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In response to overstimulation of growth factor signaling, tumor cells can reprogram their metabolism to preferentially utilize and metabolize glucose to lactate even in the presence of abundant oxygen, which is termed the “Warburg effect” or aerobic glycolysis. Long noncoding RNAs (lncRNAs) are a group of transcripts longer than 200 nucleotides and do not encode proteins. Accumulating evidence suggests that lncRNAs can affect aerobic glycolysis through multiple mechanisms, including the regulation of glycolytic transporters and key rate-limiting enzymes. In addition, maladjusted signaling pathways are critical for glycolysis. Therefore, this article mainly reviews the lncRNAs involved in the regulation of tumor glycolysis key signal pathways in recent years and provides an in-depth understanding of the role of differentially expressed lncRNAs in the key signal pathways of glucose metabolism, which may help to provide new therapeutic targets and new diagnostic and prognostic markers for human cancer.

BACKGROUND. Cytochrome P450 family 8 subfamily B member 1 (CYP8B1) generates 12α-hydroxylated bile acids (BAs) that are associated with insulin resistance in humans.METHODS. To determine whether reduced CYP8B1 activity improves insulin sensitivity, we sequenced CYP8B1 in individuals without diabetes and identified carriers of complete loss-of-function (CLOF) mutations utilizing functional assays.RESULTS. Mutation carriers had lower plasma 12α-hydroxylated/non-12α-hydroxylated BA and cholic acid (CA)/chenodeoxycholic acid (CDCA) ratios compared with age-, sex-, and BMI-matched controls. During insulin clamps, hepatic glucose production was suppressed to a similar magnitude by insulin, but glucose infusion rates to maintain euglycemia were higher in mutation carriers, indicating increased peripheral insulin sensitivity. Consistently, a polymorphic CLOF CYP8B1 mutation associated with lower fasting insulin in the AMP-T2D-GENES study. Exposure of primary human muscle cells to mutation-carrier CA/CDCA ratios demonstrated increased FOXO1 activity, and upregulation of both insulin signaling and glucose uptake, which were mediated by increased CDCA. Inhibition of FOXO1 attenuated the CDCA-mediated increase in muscle insulin signaling and glucose uptake. We found that reduced CYP8B1 activity associates with increased insulin sensitivity in humans.CONCLUSION. Our findings suggest that increased circulatory CDCA due to reduced CYP8B1 activity increases skeletal muscle insulin sensitivity, contributing to increased whole-body insulin sensitization.FUNDING. Biomedical Research Council/National Medical Research Council of Singapore.

The present study conducted a systematic review and Meta-analysis on the efficacy and safety of Biyuan Tongqiao Granules in the treatment of chronic sinusitis. CNKI, Wanfang, VIP, SinoMed, PubMed, Cochrane Library, EMbase, and Web of Science were searched for randomized controlled trials(RCTs) of Biyuan Tongqiao Granules in the treatment of chronic sinusitis. The quality of the included RCTs was assessed according to the Cochrane risk-of-bias assessment tool and the final included trials underwent Meta-analysis with RevMan 5.4.1. Fifty-four RCTs were included, with a total sample size of 7 278 cases. The results of Meta-analysis showed that the clinical efficacy of Biyuan Tongqiao Granules alone or in combination in the experimental group in the treatment of chronic sinusitis was superior to that in the control group with conventional western medicine, Chinese medicinal preparations, or surgery only(RR=1.19, 95%CI[1.15, 1.24], Plt;0.000 01). The combined use of Biyuan Tongqiao Granules on the basis of the control group was superior to the control group in improving the main symptoms and signs of chronic sinusitis [RR_(nasal congestion)=1.33, 95%CI[1.21, 1.45], Plt;0.000 01, RR_(runny nose)=1.28, 95%CI[1.18, 1.40], Plt;0.000 01, RR_(turbinate congestion or swelling)=1.28, 95%CI[1.16, 1.41], Plt;0.000 01]. Biyuan Tongqiao Granules alone or in combination could effectively reduce the Snot-20 score, which was superior to the control group(MD=-2.94, 95%CI[-3.60,-2.28], Plt;0.000 01). Biyuan Tongqiao Granules alone and in combination could effectively reduce the VAS score, which was superior to the control group(MD_(total score)=-4.44, 95%CI[-6.05,-2.82], Plt;0.000 01; MD_(nasal congestion VAS score)=-0.99, 95%CI[-1.38,-0.60], Plt;0.000 01; MD_(runny nose VAS score)=-1.19, 95%CI[-1.62,-0.76], Plt;0.000 01; MD_(dysosmia VAS score)=-0.96, 95%CI[-1.26,-0.65], Plt;0.000 01; MD_(head and face pain VAS score)=-0.73, 95%CI[-0.98,-0.47], Plt;0.000 01). The combined use of Biyuan Tongqiao Granules could effectively reduce the sinus CT score and the Lund-Mackey score of the endoscopic mucosal morphology(MD_(sinus CT score)=-3.68, 95%CI[-5.47,-1.88], Plt;0.000 1, MD_(endoscopic mucosal morphology score)=-3.06, 95%CI[-5.53,-0.59], P=0.02). Compared with the control group with conventional western medicine, Chinese medicinal preparations, or surgery only, combined use of Biyuan Tongqiao Granules did not increase the occurrence of adverse reactions(RR=0.68, 95%CI[0.26, 1.77], P=0.43). As demonstrated by the existing evidence, Biyuan Tongqiao Granules can improve the clinical efficacy of chronic sinusitis, relieve the clinical symptoms and signs, and reduce the Snot-20 score, VAS score, and Lund-Mackey score, without inducing serious adverse reactions, indicating that Biyuan Tongqiao Granules alone or in combination are more effective and safe in the treatment of chronic sinusitis than conventional western medicine, Chinese medicinal preparations, or surgical treatment. Since the quality of the included trials was generally low, large-scale, high-quality, rigorous, multi-center, and blinded-designed RCTs that meet international standards should be adopted in the future to increase the strength and level of evidence.

Teachers’ management effectiveness can reflect the comprehensive ability and effective evaluation of the teaching management objectives of the school and can also reflect the effectiveness management of the school to a certain extent. In the environment of sustainable and innovative development, the rapid development of education has made improving the management efficiency and motivation of university teachers became the key direction of university management. In order to study the impact of teachers’ management efficacy and motivation on college students’ academic achievement and postemployment social responsibility cognition under sustainable innovation, this study compares the impact of teachers in different periods on students and analyzes the changes of teachers in different periods on students. Finally, it is concluded that teachers’ management efficiency and motivation under sustainable innovation can promote students’ employment achievement and social responsibility cognition, improve the teaching quality of colleges and universities, and provide high-quality talents for the country. The educational concept of sustainable innovation is conducive to improving teachers’ independent innovation and realizing the educational function of cultivating students’ personalized development in colleges and universities.

Objective: To demonstrate differences in cardiovascular structure and function between diabetic and non-diabetic older adults. To investigate associations between acyl-carnitines and cardiovascular function as indexed by imaging measurements. Methods: A community-based cohort of older adults without cardiovascular disease underwent current cardiovascular imaging and metabolomics acyl-carnitines profiling based on current and archived sera obtained fifteen years prior to examination. Results: A total of 933 participants (women 56%, n=521) with a mean age 63±13 years were studied. Old diabetics compared to old non-diabetics had lower myocardial relaxation (0.8±0.2 vs 0.9±0.3, p=0.0039); lower left atrial conduit strain (12±4.3 vs 14±4.1, p=0.045), lower left atrial conduit strain rate (-1.2±0.4 vs -1.3±0.5, p=0.042) and lower ratio of left atrial conduit strain to left atrial booster strain (0.5±0.2 vs 0.7±0.3, p=0.0029). Higher levels of archived short chain acyl-carnitine were associated with present-day impairments in myocardial relaxation (C5:1; OR 1.03, p=0.011), worse left atrial conduit strain function (C5:1; OR 1.03, p=0.037). Increases in hydroxylated acyl-carnitines were associated with worse left atrial conduit strain [(C4-OH; OR 1.05, p=0.0017), (C16:2-OH; OR 1.18, p=0.037)]. Current, archived and changes in long chain acyl-carnitines were associated with cardiovascular functions [(C16; OR 1.02, p=0.002), (C20:3; OR 1.01, p=0.014), (C14:3; OR 1.12, p=0.033), (C18:1; OR 1.01, p=0.018), (C18:2; OR 1.01, p=0.028), (C20:4; OR 1.10, p=0.038)] (all p

Background Cryptic balanced translocations often evade detection by conventional cytogenetics. The preimplantation genetic testing (PGT) technique can be used to help carriers of balanced translocations give birth to healthy offspring; however, for carriers of cryptic balanced translocations, there is only one report about trying assisted reproduction using the PGT technique but with no pregnancy. Case presentation A couple had 3 births out of 4 pregnancies, and all died very young, with two of them having both cerebral palsy and glaucoma. The husband with oligoasthenospermia was found to be a cryptic balanced translocation carrier for t (9,13) (p24.3, q31.3) with G-banding, FISH (fluorescence in-situ hybridization), and MicroSeq techniques; live birth of a healthy baby girl was achieved with PGT/NGS (next-generation sequencing) for the couple. Conclusion Here, we report for the first time a successful live birth of a healthy baby through the PGT technique for a family in which the husband is a carrier of the cryptic balanced translocation t (9,13) (p24.3, q31.3), presumably causative for cerebral palsy and glaucoma. Our study showed that the PGT/NGS technique can effectively help families with a cryptic balanced translocation have healthy offspring.

