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Brown adipose tissue (BAT) thermogenesis is activated by feeding. Recently, we revealed a secretin-mediated gut-BAT-brain axis, which stimulates satiation in mice, but the purpose of meal-induced BAT activation in humans has been unclear. In this placebo-controlled, randomized crossover study, we investigated the effects of intravenous secretin on BAT metabolism (measured with [18F]FDG and [15O]H2O positron emission tomography) and appetite (measured with functional magnetic resonance imaging) in healthy, normal weight men (GUTBAT trial no. NCT03290846). Participants were blinded to the intervention. Secretin increased BAT glucose uptake (primary endpoint) compared to placebo by 57% (median (interquartile range, IQR), 0.82 (0.77) versus 0.59 (0.53) μmol per 100 g per min, 95% confidence interval (CI) (0.09, 0.89), P = 0.002, effect size r = 0.570), while BAT perfusion remained unchanged (mean (s.d.) 4.73 (1.82) versus 6.14 (3.05) ml per 100 g per min, 95%CI (-2.91, 0.07), P = 0.063, effect size d = -0.549) (n = 15). Whole body energy expenditure increased by 2% (P = 0.011) (n = 15). Secretin attenuated blood-oxygen level-dependent activity (primary endpoint) in brain reward circuits during food cue tasks (significance level false discovery rate corrected at P = 0.05) (n = 14). Caloric intake did not significantly change, but motivation to refeed after a meal was delayed by 39 min (P = 0.039) (n = 14). No adverse effects were detected. Here we show in humans that secretin activates BAT, reduces central responses to appetizing food and delays the motivation to refeed after a meal. This suggests that meal-induced, secretin-mediated BAT activation is relevant in the control of food intake in humans. As obesity is increasing worldwide, this appetite regulating axis offers new possibilities for clinical research in treating obesity.

Background Low serum progesterone on the day of frozen embryo transfer (FET) is associated with diminished pregnancy rates in artificial endometrium preparation cycles, but there is no consensus on whether strengthened luteal phase support (LPS) benefits patients with low progesterone on the FET day in artificial cycles. This single-centre, large-sample retrospective trial was designed to investigate the contribution of strengthened LPS to pregnancy outcomes for groups with low progesterone levels on the FET day in artificial endometrium preparation cycles. Methods Women who had undergone the first artificial endometrium preparation cycle after a freeze-all protocol in our clinic from 2016 to 2018 were classified into two groups depending on their serum progesterone levels on the FET day. Routine LPS was administered to group B (P ≥ 10.0 ng/ml on the FET day, n = 1261), and strengthened LPS (routine LPS+ im P 40 mg daily) was administered to group A (P n = 1295). The primary endpoint was the live birth rate, and the secondary endpoints were clinical pregnancy, miscarriage and neonatal outcomes. Results The results showed that the clinical pregnancy rate was significantly lower in group A than in group B (48.4% vs 53.2%, adjusted risk ratio (aRR) 0.81, 95% confidence interval (CI) 0.68, 0.96), whereas miscarriage rates were similar between the two groups (16.0% vs 14.7%, aRR 1.09, 95% CI 0.77, 1.54). The live birth rate was slightly lower in group A than in group B (39.5% vs 43.3%, aRR 0.84, 95% CI 0.70, 1.0). Birthweights and other neonatal outcomes were similar between the two groups (P > 0.05). Conclusions The results indicated that the serum progesterone level on the FET day was one of the risk factors predicting the chances of pregnancy in artificial endometrium preparation cycles, and strengthened LPS in patients with low progesterone on the FET day might help to provide a reasonable pregnancy outcome in artificial cycles, although further prospective evidence is needed to confirm this possibility.

