast an influence on the development of kidney stone disease distinctly between the two sexes.The association between age and urolithiasis presents distinct trends in the two sexesThe results will provide evidence to explore the mechanisms underlying such differences can cast light on potential therapeutic targets and promote the development of tailored therapy strategies in prospect.

Stroke is an acute cerebrovascular disease and a neurological disorder that occurs due to a cerebral arterial embolism and rupture. Acute stroke is often accompanied by dysphagia, which reduces patients' intake of food and nutrients, decreases their nutritional status, and affects their quality of life.The study intended to identify the demographic and clinical characteristics of stroke patients with dysphagia and to explore the relationship of those characteristics to nutritional status and prognosis.The research team retrospectively collected the clinical data of patients to compare the nutritional status and prognoses of patients with different demographic and clinical characteristics.The study took place in the Department of Neurology at the First People's Hospital of Shenyang in Shenyang, China.Participants were 789 stroke patients with dysphagia who had been admitted to the general ward of the neurology departments of hospitals of Grade 3 or higher in Northeast China between January 2019 and September 2020. Based on the results of the Nutrition Risk Screening (NRS-2002) and Subjective Global Assessment (SGA) scales at baseline, participants were enrolled in this study.The outcomes were the correlations between participants' demographic and clinical characteristics and their nutritional statuses and prognoses. The Modified Rankin Scale (mRS) was used to evaluate the prognosis of the patients at seven days and three months after participants' enrollment in the study. Using the SPSS 26.0, a t test, chi-square test, and F test were performed to analyze and verify the presence of fundamental differences in baseline characteristics between participants with good nutrition and those with poor nutrition. Also, a statistical correlation analysis was performed.The study showed that participants with different nutritional levels had statistically significant differences in the presence or absence of infections and body temperature and scores on the Standardized Swallowing Assessment (SSA) and National Institutes of Health Stroke Scale (NIHSS), with all P.001. At baseline seven days after enrollment, the prognoses of participants were significantly different for different previous histories of stroke (P.001), family history of stroke (P = .005), presence or absence of infections (P.001), body temperature (P.001), and SSA (P.001) and NIHSS (P.001) scale scores. At three months after enrollment, the prognoses of participants were significantly different for previous history of stroke (P = .003), different body temperatures (P.001), presence or absence of infections(P.001), and SSA (P.001) and NIHSS (P.001) scale scores. Age, gender, family history of stroke, smoking, alcohol consumption, previous history of stroke, education level, SSA scale score, NIHSS scale score, body mass index (BMI), body temperature, and infection were adjusted in the model. Nutritional status as classified by NRS-2002 and SGA was significantly correlated with prognosis (P.001). The prognosis of stroke patients with dysphagia was associated with nutritional status by unconditional logistic regression.The prognosis of stroke patients with dysphagia is related to their nutritional status. A better nutritional status indicates the better prognosis, and vice versa. In clinical treatment, attention should be paid to use of a nutritional intervention.