Background MicroRNAs (miRNAs) are widely distributed in cells and participate in the regulation of the pathophysiological process of many diseases. As an important part of non‐coding RNA, miRNAs regulate a variety of molecules and signal pathways in tumour cells. However, the evidence for regulatory mechanisms of specific miRNAs in tumour cells is still lacking. Methods In this study, we used transcriptomics analysis and integrated a variety of public databases to screen miRNAs that have key regulatory effects on breast cancer (BC). In addition, we used in vitro and in vivo studies and combined clinical samples to verify its regulatory mechanism. Results We found that among the specific miRNAs, miR‐215‐5p is a key regulator in BC. Compared with normal adjacent tissues, miR‐215‐5p has a lower expression level in BC tissues. Patients with high expression levels of miR‐215‐5p have a longer survival time. miR‐215‐5p can specifically target the 3′UTR region of RAD54B mRNA and down‐regulate the expression of RAD54B, thereby inhibiting the proliferation of BC cells and promoting the apoptosis of BC cells. Conclusions Finally, we found that miR‐215‐5p can be used as an important biomarker for BC. We have clarified its function and revealed its mechanism of targeting RAD54B mRNA for the first time. This may provide important clues to reveal the deeper molecular regulation mechanism of BC.

The adverse implications of obesity extend beyond physical health to include negative impact on quality of life (QoL), mood, and eating habits. While bariatric surgery provides successful weight loss and metabolic benefits, studies describe conflicting results on QoL and mood-related outcomes. Patients (n = 140) with class II/III obesity and T2DM were recruited from 2015 to 2019, and stratified based on medical or surgical treatment. Questionnaires including the Hospital Anxiety and Depression Scale, Euro QoL visual analogue scale (EQ-VAS), and Revised 21-item Three-Factor Eating Questionnaire (TFEQ-R21) were recorded at baseline, 6 months, and 12 months after treatment. At baseline, the surgical group (n = 55) and medical group (n = 85) had no significant difference in questionnaire outcomes. At 6 and 12 months, EQ-VAS was higher in the surgical group (12 months surgical 82.00 ± 12.64, medical 72.81 ± 16.56, p = 0.001), with greater improvement from baseline. HADS-D scores at 12 months were lower in the surgical group (surgical 2.60 ± 2.88, medical 3.90 ± 3.58, p = 0.025). At 12 months, the surgical group also had better TFEQ-R21 scores, with higher cognitive restraint scores (surgical 19.09 ± 3.00, medical 16.69 ± 3.61, p

Background Laparoscopic sleeve gastrectomy (LSG) has become the preferred bariatric procedure in many countries. However, there is one shortcoming of LSG in the long-term follow-up, and this is the onset of gastro-esophageal reflux disease (GERD) and erosive esophagitis (EE). Conversion to Roux-en-Y gastric bypass (RYGB) is considered an option in patients unresponsive to medical therapy. Currently, there is no evidence of EE improvement or resolution after conversion surgery. In this study, we objectively evaluate the effectiveness of RYGB in management of EE with upper endoscopy (EGD) to identify the significant variables in patients with GERD symptoms post LSG refractory to medical therapy and require conversion surgery. Methods Over a period of 11 years (2008–2019) at Singapore General Hospital, we retrospectively reviewed a prospectively collected database of a cohort of patients whom had conversion surgery to RYGB for refractory GERD and EE after LSG. Patient’s endoscopic findings and demographic and anthropometric data were analyzed. Results We identified a total of 14 patients who underwent LSG to RYGB conversions for endoscopic proven erosive esophagitis in our unit during the study period. Eight patients (57.1%) had concurrent hiatal hernia repaired. Nine (64.3%) patients were females. The median age of patients in this cohort was 44 (range 30–61) years. Mean weight and BMI were 87.7 kg (± 19.2) and 32.8 (± 3.09) kg/m2, respectively, on the day of conversion surgery. The median time between LSG and revision to RYGB was 36 (range 6–68) months. Seven patients (50%) had complete resolution of GERD symptoms after conversion, and 6 patients (42.9%) had partial resolution. Six out of 7 patients had complete resolution of EE. There were 4 anastomotic strictures (28.6%). Older patients, Indian ethnicity, present of hiatal hernia and lower weight loss after initial LSG were more likely to undergo conversion surgery. Conclusion Conversion to RYGB after LSG is clinically relevant and may be a feasible solution if patients have ongoing GERD refractory to medical therapy. Ninety-three percent of our patients achieved complete resolution of their GERD symptoms and significant improvement of erosive esophagitis with significant weight loss after conversion. This study has important implications as LSG is increasingly being performed and a proportion of these will need revision surgery for various reasons, particularly GERD which is extremely prevalent.

Gastrointestinal cancer is one of the most malignant tumors with high morbidity and mortality, especially colorectal cancer, which has become the second leading cause of cancer-related deaths worldwide. Targeted drug treatment and precise endoscopic resection can significantly improve the overall survival rate and greatly extend the life span. Promising biomedical applications of hydrogels would represent hopeful therapeutic alternatives for patients with different kinds of diseases, particularly providing precise therapy for cancer patients. Although the intersection field of material science and biomedical science has made tremendous advances, major challenges remain. In this review, the application of hydrogel-based technology in cancer precision medicine is the focus of attention, which is the development trend of multidisciplinary cooperation in the future. First, we provide the current clinical landscape of hydrogel applications, and then we highlight precision oncology, including personalized drug treatment and accurate endoscopic intervention. Finally, we discuss major challenges for their clinical translation that have not yet been overcome and future perspectives on cancer precision medicine.

Recent years have witnessed the increasing popularity of Location-based Social Network (LBSN) services, which provides unparalleled opportunities to build personalized Point-of-Interest (POI) recommender systems. Existing POI recommendation and location prediction tasks utilize past information for future recommendation or prediction from a single direction perspective, while the missing POI category identification task needs to utilize the check-in information both before and after the missing category. Therefore, a long-standing challenge is how to effectively identify the missing POI categories at any time in the real-world check-in data of mobile users. To this end, in this paper, we propose a novel neural network approach to identify the missing POI categories by integrating both bi-directional global non-personal transition patterns and personal preferences of users. Specifically, we delicately design an attention matching cell to model how well the check-in category information matches their non-personal transition patterns and personal preferences. Finally, we evaluate our model on two real-world datasets, which clearly validate its effectiveness compared with the state-of-the-art baselines. Furthermore, our model can be naturally extended to address next POI category recommendation and prediction tasks with competitive performance., Accepted by Neural Networks. arXiv admin note: text overlap with arXiv:2112.15285

Purpose To investigate the therapeutic effects of vitamin A (VitA) or vitamin D (VitD) against bronchopulmonary dysplasia (BPD) and the underlying mechanism from the perspective of macrophage polarization. Methods A BPD model was established on rats. Hematoxylin and eosin staining was used to evaluate the pathological state of lung tissues. The expression of CD68 was determined by immunohistochemistry assay. The infiltration of M1 and M2 macrophages was marked by immunofluorescence. The expression levels of tumor necrosis factor (TNF)-α, interleukin (IL)-10, nitric oxide synthase (NOS), and arginase-1 (Arg-1) were evaluated by quantitative reverse transcription polymerase chain reaction assay, and the ratio of M1/M2 in the bronchoalveolar lavage fluid was determined by flow cytometry. Results Disordered alveolar structure in the lung tissue, thickened alveolar septa, and infiltration of inflammatory cells around the alveolar cavity and pulmonary septa were observed in lipopolysaccharide (LPS)-treated rats. On day 21 post-natal (PN21), the pathological state was aggravated, alveolar simplification was observed, and the expression level of CD68 in the lung tissues was significantly elevated, and these results were dramatically alleviated in the VitA, VitD, and VitA+VitD groups. However, no significant synergistic effect was observed between VitA+VitD and VitA or VitD groups. After the administration with VitA or VitD, IL-10 and Arg-1 were up-regulated on PN10. TNF-α and NOS were up-regulated on PN21. The ratio of macrophage polarization and M2 macrophages increased considerably after the stimulation with LPS, and this result was significantly reversed by VitA or VitD. A significant difference was observed on the effect of different dosages of VitA or VitD on macrophage polarization, among which moderate dosages of VitA or VitD exerted the most significant influence on macrophage polarization. Conclusion The BPD-linked pulmonary injury stimulated by LPS can be ameliorated by the introduction of VitA or VitD.