Objectives We aimed to compare the efficiency of the CapitalBioMycobacterium real-time polymerase chain reaction (PCR) detection test with the standard Xpert MTB/RIF assay for the diagnosis of tuberculous meningitis (TBM). Methods We analyzed cerebrospinal fluid (CSF) from 163 patients with suspected TBM that were collected between January 1, 2018, and December 31, 2019. For both tests, we determined the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and area under the curve (AUC). Next, we compared the diagnostic accuracy of the two techniques using clinical diagnosis as a reference standard. Results The sensitivity, specificity, PPV, NPV, and AUC, of the CapitalBio Mycobacterium detection test were 48.5%, 100%, 100%, 29.6%, and 0.74, respectively, when used for the diagnosis of TBM. In comparison, the Xpert MTB/RIF assay returned values of 47.0%, 100%, 100%, 29.0%, and 0.74, respectively. Our analysis showed that the diagnostic accuracies of the CapitalBio Mycobacterium detection test and the Xpert MTB/RIF assay were very similar; the accuracy of both tests for detecting mycobacteria was significantly higher than that associated with acid­fast staining. Conclusions The CapitalBio Mycobacterium real-time PCR detection test has moderate sensitivity and very high specificity for TBM; results are very similar to those generated by the Xpert MTB/RIF assay. We recommend that the CapitalBio PCR test should be used as an initial screening method for TB.

Background Colorectal cancer (CRC) is one of the most malignant cancer worldwide, which leads to a high incidence and mortality. The molecular mechanism in CRC is still limited. The aim of this study was to identify hub genes and its related function in CRC. Methods The expression dataset (GSE44076) was downloaded from Gene Expression Omnibus (GEO) and differentially expressed genes (DEGs) analysis was done using R ‘limma’ packages. Weighted gene co-expression network analysis (WGCNA) was done and tumor-specific modules were picked up for Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. The hub gene was selected with higher inter-connectivity. Expression levels of TTI1 were verified by in clinical CRC tissues. The cell counting kit-8 (CCK-8) assay was to measure the proliferative ability of TTI1. Results Eight hundred and eight up-regulated and 929 down-regulated DEGs were screened out. Up-regulated genes enriched in cell proliferation and down-regulated genes enriched in oxidation-reduction process. After WGCNA, the yellow module was found to be the most significant tumor-specific module. Function analysis showed genes in the yellow module enriched in oxidation-reduction, cell proliferation and extracellular matrix (ECM)-receptor interaction. TTI1 was demonstrated as the hub gene. Real-time quantitative reverse transcription((qRT-PCR) results showed TTI1 significantly expressed higher in CRC tissues than adjacent normal tissues. TTI1 dramatically correlated with proliferation in CRC. Conclusions These findings regarded TTI1 as a vital promoting factor in CRC development and provided a potential biomarker for CRC treatment.

Objectives: Early fetal demise (absence of cardiac activity in a visible fetus) is a very common event, but there are no reliable biomarkers to predict it. The purpose of the study was to assess the association of platelet parameters with early fetal demise. Methods: In this case-control study, we included women with normal deliveries or those ultrasound diagnosed as early fetal demise. For those who were identified with early fetal demise, the platelet parameters were analyzed before the ultrasound diagnosis, which is based on the absence of either an embryo within a gestational sac or cardiac activity in a visible embryo in the 5-10 weeks of gestation. The association between the risk of early fetal demise with the women's mean platelet volume (MPV) and platelet counts was calculated by logistic regression. Duplicate measurements of platelet aggregation were performed with VerifyNow. Results: In total, 99 women identified with early fetal demise and 170 women who had an uncomplicated pregnancy with normal delivery from January 2017 and August 2020 were included in the study. We found that platelet counts in the early fetal demise group were significantly higher than healthy pregnancies. In addition, platelet reactivity is higher in the normal delivery group than those in early fetal demise group (p < .05). High levels of platelet counts resulted in an adjusted odds ratio (OR) of 2.075 (95% confidence interval [95% CI], 1.215–3.544; p = .008) for early fetal demise. Conclusions: Increased platelet counts in the first trimester may be a predictor for the risk of early fetal demise.

Previous studies have confirmed that miR‐195 expression is increased in cardiac hypertrophy, and the bioinformatics website predicted by Targetscan software shows that miR‐195 can directly target CACNB1, KCNJ2 and KCND3 to regulate Cavβ1, Kir2.1 and Kv4.3 proteins expression. The purpose of this study is to confirm the role of miR‐195 in arrhythmia caused by cardiac hypertrophy. The protein levels of Cavβ1, Kir2.1 and Kv4.3 in myocardium of HF mice were decreased. After miR‐195 was overexpressed in neonatal mice cardiomyocytes, the expression of ANP, BNP and β‐MHC was up‐regulated, and miR‐195 inhibitor reversed this phenomenon. Overexpression of miR‐195 reduced the estimated cardiac function of EF% and FS% in wild‐type (WT) mice. Transmission electron microscopy showed that the ultrastructure of cardiac tissues was damaged after miR‐195 overexpression by lentivirus in mice. miR‐195 overexpression increased the likelihood of arrhythmia induction and duration of arrhythmia in WT mice. Lenti‐miR‐195 inhibitor carried by lentivirus can reverse the decreased EF% and FS%, the increased incidence of arrhythmia and prolonged duration of arrhythmia induced by TAC in mice. After miR‐195 treatment, the protein expressions of Cavβ1, Kir2.1 and Kv4.3 were decreased in mice. The results were consistent at animal and cellular levels, respectively. Luciferase assay results showed that miR‐195 may directly target CACNB1, KCNJ2 and KCND3 to regulate the expression of Cavβ1, Kir2.1 and Kv4.3 proteins. MiR‐195 is involved in arrhythmia caused by cardiac hypertrophy by inhibiting Cavβ1, Kir2.1 and Kv4.3.

