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Background Theta burst stimulation (TBS), a patterned repetitive transcranial magnetic stimulation (rTMS) protocol with shorter simulation duration and lower stimulus intensity, could be a better protocol for individuals with autism spectrum disorder (ASD). Our study aimed to explore the impacts of intermittent TBS (iTBS) over the bilateral posterior superior temporal sulcus (pSTS) on intellectually able adults with ASD. Material and methods In this randomized, single-blinded, sham-controlled crossover trial, 13 adults with ASD completed iTBS for 5 consecutive days over the bilateral pSTS and inion (as a sham control) in a 16-weeks interval and in a randomly assigned order. The neuropsychological function was measured with the Wisconsin Card Sorting Test (WCST) for cognitive flexibility while the clinical outcomes were measured with both self-rate and parents-rate Autism Spectrum Quotient (AQ) before and after 5-day iTBS interventions. Results The results revealed significantly immediate effects of multi-session iTBS over the bilateral pSTS on parent-rate autistic symptoms in adults with ASD. The post-hoc analysis revealed the impacts of multi-session iTBS on cognitive flexibility were affected by baseline social-communicative impairment and baseline cognitive performance. Besides, the impacts of multi-session iTBS on clinical symptoms was affected by the concurrent psychotropic medication use and baseline autistic symptoms. Conclusions Given the caveat of the small sample size and discrepancy of multiple informants, this pilot study suggests the therapeutic potential of 5-day multi-session iTBS over the pSTS in adults with ASD. Individual factors modulating the response to rTMS should be explicitly considered in the future trial.

BACKGROUND Many studies have investigated treatment-related sequelae in Hodgkin's lymphoma (HL) in high-prevalence areas, but very few have been conducted in low-prevalence areas, including Taiwan and Japan. MATERIALS AND METHODS We retrospectively reviewed 101 HL patients who had received mediastinal radiotherapy between January 1997 and April 2013. RESULTS Nine patients had cardiac events and nine patients developed second malignancies. Univariate analysis showed that bulkiness of disease was significantly associated with higher incidence of cardiac events (HR 7.70, 95% CI 1.60-38.00, p = 0.012). Disease stage and cumulative dose of radiotherapy were significantly correlated with incidence of radiation pneumonitis (HR 1.40, 95% CI 1.00-2.10, p = 0.043 and HR 1.10, 95% CI 1.00-1.20, p = 0.009, respectively). All cases of grade III-IV radiation pneumonitis happened in patients receiving a radiation dose higher than 35 Gy and developed within 4 months after radiotherapy. CONCLUSIONS Despite the similar incidence rates of treatment-related sequelae among HL survivors between areas with high and low prevalence of HL, cardiac events and second malignancies cannot be overlooked in HL survivors in low-prevalence areas.

Qinghuan Li,1,* Yi Liang,1,* Zeng Liu,2 Chuanyun Yu1 1Oncology Radiotherapy Center, Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science, Xiangyang, Hubei, 441021, People’s Republic of China; 2Department of Oncology, Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science, Xiangyang, Hubei, 441021, People’s Republic of China*These authors contributed equally to this workCorrespondence: Chuanyun Yu Tel/Fax +86-710-2813559Email yuchuanyunxy@163.comZeng Liu Email liu8901@126.comBackground: Head and neck squamous cell carcinoma (HNSCC) ranks the sixth most common cancer worldwide. This study aims to evaluate the associations of GWAS-identified HNSCC risk loci with progression, efficacy and toxicity of radiotherapy of HNSCC treated with radiotherapy.Methods: Six GWAS-identified risk loci were genotyped and evaluated. Multivariate logistic regression was used to determine the associations of these SNPs with progression, efficacy and toxicity of radiotherapy of HNSCC treated with radiotherapy.Results: We found that rs259919 was significantly associated with higher TNM stage (allele A vs G: OR=1.49; 95% CI: 1.09– 2.03; P=0.012), while rs3135001 was significantly associated with better efficacy of radiotherapy (allele T vs C: OR=1.80, 95% CIs=1.19– 2.73, P=0.005). Both SNP rs1265081 (allele A vs C: OR=1.41, 95% CIs=1.08– 1.86, P=0.012) and rs3135001 (allele T vs allele C: OR=0.53, 95% CIs=0.35– 0.79, P=0.002) were significantly associated with the occurrence of grade 3– 4 oral mucositis.Conclusion: We identified that three GWAS-identified HNSCC risk loci were significantly associated with progression, efficacy and toxicity of radiotherapy of HNSCC. Our findings strengthen the understanding of the essential role of genetic background in the progression and therapeutic effects of HNSCC.Keywords: progression, genetic, radiotherapy, HNSCC, efficacy, toxicity

Postoperative cognitive dysfunction (POCD; cognitive change associated with anesthesia and surgery) is one of the most serious long-term postoperative complications that occur in elderly patients. Dexmedetomidine (DEX) has been shown to be beneficial for improving outcomes of postoperative cognitive function. However, the exact mechanism underlying this role requires is yet to be found. The present study aims to determine the pathways involved in the protective effects of DEX against POCD in C57BL/6 J aged mice. DEX was administered after POCD modeling in C57BL/6 J aged mice. The cognitive function was evaluated after DEX treatment using novel object recognition, open field, and Y-maze tests. We also assessed its effects on neuron apoptosis and production of TNF-α and IL-1β in mouse brain tissues as well as expression levels of DNA damage-related proteins p53, p21, and γH2AX. Interactions between early growth response 1 (EGR1) and p53, microRNA (miR)-381, and EGR1 were identified by ChIP and luciferase reporter assays, and gain- and loss-of-function experiments were performed to confirm the involvement of their interaction in POCD. DEX administration attenuated hippocampal neuron apoptosis, neuroinflammation, DNA damage, and cognitive impairment in aged mice. miR-381 targeted EGR1 and disrupted its interaction with p53, leading to a decline in hippocampal neuron apoptosis, DNA damage, neuroinflammation, and cognitive impairment. Furthermore, DEX administration resulted in the enhancement of miR-381 expression and the subsequent inhibition of EGR1/p53 to protect against cognitive impairment in aged mice. Overall, these results indicate that DEX may have a potential neuroprotective effect against POCD via the miR-381/EGR1/p53 signaling, shedding light on the mechanisms involved in neuroprotection in POCD.

Type 2 diabetes mellitus (T2DM) is associated with cognitive impairment and may progress to dementia. However, the brain functional mechanism of T2DM‐related dementia is still less understood. Recent resting‐state functional magnetic resonance imaging functional connectivity (FC) studies have proved its potential value in the study of T2DM with cognitive impairment (T2DM‐CI). However, they mainly used a mass‐univariate statistical analysis that was not suitable to reveal the altered FC “pattern” in T2DM‐CI, due to lower sensitivity. In this study, we proposed to use high‐order FC to reveal the abnormal connectomics pattern in T2DM‐CI with a multivariate, machine learning‐based strategy. We also investigated whether such patterns were different between T2DM‐CI and T2DM without cognitive impairment (T2DM‐noCI) to better understand T2DM‐induced cognitive impairment, on 23 T2DM‐CI and 27 T2DM‐noCI patients, as well as 50 healthy controls (HCs). We first built the large‐scale high‐order brain networks based on temporal synchronization of the dynamic FC time series among multiple brain region pairs and then used this information to classify the T2DM‐CI (as well as T2DM‐noCI) from the matched HC based on support vector machine. Our model achieved an accuracy of 79.17% in T2DM‐CI versus HC differentiation, but only 59.62% in T2DM‐noCI versus HC classification. We found abnormal high‐order FC patterns in T2DM‐CI compared to HC, which was different from that in T2DM‐noCI. Our study indicates that there could be widespread connectivity alterations underlying the T2DM‐induced cognitive impairment. The results help to better understand the changes in the central neural system due to T2DM., We used high‐order functional connectivity to reveal the abnormal connectomics pattern in T2DM with cognitive impairment with a multivariate, machine learning‐based strategy. We also investigated whether such patterns were different between T2DM with cognitive impairment and T2DM without cognitive impairment to better understand T2DM‐induced cognitive impairment. Our study is well suited for publication in Human Brain Mapping as we used this method is highly advanced and desirable for extensive applications in the future. Meanwhile, it is of great help for standardizing the methodology and boosting clinical applications of the functional imaging‐based machine learning with improved reproducibility, generalizability, and interpretability.