BACKGROUND Reliable noninvasive biomarkers for hepatocellular carcinoma (HCC) diagnosis and prognosis are urgently needed. We explored the potential of not only microRNAs (miRNAs) but other types of noncoding RNAs (ncRNAs) as HCC biomarkers. METHODS Peripheral blood samples were collected from 77 individuals; among them, 57 plasma cell-free RNA transcriptomes and 20 exosomal RNA transcriptomes were profiled. Significantly upregulated ncRNAs and published potential HCC biomarkers were validated with reverse transcription (RT)-qPCR in an independent validation cohort (60–150 samples). We particularly investigated the diagnosis and prognosis performance and biological function for 1 ncRNA biomarker, RN7SL1, and its S fragment. RESULTS We identified certain circulating ncRNAs escaping from RNase degradation, possibly through binding with RNA-binding proteins: 899 ncRNAs were highly upregulated in HCC patients. Among them, 337 genes were fragmented long noncoding RNAs, 252 genes were small nucleolar RNAs, and 134 genes were piwi-interacting RNAs. Forty-eight candidates were selected and validated with RT-qPCR, of which, 16 ncRNAs were verified to be significantly upregulated in HCC, including RN7SL1, SNHG1, ZFAS1, and LINC01359. Particularly, the abundance of RN7SL1 S fragment discriminated HCC samples from negative controls (area under the curve, 0.87; 95% CI, 0.817–0.920). HCC patients with higher concentrations of RN7SL1 S fragment had lower survival rates. Furthermore, RN7SL1 S fragment alone promoted cancer cell proliferation and clonogenic growth. CONCLUSIONS Our results show that various ncRNA species, not only miRNAs, identified in the small RNA sequencing of plasma are also able to serve as noninvasive biomarkers. Particularly, we identified a domain of srpRNA RN7SL1 with reliable clinical performance for HCC diagnosis and prognosis.

Data on attitudes and perceptions towards obesity are lacking in Asia. Participants who attended an obesity public forum were surveyed concerning obesity and its treatment options. Although obesity is generally accepted as a disease with biological underpinnings such as hormonal imbalances and slow metabolic rate, it is also regarded as an issue of personal responsibility. 65.1% believed that weight-loss medications are dangerous. 20.6% thought that pharmacotherapy is effective for weight loss, whereas 41.1% were unsure. Most believed that bariatric surgery could improve health (81.9%) and diabetes control (74.0%) although 64.1% were unsure of its risks.

Background: Whether a vegetarian diet is appropriate for pregnancy remains unclear.Objective: This study aimed to determine the association between vegetarian diet during pregnancy and various maternal–fetal outcomes.Method: PubMed-Medline, EMBASE, and Cochrane Library databases were searched for relevant articles published by August 30, 2017. Quantitative data were analyzed by a random-effects model with pooled odds ratios or weighted mean difference (WMD) and 95% confidence interval as aggregate estimations.Results: A total of 19 observational studies were identified for each of meta-analysis and narrative review. The overall estimated relation between vegetarian pregnancy and low birth weight (LBW) was marginally significant (1.27 (0.98, 1.65), P = 0.07, I2 = 0%). Asian (India/Nepal) vegetarian mothers exhibited increased risks to deliver a baby with LBW (1.33 (1.01, 1.76), P = 0.04, I2 = 0%). However, the WMD of neonatal birth weight in five studies suggested no difference between vegetarians ...

The mechanism underlying postprandial glucagon-like peptide-1 (GLP-1) changes after metabolic surgery remains mostly unclarified. This investigation aimed to address whether the vagus nerve-spleen anti-inflammatory axis is involved in the rise in postprandial GLP-1 levels in type 2 diabetes mellitus (T2DM) rats following metabolic surgery.T2DM rat model was established with a high-fat diet and a low dose of streptozotocin and subjected to Roux-en-Y gastric bypass (RYGB) and splenic denervation. A mixed-meal tolerance test for postprandial GLP-1 response was performed. TNF-α in the plasma, spleen, and ileum was measured by ELISA, and alpha 7 nicotinic acetylcholine receptor (α7nAChR) expression in the spleen was analyzed by Western blot.Postprandial GLP-1 improvement by RYGB was accompanied by the reduction of TNF-α levels in spleen and ileum and up-regulation of splenic α7nAChR in T2DM rats. Splenic denervation abrogates a rise in postprandial GLP-1 levels in response to the mixed-meal challenge, along with higher TNF-α levels in spleen and ileum and down-regulation of splenicα7nAChR, compared with denervated sham rats.Our results reveal that the vagus nerve-spleen anti-inflammatory axis mediates the rise of postprandial GLP-1 response after RYGB through lowering TNF-α contents in the intestinal tissue in T2DM rats.

Background Parent-child separation is a considerable adversity for left-behind children (LBC), but there is little evidence on the association between detailed characteristics of parent-child separation and social-emotional development among LBC. This study examined the characteristics of parent-child separation and its impacts on developmental delay among under-3 LBC in poor rural China. Methods We used data from 811 LBC surveyed in five poor counties in rural China in 2018. Detailed characteristics of their parental migration were recalled by their primary caregivers in face-to-face interviews. The children’s social-emotional development was measured by using the Ages and Stages Questionnaire: Social-Emotional. Logistic regression was employed to examine the association of detailed characteristics of parent-child separation with early social-emotional problems after adjusting for the children’s and primary caregivers’ sociodemographic characteristics. Results 287 (35.4%) children were left behind by fathers and cared for by mothers (FM-MC), while 524 (64.6%) were left behind by both parents and cared for by grandparents (PM-GC). The rate of social-emotional problems among LBC was 36.8% (PM-GC vs FM-MC: 40.6% vs 29.5%; aOR 1.51, 95% CI: 1.06 to 2.16). For paternal migration, the medians of the child’s age at the first migration and average duration per migration were 3 months (IQR: 1 to 9 months) and 4.48 months (IQR: 2.38 to 7.54 months), respectively. For maternal migration, the corresponding values were 9 months (IQR: 6 to 13 months) and 4.65 months (IQR: 2.71 to 7.62 months), respectively. On average, LBC had been separated from fathers for 72% of their life due to paternal migration and from mothers for 52% of their life due to maternal migration. No significant association was found between the detailed characteristics of paternal migration and social-emotional development among LBC, while social-emotional problems among LBC were significantly associated with the proportion of cumulative duration of maternal migration in the child’s lifetime (aOR 2.83; 95% CI: 1.13 to 7.10). Conclusions LBC under 3 years had a high risk of social-emotional problems in poor rural China. Cumulative exposure to maternal migration may be detrimental to LBC’s early social-emotional development. Programs are necessary to support these children as well as their families.

Objective To explore whether the whole brain resting-state functional connectivity (rs-FC) could predict episodic memory performance in individuals with subjective cognitive decline and amnestic mild cognitive impairment . Method This study included 33 cognitive normal (CN), 26 subjective cognitive decline (SCD) and 27 amnestic mild cognitive impairment (aMCI) patients, and all the participants completed resting-state fMRI (rs-fMRI) scan and neuropsychological scale test data. Connectome-based predictive modeling (CPM) based on the rs-FC data was used to predict the auditory verbal learning test-delayed recall (AVLT-DR) scores, which measured episodic memory in individuals. Pearson correlation between each brain connection in the connectivity matrices and AVLT-DR scores was computed across the patients in predementia stages of Alzheimer’s disease (AD). The Pearson correlation coefficient values separated into a positive network and a negative network. Predictive networks were then defined and employed by calculating positive and negative network strengths. CPM with leave-one-out cross-validation (LOOCV) was conducted to train linear models to respectively relate positive and negative network strengths to AVLT-DR scores in the training set. During the testing procedure, each left-out testing subject's strengths of positive and negative network was normalized using the parameters acquired during training procedure, and then the trained models were used to predict the testing participant’s AVLT-DR score. Results The negative network predictive model tested LOOCV significantly predicted individual differences in episodic memory from rs-FC. Key nodes that brain regions contributed to the prediction model were mainly located in the prefrontal cortex, frontal cortex, parietal cortex and temporal lobe. Conclusion Our findings demonstrated that rs-FC among multiple neural systems could predict episodic memory at the individual level.

IntroductionLower extremity amputation uniformly impairs a person’s vocational, social and recreational capacity. Rehabilitation in traditional socket prostheses (TSP) is associated with a spectrum of complications involving the socket-residuum interface which lead to reduced prosthetic use and quality of life. Osseointegration has recently emerged as a novel concept to overcome these complications by eliminating this interface and anchoring the prosthesis directly to bone. Though the complications of TSPs affect both transfemoral and transtibial amputees, Osseointegration has been predominantly performed in transfemoral ones assuming a greater benefit/risk ratio. However, as the safety of the procedure has been established, we intend to extend the concept to transtibial amputees and document the outcomes.Methods and analysisThis is protocol for a prospective cohort study, with patient enrolment started in 2014 and expected to be completed by 2022. The inclusion criteria are age over 18 years, unilateral, bilateral and mixed transtibial amputation and experiencing socket-related problems. All patients receive osseointegrated implants, the type of which depend on the length of the residuum and quality of bone, which are press-fitted into the residual bone. Objective functional outcomes comprising 6-Minute Walk Test, Timed Up-and-Go test and K-level, subjective patient-reported-quality-of-life outcomes (Short Form Health Survey 36, daily prosthetic wear hours, prosthetic wear satisfaction) and adverse events are recorded preoperatively and at postoperative follow-up intervals of 3, 6, 12 months and yearly, and compared with the preoperative values using appropriate statistical tests. Multivariable multilevel logistic regression will be performed with a focus to identify factors associated with outcomes and adverse events, specifically infection, periprosthetic fracture, implant fracture and aseptic loosening.Ethics and disseminationThe Ethics approval for the study has been received from the University of Notre Dame, Sydney, Australia (014153S). The outcomes of this study will be disseminated by publications in peer-reviewed academic journals and scientific presentations at relevant orthopaedic conferences.