Paraneoplastic neurological syndromes (PNS) are rare disorders affecting any part of the central, peripheral or autonomic nervous system that occur in association with cancer. Among cancer patients, less than 1% overall develop PNS. Anti-SOX1 antibodies' positive paraneoplastic neurological disorders are rare and are usually associated with small cell lung cancer (SCLC). Here, we report a case of a 61-year-old male patient who presented with an unusual anti-SOX1 positive PNS. The right tibialis anterior showed noticeable low-amplitude motor unit potentials and high amplitude motor potentials in electrodiagnostic study, suggesting the presence of Lambert-Eaton myasthenic syndrome (LEMS). Typical MRI and PET-CT found a hyperintense lesion with contrast enhancement in the thorax in front of 5-6 centrum of vertebrae, and thoracoscopic biopsy revealed pathological findings for SCLC. The patient underwent several lines of chemotherapy and radiotherapy and survived for 15 months after the diagnosis of SCLC.

The cardiac benefits of gastrointestinal hormones have been of interest in recent years. The aim of this study was to explore the myocardial and renal effects of the gastrointestinal hormone secretin in the GUTBAT trial (NCT03290846). A placebo-controlled crossover study was conducted on 15 healthy males in fasting conditions, where subjects were blinded to the intervention. Myocardial glucose uptake was measured with [F-18]2-fluoro-2-deoxy-o-glucose ([F-18]FDG) positron emission tomography. Kidney function was measured with [F-18]FDG renal clearance and estimated glomerular filtration rate (eGFR). Secretin increased myocardial glucose uptake compared with placebo (secretin vs. placebo, means +/- SD, 15.5 +/- 7.4 vs. 9.7 +/- 4.9 gmol/100 g/min, 95% confidence interval (CI) [2.2, 9.4], P = 0.004). Secretin also increased [F-18]FDG renal clearance (44.5 +/- 5.4 vs. 39.5 8.5 mL/min, 95%CI [1.9, 8.1], P = 0.004), and eGFR was significantly increased from baseline after secretin, compared with placebo (17.8 +/- 9.8 vs. 6.0 +/- 5.2 Delta mL/min/1.73 m(2),( ) 95%CI [6.0, 17.6], P = 0.001). Our results implicate that secretin increases heart work and renal filtration, making it an interesting drug candidate for future studies in heart and kidney failure. NEW & NOTEWORTHY Secretin increases myocardial glucose uptake compared with placebo, supporting a previously proposed inotropic effect. Secretin also increased renal filtration rate.

Objective: Using three-dimensional speckle-tracking echocardiography (3D-STE), we aimed to evaluate left ventricular (LV) function in type 2 diabetes mellitus (T2DM) patients with non-alcoholic fatty liver disease (NAFLD). Methods: In total, 97 T2DM patients were categorized into three groups based on hepatic ultrasonography: group A (those without NAFLD, n=30), group B (those with mild NAFLD, n=32), and group C (those with moderate-to-severe NAFLD, n=35). Our conventional echocardiographic parameters included transmitral peak early and late diastolic velocity (E and A), septal and lateral early (e') mitral annular diastolic tissue velocities, and left atrial maximum volume index (LAVImax). LV end-diastolic and -systolic volume, LV mass index (LVMI), and LV ejection fraction were measured using real-time three-dimensional echocardiography. The 3D-STE parameters included LV global radial strain (GRS), global longitudinal strain (GLS), global area strain (GAS), and global circumferential strain (GCS). Results: Our results showed that in group C, GCS, GRS, GLS, GAS, and septal and lateral e' velocity decreased, whereas average E/e' and LAVImax increased compared to groups B and A (p