Introduction Metastasis is the primary cause of lung cancer-related death. Nevertheless, the underlying molecular mechanisms and evolutionary patterns of lung cancer metastases are still elusive. Methods We performed whole-exome sequencing for 40 primary tumors (PTs) and 61 metastases from 47 patients with lung cancer, of which 40 patients had paired PTs and metastases. The PT-metastasis genomic divergence, metastatic drivers, timing of metastatic dissemination, and evolutionary origins were analyzed using appropriate statistical tools and mathematical models. Results There were various degrees of genomic heterogeneity when comparing the paired primary and metastatic lesions or comparing metastases of different sites. Multiple metastasis-selected/enriched genetic alterations were found, such as MYC amplification, NKX2-1 amplification, RICTOR amplification, arm 20p gain, and arm 11p loss, and these results were were also featured in a meta-analysis cross-validated using an independent cohort from Memorial Sloan-Kettering Cancer Center database. To elucidate the metastatic seeding time, we applied a metastatic model and found 61.1% of the tumors were late dissemination, in which the metastatic seeding happened approximately 2.74 years before clinical detection. One exception was lymph node metastases whose dissemination time was relatively early. By analyzing the evolutionary origins, we reported that nonlymph node metastases were mainly seeded by the PT (87.5%) rather than the earlier colonized lymph node metastases. Conclusions Our results shed light on the molecular features that potentially drive lung cancer metastases. The distinct temporospatial pattern of disease progression revealed that lung cancer was susceptible to either late dissemination or indolent early lymph node metastases, leaving a potential time window to minimize metastases by early cancer detection.

Summary Background & aims To date, the prevalence of Gestational diabetes mellitus (GDM) in China was 17.5%. Given the substantial relevance of GDM for medium- and long-term health of both mother and offspring and the paucity of existing data on the link between maternal diet and glucose homeostasis during pregnancy in Asian population, additional studies are needed. To examine the relevance of dietary glycemic index (GI), glycemic load (GL) and fiber intake before and during pregnancy for the development of GDM and glucose homeostasis over the course of pregnancy. Methods Cox proportional hazards analysis and linear mixed effects regressions were performed on data from 9317 women for whom three food frequency questionnaires (pre-pregnancy, 1st and 2nd trimesters) and biochemical measures during pregnancy were available. Investigated outcome variables included GDM risk, fasting plasma glucose (FPG), glycated hemoglobin (HbA1C), and homeostasis model assessment insulin resistance (HOMA-IR) in the 1st, 2nd and 3rd trimesters. Results Women in the highest tertile of dietary GI (or GL) before pregnancy, in the 1st, or the 2nd trimester respectively had a 12% (15%), 25% (23%) or 29% (25%) higher risk of developing GDM than those in the lowest tertile (all p for trend ≤ 0.02). Women with the highest dietary fiber intake before pregnancy, in the 1st or 2nd trimester had a 11%, 17% or 18% lower GDM risk (all p for trend ≤ 0.03). Moreover, increases in GI or GL and decreases in fiber intake over the course of pregnancy (1st to 3rd trimesters) were independently associated with adverse concurrent developments in FPG, HbA1C and HOMA-IR (p ≤ 0.03). Conclusions Our study indicates that dietary GI, GL and fiber intake before and during pregnancy affects glucose homeostasis of pregnant Chinese women.

Yang Liu,1,* Feng-Jiao Zhang,2,* Xi-Xi Zhao,3,* Yuan Yang,4 Chun-Yi Liang,3 Li-Li Feng,5 Xiang-Bo Wan,5 Yi Ding,1 Yao-Wei Zhang1 1Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, 510515, People’s Republic of China; 2Shanghai Concord Medical Cancer Center, Shanghai, 200001, People’s Republic of China; 3Medical Imaging Center, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, 510515, People’s Republic of China; 4Guangdong Provincial Key Laboratory of Medical Image Processing, School of Biomedical Engineering, Southern Medical University, Guangzhou, Guangdong, 510515, People’s Republic of China; 5Department of Radiation Oncology, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, 510655, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yi Ding; Yao-Wei Zhang Tel +86 20-62786616Email dingyi197980@126.com; weiyaozhang2@163.comPurpose: Neoadjuvant chemoradiotherapy (nCRT) has become the standard treatment for locally advanced rectal cancer (LARC). However, the accuracy of traditional clinical indicators in predicting tumor response is poor. Recently, radiomics based on magnetic resonance imaging (MRI) has been regarded as a promising noninvasive assessment method. The present study was conducted to develop a model to predict the pathological response by analyzing the quantitative features of MRI and clinical risk factors, which might predict the therapeutic effects in patients with LARC as accurately as possible before treatment.Patients and Methods: A total of 82 patients with LARC were enrolled as the training cohort and internal validation cohort. The pre-CRT MRI after pretreatment was acquired to extract texture features, which was finally selected through the minimum redundancy maximum relevance (mRMR) algorithm. A support vector machine (SVM) was used as a classifier to classify different tumor responses. A joint radiomics model combined with clinical risk factors was then developed and evaluated by receiver operating characteristic (ROC) curves. External validation was performed with 107 patients from another center to evaluate the applicability of the model.Results: Twenty top image texture features were extracted from 6192 extracted-radiomic features. The radiomics model based on high-spatial-resolution T2-weighted imaging (HR-T2WI) and contrast-enhanced T1-weighted imaging (T1+C) demonstrated an area under the curve (AUC) of 0.8910 (0.8114– 0.9706) and 0.8938 (0.8084– 0.9792), respectively. The AUC value rose to 0.9371 (0.8751– 0.9997) and 0.9113 (0.8449– 0.9776), respectively, when the circumferential resection margin (CRM) and carbohydrate antigen 19-9 (CA19-9) levels were incorporated. Clinical usefulness was confirmed in an external validation cohort as well (AUC, 0.6413 and 0.6818).Conclusion: Our study indicated that the joint radiomics prediction model combined with clinical risk factors showed good predictive ability regarding the treatment response of tumors as accurately as possible before treatment.Keywords: rectal cancer, neoadjuvant chemoradiotherapy, magnetic resonance imaging, tumor response

A 60‐year‐old man was hospitalized because of numbness and weakness in the right upper limb. Magnetic resonance imaging revealed a large mass in the right upper lobe invading the right eighth cervical and first thoracic nerve root. Biopsy pathology confirmed primary lung adenocarcinoma with a clinical stage of cT4N0M0 IIIA, negative for anaplastic lymphoma kinase fusion gene and epidermal growth factor receptor mutations but positive for programmed death ligand 1 (3%). Neoadjuvant tislelizumab and chemotherapy were offered to this patient with Pancoast tumor, and tumor shrinkage of 71% was achieved. After the operation, surgical pathology indicated pathologic complete response (pCR). Circulating tumor cells testing was negative after the first adjuvant treatment. In this case, we provide real‐world evidence of encouraging pCR with neoadjuvant tislelizumab and chemotherapy for a patient with Pancoast tumor., • Neoadjuvant tislelizumab and chemotherapy was offered for a patient with Pancoast tumor (TNM stage, cT4N0M0 IIIA). • Surgical resection was successfully performed and a pCR was achieved.

Purpose Studies regarding the association between dietary fat intake and gestational diabetes mellitus (GDM) are limited and provide conflicting findings. Thus, the study aims to examine the association of dietary fat intake in the year preceding pregnancy and during pregnancy with the risk of GDM, taking the relevance of dietary protein intake on GDM into consideration. Methods A prospective study was conducted in 6299 singleton pregnancies, using the data from the Nutrition in Pregnancy and Growth in Southwest China (NPGSC). A validated food frequency questionnaire was used to assess dietary fat intake in the year preceding pregnancy and during the first and second trimesters of pregnancy. Logistic regression analysis was used to assess the prospective associations of dietary fat intake and the type and source of dietary fats in different time windows with GDM risk. Results Higher intake of total fat [OR (95% CI): 2.21 (1.19–4.20), P = 0.02] during 12–22 weeks of gestation was associated with higher GDM risk. However, adjustment for animal protein intake greatly attenuated this association [OR (95% CI): 1.81 (0.93, 3.64), P = 0.11]. Total fat intake neither in the year preceding pregnancy nor during the early pregnancy was associated with GDM risk. Moreover, insignificant associations were observed between intakes of vegetable fat, animal fat, cholesterol, saturated fatty acid, monounsaturated fatty acid and polyunsaturated fatty acid one year before pregnancy and during the first and second trimesters and GDM risk. Conclusion Our study indicated that dietary fat intake one year before pregnancy and across the two pregnancy trimesters preceding the diagnosis of GDM has no relevance on GDM risk among Chinese women, particularly those with normal BMI, low, or normal calorie intake.

Interleukin (IL)-17 and its related cytokines have been shown to be involved in myocardial fibrosis and irreversible ventricular remodelling, which have predictive values in the development of left ventricular diastolic dysfunction (LVDD). This study aimed to assess the correlation between IL-17 and LVDD, and investigate the prognostic value of IL-17 among patients with normal left ventricular ejection fraction (LVEF).A total of 120 patients with normal LVEF underwent left ventricular (LV) catheterisation for LV end-diastolic pressure (LVEDP) measurement and routine echocardiography. The follow-up period was 30 (18, 35) months.The levels of IL-17 and IL-6 from the systemic blood were significantly increased in non-heart failure (HF) patients with LVDD (p0.001). Receiver operating characteristic (ROC) revealed that the combination of IL-17 and IL-6 showed the highest diagnostic accuracy in predicting LVDD (AUC, 0.890; 95% CI, 0.835-0.945; p0.001), and the cut-off value was 41.5 pg/mL. On logistic regression analysis, the increment of the combination of IL-17 and IL-6 was an independent predictor for the prognosis of LVDD (odds ratio, 1.25; 95% CI, 1.01-1.12; p0.05). According to the cut-off value of the combination of IL-17 and IL-6, the patients with lower levels of IL-17 and IL-6 (41.5 pg/mL group) had a better prognosis. The increased levels of IL17 and IL-6 were significantly correlated with the levels of fibrotic parameters.Assessment of LVDD by measuring the combination of IL-17 and IL-6 might provide valuable prognostic significance for non-HF patients with LVDD.