BACKGROUND Plasma concentrations of branched-chain amino acids (BCAAs) are elevated in obese individuals with insulin resistance (IR) and decrease after bariatric surgery. However, the metabolic mechanisms are unclear. OBJECTIVES Our objectives are to compare leucine kinetics between morbidly obese and healthy-weight individuals cross-sectionally, and to prospectively evaluate changes in the morbidly obese after sleeve gastrectomy. We hypothesized that leucine oxidation is slower in obese individuals and increases after surgery. METHODS Ten morbidly obese [BMI (in kg/m2) ≥32.5, age 21-50 y] and 10 healthy-weight participants (BMI

Summary Stimulation of adipose tissue thermogenesis is regarded as a promising avenue in the treatment of obesity. However, pharmacologic engagement of this process has proven difficult. Using the Connectivity Map (CMap) approach, we identified the phytochemical hyperforin (HPF) as an anti-obesity agent. We found that HPF efficiently promoted thermogenesis by stimulating AMPK and PGC-1α via a Ucp1-dependent pathway. Using LiP-SMap (limited proteolysis-mass spectrometry) combined with a microscale thermophoresis assay and molecular docking analysis, we confirmed dihydrolipoamide S-acetyltransferase (Dlat) as a direct molecular target of HPF. Ablation of Dlat significantly attenuated HPF-mediated adipose tissue browning both in vitro and in vivo. Furthermore, genome-wide association study analysis indicated that a variation in DLAT is significantly associated with obesity in humans. These findings suggest that HPF is a promising lead compound in the pursuit of a pharmacological approach to promote energy expenditure in the treatment of obesity.

BackgroundNon-alcoholic fatty liver disease (NAFLD) is increasingly widespread with an overall global estimated prevalence of 25%. Type 2 diabetes Mellitus (T2DM) is a key contributor to NAFLD progression and predicts moderate-severe liver fibrosis and mortality. However, there is currently no uniform consensus on routine NAFLD screening among T2DM patients, and the risk factors of NAFLD and advanced fibrosis among T2DM patients remain to be clarified fully.AimWe explored the prevalence, clinical spectrum, and risk factors of NAFLD and liver fibrosis among T2DM patients.MethodsThis is a cross-sectional study that enrolled subjects from a primary care clinic and a diabetes centre in Singapore. Subjects aged 21 to 70 years of all ethnic groups with an established T2DM diagnosis were included. Subjects with chronic liver diseases of other aetiologies were excluded. All subjects underwent transient elastography for hepatic steatosis and fibrosis assessment. Their demographics, anthropometric measurements and clinical parameters were collected. Statistical analysis was performed using STATA/SE16.0 software.ResultsAmong 449 enrolled T2DM subjects, 436 with complete data and valid transient elastography results were analysed. Overall, 78.72% (344/436) of the T2DM subjects had NAFLD, of which 13.08% (45/344) had increased liver stiffness. Higher ALT level (OR = 1.08; 95% CI: 1.03-1.14; p = 0.004), obesity (BMI ≥ 27.5 kg/m2, OR = 2.64; 95% CI: 1.28-5.44; p = 0.008) and metabolic syndrome (OR = 4.36; 95% CI 1.40-13.58; p = 0.011) were independent factors associated with increased CAP (NAFLD). Higher AST level (OR = 1.06; 95% CI: 1.02-1.11; p = 0.008), CAP value (OR = 1.02; 95% CI: 1.00-1.03; p = 0.003), lower platelet count (OR = 0.99; 95% CI: 0.98-1.00; p = 0.009) and concomitant hypertension (OR = 4.56; 95% CI: 1.18-17.62; p = 0.028) were independent factors associated with increased liver stiffness.ConclusionsOur study demonstrated a considerably high prevalence of NAFLD among T2DM patients, with the proportion of advanced liver fibrosis among T2DM NAFLD patients much higher than the general population. Given that NAFLD is largely asymptomatic, increased awareness and vigilance for identifying NAFLD and increased liver stiffness among T2DM patients should be advocated.

Background Branched-chain amino acids (BCAAs) are elevated in the insulin-resistant (IR) state. The reasons for this increase remain unclear, but it may be related to abnormalities in BCAA metabolism and free fatty acid (FFA) metabolism. Objective In this study, we quantified BCAA and FFA kinetics of IR and insulin-sensitive (IS) nonobese Asian men with the use of stable-isotope tracers. We hypothesized that in addition to greater substrate flux, the BCAA oxidative pathway is also impaired to account for the higher plasma BCAA concentration in the IR state. Design We recruited 12 IR and 14 IS nonobese and healthy Asian men. Oral-glucose-tolerance tests (OGTTs) were performed to quantify insulin sensitivity, and subjects underwent 2 stable-isotope infusion studies. [U-13C6]Leucine was infused to measure leucine flux and oxidation as indexes of BCAA metabolism, whereas [U-13C16]palmitate was infused to measure palmitate flux and oxidation to represent FFA metabolism, The 2H2O dilution method was used to estimate body composition. Results IR subjects had greater adiposity and significantly higher fasting and post-OGTT glucose and insulin concentrations compared with the IS group. However, none of the subjects were diabetic. Despite similar dietary protein intake, IR subjects had a significantly higher plasma BCAA concentration and greater leucine flux. Leucine oxidation was also greater in the IR group, but the relation between leucine oxidation and flux was significantly weaker in the IR group than in the IS group (r = 0.530 compared with 0.695, P

Laparoscopic sleeve gastrectomy (LSG) has become the preferred bariatric procedure in many countries. However, there is one shortcoming of LSG in the long-term follow-up and this is the onset of GERD and erosive esophagitis (EE). Current evidence of the effect of SG on GERD did not consolidate to a consensus. In this study, we objectively evaluate the incidence of EE 1 year post-LSG with upper endoscopy (EGD) and try to identify the significant variables and possible underlying mechanisms of the EE post-LSG. Over a period of 5 years (2011–2016) at Singapore General Hospital, we retrospectively reviewed a prospectively collected database of a cohort of patients whom had LSG by a single surgeon who routinely performed EGD pre-operative and 1 year post-operative to assess EE and hiatal hernia. Patient’s endoscopic findings and demographic and anthropometric data were analyzed. We identified a total of 97 obese patients who underwent LSG at our hospital by studied surgeon. Sixty-three patients (64.9% of original sample) were finally evaluated in the present study, 40 (59.7%) of whom were female. The mean (range) age of patients was 38.2 (18–66) years, and mean BMI was 36.3 ± 4.1 kg/m2. Median time to follow-up EGD was 13 months (range, 12–15). Following LSG, there was a significant decrease in both BMI (42.1 ± 1.2 vs. 29.9 ± 1.0 kg/m2) and percentage excess weight loss of 56.6 ± 3.6%. The prevalence of EE on endoscopy increased from 9 (14.3%) to 28 (44.4%) patients. Of which 15 (23.8%) were grade A, 11 (17.5%) were grade B, and 2 (3.2%) were grade C. There was no correlation between GERD symptoms with EE; however, our study found a trend suggesting higher prevalence of EE with a sleeve diameter measuring > 2 cm wide (p = 0.069). Although LSG is effective in treating obesity and its metabolic syndromes, the prevalence of EE increased significantly 1 year after the surgery. Since we do not fully understand the long-term impact of chronic esophagitis in post-sleeve population, we recommend follow-up EGD assessment post-operatively and treat the esophagitis if present.

INTRODUCTION Obesity is a key risk factor in the development of Type 2 diabetes mellitus (T2DM). Bariatric surgery causes a large amount of durable weight loss in those with clinically severe obesity. We reported the effect of weight loss via bariatric surgery on DM prevention in those at high risk of developing DM. METHODS This was a retrospective cohort study of 44 patients with obesity (mean body mass index 43.8 kg/m2) and pre-DM who underwent bariatric surgery and were followed up for up to three years. We also reviewed a non-surgical cohort of patients with obesity and pre-DM seen at the weight management clinic. RESULTS 91% of patients attained normal glycaemic status at one year after bariatric surgery. At the three-year follow-up, 87.5% of the patients maintained normoglycaemia. None of the patients developed T2DM after surgery. 26.9% of patients achieved absolute weight loss at one year after bariatric surgery and maintained this at two and three years post surgery (p < 0.001 vs. baseline). The homeostatic model assessment-insulin resistance index in patients also decreased from 5.50 at baseline to 1.20, 1.14 and 1.44 at one, two and three years, respectively (p < 0.001). CONCLUSION Bariatric surgery produces significant weight loss, and leads to reversion from the pre-diabetic state to normal glycaemic status and reduction of the incident DM rate in those with pre-DM and morbid obesity.