Background: Oral progestin has been used to prevent premature ovulation during follicle stimulation protocols performed in combination with a freeze-only strategy. However, no studies have determined how oral progestin clinically compares to gonadotropin-releasing hormone (GnRH) antagonists in women with normal ovulation. This study aimed to compare the efficacy and safety of controlled ovarian stimulation between progestin-primed ovarian stimulation (PPOS) protocol and GnRH antagonist (GnRH-ant) protocol.Methods: Young women with infertility and normal ovarian reserve who underwent in vitro fertilisation (IVF) treatments were screened and randomly allocated to the PPOS or GnRH-ant group. Women in the PPOS group underwent freeze-all and delayed embryo transfer, whilst fresh embryo transfer was preferred for those in the GnRH-ant group. The primary endpoint was the cumulative live birth rate (CLBR). Secondary endpoints included the incidence of premature luteinising hormone (LH) surge and the number of viable embryos.Results: CLBRs were similar in the PPOS and GnRH-ant group (55.75% vs. 52.87%, respectively, P > 0.05). No premature LH surge was observed during ovarian stimulation in the PPOS group, although six (3.45%) cases were observed in the GnRH-ant group. On the trigger day, LH level was lower in the PPOS group than in the GnRH-ant group (2.30 ± 1.78 mIU/ml vs. 3.66 ± 3.52 mIU/ml, P < 0.01). There were no differences in the number of retrieved oocytes, mature oocytes, or viable embryos between the two groups. Other clinical outcomes including implantation rates (37.27% vs. 36.77%), clinical pregnancy rates (55.75% vs. 55.89%), and miscarriage rates (12.28% vs. 13.76%) were comparable between the PPOS group and GnRH-ant group (P > 0.05). There was also no significant differences in newborn weights for singleton or twin births between the two groups (P > 0.05).Conclusion: Live birth outcomes are similar for PPOS and GnRH antagonist protocols in women with normal ovarian reserve. PPOS is likely to play a promising role in the freeze-only strategy given its simplicity and convenience for the patient. Trial registration: This trial was registered in the China Clinical Trial Registry on September 6, 2018 (number: ChiCTR1800018246).

Laughter is a contagious prosocial signal that conveys bonding motivation; adult crying conversely communicates desire for social proximity by signalling distress. Endogenous mu-opioid receptors (MORs) modulate sociability in humans and non-human primates. In this combined PET-fMRI study (n=17) we tested whether central MOR tone is associated with regional brain responses to social signals of laughter and crying sounds. MOR availability was measured with positron emission tomography using high-affinity agonist radioligand [11C]carfentanil. Haemodynamic responses to social laughter and crying sounds were measured using functional magnetic resonance imaging (fMRI). Social laughter evoked activation in the auditory cortex, insula, cingulate cortex, amygdala, primary and secondary somatosensory cortex, primary and secondary motor cortex; crying sounds led to more restricted activation in auditory cortex and nearby areas. MOR availability was negatively correlated with the haemodynamic responses to social laughter in primary and secondary somatosensory cortex, primary and secondary motor cortex, posterior insula, posterior cingulate cortex, precuneus, cuneus, temporal gyri, and lingual gyrus. For crying-evoked activations, MOR availability was negatively correlated with medial and lateral prefrontal haemodynamic responses. Altogether our findings highlight the role of MOR system in modulating acute brain responses to both positive and negative social signals.

Sepsis, with its high morbidity and mortality, is a difficult problem in critical care medicine. The purpose of this study is to investigate the involvement of GRB2-associated binding protein 1 (GAB1) in septic lung injury. Lipopolysaccharide (LPS)-induced mouse model and A549 cell model were used to simulate septic lung injury. Haematoxylin and eosin (H&E) staining was used to observe the pathological changes. The terminal-deoxynucleotidyl transferase/(TdT)-mediated dUTP-biotin nick end labelling (TUNEL) staining and flow cytometry were used to detect apoptosis. The levels of inflammatory factors in the bronchoalveolar lavage fluid (BALF) were determined by enzyme-linked immunosorbent assay (ELISA). In LPS-induced sepsis mice, GAB1 expression was markedly reduced, and GAB1 overexpression significantly attenuated cell apoptosis and decreased levels of macrophages, neutrophils, and inflammatory factors in the BALF. Our results also demonstrated that GAB1 overexpression significantly reduced LPS-induced apoptosis and inflammation of A549 cells. More importantly, GAB1 overexpression significantly inhibited the Toll-like receptor/ NFkappaB (TLR4/NF-κB) pathway, while silencing GAB1 significantly activated the TLR4/NF-κB pathway and induced apoptosis and increased expression of inflammatory factors. However, the TLR4 inhibitor TAK-242 eliminated the effect of GAB1 silencing on A549. In conclusion, GAB1 is a key regulator of sepsis by inhibiting TLR4/NF-κB mediated apoptosis and inflammation.