Purpose: Although enzalutamide (ENZ) has been widely used to treat de novo or castration-resistant metastatic prostate cancer, resistance develops and disease progression is ultimately inevitable. There are currently no approved targeted drugs to specifically delay or overcome ENZ resistance. Experimental Design: We selected several ENZ-resistant cell lines that replicated clinical characteristics of the majority of patients with ENZ-resistant disease. A high-throughput pharmacologic screen was utilized to identify compounds with greater cytotoxic effect for ENZ-resistant cell lines, compared with parental ENZ-sensitive cells. We validated the potential hits in vitro and in vivo, and used knockdown and overexpression assays to study the dependencies in ENZ-resistant prostate cancer. Results: ABT199 (BCL-2 inhibitor) and IMD0354 (IKKB inhibitor) were identified as potent and selective inhibitors of cell viability in ENZ-resistant cell lines in vitro and in vivo which were further validated using loss-of-function assays of BCL-2 and IKKB. Notably, we observed that overexpression of BCL-2 and IKKB in ENZ-sensitive cell lines was sufficient for the emergence of ENZ resistance. In addition, we confirmed that BCL-2 or IKKB inhibitors suppressed the development of ENZ resistance in xenografts. However, validation of both BCL-2 and IKKB in matched castration-sensitive/resistant clinical samples showed that, concurrent with the development of ENZ/abiraterone resistance in patients, only the protein levels of IKKB were increased. Conclusions: Our findings identify BCL-2 and IKKB dependencies in clinically relevant ENZ-resistant prostate cancer cells in vitro and in vivo, but indicate that IKKB upregulation appears to have greater relevance to the progression of human castrate-resistant prostate cancer.

The diagnosis and treatment of massive hemoptysis remain challenging. We report a 28-year-old woman with refractory massive hemoptysis caused by a mediastinal hemangioma. Despite multiple bronchial artery embolizations and fiberoptic bronchoscopy treatments, effective control of the bleeding and clearing of the airway was not possible. Finally, with the support of venovenous extracorporeal membrane oxygenation, mediastinal hemangioma resection and right upper lobe sleeve resection were simultaneously performed. During the operation, many blood clots in the airway were removed. The airway bleeding was effectively controlled, and the patient recovered.

Little research has examined burn injury in the pediatric population with autism spectrum disorder (ASD). We used data from Taiwan’s National Health Insurance Research Database to identify 15,844 participants aged

Peripheral inflammation and nerve injury usually accompany each other. However, whether inflammatory and neuropathic pain share similar mechanisms at all stages is unknown. TRPV1 and P2X3 are two major ion channels in dorsal root ganglia (DRGs) and are involved in chronic pain. Here, their function and expression in DRGs at different phases of the two types of pain were investigated. Both the paw withdrawal threshold (PWT) and paw withdrawal latency were decreased in rats injected with complete Freud's adjuvant (CFA). However, only the PWT was decreased in rats with spared nerve injury (SNI). CFA increased the magnitude of the TRPV1-mediated Ca2+ response but not the P2X3-mediated Ca2+ response 14 days after injection. Consistent with this result, the P2X3 expression level in CFA rats was increased only at 3 days after injection. SNI surgery increased the magnitudes of the TRPV1- and P2X3-mediated Ca2+ responses and upregulated both TRPV1 and P2X3 expression in lumbar DRGs. The distributions of TRPV1 and P2X3 in DRGs after modeling were observed, and TRPV1 was found to be highly expressed mainly in the L4-L5 DRGs in CFA rats and in the L5-L6 DRGs in SNI rats. P2X3 was highly expressed in the L4-L6 DRGs in CFA rats 3 days after injection but was only highly expressed in the L4 DRG 14 days after modeling. On the other hand, SNI promoted the P2X3 expression L4-L5 DRGs 3 days after surgery, but only L6 DRG 14 days after modeling. All the results indicate that P2X3 and TPRV1 are involved in inflammatory and neuropathic pain by different expression levels and distributions in the lumbar DRG in the chronic stage.

Amyotrophic lateral sclerosis (ALS) was initially thought to be associated with oxidative stress when it was first linked to mutant superoxide dismutase 1 (SOD1). The subsequent discovery of ALS-linked genes functioning in RNA processing and proteostasis raised the question of how different biological pathways converge to cause the disease. Both familial and sporadic ALS are characterized by the aggregation of the essential DNA- and RNA-binding protein TDP-43, suggesting a central role in ALS etiology. Here we report that TDP-43 aggregation in neuronal cells of mouse and human origin causes sensitivity to oxidative stress. Aggregated TDP-43 sequesters specific microRNAs (miRNAs) and proteins, leading to increased levels of some proteins while functionally depleting others. Many of those functionally perturbed gene products are nuclear-genome-encoded mitochondrial proteins, and their dysregulation causes a global mitochondrial imbalance that augments oxidative stress. We propose that this stress-aggregation cycle may underlie ALS onset and progression.

Drug refractory epilepsy (RE) is believed to be associated with structural lesions, but some RE patients show no significant structural abnormalities (RE-no-SA) on conventional magnetic resonance imaging scans. Since most of the medically controlled epilepsy (MCE) patients also do not exhibit structural abnormalities, a reliable assessment needs to be developed to differentiate RE-no-SA patients and MCE patients to avoid misdiagnosis and inappropriate treatment. Using resting-state scalp electroencephalogram (EEG) datasets, we extracted the spatial pattern of network (SPN) features from the functional and effective EEG networks of both RE-no-SA patients and MCE patients. Compared to the performance of traditional resting-state EEG network properties, the SPN features exhibited remarkable superiority in classifying these two groups of epilepsy patients, and accuracy values of 90.00% and 80.00% were obtained for the SPN features of the functional and effective EEG networks, respectively. By further fusing the SPN features of functional and effective networks, we demonstrated that the highest accuracy value of 96.67% could be reached, with a sensitivity of 100% and specificity of 92.86%. Overall, these findings not only indicate that the fused functional and effective SPN features are promising as reliable measurements for distinguishing RE-no-SA patients and MCE patients but also may provide a new perspective to explore the complex neurophysiology of refractory epilepsy.

Hepatocellular carcinoma (HCC), is one of the most common malignancies worldwide, which is globally the third most common cause of cancer-related mortality. This study aims to identify new potential early-stage diagnostic and prognostic biomarker for HCC. The candidate gene SLC26A6 expression was analyzed based on the Oncomine and Tumor Immune Estimation Resource (TIMER) databases and verified forwards with Gene Expression Omnibus (GEO) datasets. The protein expression was retrieved from Human Protein Atlas (HPA) database. We also validated the diagnostic and prognostic value in HCC, and the relationship between SLC26A6 and clinicopathologic parameters were also accessed. The Gene Set Enrichment Analysis (GSEA) and Protein-Protein Interaction (PPI) network were constructed to analyze the SLC26A6-related pathway. These results reveal that SLC26A6 expression was elevated in HCC, and the diagnostic sensitivity of SLC26A6 was higher than α-fetoprotein (AFP). SLC26A6 expression was independent prognostic factor for HCC. SLC26A6 up-regulation was mainly associated with excision repair, DNA replication, etc. SLC26A6-related mR-NAs was enriched in PI3K-AKT signaling pathway, axon guidance, pathways in cancer, and so on. PPI network indicated that SLC26A6 was interacted with solute carrier members, ABC transporters and other ion transport molecule. We further analyzed three positively correlated microRNAs and 10 negatively correlated microRNAs, all of these were reported participating or inhibiting in cancer progression. This is the first study demonstrated that SLC26A6 is up-regulated in HCC and correlated with poor prognosis, which might be served as a diagnostic marker or prognostic biomarker for HCC.