Association of Alzheimer’s disease (AD) with cerebral glucose hypometabolism, likely due to impairments of insulin signaling, has been reported recently, with encouraging results when additional insulin is provided to AD patients. Here, we tested the potential effects of the anti-diabetic vanadium, vanadyl (IV) acetylacetonate (VAC), on AD in vitro and in vivo models. The experimental results showed that VAC at sub-micromolar concentrations improved the viability of neural cells with or without increased β-amyloid (Aβ) burden; and in APP/PS1 transgenic mice, VAC treatment (0.1 mmol kg−1 d−1) preserved cognitive function and attenuated neuron loss, but did not reduce brain Aβ plaques. Further studies revealed that VAC attenuated Aβ pathogenesis by (i) activation of the PPARγ-AMPK signal transduction pathway, leading to improved glucose and energy metabolism; (ii) up-regulation of the expression of glucose-regulated protein 75 (Grp75), thus suppressing p53-mediated neuronal apoptosis under Aβ-related stresses; and (iii) decreasing toxic soluble Aβ peptides. Overall, our work suggested that vanadyl complexes may have great potential for effective therapeutic treatment of AD.

Aims/Introduction Indian individuals are more insulin resistant (IR) than Chinese individuals, even among those with a non‐obese body mass index (BMI). However, BMI often underestimates body fat in Indian individuals, and it remains unclear whether Indians would remain more IR than Chinese individuals when both BMI and body fat are equally matched. Materials and Methods Using the hyperinsulinemic‐euglycemic clamp with stable‐isotope infusion, we comprehensively assessed IR between 13 non‐obese Indian men with 13 Chinese men matched for age, BMI and body fat. We further compared the differences in insulin metabolic clearance rate (MCR) between the two groups and its relationship with various metabolic parameters. The response of lipid and amino acid metabolism to insulin stimulation was also evaluated using metabolomic profiling. Results The rates of endogenous glucose production during fasting were similar, and endogenous glucose production was completely suppressed during insulin clamp for both ethnic groups. Glucose disappearance during insulin clamp was also similar between the two groups, even after accounting for differences in insulin concentration. Metabolomic profiles of amino acids and various acylcarnitines were similar during both fasting and insulin clamp. However, plasma insulin during clamp was significantly higher in Indian men, indicating that insulin MCR was lower. Insulin MCR correlated significantly with total adiposity and skeletal muscle insulin sensitivity. Conclusion When equally matched for body fat, non‐obese Indian men had similar skeletal muscle insulin sensitivity and endogenous glucose production to Chinese men. The effects of insulin on lipid and amino acid metabolism were also similar. Low insulin MCR is associated with greater adiposity and lower skeletal muscle insulin sensitivity.

Summary Transition from primed to naive pluripotency is associated with dynamic changes in transposable element (TE) expression and demethylation of imprinting control regions (ICRs). In mouse, ICR methylation and TE expression are each regulated by TRIM28; however, the role of TRIM28 in humans is less clear. Here, we show that a null mutation in TRIM28 causes significant alterations in TE expression in both the naive and primed states of human pluripotency, and phenotypically this has limited effects on self-renewal, instead causing a loss of germline competency. Furthermore, we discovered that TRIM28 regulates paternal ICR methylation and chromatin accessibility in the primed state, with no effects on maternal ICRs. Taken together, our study shows that abnormal TE expression is tolerated by self-renewing human pluripotent cells, whereas germline competency is not., Graphical Abstract, Highlights • Primed and naive hESC self-renewal does not depend on TRIM28 • Human germ cell formation in vitro requires TRIM28 • TRIM28 differentially regulates transposons in primed and naive hESCs • DNA methylation of H19 and MEG3 requires TRIM28, In this article, Clark and colleagues show that both primed and naive hESCs are compatible with a TRIM28 deletion, despite massive deregulation of transposable elements. However, human germline competency and paternal imprint methylation are compromised upon loss of TRIM28.

In Asia, metabolic-bariatric surgery (MBS) rates have grown rapidly in parallel with rising prevalence of obesity and type 2 diabetes (T2D). The objective of this study was to identify factors that influence glycemic outcomes and diabetes remission 12 months after sleeve gastrectomy (SG) or gastric bypass (GB) in a multiethnic Asian cohort. The study’s setting was in a tertiary hospital in Singapore. Data from 145 T2D patients who had SG (37%) or GB (63%) and at least 1-year follow-up were analyzed. Diabetes remission was defined as hemoglobin A1c ≤ 6.0% without diabetes medications. Analysis involved binary logistic regression to identify predictors and general linear regression for variables associated with glycemic improvement after surgery. Baseline parameters are as follows: BMI 40.0 ± 7.6 kg/m2, A1c 8.4 ± 1.6%, diabetes duration 9.3 years, ethnic composition: Chinese (51.7%), Malay (23.4%), Indian (20.7%), Others (4.1%). 55.9% achieved diabetes remission at 1 year. Baseline A1c, baseline BMI, and diabetes duration were significant pre-operative factors for remission (cumulative R 2 = 0.334). At 12 months, percentage weight loss was similar after SG (24.1 ± 7.4%) and GB (25.4 ± 7.4%, p = 0.31). Greater A1c decrease was seen with GB compared to SG (2.7 ± 1.6 vs 2.0 ± 1.5%, p = 0.006), significant even after adjustment for weight loss, age, BMI, baseline A1c, and diabetes duration (p = 0.033). Weight loss at 12 months also correlated independently with A1c reduction. Ethnicity did not influence weight loss, diabetes remission, or glycemic control after MBS. Baseline A1c, baseline BMI, and diabetes duration independently predict diabetes remission after MBS. GB is more effective in controlling T2D compared to SG despite similar weight loss, whereas ethnicity does not play a significant role in the multiethnic Asian cohort.

Purpose: Many genes have been associated with primary open-angle glaucoma (POAG). This study was conducted to investigate whether catalase (CAT) polymorphisms play a significant role in POAG in a Chinese population. Methods: A cohort of 416 unrelated POAG patients and 997 unrelated control subjects was included in this case–control association study. CAT functional single-nucleotide polymorphisms (SNPs), including rs1001179, rs7943316, and rs769217, were genotyped by SNaPshot method. The genotype and allele frequencies were evaluated using the χ2 tests. The linkage disequilibrium (LD) and haplotype block structure association were examined using the program Haploview (Broad Institute, Cambridge, MA). Results: There was a statistically significant difference for CAT functional SNP rs769217 between POAG cases and controls in the allelic model (p = 0.004, OR = 1.27, 95% CI 1.08–1.49). At this SNP, the allele frequency of the C allele in POAG cases was 0.587, which was higher than that in controls (0.528). However, no association was found for rs1001179 and rs7943316 with POAG. Pairwise LD analysis showed high LD between rs769217 and rs7943316 (D’ = 0.857, r2 = 0.252, confidence bounds 0.71–0.93). After the association analysis for haplotype block structure generated from rs769217 with rs7943316, the data showed no significant association between the cases and controls. Conclusions: This study showed that CAT functional SNP rs769217 was significantly associated with POAG, implying that the CAT gene variants may play a role in the pathogenesis of POAG in the Chinese population.

Our aim was to evaluate the association of genetic polymorphisms of immunoregulatory molecules with susceptibility to hepatocellular carcinoma (HCC). The polymorphisms in CTLA-4 (-318 T/C, CT60 G/A), TNF (-238 G/A, -308 G/A) and IL10 (-592 C/A, -819 C/T) were genotyped by PCR and DNA sequencing. The functional relevance of the polymorphisms was examined by ELISAs, in vitro lymphocyte proliferation assay and cytotoxic assay. The CTLA-4 -318 TC/TT, CTLA-4 CT60 GG, IL10 -592 CA and -819 CT/TT variants, CTLA-4 -318 T and IL 10 -819 T alleles were positively associated with HCC risk (P

Purpose The aim of this study was to evaluate the role of mesh technique in the reconstruction of the extensor mechanism after resection of proximal tibial tumors. Methods We retrospectively analyzed the cases of 14 patients who were diagnosed with proximal tibial tumors at our center and reconstructed with tumor prosthesis, gastrocnemius muscle, and mesh between 2012 and 2017. The treatment strategies for patellar tendon reconstruction primarily involve gastrocnemius reconstruction to cover the tumor prosthesis and mesh reconstruction for the patellar ligament. Results Among the 14 patients, the mean was 1.57° (range 0–12°) for active extension versus 105.00° (range 80–120°) for active flexion. The mean for passive extension was 0°. The passive flexion mean was 115.00° (range 90–120°). The extensor lag averaged 1.57° (range 0–12°), and the mean Musculoskeletal Tumor Society score (MSTS) was 23.57 (range 19–27). The average follow-up for all patients was 23.50 months (range 14–37). During the recent follow-up, all patients were able to walk without crutches. Two patients underwent above-the-knee amputation for local recurrence of the tumor, and lung metastasis occurred in three patients after operation. There were no postoperative complications. Conclusions Extensor lag was remarkably reduced in the surgery group in comparison to previous study reports. Surgical resection is a simple, reliable, and effective method to remove and control the tumor. Mesh reconstruction of patellar ligament is effective to reconstruct the extensor mechanism of the knee after excision of tumor.