Case-based payment has extensively been adopted to replace the fee-for-service payment in China. This paper aims to assess the impacts of case-based payment reform on the providers' behaviour using cataract surgery as an example.A total of 400 cataract inpatients were sampled in a tertiary hospital. Data analysis consisted of descriptive statistics, Wilcoxon rank-sum test and Chi-square test.The number of routine preoperative laboratory tests and drugs significantly declined after the case-based payment reform (p 0.001). Healthcare providers significantly reduced the use frequency of systemic glucocorticoids (GCs) and antibiotics, adjuvant drugs, multiple antibiotic eye drops, generic drugs in cataract surgery after reform (p 0.001), and they reduced non-ophthalmic medications after reform (p 0.01). Notably, all patients were prescribed GC eye drops, antibiotic eye drops, and original drugs in both groups. Moreover, the preoperative, postoperative, and total length of stay (LOS) declined after the reform (p 0.001). Nonetheless, no significant difference was noted in the care quality between the two group.The case-based payment reform decreased the intensity of care by reducing unnecessary drugs and retaining necessary drugs on cataract surgery. Besides, the LOS was shortened. Further, an impaired care quality was not witnessed, however, cost-shifting warrants further attention.

Objective findings of brain injury or dysfunction are typically lacking in mild traumatic brain injury (MTBI) despite prolonged post-concussion symptoms in some patients. Thus, there is a need for objective biomarkers of MTBI that reflect altered brain physiology underlying subjective symptoms. We have previously reported increased attention to threat-related stimuli in subjects with MTBI, suggesting a physiological vulnerability to depression. Vulnerability to depression has been linked with relatively greater activity of the right than left frontal cortex reflected in inverse pattern in frontal alpha with greater power on the left than right. We investigated whether patients with previous MTBI show this pattern of frontal activity reflected in more negative frontal alpha asymmetry (FAA) scores. Furthermore, in search for potential biomarkers of MTBI, we created a novel index, emotional modulation of FAA (eFAA) and investigated whether it correlates with subjective symptoms. EEG was recorded while subjects with previous MTBI and controls performed a computer-based reaction time task integrating different cognitive executive functions and containing either threat-related or emotionally neutral visual stimuli. Post-concussion symptoms and depression were assessed using the Rivermead Post-Concussion Symptoms Questionnaire (RPQ) and Beck’s depression inventory (BDI). Task-induced FAA was assessed and eFAA calculated by subtracting FAA in the context of neutral stimuli from FAA in the context of emotional stimuli. The MTBI group showed FAA scores reflecting relatively greater right-sided frontal activity compared to healthy controls. eFAA differentiated the symptomatic MTBI from non-symptomatic MTBI group and from healthy controls. eFAA also correlated with RPQ and BDI scores. In conclusion, FAA pattern previously linked with vulnerability to depression, was observed in patients with previous MTBI. Furthermore, eFAA has potential as a biomarker of altered affective brain functions in MTBI. publishedVersion