Complex regional pain syndrome (CRPS) results in chronic and excruciating pain in patients. Conventional therapies lack effectiveness, rendering it one of the most difficult to treat neurological conditions.. Electroacupuncture (EA) is an effective alternative therapy for pain relief. Here, we investigated whether EA exerts analgesic effect on a rat model of CRPS type-I (CRPS-I) and related mechanisms. The rat chronic postischemic pain (CPIP) model was established to mimic CRPS-I. 100Hz EA exerted robust and persistent antiallodynic effect on CPIP model compared with 2 Hz EA or sham EA. EA markedly suppressed the overexpression of CXCL12/CXCR4 in spinal cord dorsal horn (SCDH) of CPIP model, leading to substantial decrease in neuronal and glial cell activities in SCDH. Pharmacological blocking CXCR4 mimicked EA-induced antiallodynic effect and related cellular events in SCDH, whereas exogenous CXCL12 abolished EA's effect. CXCR4 signaling resulted in ERK activation in SCDH, contributing to mechanical allodynia of CPIP model rats, whereas EA markedly reduced ERK activation. Therefore, we demonstrated that EA interferes with CXCL12/CXCR4 signaling in SCDH and downstream ERK pathway to exert robust antiallodynic effect on an animal model of CRPS-I. Our work suggests that EA may be a potential therapeutic option for CRPS-I in clinic. PERSPECTIVE: Our work identified that EA exerts robust antiallodynic effect on an animal model of CRPS-I, via mechanisms involving inhibition of CXCL12/CXCR4 signaling. EA further attenuates downstream neuronal and glial cell activation and ERK pathway in SCDH. This work suggests that EA may be a potential therapeutic option for CRPS-I management in clinic.

Background Small supernumerary marker chromosomes (sSMCs), are additional abnormal chromosomes, which can’t be detected accurately by banding cytogenetic analysis. Abnormal phenotypes were observed in about 30% of SMC carriers. Duplication of chromosome 15 and related disorders, characterized by hypotonia motor delays, autism spectrum disorder (ASD), intellectual disability, and epilepsy including infantile spasms, might be account for 50% of the total sSMCs. Case presentation An 11-month-old infant with an sSMC found by banding cytogenetics was referred to our clinic because of developmental retardation and autism spectrum disorder. After several months of rehabilitation treatment, the progress of motor development was obvious, but the consciousness was still far from satisfied. High-resolution karyotype analysis, multiplex ligation-dependent probe amplification and copy number variation sequencing (CNV-Seq) were conducted to confirm the identity of the sSMC. A bisatellited dicentric sSMC was observed clearly in high-resolution karyotype analysis and a 10.16-Mb duplication of 15q11.1q13.2 (3.96 copies) together with a 1.84-Mb duplication of 15q13.2q13.3 (3 copies) was showed by CNV-Seq in the proband. It suggested that the molecular cytogenetic karyotype was 47,XY,+dic(15;15)(q13.2;q13.3). Furthermore, the clinical symptoms of the proband mostly fit 15q duplication related disorders which are characterized by hypotonia motor delays, autism spectrum disorder (ASD), and intellectual disability. Conclusion We reported for the first time using CNV-Seq to detect sSMCs and find a partial trisomy and tetrasomy of 15q11-q13 associated with developmental delay and autism spectrum disorder. Our report indicates that CNV-seq is a useful and economical way for diagnosis of dup15q and related disorders.

BackgroundModerate-to-severe postoperative pain following craniotomy has a high incidence in pediatric patients. Such pain may cause agitation, intracranial hypertension, epileptic seizures, and postoperative hematoma, which affect morbidity and mortality. Although scalp nerve block (SNB) achieves satisfactory pain relief except for suboccipital mid-craniotomy in adults and ropivacaine is widely used as a long-acting peripheral nerve block agent in children, there are few studies of SNB with ropivacaine in pediatric patients undergoing craniotomy. In addition, the neurosurgery operation time is relatively long, but the duration of action of SNB is limited. It is generally believed that postoperative SNB is better than preoperative SNB for postoperative analgesia. However, considering the concept of preemptive analgesia, we believe that preoperative SNB may achieve a longer postoperative analgesia effect than we expected.MethodsThis trial is a single-institution, prospective, randomized, controlled, double-blind study. A total of 180 children aged between 1 and 12 years who are undergoing elective craniotomy will be randomly allocated in a 1:1:1 ratio to three groups: group B (preoperative ropivacaine block group), group A (postoperative ropivacaine block group), and group N (nonblocking control group). This randomization will be stratified by age in two strata (1–6 years and 7–12 years). The primary outcome is the total consumption of sufentanil within 24 h after surgery. The secondary outcomes include assessment of pain scores, total consumption of sufentanil and emergency-remedy medicine consumption at observation points, the occurrence of postoperative complications, and the length of hospitalization after surgery.DiscussionThis study is designed to explore the effect and feasibility of SNB with ropivacaine for postoperative analgesia in pediatric patients undergoing craniotomy. Further aims are to compare the effects of preoperative and postoperative SNB on postoperative analgesia in order to identify whether there is a preemptive analgesic effect and determine the better time to implement SNB in pediatric patients during craniotomy.Trial registrationChinese Clinical Trial RegistryChiCTR1800017386. Registered on 27 July 2018.

Background Acute pain can transition to chronic pain, presenting a major clinical challenge. Electroacupuncture (EA) can partly prevent the transition from acute to chronic pain. However, little is known about the mechanisms underlying the effect of EA. This study investigated the effect of EA on pain transition and the activation of metabotropic glutamate receptor 5 (mGluR5)-protein kinase C epsilon (PKCe) signaling pathway in the dorsal root ganglia (DRG). Methods The hyperalgesic priming model was established by the sequential intraplantar injection of carrageenan (1%, 100 μL) and prostaglandin E2 (PGE2) into the left hind paw of rats. EA treatment (2/100 Hz, 30 min, once/day) was applied at bilateral Zusanli (ST36) and Kunlun (BL60) acupoints in rats. Von Frey filaments were used to investigate the mechanical withdrawal threshold (MWT) at different time points. The protein expression levels of mGluR5 and PKCe in the ipsilateral L4-L6 DRGs of rats were detected by Western blot. Some pharmacological experiments were performed to evaluate the relationship between mGluR5, PKCe and the MWT. It was also used to test the effects of EA on the expression levels of mGluR5 and PKCe and changes in the MWT. Results Sequential injection of carrageenan and PGE2 significantly decreased the MWT of rats and up-regulated the expression level of mGluR5 and PKCe in the ipsilateral L4-L6 DRGs. EA can reverse the hyperalgesic priming induced by sequential injection of carrageenan/PGE and down-regulate the protein expression of mGluR5 and PKCe. Glutamate injection instead of PGE2 can mimic the hyperalgesic priming model. Pharmacological blocking of mGluR5 with specific antagonist MTEP can prevent the hyperalgesic priming and inhibit the activation of PKCe in DRGs. Furthermore, EA also produced analgesic effect on the hyperalgesic priming rats induced by carrageenan/mGluR5 injection and inhibited the high expression of PKCe. Sham EA produced none analgesic and regulatory effect. Conclusion EA can regulate pain transition and it may relate with its inhibitory effect on the activation of mGluR5-PKCe signaling pathway in the DRGs.

Conventional treatment for treating primary central nervous system lymphoma (PCNSL) has consisted of either whole-brain radiotherapy (WBRT) or methotrexate (MTX)-based combined modality therapy. However, delayed cognitive sequelae have emerged as a significant debilitating complication in PCNSL patients. A prospective observational case-series study with prospective assessments of neurocognitive functions (NCFs), neuroimaging, and activities of daily living in newly-diagnosed PCNSL patients was undertaken. A battery of neuropsychological measures, used to evaluate NCFs, is composed of ten standardized NCF tests, representing four domains sensitive to disease and treatment effects (executive function, attention, verbal memory, psychomotor speed), and activities of daily living. A total of 15 patients with newly-diagnosed PCNSL were consecutively enrolled in this study. Comparing the NCF scores between the baseline (before WBRT) and post-treatment (after combined chemoradiation therapy) intervals (Mean = 122.33 days, SD = 34.49, range = 77-196), neurobehavioral outcomes consistently remained improving or stable in almost each domain of NCF. Specifically, the scores on Paced Auditory Serial Addition Test-Revised (PASAT-R) were significantly improved between the baseline and post-chemoradiation assessment. Under the multidisciplinary treatment guidelines for treating patients with newly-diagnosed PCNSL, multi-domain NCF become stabilized and even improved after the course of conformal WBRT combined with or without MTX-based chemotherapy.

Effective therapeutic targets for triple-negative breast cancer (TNBC), a special type of breast cancer (BC) with rapid metastasis and poor prognosis, are lacking, especially for patients with chemotherapy resistance. Decitabine (DCA) is a Food and Drug Administration-approved DNA methyltransferase inhibitor that has been proven effective for the treatment of tumors. However, its antitumor effect in cancer cells is limited by multidrug resistance. Cancer stem cells (CSCs), which are thought to act as seeds during tumor formation, regulate tumorigenesis, metastasis, and drug resistance through complex signaling. Our previous study found that miR-155 is upregulated in BC, but whether and how miR-155 regulates DCA resistance is unclear. In this study, we demonstrated that miR-155 was upregulated in CD24- CD44+ BC stem cells (BCSCs). In addition, the overexpression of miR-155 increased the number of CD24- CD44+ CSCs, DCA resistance and tumor clone formation in MDA-231 and BT-549 BC cells, and knockdown of miR-155 inhibited DCA resistance and stemness in BCSCs in vitro. Moreover, miR-155 induced stemness and DCA resistance by inhibiting the direct target gene tetraspanin-5 (TSPAN5). We further confirmed that overexpression of TSPAN5 abrogated the effect of miR-155 in promoting stemness and DCA resistance in BC cells. Our data show that miR-155 increases stemness and DCA resistance in BC cells by targeting TSPAN5. These data provide a therapeutic strategy and mechanistic basis for future possible clinical applications targeting the miR-155/TSPAN5 signaling axis in the treatment of TNBC.