Obesity-induced insulin resistance leads to abnormalities in glucose, lipid, and amino acid metabolism. Our study examined the differences in insulin-mediated glucose, amino acid, and lipid metabolism between morbidly obese subjects with non-obese controls and the associated changes following sleeve gastrectomy (SG). Non-obese controls and individuals with morbid obesity and scheduled for SG were recruited. Metabolic assessments were performed for all subjects at baseline and at 6 months after SG for eight subjects. The hyperinsulinemic-euglycemic clamp technique together with comprehensive metabolomic profiling was used to quantify insulin-mediated glucose, amino acid, and lipid metabolism. Eleven morbidly obese non-diabetic subjects scheduled for SG and nine non-obese controls were recruited. Compared to controls, obese subjects had significantly lower glucose uptake (4.4 ± 0.6 vs. 17.3 ± 2.4 mg/kg FFM/min per μU/mL·100) and higher concentration of branched-chain amino acids (BCAAs, 332.5 ± 26.8 vs. 235.3 ± 11.0 μM), non-esterified fatty acid (52.9 ± 9.9 vs. 25.6 ± 6.7 μM), and lipid-related acylcarnitines (intermediate chain 389.8 ± 32.5 vs. 285.9 ± 20.5; long chain 301.7 ± 22.1 vs. 236.0 ± 13.3 nM) during insulin clamp. Body weight significantly reduced at 6 months after bariatric surgery (92.5 ± 6.3 vs. 115.2 ± 6.9 kg), together with improvements in insulin-mediated glucose uptake, and suppression of BCAAs, non-esterified fatty acids, and lipid-related metabolites. Morbid obesity in Asian individuals was associated with impairment in the regulatory actions of insulin on glucose, amino acid, and lipid metabolism, and these obesity-induced regulatory dysfunctions improved significantly 6 months after SG.

INTRODUCTION We aimed to compare the malignancy risk stratification of histologically proven thyroid nodules using the 2015 American Thyroid Association (ATA) Management Guidelines, 2014 British Thyroid Association (BTA) Guidelines for the Management of Thyroid Cancer and the Thyroid Imaging Reporting and Data System (TIRADS). METHODS Thyroid nodules measuring > 1 cm resected over 5.5 years were retrospectively studied. Demographic information as well as cytology and histopathology results were collected. Static ultrasonography (US) images and radiologists' reports of each resected nodules were reviewed and classified based on the above risk classification systems. RESULTS A total of 167 thyroid nodules from 150 patients were examined. More malignant nodules were solid (78.4% vs. 62.5%; p = 0.049) or hypoechoic (70.6% vs. 28.6%; p < 0.001), and had irregular margins (35.3% vs. 8.0%; p < 0.001), taller-than-wide morphology (9.8% vs. 2.7%; p = 0.031), microcalcifications (33.3% vs. 8.0%; p < 0.001), disrupted rim calcifications (9.8% vs. 0.9%; p = 0.012) or associated abnormal cervical lymphadenopathy (13.7% vs. 0.9%; p = 0.001) compared with benign nodules. The guidelines' diagnostic performance was: ATA - sensitivity 98.0%, specificity 17.3%, positive predictive value (PPV) 35.0%, negative predictive value (NPV) 95.0%; BTA - sensitivity 90%, specificity 50.9%, PPV 45.5%, NPV 91.8%; and TIRADS - sensitivity 94.0%, specificity 28.2%, PPV 37.3%%, NPV 91.2%. CONCLUSION Sonographic patterns outlined by the three guidelines displayed high sensitivity and NPV. Although isolated suspicious US features cannot predict malignancy risk, they should be considered when risk stratifying nodules that do not fit into particular sonographic patterns based on current guidelines.

BACKGROUND: Aerobic capacity is a powerful predictor of cardiovascular disease and all‐cause mortality, and it declines with advancing age. HYPOTHESIS: Since physical activity alters body metabolism, metabolism markers will likely differ between subjects with high vs low aerobic capacities. METHODS: Community‐based participants without physician‐diagnosed heart disease, stroke or cancer underwent same‐day multimodal assessment of cardiovascular function (by echocardiography and magnetic resonance feature tracking of left atrium) and aerobic capacity by peak oxygen uptake (VO(2)) metrics. Associations between VO(2) and cardiovascular and metabolomics profiles were studied in adjusted models including standard covariates. RESULTS: We studied 141 participants, of whom 82 (58.2%) had low VO(2), while 59 (41.8%) had high VO(2). Compared to participants with high VO(2), participants with low VO(2) had more adverse cardiovascular parameters, such as lower ratio of peak velocity flow in early diastole to peak velocity flow in late diastole by atrial contraction of >0.8 (76% vs 35%, adjusted odd ratio [OR] = 4.1, 95% confidence interval [CI] [1.7‐9.5], P = 0.001) and lower left atrial conduit strain (11.3 ± 4.0 vs 15.6 ± 6.1%, adjusted OR = 1.1, 95% CI [1.002‐1.3], P = 0.045). High VO(2) was associated with lower accumulation of wide‐spectrum acyl‐carnitines (OR = 0.6, 95% CI [0.4‐0.9], P = 0.013), alanine (OR = 0.1, 95% CI [0.01‐0.9], P = 0.044) and glutamine /glutamate (OR = 0.1, 95% CI [0.01‐0.5], P = 0.007), compared to low VO(2.) CONCLUSION: Elderly adults with low VO(2) have adverse cardiovascular and metabolic parameters compared to their counterparts with high VO(2). Combined cardiac and metabolomics phenotyping may be a promising tool to provide insights into physiological states, useful for tracking future interventions related to physical activity among community cohorts.

Ulcerative colitis (UC) is a chronic nonspecific inflammation mainly involving rectum and colon mucosa, which seriously affects the health and quality of life of patients, and is listed as one of modern refractory diseases by WHO. Professor XU Jing-fan, a great master of traditional Chinese medicine, has accumulated rich experiences in the treatment of UC. The study collected Professor XU's 77 prescriptions of treating UC, analyzed the frequency of traditional Chinese medicines and there categories, and investigated the medication regularity by the system clustering method. The findings showed that the most frequently used drugs were clearing-heat herbs, which were followed by hemostatic herbs, excreting-dampness herbs, improving-digestion herbs and tonifying-Qi herbs. At the same time, the commonly combined drugs were excavated. Finally, in order to analyze potential molecular targets of the frequently used herbs, GO enrichment analysis and KEGG signal pathway enrichment analysis were performed with bioinformatics analysis tool for molecular mechanism of traditional Chinese medicine (BATMAN-TCM). The results indicated that Chinese herbal compounds may treat UC by activating PPAR-γ pathway and regulating intestinal inflammation. The exact mechanisms shall be verified through subsequent molecular biological experiments.

Retinitis pigmentosa (RP) is highly heterogeneous in both clinical and genetic fields. Accurate mutation screening is very beneficial in improving clinical diagnosis and gene-specific treatment of RP patients. The reason for the difficulties in genetic diagnosis of RP is that the ethnic-specific mutation databases that contain both clinical and genetic information are largely insufficient. In this study, we recruited 98 small Han Chinese families clinically diagnosed as RP, including of 22 dominant, 19 recessive, 52 sporadic, and five X-linked. We then used whole exome sequencing (WES) analysis to detect mutations in the genes known for RP in 101 samples from these 98 families. In total, we identified 57 potential pathogenic mutations in 40 of the 98 (41%) families in 22 known RP genes, including 45 novel mutations. We detected mutations in 13 of the 22 (59%) typical autosomal dominant families, 8 of the 19 (42%) typical autosomal recessive families, 16 of the 52 (31%) sporadic small families, and four of the five (80%) X-linked families. Our results extended the mutation spectrum of known RP genes in Han Chinese, thus making a contribution to RP gene diagnosis and the pathogenetic study of RP genes.

The identification of cancer genes remains a main aim of cancer research. With the advances of high-throughput sequencing technologies, thousands of novel cancer genes were identified through recurrent mutation analyses and differential expression analyses between normal tissues and tumors in large populations. Many databases were developed to document the cancer genes. However, no public database providing both cancer protein-coding genes and cancer lncRNAs is available presently. Here, we present the Catalogue of Cancer Genes (CCG) database (http://ccg.xingene.net), a catalogue of cancer genes. It includes both well-supported and candidate cancer protein-coding genes and cancer lncRNAs collected from literature search and public databases. In addition, uniform genomic aberration information (such as somatic mutation and copy number variation) and drug-gene interactions were assigned to cancer genes in the database. CCG represents an effort on integrative assembly of well-supported and candidate cancer protein-coding and long noncoding RNA genes and takes advantages of high-throughput sequencing results on large populations. With the help of CCG, users can easily access a comprehensive list of cancer genes as well as genomic aberration related with these genes. The availability of integrative information will facilitate the understanding of cancer mechanisms. In addition, drug-gene information in CCG provides a useful guide to the development of new anti-cancer drugs and selection of rational combination therapies.