APL patients have recurrent alterations in FLT3, WT1, NRAS and KRAS. Gene mutations have a strong potential for involvement in pathogenesis and may have potential effects on the clinical manifestations. Gene mutations may even be associated with early death (ED) in APL patients. However, there is little published information on mutations in APL patients and whether they are attributed to early death. In this study, we retrospectively analyzed the clinical data and gene mutations of 134 de novo APL patients. We detected the gene mutations by next-generation sequencing (NGS) to investigate the genetic predictors of early death in APL patients. According to the number of gene mutations per patient, the 134 APL patients were divided into three groups. All patients received arsenic trioxide (ATO) alone as induction therapy. The clinical data and gene mutations were compared and analyzed. A total of 134 APL patients were involved in the study. The clinical data of sex, WBC, PT, and DD, UA, and LDH level were significantly different between the three groups (P = 0.000, P = 0.000, P = 0.009, P = 0.020, P = 0.030, P = 0.001 and P = 0.014, respectively). Meanwhile, among them, the Sanz risk stratification and early death rate were significantly different (P = 0.001). The early death rate was 10.4%, and the median time to early death was 6.6 days (range 2–15 days). For the next-generation sequencing, a mean of 1.28 ± 1.06 mutations per patient was detected (range: 0–5). The univariate and the multivariate regression analysis showed that age > 50[HR = 1.666, CI (1.027–2.702), P = 0.039], high WBC count [HR = 4.702, CI (1.026–21.543), P = 0.046] and low ALB levels [HR = 4.547, CI (1.088–18.995), P = 0.038] were independent risk factors for early death in APL patients. Furthermore, Kaplan–Meier survival analysis, univariate analysis, and the multivariate regression analysis showed that patients with multiple gene mutations [HR = 2.258, CI (1.115–4.571), P = 0.024], KRAS [HR = 5.136, CI (1.356–19.455), P = 0.016] and/or GATA2 [HR = 4.070, CI (1.287–12.877), P = 0.017] have a significantly higher early death rate. The results of this investigation show that both molecular markers and clinical variables should be used as potential predictors for early death in APL patients. Our results suggested that age > 50, high WBC count, low ALB levels, and the presence of multiple gene mutations, KRAS and/or GATA2 at the time of diagnosis were independent risk factors for early death in APL patients. For these patients, clinicians should be more cautious during the course of induction treatment.

This study aims to evaluate the clinical value of PCR-fluorescent probes for detecting the mutation gene associated with extensively drug-resistant tuberculosis (XDR-TB). The molecular species identification of 900 sputum specimens was performed using polymerase chain reaction (PCR)-fluorescent probe. The mutations of the drug resistance genes rpoB, katG, inhA, embB, rpsL, rrs, and gyrA were detected. The conventional drug susceptibility testing (DST) and PCR-directed sequencing (PCR-DS) were carried out as control. DST demonstrated that there were 501 strains of rifampicin resistance, 451 strains of isoniazid resistance, 293 strains of quinolone resistance, 425 strains of streptomycin resistance, 235 strains of ethambutol resistance, and 204 strains of amikacin resistance. Furthermore, 427 (47.44%) or 146 (16.22%) strains were MDR-TB or XDR-TB, respectively. The mutations of the rpoB, katG, inhA, embB, rpsL, rrs, and gyrA genes were detected in 751 of 900 TB patients by PCR-fluorescent probe method, and the rate of drug resistance was 751/900 (83.44%). No mutant genes were detected in the other 149 patients. Compared with DST, the mutant rates of rpoB, katG/inhA, rpsL, rrs, embB, and gyrA of six drugs were higher than 88%; five of six drugs were higher than 90% except for SM (88.11%). The MDR and XDR mutant gene types were found in 398 (42.22%) and 137 (15.22%) samples. PCR-DS was also employed and confirmed the PCR-fluorescent probe method with the accordance rate of 100%. The PCR-fluorescent probe method is rapid and straightforward in detecting XDR-TB genotypes and is worthy of being applied in hospitals.

BACKGROUND Allergic rhinitis is a chronic inflammatory disease with a high incidence, affecting the quality of life of patients. The aim of the present study was to explore the expression and clinical significance of vascular endothelial cell adhesion molecule-1 (VCAM-1), interleukin (IL)-6, and IL-17A in patients with allergic rhinitis. METHODS A total of 180 patients with allergic rhinitis, who were admitted to our hospital from March 2017 to March 2020, were enrolled as the observation group. Patients were further divided into 3 subgroups according to the degree of severity of allergic rhinitis as follows: the mild group (n=66), the moderate group (n=60), and the severe group (n=54). During the same period, 188 people without allergic rhinitis, who underwent physical examination in our hospital, were enrolled as the control group. VCAM-1, IL-6, and IL-17A levels were compared between these groups, and the correlation between the 3 levels and allergic rhinitis was analyzed. RESULTS VCAM-1, IL-6, and IL-17A levels in the observation group were significantly higher than those in the control group, and the difference was statistically significant (P