Owing to the existence of the blood–brain barrier (BBB), most treatments cannot achieve significant effects on gliomas. In this study, synergistic multitarget Ang-TAT-Fe3O4-pDNA-(ss)373 lipid-polymer hybrid nanoparticles (LPNPs) were designed to penetrate the BBB and deliver therapeutic genes to glioma cells. The basic material of the nanoparticles was PCL3750-ss-PEG7500-ss-PCL3750, and is called (ss)373 herein. (ss)373 NPs, Fe3O4 magnetic nanoparticles (MNPs), DOTAP, and DSPE-PEG-MAL formed the basic structure of LPNPs by self-assembly. The Fe3O4 MNPs were wrapped in (ss)373 NPs to implement magnetic targeting. Then, the Angiopep-2 peptide (Ang) and transactivator of transcription (TAT) were coupled with DSPE-PEG-MAL. Both can enhance BBB penetration and tumor targeting. Finally, the pDNA was compressed on DOTAP to form the complete gene delivery system. The results indicated that the Ang-TAT-Fe3O4-pDNA-(ss)373 LPNPs were 302.33 nm in size. In addition, their zeta potential was 4.66 mV, and they had good biocompatibility. The optimal nanoparticles/pDNA ratio was 5 : 1, as shown by gel retardation assay. In this characterization, compared with other LPNPs, the modified single Ang or without the addition of the Fe3O4 MNPs, the penetration efficiency of the BBB model formed by hCMEC/D3 cells, and the transfection efficiency of C6 cells using pEGFP-C1 as the reporter gene were significantly improved with Ang-TAT-Fe3O4-pDNA-(ss)373 LPNPs in the magnetic field.

Background A distinct serum metabonomic pattern has been previously revealed to be associated with various forms of liver disease. Here, we aimed to apply mass spectrometry to obtain serum metabolomic profiles from individuals with cholangiocarcinoma and benign hepatobiliary diseases to gain an insight into pathogenesis and search for potential early-disease biomarkers. Methods Serum samples were profiled using a hydrophilic interaction liquid chromatography platform, coupled to a mass spectrometer. A total of 47 serum specimens from 8 cholangiocarcinoma cases, 20 healthy controls, 8 benign disease controls (bile duct strictures) and 11 patients with hepatocellular carcinoma (as malignant disease controls) were included. Data analysis was performed using univariate and multivariate statistics. Results The serum metabolome disparities between the metabolite profiles from healthy controls and patients with hepatobiliary disease were predominantly related to changes in lipid and lipid-derived compounds (phospholipids, bile acids and steroids) and amino acid metabolites (phenylalanine). A metabolic pattern indicative of inflammatory response due to cirrhosis and cholestasis was associated with the disease groups. The abundance of phospholipid metabolites was altered in individuals with liver disease, particularly cholangiocarcinoma, but no significant difference was seen between profiles from patients with benign biliary strictures and cholangiocarcinoma. Conclusion The serum metabolome in cholangiocarcinoma exhibited changes in metabolites related to inflammation, altered energy production and phospholipid metabolism. This study serves to highlight future avenues for biomarker research in large-scale studies.

Objective: Gout, induced by monosodium urate (MSU) crystal deposition in joint tissues, provokes severe pain and impacts life quality of patients. However, the mechanisms underlying gout pain are still incompletely understood. Methods: We established a mouse gout model by intra-articularly injection of MSU crystals into the ankle joint of wild type and genetic knockout mice. RNA-Sequencing, in vivo molecular imaging, Ca2+ imaging, reactive oxygen species (ROS) generation, neutrophil influx and nocifensive behavioral assays, etc. were used. Results: We found interleukin-33 (IL-33) was among the top up-regulated cytokines in the inflamed ankle. Neutralizing or genetic deletion of IL-33 or its receptor ST2 (suppression of tumorigenicity) significantly ameliorated pain hypersensitivities and inflammation. Mechanistically, IL-33 was largely released from infiltrated macrophages in inflamed ankle upon MSU stimulation. IL-33 promoted neutrophil influx and triggered neutrophil-dependent ROS production via ST2 during gout, which in turn, activated transient receptor potential ankyrin 1 (TRPA1) channel in dorsal root ganglion (DRG) neurons and produced nociception. Further, TRPA1 channel activity was significantly enhanced in DRG neurons that innervate the inflamed ankle via ST2 dependent mechanism, which results in exaggerated nociceptive response to endogenous ROS products during gout. Conclusions: We demonstrated a previous unidentified role of IL-33/ST2 in mediating pain hypersensitivity and inflammation in a mouse gout model through promoting neutrophil-dependent ROS production and TRPA1 channel activation. Targeting IL-33/ST2 may represent a novel therapeutic approach to ameliorate gout pain and inflammation.

The efficacy and tolerability of adding chemotherapy to radiotherapy in the era of intensity-modulated radiation therapy (IMRT) remain controversial among older patients with nasopharyngeal carcinoma (NPC). The present study compared IMRT alone with IMRT in combination with chemotherapy in elderly NPC patients. Between January 2011 and December 2014, 102 patients aged >65 years with NPC who received IMRT alone (IMRT group) or IMRT in combination with chemotherapy (IMRT/CT group) were enrolled. Patients from both treatment arms were pair-matched (1:1 ratio) based on six clinical factors. Differences in overall survival (OS), disease-free survival (DFS), locoregional relapse-free survival (LRRFS), and distant metastasis-free survival (DMFS) were assessed using the Kaplan–Meier method and Cox proportional hazards models, whereas the toxicity profile was assessed using Common Terminology Criteria for Adverse Events (CTCAE) version 4. No significant differences were noted in OS (72.1% vs. 72.5%, p = 0.799), DFS (65.9% vs. 70.1%, p = 0.733), LRRFS (76.4% vs. 71.6%, p = 0.184), and DMFS (90.8% vs. 98.0%, p = 0.610) between the IMRT and IMRT/CT groups. Multivariate analyses showed that chemotherapy was not an independent factor for OS, DFS, LRRFS, and DMFS. However, the incidences of grade 3 vomiting/nausea (p = 0.000), leukopenia/neutropenia (p = 0.000), thrombocytopenia (p = 0.041), and anemia (p = 0.040) were significantly higher in the IMRT/CT group compared with the IMRT group. No grade 4 toxicities were observed. IMRT alone was similar to IMRT/CT in treating elderly NPC patients (age >65 years), with comparable survival outcomes and less grade 3 toxicities.

Background. Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder with recurrent abdominal pain and altered defecation habits. We here attempted to determine the effect of acupuncture on IBS. Methods. Randomized controlled trials (RCTs) published in CNKI, VIP, Wanfang, PubMed, Cochrane Library, EMBASE, Web of science, and ClinicalTrials.gov till July 17, 2019 were searched. Outcomes were total efficacy rates, overall IBS symptom scores, or global quality of life scores. Standardized mean difference (SMD) with 95% confidence intervals (CI) and risk ratio (RR) with 95% CI were calculated for meta-analysis. Results. We included 41 RCTs involving 3440 participants for analysis. 8 RCTs compared acupuncture with sham acupuncture, among which 3 trials confirmed the biological effects of acupuncture, especially in treating abdominal pain, discomfort, and stool frequency. No significant difference was found when acupuncture was compared with sham acupuncture, in terms of effects on IBS symptoms and quality of life (SMD = 0.18, 95% CI −0.26∼0.63, P=0.42; SMD = −0.10, 95% CI −0.31∼0.11, P=0.35), but the pooled efficacy rate data showed a better outcome for true acupuncture (RR = 1.22, 95% CI 1.01∼1.47, P=0.04), which was not supported by sensitivity analysis. Acupuncture was more effective relative to western medicine in alleviating IBS symptoms (RR = 1.17, 95% CI 1.12∼1.23, I2 = 0%, P<0.00001), whose effect might last 3 months. Besides, acupuncture as an adjunct to western medicine, Chinese medications, or tuina was superior over the single latter treatment (RR = 1.68, 95% CI 1.18 to 2.40, P=0.004; 1.19, 1.03 to 1.36, P=0.02; 1.36, 1.08 to 1.72, P=0.009, respectively), with high heterogeneities. Conclusions. Relative to sham controls, acupuncture showed no superiority for treating IBS, while the advantage over western medicine was significant. Acupuncture could be used as an adjunct in clinical settings to improve efficacy. Future high-quality and large-sample-size studies with adequate quantity-effect design need to be conducted.