Underrepresentation of Asian genomes has hindered population and medical genetics research on Asians, leading to population disparities in precision medicine. By whole-genome sequencing of 4,810 Singapore Chinese, Malays, and Indians, we found 98.3 million SNPs and small insertions or deletions, over half of which are novel. Population structure analysis demonstrated great representation of Asian genetic diversity by three ethnicities in Singapore and revealed a Malay-related novel ancestry component. Furthermore, demographic inference suggested that Malays split from Chinese ∼24,800 years ago and experienced significant admixture with East Asians ∼1,700 years ago, coinciding with the Austronesian expansion. Additionally, we identified 20 candidate loci for natural selection, 14 of which harbored robust associations with complex traits and diseases. Finally, we show that our data can substantially improve genotype imputation in diverse Asian and Oceanian populations. These results highlight the value of our data as a resource to empower human genetics discovery across broad geographic regions. Agency for Science, Technology and Research (A*STAR) National Medical Research Council (NMRC) National Research Foundation (NRF) Accepted version We acknowledge H.M. Kang, S. Das, A. Tan, F. Zhang, J. Terhorst, P.-R. Loh, and G. Hellenthal for helpful discussions and support from all participants and clinical research coordinators of the contributing cohorts and studies: the TTSH Healthy Control Workgroup, the SEED cohort, the Asian Sudden Cardiac Death in Heart Failure Study, the Singapore Heart Failure Outcomes and Phenotypes (SHOP) cohort, the Asian neTwork for Translational Research and Cardiovascular Trials (ATTRaCT), the Parkinson’s Disease Study, the Peranakan Genome Study, the Platinum Asian Genomes Project, the Bariatric Surgery Study, the National Heart Centre Singapore Biobank and SingHEART cohorts, and the GUSTO and S-PRESTO study groups. This study was supported by Singapore’s A*STAR (core funding and IAF-PP H17/01/a0/007), BMRC (SPF2014/001, SPF2013/002, SPF2014/003, SPF2014/004, and SPF2014/005), NMRC (CIRG/1371/2013, CIRG/1417/2015, CIRG/1488/ 2018, CSA-SI/0012/2017, CG/017/2013, CG/M006/2017_NHCS, TCR/013- NNI/2014, STaR/0011/2012, STaR2013/001, STaR/014/2013, STaR/0026/ 2015, TCR/006-NUHS/2013, TCR/012-NUHS/2014, TCR/004-NUS/2008, TCR/012-NUHS/2014, and center grants 2010-13 and 2013-2017), NRF (NRFF2016-03), National University of Singapore, SingHealth and DukeNUS, and Alexandra Health small innovative grant SIGII/15203 and funding from Huazhong University of Science and Technology, the Tanoto Foundation, the Lee Foundation, the Boston Scientific Investigator Sponsored Research Program and Bayer, the NSF (DEB-1753489), and the Alfred P. Sloan Foundation. The computation was partially performed on resources of the National Supercomputing Centre, Singapore (https://www.nscc.sg).

INTRODUCTION: Obesity is a risk factor for type 2 diabetes mellitus (T2DM). Metabolic-bariatric surgery (MBS) results in significant weight loss with dramatic improvement in T2DM. This study analysed the effects of MBS on patients with T2DM in a tertiary centre in Singapore. METHODS: Individuals with T2DM who underwent MBS in a single centre from September 2008 to May 2012, with at least 12 months of regular follow-up, were included in our study. The primary outcome measure was good glycaemic control (glycated haemoglobin [HbA1c] < 6.5%, with or without medications) 12 months after surgery. Secondary outcome measures were partial DM remission (fasting blood glucose [FBG] < 7.0 mmol/L and HbA1c < 6.5% without DM medications), complete DM remission (FBG < 5.6 mmol/L and HbA1c < 6.0% without DM medications), weight, body mass index, blood pressure, and fasting serum lipid, serum glucose and serum insulin levels. RESULTS: Of the 19 patients who met the inclusion criteria, 14 underwent gastric bypass and 5 underwent sleeve gastrectomy. At 12 months postoperatively, 17 (89.5%) patients achieved good glycaemic control. DM remission was achieved in 14 (73.7%) patients, with 10 (52.6%) attaining complete remission. CONCLUSION: In Singapore, MBS is an effective treatment modality for obese patients with T2DM. Despite the small sample size and lack of matched controls, the present study suggests that MBS is effective in achieving significant weight loss and eliciting a significant and sustainable improvement in the glycaemic control of patients with T2DM, for up to 12 months.

Bismuth type IV hilar cholangiocarcinoma (HC) tumors are usually considered unresectable. The strategies of high hilar resection while preserving liver parenchyma can achieve potentially one-stage curative resection for this condition. The aim of the present study was to investigate the feasibility and safety of available strategies. Fifty-one consecutive patients with bismuth type IV HC who underwent one-stage resection were retrospectively reviewed with regard to curative resection rate, remnant liver volume, morbidity, mortality, and survival time. The total median survival time was 29 months. The R0 (curative resection) rate was 57.8 %. The ratio of the remnant liver volume (RLV) to the standard liver volume (SLV) ranged from 35.0 to 60.6 %, with a mean of 44.5 %. The in-hospital mortality and morbidity rates were 3.9 and 37.2 %, respectively. In the R0 patients’ survival, there was not a significant difference between bilioenteric anastomosis and hepatoenteric anastomosis (P = 0.714). Combined caudate lobe and high hilar resection (CCHR) is technically safe and oncologically justifiable and could be adopted with a high cure rate as a one-stage resection procedure for most patients with Bismuth type IV HC whose total bilirubin level is less than 20 mg/L and whose direct bilirubin is more than 60 % of total bilirubin.

BACKGROUND Early post-operative hyperglycemia is commonly encountered in patients without pre-existing diabetes mellitus who are undergoing kidney transplantation. The aim of this study was to determine the effect of early post-operative hyperglycemia on graft and patient survival after kidney transplantation in our center. MATERIAL AND METHODS This was a single-center retrospective review of solitary kidney recipients transplanted in our center between January 1998 and December 2007. Of a total of 432 patients, 377 were eligible for the study. Fasting plasma glucose (FPG) levels at day 1 (D1) and day 5 (D5) after transplantation were recorded. Hyperglycemia was defined as FPG ≥ 7.0 mmol/l. Outcome events recorded included deaths and graft failures. RESULTS The mean age at transplantation was 43.2 ± 9.5 years and 50.4% were male. The mean FPG levels at D1 and D5 were 7.5 ± 1.3 mmol/L and 5.3 ± 1.3 mmol/L, respectively; 64.2% of recipients had FPG ≥ 7.0 mmol/L on D1 and this was reduced to 8.5% on D5. Recipients with D1 FPG ≥ 7.0 mmol/L had significantly poorer graft survival (39 events) compared to those without D1 hyperglycemia (6 events), with a hazard ratio of 3.708 (95% CI, 1.568-8.766, P=0.003). There was a trend towards better patients survival in recipients with D1 FPG

The serum metabolomic profile and its relationship to physiological changes during hyperthyroidism and restoration to euthyroidism are not known. This study aimed to examine the physiological, adipokine, and metabolomic changes that occur when subjects with Graves' disease transition from hyperthyroidism to euthyroidism with medical treatment.Chinese women between 21 and 50 years of age and with newly diagnosed Graves' disease attending the endocrine outpatient clinics in a single institution were recruited between July 2012 and September 2014. All subjects were treated with thioamides to achieve euthyroidism. Clinical parameters (body weight, body composition via bioelectrical impedance analysis, resting energy expenditure and respiratory quotient via indirect calorimetry, and reported total energy intake via 24 h food diary), biochemical parameters (thyroid hormones, lipid profile, fasting insulin and glucose levels), serum leptin, adiponectin, and metabolomics profiles were measured during hyperthyroidism and repeated in early euthyroidism.Twenty four Chinese women with an average age of 36.3 ± 8.6 years were included in the study. The average duration of treatment that was required to reach euthyroidism for these subjects was 38 ± 16.3 weeks. There was a significant increase in body weight (52.6 ± 9.0 kg to 55.3 ± 9.4 kg; p 0.001) and fat mass (14.3 ± 6.9 kg to 16.8 ± 6.5 kg; p = 0.005). There was a reduction in resting energy expenditure corrected for weight (28.7 ± 4.0 kcal/kg to 21.5 ± 4.1 kcal/kg; p 0.001) and an increase in respiratory quotient (0.76 to 0.81; p = 0.037). Resting energy expenditure increased significantly with increasing free triiodothyronine levels (p = 0.007). Significant increases in total cholesterol, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol were noted. There was no significant change in leptin levels, but adiponectin levels increased significantly (p = 0.018). Significant reductions in fasting C2, medium-chain, long-chain, and total acylcarnitines were observed, but no changes in the fat-free mass, branched chain amino acid levels, or insulin sensitivity during recovery from hyperthyroidism were noted.Serum metabolomics profile changes complemented the physiological changes observed during the transition from hyperthyroidism to euthyroidism. This study provides a comprehensive and integrated view of the changes in fuel metabolism and energy balance that occur following the treatment of hyperthyroidism.