ObjectiveOesophageal squamous cell carcinoma (OSCC), like other squamous carcinomas, harbour highly recurrent cell cycle pathway alterations, especially hyperactivation of the CCND1/CDK4/6 axis, raising the potential for use of existing CDK4/6 inhibitors in these cancers. Although CDK4/6 inhibition has shown striking success when combined with endocrine therapy in oestrogen receptor positive breast cancer, CDK4/6 inhibitor palbociclib monotherapy has not revealed evidence of efficacy to date in OSCC clinical studies. Herein, we sought to elucidate the identification of key dependencies in OSCC as a foundation for the selection of targets whose blockade could be combined with CDK4/6 inhibition.DesignWe combined large-scale genomic dependency and pharmaceutical screening datasets with preclinical cell line models, to identified potential combination therapies in squamous cell cancer.ResultsWe identified sensitivity to inhibitors to the ERBB family of receptor kinases, results clearly extending beyond the previously described minority of tumours with EGFR amplification/dependence, specifically finding a subset of OSCCs with dual dependence on ERBB3 and ERBB2. Subsequently. we demonstrated marked efficacy of combined pan-ERBB and CDK4/6 inhibition in vitro and in vivo. Furthermore, we demonstrated that squamous lineage transcription factor KLF5 facilitated activation of ERBBs in OSCC.ConclusionThese results provide clear rationale for development of combined ERBB and CDK4/6 inhibition in these cancers and raises the potential for KLF5 expression as a candidate biomarker to guide the use of these agents. These data suggested that by combining existing Food and Drug Administration (FDA)-approved agents, we have the capacity to improve therapy for OSCC and other squamous cancer.

Background Firefighters have increased cancer incidence and mortality rates compared to the general population, and are exposed to multiple products of combustion including known and suspected carcinogens. Objective The study objective was to quantify fire response exposures by role and self-reported exposure risks. Methods Urinary hydroxylated metabolites of polycyclic aromatic hydrocarbons (PAH-OHs) were measured at baseline and 2–4 h after structural fires and post-fire surveys were collected. Results Baseline urine samples were collected from 242 firefighters. Of these, 141 responded to at least one of 15 structural fires and provided a post-fire urine. Compared with baseline measurements, the mean fold change of post-fire urinary PAH-OHs increased similarly across roles, including captains (2.05 (95% CI 1.59–2.65)), engineers (2.10 (95% CI 1.47–3.05)), firefighters (2.83 (95% CI 2.14–3.71)), and paramedics (1.84 (95% CI 1.33–2.60)). Interior responses, smoke odor on skin, and lack of recent laundering or changing of hoods were significantly associated with increased post-fire urinary PAH-OHs. Significance Ambient smoke from the fire represents an exposure hazard for all individuals on the fireground; engineers and paramedics in particular may not be aware of the extent of their exposure. Post-fire surveys identified specific risks associated with increased exposure.

Background Dysregulated microRNA (miRNA) expression could provide a mechanism linking firefighter exposure to increased cancer risk. Objective To determine if changes in longitudinal miRNA expression in firefighters are associated with occupational exposures. Methods Whole blood MiRNA was evaluated in 52 new recruits prior to live-fire training and 20–37 months later. Linear mixed effects models adjusted for age, ethnicity, BMI, and batch effects were used to determine associations separately for all fires and structure fires only between employment duration, cumulative fire-hours and fire-runs, and time since most recent fire with (1) nine a priori and (2) the full array of 799 miRNAs. Results For multivariable models including all fires, two a priori miRNAs were associated with employment duration and four with time since most recent fire. For multivariable models restricted to structure fires, three a priori miRNAs were associated with employment duration and one with fire-runs. Additional miRNAs from the full array were associated with employment duration for all fires and/or structure fires. In general, tumor suppressive miRNAs decreased and oncogenic miRNAs increased with exposure. Significance Changes in miRNAs may serve as biomarkers of exposure effects and a mechanism for increased cancer risk in firefighters.