BACKGROUND Extracorporeal membrane oxygenation (ECMO) plays an important role in thoracic surgery. This retrospective study from a single center aimed to evaluate patient outcomes from the use of perioperative ECMO in 22 patients undergoing thoracic surgery during an 8-year period. MATERIAL AND METHODS Data were collected retrospectively from 22 patients who received ECMO (veno-arterial and veno-venous ECMO) as perioperative treatment during general thoracic surgery from January 2012 to October 2020. Patients required ECMO due to perioperative cardiopulmonary resuscitation (CPR) (2 cases), perioperative pulmonary embolism (PE) (2 cases), lung transplant (4 cases), undergoing complicated thoracic surgery (5 cases), postoperative acute respiratory distress syndrome (ARDS) (6 cases), and thoracic trauma (3 cases). RESULTS Veno-arterial ECMO was used for circulatory support in 13 cases and veno-venous ECMO was used for respiratory support in 9 cases. The average ECMO support time was 71.6±42.4 h. Twenty patients (90.9%) were successfully decannulated and 17 (77.2%) survived to discharge. Complications included severe hemorrhage (3/22 patients, 13.6%), sepsis (3/22, 13.6%), and destruction of blood cells (1/22, 4.5%). There were no significant differences in survival rates between patients receiving pre- or postoperative ECMO (P=0.135) or between veno-venous ECMO (V-V ECMO) and veno-arterial ECMO (V-A ECMO) (P=0.550). CONCLUSIONS The findings from this small retrospective study from a single center showed that perioperative ECMO improved cardiac and respiratory function in patients undergoing thoracic surgery. Optimal results require surgeons to have an understanding of the indications and ability to control the complications of ECMO.

Background: Dingji Fumai Decoction (DFD), a traditional herbal mixture, has been widely used to treat arrhythmia in clinical practice in China. However, the exploration of the active components and underlying mechanism of DFD in treating atrial fibrillation (AF) is still scarce.Methods: Compounds of DFD were collected from TCMSP, ETCM, and literature. The targets of active compounds were explored using SwissTargetPrediction. Meanwhile, targets of AF were collected from DrugBank, TTD, MalaCards, TCMSP, DisGeNET, and OMIM. Then, the H-C-T-D and PPI networks were constructed using STRING and analyzed using CytoNCA. Meanwhile, VarElect was utilized to detect the correlation between targets and diseases. Next, Metascape was employed for systematic analysis of the mechanism of potential targets and protein complexes in treating AF. AutoDock Vina, Pymol, and Discovery Studio were applied for molecular docking. Finally, the main findings were validated through molecular biology experiments.Results: A total of 168 active compounds and 1,093 targets of DFD were collected, and there were 89 shared targets between DFD and AF. H-C-T-D network showed the relationships among DFD, active compounds, targets, and AF. Three functional protein complexes of DFD were extracted from the PPI network. Further systematic analysis revealed that the regulation of cardiac oxidative stress, cardiac inflammation, and cardiac ion channels were the potential mechanism of DFD in treating AF. Addtionally, molecular docking verified the interactions between active compounds and targets. Finally, we found that DFD significantly increased the level of SIRT1 and reduced the levels of ACE, VCAM-1, and IL-6.Conclusions: DFD could be utilized in treating AF through a complicated mechanism, including interactions between related active compounds and targets, promoting the explanation and understanding of the molecular biological mechanism of DFD in the treatment of AF.

Objectives: Small airway dysfunction is considered as a precursor of chronic obstructive pulmonary disease and asthma. Our aim was to explore the joint effects of carbon black (CB) exposure and antioxidant vitamin intake on small airway dysfunction.Methods: A total of 70 CB packers (CBPs) and 107 non-CBPs were enrolled from an established cohort of CBP. Carbon content in airway macrophage (CCAM) quantified in induced sputum was used as a bio-effective dosimetry for exposure to CB. Logistic regression models were used to examine the odds ratios (ORs) of CB and dietary intake of antioxidant vitamins on small airway dysfunction, and the dose–response association.Results: The prevalence of small airway dysfunction was 32.9% (23 of 70) among CBPs, and 19.6% (21 of 107) among non-CBPs. For each 2.72-fold increase in CCAM, the OR of small airway dysfunction was 2.31 (95% CI = 1.20–4.44). For every 10 mg day−1 increase of the vitamin C intake, the risk of small airway dysfunction decreased by 6% (OR = 0.94, 95% CI = 0.88–0.99). Compared to non-CB exposure and higher vitamin C intake, CB exposure and lower vitamin C intake (OR = 7.56, 95% CI = 1.80 to 31.81) were associated with an increased risk of small airway dysfunction.Conclusions: Chronic exposure to a high level of CB aerosol increased the risk of small airway dysfunction in CB baggers. Dietary intake of vitamin C might be a modifiable factor for preventing small airway dysfunction.

Diabetes with high blood glucose levels may damage the brain nerves and thus increase the risk of dementia. Previous studies have shown that dementia can be reflected in altered brain structure, facilitating computer-aided diagnosis of brain diseases based on structural magnetic resonance imaging (MRI). However, type 2 diabetes mellitus (T2DM)-mediated changes in the brain structures have not yet been studied, and only a few studies have focused on the use of brain MRI for automated diagnosis of T2DM. Hence, identifying MRI biomarkers is essential to evaluate the association between changes in brain structure and T2DM as well as cognitive impairment (CI). The present study aims to investigate four methods to extract features from MRI, characterize imaging biomarkers, as well as identify subjects with T2DM and CI.

Although various drugs are currently used for restless legs syndrome (RLS) in clinic, selecting appropriate drugs for patients is difficult. This network meta-analysis (NMA) aimed to compare the efficacy and safety of different drugs. After literature searching and screening, 46 trials, including 10,674 participants are included in this NMA. The pooled results showed that, compared with placebo, only levodopa is inefficient to relieve symptoms of RLS. Cabergoline decreases IRLS scores to the greatest extent among all drugs (MD −11.98, 95% CI −16.19 to −7.78). Additionally, pramipexole is superior to ropinirole in alleviating symptoms of RLS (MD −2.52, 95% CI −4.69 to −0.35). Moreover, iron supplement alleviates RLS symptoms significantly compared with placebo in patient with iron deficiency (MD −5.15, 95% CI −8.99 to −1.31), but not for RLS patients with normal serum ferritin level (MD −2.22, 95% CI −6.99 to 2.56). For primary RLS, these drugs are also effective, while there is insufficient data to analyze drug efficacy in secondary RLS. We analyzed risk of common adverse effects of drugs including nausea, somnolence, fatigue, headache and nasopharyngitis. Alpha-2-delta ligands and DAs are favorable choices for both primary and secondary RLS because of their significant efficacy and good tolerability. Iron supplement can significantly alleviate symptoms of RLS patients with iron deficiency than placebo. We recommend gabapentin, gabapentin enacarbil, and pregabalin for clinicians for first consideration mainly because that they rarely cause augmentation. Oxycodone-naloxone could be considered in patients with severe or very severe RLS who failed in treatment with above drugs.

Background Inflammatory bowel disease (IBD) consists of a spectrum of disorders including ulcerative colitis and Crohn’s disease, with a rising incidence worldwide. However, despite this prevalence the etiology of IBD remains uncertain. It has been suggested that an episode of gastroenteritis may precipitate IBD. Methods Studies were identified using a literature search of Pubmed/Medline and Embase/Ovid. This review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. The primary outcome was incidence of new-onset IBD after gastroenteritis. Secondary outcomes included incidence of IBD after bacterial, viral, and parasitic gastrointestinal infections. Results Eleven studies (n = 923 608 patients) were included. Four studies assessed patients with gastroenteritis, subsequently developing IBD as the primary outcome. Patients with gastroenteritis had a higher incidence of subsequent IBD but this did not reach statistical significance (odds ratio [OR] 3.81, 95% CI 0.52–27.85, P = .19). Seven studies examined the incidence of antecedent gastroenteritis (primary outcome) in patients with a confirmed diagnosis of IBD, compared to the controlled population. There was no difference between incidence of antecedent gastroenteritis across the 2 population groups (OR 1.07, 95% CI 0.55–2.08, P = .85). There was no association between IBD and bacterial, viral, or parasitic infections. Conclusions In summary, our meta-analysis has shown that there is considerable heterogeneity in the literature regarding the role of gastroenteritis in the development of IBD. Further higher quality studies need to be performed to ascertain the true nature of this.