To assess the association of single nucleotide polymorphisms (SNPs) of PLEKHA7, COL11A1 and PCMTD1-ST18 genes and primary angle closure glaucoma (PACG) among ethnic Han Chinese from Sichuan Province.In this study, 362 subjects with PACG and 1056 age- and sex-matched healthy controls were recruited. Genotypes of 3 reported SNPs, including PLEKHA7 rs11024102, COL11A1 rs3753841 and PCMTD1-ST18 rs1015213 were determined with a SNaPshot method.The P values for the genotype frequencies of rs11024102, rs3753841 and rs1015213 between the patient and control groups were 0.62 (OR=1.09, 95%CI: 0.91-1.30), 0.42 (OR=1.04, 95%CI: 0.87-1.41) and 0.34 (OR=1.35, 95%CI: 0.73-2.49), respectively. And the P values for the allele frequency distributions of PLEKHA7 rs11024102, COL11A1 rs3753841 and PCMTD1-ST18 rs1015213 between the two groups were 0.347, 0.698 and 0.344, respectively.No significant association of PLEKHA7 rs11024102, COL11A1 rs3753841 and PCMTD1-ST18 rs1015213 with PACG was found among ethnic Han Chinese from Sichuan.

Weight loss, early after Roux-en-Y gastric bypass (GB) surgery, is associated with reduced concentrations of plasma branched-chain amino acids (BCAAs) and improved insulin sensitivity. Herein, we evaluated whether changes in BCAAs and insulin sensitivity persist with weight stabilization (1 year) after GB or sleeve gastrectomy (SG). We prospectively examined 22 severely obese patients (mean age 40.6 ± 2.1 years, BMI 38.8 ± 1.3 kg/m2, and 59.1 % female) who underwent SG (n = 12) or GB (n = 10) for morbid obesity. Body fat composition was measured with dual X-Ray absorptiometry and abdominal fat volume with computed tomography. BCAAs and acylcarnitines were profiled using liquid chromatography with tandem mass spectrometry. Insulin resistance was calculated using the homeostasis model assessment for insulin resistance (HOMA-IR) formula. At 1-year follow-up, the decrease in BMI, body weight, total fat mass (TFM), fat free mass, and visceral adipose tissue (VAT) was similar between SG and GB. HOMA-IR was associated with BCAA concentrations, and both were decreased equally in both surgical groups. In multivariate analysis with BCAAs, TFM, and VAT as independent factors, only VAT remained significantly associated with insulin resistance. The metabolic benefits from bariatric surgery, including the changes in BCAA profile, are comparable between SG and GB. The reduction in BCAAs and improvement in the AC profiles after bariatric surgery persists up to 12 months after surgery and may not be surgical related but is influenced primarily by the amount of weight loss, in particular the reduction in visceral adiposity.

Vacuolar H(+)-ATPase (V-ATPase) is a membrane-bound multisubunit enzyme complex composed of at least 14 different subunits. The complex regulates the physiological processes of a cell by controlling the acidic environment, which is necessary for certain activities and the interaction with the actin cytoskeleton through its B and C subunits in both humans and yeast. Arabidopsis V-ATPase has three B subunits (AtVAB1, AtVAB2, and AtVAB3), which share 97.27% sequence identity and have two potential actin-binding sites, indicating that these AtVABs may have crucial functions in actin cytoskeleton remodeling and plant cell development. However, their biochemical functions are poorly understood. In this study, we demonstrated that AtVABs bind to and co-localize with F-actin, bundle F-actin to form higher order structures, and stabilize actin filaments in vitro. In addition, the AtVABs also show different degrees of activities in capping the barbed ends but no nucleating activities, and these activities were not regulated by calcium. The functional similarity and differences of the AtVABs implied that they may play cooperative and distinct roles in Arabidopsis cells.

Purpose Recently, three large genome-wide association studies have identified multiple variants associated with primary open angle glaucoma (POAG) near the ABCA1 gene. Considering that POAG and primary angle closure glaucoma (PACG) share many similar clinical manifestations, the present study was conducted to investigate whether these genetic variants were also associated with PACG in a Han Chinese population. Methods A case-control association study of 1122 cases (PACG/PAC) and 1311 normal, matched controls was undertaken. Seven single-nucleotide polymorphisms (SNPs) near the ABCA1 gene, including rs2422493, rs2487042, rs2472496, rs2472493, rs2487032, rs2472459, and rs2472519, were genotyped. Genotype and allele frequencies were assessed using χ² tests. Linkage disequilibrium (LD) structure was analyzed by computer software. Results Among the SNPs genotyped, no association was observed between these SNPs and PACG. However, we discovered that two haplotypes, CATTTAC (corrected P = 0.048) and CGCCCGC (corrected P = 0.048), remained significantly associated with PACG/PAC after Bonferroni correction. Subjects with the CATTTAC haplotype have a 1.71-fold increased possibility of having PACG/PAC, whereas subjects with the CGCCCGC haplotype have 0.47-fold decreased possibility of developing PACG. Conclusions Our findings suggest that the genetic backgrounds of PACG and POAG might be different. However, whether or not ABCA1 plays a role in the development of PACG is still not made certain by this study. Thus, further research is needed to find the role of ABCA1 in the progress of PACG.

Consumptive hypothyroidism (CH) is a rare form of hypothyroidism due to increased catabolic activity of type 3 iodothyronine deiodinase (DIO3) that can occur in large tumors. PATIENTs with CH typically present with markedly increased requirements for exogenous thyroid hormone and resolution after removal of the source of ectopic DIO3. DIO3 is encoded by DIO3, an imprinted gene expressed on the paternal allele that is located in a DIO3/delta-like 1 homolog (DLK1) gene locus regulated by a common control region, intergenic differentially methylated region (IGDMR). Because DIO3 is an imprinted gene, loss of imprinting at the IGDMR is thought to play a role in its increased expression; however, the molecular mechanism for DIO3 in CH currently is not known.The aim of the study was to determine the molecular mechanism for CH in an adult patient.The study was conducted in the Department of Endocrinology of a tertiary care center in Singapore.We report the case of an adult Asian female patient with a large intrathoracic fibrous tumor and severe hypothyroidism that resolved after tumor resection.The patient's tumor expressed increased levels of DIO3 and DLK1 mRNA and protein levels. Methylation-specific PCR of the IGDMR showed similar hypomethylation in placenta, thyroid, leukocytes, and tumor. Western blotting showed activation of sonic hedgehog (SHH) and MAPK signaling pathways that can increase DIO3 and DLK1 expression.Loss of imprinting did not account for overexpression of DIO3 in the patient's tumor. Instead SHH and MAPK/ERK pathway activation was associated with systemic thyroid hormone catabolism and growth of the tumor. These findings raise the possibility that other tumors that have increased SHH and MAPK/ERK signaling also may have intratumor or systemic effects on thyroid hormone function.

To explore curative effects of advanced elastic intramedullary nail technology in treating children with femoral subtrochanteric fracture.Form March 2009 to December 2010, 16 children with femoral subtrochanteric fracture were treated with advanced elastic intramedullary nail technology. There were 12 males and 4 females ranging in age from 7 to 15 years old with a mean of 9.8 years old. According to fracture classification, 9 cases were stable fractures (traverse or short oblique type) and 7 cases were unstable fractures (comminuted or long oblique type). Radiographs and complications were retrospectively reviewed. Fracture healing were evaluated according to Flynn criteria.All children were followed up from 11 to 32 months with an average of 21 months. No incision infecton,bone nonunion and breakage of screw occurred. The fracture healing time was from 8 to 16 weeks with an average of 10.1 weeks. According to Flynn criteria, 14 cases got excellent results, 1 moderate and 1 poor.Advanced elastic intramedullary nail technology for the treatment of children with femoral subtrochanteric fracture is a safe and effective fixation, which is good for early mobilization, shorter the duration of hospital stays and reduce complications.

This study was aimed to identify the potential indications for simultaneous resection of abdominal cancer and synchronous pancreaticoduodenal metastasis (SRAPM) and improve the efficacy of SRAPM.The data of 34 patients who underwent SRAPM were retrospectively reviewed. The intraoperative findings, morbidity and mortality, patterns of tumor invasion in the pancreas and duodenum, lymph node metastases, long-term outcomes and causes of death were evaluated.Fourteen patients (41.2%) developed complications, and 2 died of pancreatic fistulas with abdominal bleeding. The in-hospital mortality was 5.9%. The overall 1-year, 2-year and 3-year survival rates were 52.9%, 32.3% and 21.8%, respectively. The survival rates depended on the primary tumor, the invasion pattern, the presence of metastatic lymph nodes at the paraaortic site and the presence of residual tumor. The follow-up outcomes revealed that the main causes of death were as follows: systemic metastasis (n = 7), peritoneal metastasis (n = 6) and intrahepatic metastasis (n = 6).SRAPM is indicated for low-grade malignant tumors and in cases with direct invasion of the pancreaticoduodenum. The presence of metastatic lymph nodes at the paraaortic site, intrahepatic metastasis, micro-peritoneal metastasis, and distinct metastasis should be contraindications for the surgical procedure.