Our previous studies revealed that MYCN downregulates the expression of DKK3, activates the Wnt/β-catenin signalling pathway at the transcriptional level, and thereby promotes the development of B cell acute lymphocytic leukaemia (B-ALL) but does not affect the methylation of the DKK3 promoter. Some studies have shown that MYCN is associated with histone acetylation. We speculate that histone deacetylase inhibitors (HDACis) can inhibit the Wnt/β-catenin signalling pathway by inhibiting MYCN and increasing the expression of DKK3. Based on previous experiments, we tested this hypothesis by analysing the changes in MYCN, DKK3 and the Wnt/β-catenin signalling pathways in B-ALL cells after treatment with the selective HDACi chidamide. The in vitro and in vivo experiments confirmed that chidamide inhibited the expression of MYCN and increased the expression of DKK3 by inhibiting the activity of histone deacetylase, and these effects resulted in inhibition of the Wnt/β-catenin signalling pathway and the proliferation of B-ALL cells. These findings indicate that chidamide might be used alone or in combination with other chemotherapy regimens for patients with B-ALL and thus provide a new approach to the treatment of B-ALL.

Background Aim of this multicenter, observational, cross-sectional study was to evaluate health-related quality of life (HRQoL) and treatment satisfaction of current medications in Chinese knee OA patients. Methods Brief Pain Inventory (BPI), Treatment Satisfaction Questionnaire (TSQM-1.4), and HRQoL (EQ-5D-5L) were assessed in total of 601 OA of knee patients. Impact on QoL (EQ-5D-5L) and treatment satisfaction (TSQM-1.4) by BPI-Severity score ( Results Mean score of EQ-5D-5L of patients with BPI-Severity ≥4 was significantly lower than those with BPI-Severity Conclusion Chronic knee OA pain has a significant impact on patients’ HRQoL. More severe patients with OA were less satisfied with current treatments.

Objective The aim of the present study was to investigate the effectiveness and safety of a novel lateral in-plane approach for ultrasound-guided transforaminal cervical nerve root block (US-guided TF-CNRB) in the treatment of cervical radiculopathic pain. Design The design of the present study consisted of an institutional, retrospective case series. Setting The present study was conducted at a university hospital. Subjects Thirty-two patients with cervical radiculopathy who were resistant to conservative therapies and regular US-guided CNRB were included as participants. Methods The included patients were treated with US-guided TF-CNRB. During the treatments, using real-time fluoroscopy, we monitored the spreading patterns of a contrast medium and double confirmed the positions of needle tips. Pain numeric rating scales (NRS) and symptom relief grades were determined via telephone interviews at one, four, and 12 weeks after the procedures. Results US-guided TF-CNRB was performed at the C5 level in six patients, the C6 level in 18 patients, and the C7 level in eight patients. Compared with NRS at baseline, pain scores decreased throughout the observation period. Symptom relief rates of US-guided TF-CNRB at one, four, and 12 weeks were 72%, 69%, and 63%, respectively. Venous blood was aspirated during the procedures in two patients, and the needle tips were corrected. No intravascular injections or neurologic injuries were observed. Conclusion US-guided TF-CNRB produced circumferential spreading around the involved cervical nerve root and showed significant clinical effectiveness in patients resistant to regular US-guided CNRB.

Background Body composition has been shown closely related to the outcome in surgical patients. The aim of the present study was to investigate whether preoperative skeletal muscle condition and postoperative nutrition would affect major complications in patients underwent pancreaticoduodenectomy (PD). Methods This retrospective study included 265 patients underwent PD. Body composition data was extracted from the L3 level of the preoperative CT scan. Univariable and multivariable regression analyses were performed to investigate correlations between body composition data and postoperative complications. Furthermore, a subgroup analysis was conducted to explore the relationship between postoperative nutrition strategy and the outcome. Results Of all the 265 patients, major complications occurred in 81 patients (30.6%). Cutoff values for skeletal muscle depletion were defined by ROC curve analysis from postoperative complications in skeletal muscle index (SMI) (male 47.32 cm2/m2 and female 40.65 cm2/m2). Univariable analysis and multivariable regression revealed age (OR 1.49, 95% CI 1.22-1.83, p = 0.026), SMI (OR 0.77, 95% CI 0.51-0.94, p = 0.015) and skeletal muscle density (SMD) (OR 0.85, 95% CI 0.64-1.03, p = 0.029) were independent predictors for major complications. Subgroup analysis showed the initial parenteral nutrition time (IPNT) (OR 1.89, 95% CI 1.43-2.49, p = 0.032) and average protein delivery (APD) (OR 0.76, 95% CI 0.53-0.89, p = 0.021) were significantly associated with major complications in patients with lower SMI. Conclusions Preoperative skeletal muscle index and density were independently associated with major complications in patients underwent PD. In patients with lower SMI, early parenteral nutrition and higher protein delivery were related to better outcome.