Intrahepatic cholestasis of pregnancy (ICP) is one of the more common complications in the middle and late stages of pregnancy, which requires early detection and intervention. The aim of the study is to investigate the changes in the metabolic profile of bile acids (BAs) in plasma of pregnant women with ICP and to look biomarkers for the diagnosis and grading of ICP, and to explore the disease mechanism. The targeted metabolomics based on high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) was used to analyze plasma BAs. Twenty-seven BAs can be quantified in all participants. Among them, 22 BAs were identified as differential BAs between ICP and control groups. Five BAs include 3β-CA, 3β-DCA, CDCA-3Gln, NCA, and Tβ-MCA, were found to be associated with ICP for the first time. Nine BAs include NCA, GCA, GCDCA, GHCA, GUDCA, HCA, TCA, TCDCA and THCA, can be used as possible ICP diagnostic biomarkers. Four BAs, i.e., GLCA, THCA, GHCA and TLCA-3S may be used as potential biomarkers for ICP grading. There were significant differences in plasma BA profiles between ICP patients and the control. The BA profiles of mild ICP group and severe ICP group partially overlapped. Potential diagnostic and grading BA markers were identified. A significant characteristic of ICP group was the increase of conjugated BAs. A mechanism to sustain the equilibrium of BA metabolism and adaptive response has been developed in ICP patients to accelerate excretion and detoxification.

Objective Long non-coding RNAs (lncRNAs) play critically in the pathogenesis of myocardial ischemia–reperfusion (I/R) injury. Thus, it was proposed to investigate the mechanism of LINC00461 in the disease through mediating microRNA-185-3p (miR-185-3p)/myeloid differentiation primary response gene 88 (Myd88) axis. Methods miR-185-3p, LINC00461 and Myd88 expression in mice with I/R injury was measured. Mice with I/R injury were injected with the gene expression-modified vectors, after which cardiac function, hemodynamics, myocardial enzyme, oxidative stress, and cardiomyocyte apoptosis were analyzed. Results I/R mice showed LINC00461 and Myd88 up-regulation and miR-185-3p down-regulation. Down-regulating LINC00461 or up-regulating miR-185-3p recovered cardiac function, reduced myocardial enzyme levels, and attenuated oxidative stress and cardiomyocyte apoptosis in mice with I/R. miR-185-3p overexpression rescued the promoting effect of LINC00461 upregulation on myocardial injury in I/R mice. Conclusion LINC00461 knockdown attenuates myocardial I/R injury via elevating miR-185-3p expression to suppress Myd88 expression.

Objective: Cognitive impairment in type 2 diabetes mellitus (T2DM) patients is related to changes in hippocampal structure and function. However, the alternation of hippocampal subfields volumes and their relationship with cognitive function are unclear. This study explored morphological alterations in the hippocampus and its subfields in T2DM patients and their relationship with cognitive function.Methods: Thirty T2DM patients and 20 healthy controls (HCs) were recruited and underwent 3-dimensional, high-resolution T1-weighted sequence (3D-T1) and a battery of cognitive tests. Freesurfer 6.0 was performed to segment the hippocampus into 12 subregions automatically. Then relationships between hippocampal subfield volumes and neurocognitive scale scores in the T2DM group were evaluated.Results: Immediate memory scores on the auditory verbal learning test (AVLT) and Montreal Cognitive Assessment (MoCA) scores in T2DM patients were lower than in the HCs. T2DM patients showed that volumes of the bilateral hippocampus were significantly reduced, mainly in the bilateral molecular layer, granule cell and molecular layer of the dentate gyrus (GC-ML-DG), cornu ammonis 4 (CA4), fimbria, and left subiculum and the right hippocampus amygdala transition area (HATA) compared to HCs. In addition, T2DM patients showed the FINS was negatively correlated with volume of left GC-ML-DG (r = −0.415, P = 0.035) and left CA4 (r = −0.489, P = 0.011); the FBG was negatively correlated with volume of right fimbria (r = −0.460, P = 0.018); the HOMA-IR was negatively correlated with volume of left GC-ML-DG (r = −0.367, P = 0.046) and left CA4(r = 0.462, P = 0.010). Partial correlation analysis found that the volume of right HATA in T2DM group was positively correlated with AVLT (immediate) scores (r = 0.427, P = 0.03).Conclusion: This study showed the volumes of multiple hippocampal subfields decreased and they were correlated with FINS, FBG and HOMA-IR in T2DM patients. We hypothesized that decreased hippocampal subfields volumes in T2DM patients was related to insulin resistance and impaired vascular function. In addition, we also found that abnormal hippocampal subfields volumes were related to memory function in T2DM patients, suggesting that reduced volumes in specific hippocampal subfields may be the potential mechanism of memory dysfunction in these patients.

Background Headache attacks severely impaired life quality and increase the economic burden of migraineurs. Electroacupuncture (EA) has been used worldwidely to treat several pain-related diseases including migraines. However, whether EA with low or high frequency exerts a distinct analgesic effect remains unknown and needs further study. Methods/Design This study is a randomised, single-blinded, placebo-controlled trial with three parallel arms. A total of 144 migraine outpatients will be randomly allocated to the 2 Hz EA group, 100 Hz EA group and placebo control group. The duration of the trial is 20 weeks, including a 4-week-long baseline assessment period (weeks − 4–0), a 4-week-long treatment period (weeks 1–4) and a 12-week-long follow-up period (weeks 5–16). Twelve treatment sessions will be performed over a 4-week period (weeks 1–4). The primary outcome will be measured by the frequency of migraine attacks in the past 4 weeks at the end of week 4 post-randomisation. The secondary outcome will be measured by the frequency of migraine attacks in the past 4 weeks at the end of weeks 8, 12 and16 post-randomisation; number of days with migraine; dosage of ibuprofen; the scores of visual analogue scale (VAS); Self-Rating Anxiety Scale (SAS); Self-Rating Depression Scale (SDS); and Migraine Specific Quality of Life questionnaire (MSQ) in the past 4 weeks at the end of weeks 4, 8, 12 and 16 post-randomisation. Safety assessment, compliance and blinding evaluation will be carried out at the end of week 16 post-randomisation. Discussion The recruitment will be started on 1 June 2021 and expected to finish on 31 May 2023. We aimed to clarify the dominant frequency of EA on headache attacks in a migraineur. Trial registration Chinese Clinical Trial Registry ChiCTR-1800017259. Registered on 20 July 2018.

Opioids are considered the most effective analgesics for the treatment of both acute and chronic pain. However, prolonged opioid use can induce a certain level of tolerance to its analgesic effects, leading to a reduction in its effectiveness, addiction and abuse. A better understanding of the mechanisms underlying opioid tolerance may provide insights into this phenomenon and aid in the development of novel methods to combat the side effects of opioid tolerance. The present review focused on two major contributors to tolerance, opioid receptors and inflammatory mediators. The molecular mechanisms involved in the desensitization of the opioid receptors were briefly described, including their phosphorylation, internalisation and recycling. Subsequently, the effects of Toll like receptor 4/NOD-like receptor family pyrin domain containing 3-mediated proinflammatory responses in opioid tolerance were discussed, aiming in supporting the identification of novel therapeutic targets.

Background Patients with Parkinson’s disease (PD) can develop impulse control disorders (ICDs) while undergoing a pharmacological treatment for motor control dysfunctions with a dopamine agonist (DA). Conventional clinical interviews or questionnaires can be biased and may not accurately diagnose at the early stage. A wearable electroencephalogram (EEG)-sensing headset paired with an examination procedure can be a potential user-friendly method to explore ICD-related signatures that can detect its early signs and progression by reflecting brain activity. Methods A stereotypical Go/NoGo test that targets impulse inhibition was performed on 59 individuals, including healthy controls, patients with PD, and patients with PD diagnosed by ICDs. We conducted two Go/NoGo sessions before and after the DA-pharmacological treatment for the PD and ICD groups. A low-cost LEGO-like EEG headset was used to record concurrent EEG signals. Then, we used the event-related potential (ERP) analytical framework to explore ICD-related EEG abnormalities after DA treatment. Results After the DA treatment, only the ICD-diagnosed PD patients made more behavioral errors and tended to exhibit the deterioration for the NoGo N2 and P3 peak amplitudes at fronto-central electrodes in contrast to the HC and PD groups. Particularly, the extent of the diminished NoGo-N2 amplitude was prone to be modulated by the ICD scores at Fz with marginal statistical significance (r = − 0.34, p = 0.07). Conclusions The low-cost LEGO-like EEG headset successfully captured ERP waveforms and objectively assessed ICD in patients with PD undergoing DA treatment. This objective neuro-evidence could provide complementary information to conventional clinical scales used to diagnose ICD adverse effects.

A novel polysaccharide (CMP-2B) was purified from Centipeda minima by anion-exchange and gel-permeation chromatography. Structural characterization revealed that CMP-2B was a homogeneous heteropolysaccharide with an average molecular weight of 113.193 KDa. CMP-2B was made up of mannose, galacturonic acid, galactose and arabinose with a molar ratio of 0.27:0.12:0.42:0.17. The backbone chain of CMP-2B consisted of 3,6)-α-D-Manp-(1 and 4,6)-β-D-Galp-(1, and the branches were comprised of 4)-α-D-GalpA-(1, 6)-β-D-Galp-(1, T-α-L-Araf-(1 and 3)-α-L-Araf -(1. Besides, the results of antioxidant assays revealed that CMP-2B possessed signifcant free radical scavenging ability. Moreover, the results of hypoglycemic assays showed that CMP-2B displayed α-glucosidase inhibitory activities, and could significantly improve glucose consumption, glycogen synthesis and the activity of pyruvate kinase of insulin-resistance HepG2 cells. Overall, these results suggested that CMP-2B could be a new source for functional foods.