Background The payment card (PC) format and the open-ended (OE) format are common methods in eliciting willingness-to-pay (WTP) of one additional quality-adjusted life year (QALY). The aim of this research is to compare these two formats in eliciting the monetary value of a QALY. Methods A contingent valuation survey was carried out using a pre-designed questionnaire with various hypothetical scenarios. The difference between the PC and the OE formats was evaluated by a two-sample equality test. Furthermore, generalized linear models were carried out to control observed heterogeneity and to test theoretical validity. Results In total, 461 individuals were involved, among whom 235 (51%) answered the PC question, while 226 (49%) answered the OE question. Excluding zero response, the mean WTP values of these two formats for different scenarios varied dramatically, which was from 13,278 to 280,177 RMB for the PC, 18,119 to 620,913 RMB for the OE. The OE format tended to elicit lower values for less serious condition and higher values for more serious condition. However, equality test of mean and median demonstrated insignificant difference of these two formats for all scenarios. For both OE and PC format, most variables were found to have significant effect on the value of WTP/QALY. Moreover, joint estimation indicated a statistically significant positive effect on the OE results. Further analysis demonstrated that the imbalanced zero response distribution caused the main difference of these two formats. Conclusions This research indicated insignificantly different WTP/QALY estimates of the PC format and OE format with the grouped data whereas significantly higher estimates of the OE format from the pooled data. These two formats were found to be valid. More research about the difference and the validity of various WTP eliciting methods would be recommended for a robust estimation of WTP/QALY.

Background: Inflammation might play a critical role in the pathogenesis and progression of Philadelphia-negative myeloproliferative neoplasms (Ph−MPNs) with elevated inflammatory cytokines in peripheral blood (PB). However, the inflammatory status inside the bone marrow (BM), which is the place of malignancy origin and important microenvironment of neoplasm evolution, has not yet been elucidated.Methods: Inflammatory cytokine profiles in PB and BM of 24 Ph-MPNs patients were measured by a multiplex quantitative inflammation array. Cytokines that correlated between PB and BM were selected and then validated by ELISA in a separate cohort of 52 MPN patients. Furthermore, a panel of cytokines was identified and examined for potential application as non-invasive markers for the diagnosis and prediction of fibrosis progress of MPN subtypes.Results: The levels of G-CSF, I-309, IL-1β, IL-1ra, IL-12p40, IL-15, IL-16, M-CSF, MIG, PDGF-BB, and TIMP-1 in BM supernatants were significantly higher than those in PB (all p < 0.05). Linear correlations between BM and PB levels were found in 13 cytokines, including BLC, Eotaxin-2, I-309, sICAM-1, IL-15, M-CSF, MIP-1α, MIP-1δ, RANTES, TIMP-1, TIMP-2, sTNFRI, and sTNFRII (all R > 0.4 and p < 0.05). Levels of BLC, Eotaxin-2, M-CSF, and TIMP-1 in PB were significantly different from those in health controls (all p < 0.05). In PB, levels of TIMP-1 and Eotaxin-2 in essential thrombocythemia (ET) group were significantly lower than those in groups of prefibrotic primary myelofibrosis (pre-PMF) [TIMP-1: 685.2 (322.2–1,229) ng/ml vs. 1,369 (1,175–1,497) ng/ml, p = 0.0221; Eotaxin-2: 531.4 (317.9–756.6) pg/ml vs. 942.4 (699.3–1,474) pg/ml, p = 0.0393] and primary myelofibrosis (PMF) [TIMP-1: 685.2 (322.2–1229) ng/ml vs. 1,365 (1,115–1,681) ng/ml, p = 0.0043; Eotaxin-2: 531.4 (317.9–756.6) pg/ml vs. 1,010 (818–1,556) pg/ml, p = 0.0030]. The level of TIMP-1 in myelofibrosis (MF) >1 group was significantly higher than that in MF ≤ 1 group.Conclusion: Abnormal inflammatory status is present in MPN, especially in its BM microenvironment. Consistency between PB and BM levels was found in multiple inflammatory cytokines. Circulating cytokine levels of BLC, M-CSF, Eotaxin-2, and TIMP-1 reflected inflammation inside BM niche, suggesting potential diagnostic value for MPN subtypes and prognostic value for fibrosis progression.