The low rate of durable response against relapsed and/or refractory multiple myeloma (RRMM) in recent studies indicates that chimeric antigen receptor T‐cell (CART) treatment is yet to be optimized. This study aims to investigate the safety and efficacy of sequential infusion of CD19‐CART and B‐cell maturation antigen (BCMA)‐CARTs for RRMM with a similar 3 + 3 dose escalation combined with a toxicity sentinel design. We enrolled 10 patients, among whom 7 received autologous infusion and 3 received allogeneic infusion. The median follow‐up time was 20 months. The most common grade 3/4 treatment‐emergent toxicities were hematological toxicities. Cytokine‐release syndrome (CRS) adverse reactions were grade 1/2 in 9 out of 10 subjects. No dose‐limited toxicity (DLT) was observed for BCMA‐CAR‐positive T cells ≤5 × 107/kg), while two patients with dose‐levels of 5–6.5 × 107/kg experienced DLTs. The overall response rate was 90% (five partial responses and four stringent complete responses). Three out of four patients with stringent complete responses to autologous CART had progression‐free survival for over 2 years. The three patients with allogeneic CART experienced disease progression within 2 months. These results evidence the sequential infusion's preliminarily tolerability and efficacy in RRMM, and present a simple and safe design applicable for the establishment of multiple CART therapy., We conducted a pilot study to assess the feasibility of the sequential infusion of CD19 and B‐cell maturation antigen (BCMA)‐specific chimeric antigen receptor T‐cell (CART) for relapsed and/or refractory multiple myeloma treatment with a similar 3 + 3 dose escalation design. Translational Significance: The favorable and persistent responses against RRMM were observed in those patients with a combined infusion of autologous CD19‐CART and BCMA‐CART. The emergence of intolerant adverse event (neurotoxicity and sever CRS) was associated with increased dose level of BCMA‐CARTs infusion.

Aims The association of glycemic variability with microvascular disease complications in type 2 diabetes (T2D) has been under-studied and remains unclear. We investigated this relationship using both Action to Control Cardiovascular Risk in Diabetes (ACCORD) and the Veteran Affairs Diabetes Trial (VADT). Methods In ACCORD, fasting plasma glucose (FPG) was measured 1 to 3 times/year for up to 84 months in 10 251 individuals. In the VADT, FPG was measured every 3 months for up to 87 months in 1791 individuals. Variability measures included coefficient of variation (CV) and average real variability (ARV) for fasting glucose. The primary composite outcome was time to either severe nephropathy or retinopathy event and secondary outcomes included each outcome individually. To assess the association, we considered variability measures as time-dependent covariates in Cox proportional hazard models. We conducted a meta-analysis across the 2 trials to estimate the risk of fasting glucose variability as well as to assess the heterogenous effects of FPG variability across treatment arms. Results In both ACCORD and the VADT, the CV and ARV of FPG were associated with development of future microvascular outcomes even after adjusting for other risk factors, including measures of average glycemic control (ie, cumulative average of HbA1c). Meta-analyses of these 2 trials confirmed these findings and indicated FPG variation may be more harmful in those with less intensive glucose control. Conclusions This post hoc analysis indicates that variability of FPG plays a role in, and/or is an independent and readily available marker of, development of microvascular complications in T2D.