Background: We have recently shown that there is a positive correlation between severe caries and developing psychomotor deficiency in preschool children. To fully re-assess such a relationship, we embarked on a 3-year longitudinal follow-up study of kindergarteners, where we aimed to: (i) confirm whether early childhood caries is causally related to the development of psychomotor deficiency as proposed, and (ii) address any significant role or contribution of socio-economic status associated with caries–psychomotor interactions in the preschooler family cohorts studied, over time. Methods: A longitudinal study was designed where the total sum of 159 kindergarteners aged 3–6 from the central and southern regions of Taiwan were randomly selected and recruited for clinical examination of caries, together with questionnaires for personal, demographic and dietary information, socio-economic status, and the children’s psychomotor development scales which were collected and analyzed over time. Student’s t test, chi-squared test, correlation coefficients, and multiple linear regression analysis with R2 determinants were employed to assess any attributable differences (of 0~1) between SES vs. psychomotor manifests and caries measured among all variables computed. Results: The results of our preliminary analyses show that: (i) there was likely a causal relationship between caries activities and aspects of general development scale via the Chinese Child Development Inventory over time (4.01 ± 3.47 vs. 5.88 ± 2.58, respectively) in the 3–6-year-old preschoolers, and (ii) there was significantly more attributable influence (via higher R-squared values) from SES and psychomotor manifests than that of caries and the Chinese Child Development Inventory counterparts, as detected over time. Conclusion: Collectively, the resulting analyses support our previous findings and confirm that there is likely a causal relationship between severe caries and psychomotor deficiency in growing preschoolers, the resulting analyses revealed that such causally related interactions may be attributably explainable by a content-reliant association via socio-economic status analyzed in the kindergartener family cohorts studied. Thus, the socio-economic status or its constituents/factors will have a much broader influence not only associated with developing early childhood caries (a biologic trait), but also for psychomotor deficiency (a social trait) in vulnerable children at risk.

Background: Aelectasis after anesthesia induction in most patients undergoing general anesthesia may lead to postoperative pulmonary complications (PPCs) and affect postoperative outcomes. However, there is still no existing effective method used for the prevention of perioperative atelectasis. S-ketamine may prevent atelectasis due to airway smooth muscle relaxation and anti-inflammatory effects. Lung ultrasound is a portable and reliable bedside imaging technology for diagnosing anesthesia-induced atelectasis. In this study, we aim to assess whether a small dose of S-ketamine can reduce the incidence of atelectasis after intubation under general anesthesia using lung ultrasound, in order to prevent the early formation of perioperative atelectasis and PPCs.Methods: This is a single-institution, prospective, randomized controlled, parallel grouping, and double-blind study. From October 2020 to March 2022, 100 patients (18-60 years old) scheduled for elective surgery will be recruited from Beijing Tiantan Hospital, Capital Medical University, and randomly assigned to the S-ketamine group (Group S) and the normal saline group (Group N) at a ratio of 1:1. The label-masked agents will be administered 5 min before induction, and all patients will undergo a standardized general anesthesia protocol. Related data will be collected at three-time points: after radial artery puncture (T1), 15 min after tracheal intubation (T2), and before extubation (T3). The primary outcome will be the total lung ultrasound scores (LUS) at T2. Secondary outcomes will include LUS in six chest regions at T2, total LUS at T3, arterial blood-gas analysis results (PaCO2, PaO2) and PaO2/FiO2 at T2 and T3, plateau pressure(Pplat) and dynamic lung compliance (Cdyn) at T2 and T3. The incidence of postoperative complications associated with S-ketamine and PPCs at 2 h and 24 h after surgery will be recorded.Discussion: This trial aims to explore whether a simple and feasible application of S-ketamine before the induction of general anesthesia can prevent atelectasis. The results of this study may provide new ideas and direct clinical evidence for the prevention and treatment of perioperative pulmonary complications during anesthesia.Trial registration: ClinicalTrials.gov identifier: NCT04745286.

Increasing studies strongly prove that renal denervation, a minimally invasive surgery, is a promising new non-drug treatment method that can effectively control blood pressure in patients with resistant hypertension, but the evaluation of the long-term blood pressure control effect of renal denervation for resistant hypertension is still lacking. Here, we critically review current long-term follow-up data about the use of renal denervation for RH to comprehensively evaluate the effectiveness of renal denervation for RH, and to provide practical guidance for practitioners who are establishing a renal denervation service. Limited by the current research, many problems need to be solved before renal denervation is applied to RH. In addition, ambulatory blood pressure should be the first choice for the evaluation of blood pressure. Finally, the continuous antihypertensive effect of renal denervation in different renal denervation systems also needs to be strictly compared.

Chronic pain is a costly health problem that impairs health-related quality of life when not effectively treated. Regulating the transition from acute to chronic pain is a new therapeutic strategy for chronic pain that presents a major clinical challenge. The underlying mechanisms of pain transition are not entirely understood, and strategies for preventing this transition are lacking. Here, a hyperalgesic priming model was used to study the potential mechanism by which γ-aminobutyric acid receptor type A (GABAAR) in the dorsal root ganglion (DRG) contributes to pain transition. Furthermore, electroacupuncture (EA), a modern method of acupuncture, was administered to regulate pain transition, and the mechanism underlying EA’s regulatory effect was investigated. Hyperalgesic priming was induced by intraplanar injection of carrageenan (Car)/prostaglandin E2 (PGE2). The decrease in mechanical withdrawal threshold (MWT) induced by PGE2 returned to baseline 4 h after injection in NS + PGE2 group, and still persisted 24 h after injection in Car + PGE2 group. Lower expression of GABAAR in the lumbar DRG was observed in the model rats. Furthermore, activating or blocking GABAAR could reversed the long-lasting hyperalgesia induced by Car/PGE2 injection or produced a persistent hyperalgesia. In addition, GABAAR may be involved in Protein Kinase C epsilon (PKCε) activation in the DRG, a mark molecular of pain transition. EA considerably increased the mechanical pain thresholds of hyperalgesic priming model mammals in both the acute and chronic phases. Furthermore, EA upregulated the expression of GABAAR and inhibited the activation of PKCε in the DRG. In addition, peripheral administration of picrotoxin blocked the analgesic effect of EA on the model rats and abolished the regulatory effect of EA on PKCε activation. These findings suggested that GABAAR plays a key role in both the transition from acute to chronic pain and the analgesic effect of EA on hyperalgesic priming.

Ribonucleic acid export 1 (Rae1) is an important nucleoporin that participates in mRNA export during the interphase of higher eukaryotes and regulates the mitotic cell cycle. In this study, small RNA interference technology was used to knockdown Rae1, and immunofluorescence, immunoblotting, and chromosome spreading were used to study the role of Rae1 in mouse oocyte meiotic maturation. We found that Rae1 is a crucial regulator of meiotic maturation of mouse oocytes. After the resumption of meiosis (GVBD), Rae1 was concentrated on the kinetochore structure. The knockdown of Rae1 by a specific siRNA inhibited GVBD progression at 2 h, finally leading to a decreased 14 h polar body extrusion (PBE) rate. However, a comparable 14 h PBE rate was found in the control, and the Rae1 knockdown groups that had already undergone GVBD. Furthermore, we found elevated PBE after 9.5 h in the Rae1 knockdown oocytes. Further analysis revealed that Rae1 depletion significantly decreased the protein level of securin. In addition, we detected weakened kinetochore–microtubule (K-MT) attachments, misaligned chromosomes, and an increased incidence of aneuploidy in the Rae1 knockdown oocytes. Collectively, we propose that Rae1 modulates securin protein levels, which contribute to chromosome alignment, K-MT attachments, and aneuploidy in meiosis.

Background Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease that is regionally distributed in Asia, with high fatality. Constructing the transmission model of SFTS could help provide clues for disease control and fill the gap in research on SFTS models. Methods We built an SFTS transmission dynamics model based on the susceptible–exposed–infectious–asymptomatic–recovered (SEIAR) model and the epidemiological characteristics of SFTS in Jiangsu Province. This model was used to evaluate the effect by cutting off different transmission routes and taking different interventions into account, to offer clues for disease prevention and control. Results The transmission model fits the reported data well with a minimum R2 value of 0.29 and a maximum value of 0.80, P Conclusions The model we have built can be used to simulate the transmission of SFTS to help inform disease control. It is noteworthy that cutting off the environment-to-humans transmission route in the model had the greatest effect on SFTS prevention and control. Graphical Abstract