Background β-Catenin/T-cell factor 4 (TCF4) signaling is enhanced in ischemic heart disease in which ventricular tachycardia (VT)/ventricular fibrillation occurs frequently. How this signaling links to arrhythmogenesis remains unclear. Objective The purpose of this study was to investigate the role of β-catenin gain of function in the development of arrhythmia. Methods A mouse model with a conditional deletion of CTNNB1 exon 3 resulting in cardiac exon 3–deleted and stabilized β-catenin (β-catΔE3) was used to determine the role of β-catenin gain of function in the regulation of cardiac rhythm. Results Western blotting showed β-catΔE3 expression and significantly decreased NaV1.5 protein in CTNNB1 E3−/− and CTNNB1 E3+/− mouse hearts. Real-time qRT-PCR revealed significantly decreased NaV1.5 messenger RNA with no changes in Na+ channel β1 to β4 expression in these hearts. Immunofluorescence revealed accumulation of β-catΔE3 in the nuclei of CTNNB1 E3−/− cardiomyocytes. Immunohistochemistry demonstrated nuclear localization of β-catenin in cardiomyocytes, which was associated with significantly decreased NaV1.5 messenger RNA in human ischemic hearts. Immunoprecipitation revealed that β-catΔE3 interacted with TCF4 in CTNNB1 E3−/− cardiomyocytes. Whole-cell recordings showed that Na+ currents and depolarization and amplitude of action potentials were significantly decreased in CTNNB1 E3−/− ventricular myocytes. Electrocardiographic recordings demonstrated that in mice with cardiac CTNNB1 E3−/−, the QRS complex was prolonged and VT was induced by the Na+ channel blocker flecainide. However, cardiac function, as determined by echocardiography and heart/body weight ratios, remained unchanged. Conclusion Enhancement of β-catenin/TCF4 signaling led to the prolongation of the QRS complex and increase in susceptibility to VT by suppression of NaV1.5 expression and Na+ channel activity in mice.

Background The comparative performance of the 3-level EuroQol 5-dimension and Short Form 6-dimension (SF-6D) has been investigated in patients with low back pain (LBP). The aim of this study was to explore the performance including agreement, convergent validity as well as known-groups validity of the 5-level EuroQol 5-dimension (EQ-5D-5 L) and SF-6D in Chinese patients with LBP. Methods Individuals with LBP were recruited from a large tertiary hospital in China. All subjects were interviewed using a standardized questionnaire including the EQ-5D-5 L, 36-item Short Form Health Survey (SF-36), the Oswestry questionnaire and socio-demographic questions from June 2017 to October 2017. Agreement was evaluated by intra-class correlation coefficients (ICCs) and Bland–Altman plots. Spearman’s rank correlation coefficients were applied to assess convergent validity. For known-groups validity, the Mann–Whitney U test or Kruskal-Wallis H test were used, effect size (ES) and relative efficiency (RE) were also reported. The efficiency of detecting clinically relevant differences was measured by receiver operating characteristic (ROC) curves between pre-specified groups based on Oswestry disability index (ODI), ES and RE statistics were also reported. Results Two hundred seventy-two LBP patients (age 38.1, 38% female) took part in the study. Agreement between the EQ-5D-5 L and the SF-6D was good (ICC 0.661) but with systematic discrepancy in the Bland–Altman plots. In terms of convergent validity, most priori assumptions were more related to EQ-5D-5 L than SF-6D, but MCS derived from SF-36 was more associated with SF-6D. EQ-5D-5 L demonstrated better performance for most groups except location and general health grouped by the general assessment of health item from SF-36. Furthermore, when we applied ODI as external indicator of health status, the area under the ROC curve for EQ-5D-5 L was larger than that for the SF-6D (0.892, 95% CI 0.853 to 0.931 versus 0.822, 95% CI 0.771 to 0.873), the effect size was 0.63 for EQ-5D-5 L and 0.44 for SF-6D, and it was proved that EQ-5D-5 L was 42% more efficient than SF-6D at detecting differences measured by ODI. Conclusions Both EQ-5D-5 L and SF-6D are valid measures for LBP patients. Even though these two measures had good agreement, they cannot be used interchangeably. The EQ-5D-5 L was superior to the SF-6D in Chinese low back pain patients in this research, with stronger correlation to ODI and better known-groups validity. Further study needs to evaluate other factors, such as responsiveness and reliability.

The prognostic role of c-Met expression in patients with head and neck cancer were controversial among different studies. Thus, we performed a meta-analysis to evaluate the relationships between c-Met expression and survival and clinical parameters of head and neck cancer patients. Summary hazard ratio (HR) and 95% confidence intervals (CIs) were calculated to analyze the correlations between c-Met expression and overall survival (OS), and disease-free survival (DFS). Furthermore, odds ratios (ORs) and 95% CIs were used to describe the relationships between c-Met expression and different clinicopathological parameters. A total of 2417 patients from 19 studies were enrolled in the final analysis. The results showed that patients with higher c-Met expression had a poor OS (HR, 1.65; 95% CI, 1.20-2.27) and DFS (HR, 1.48; 95% CI, 0.99-2.20). In addition, c-Met expression was associated with the N classification of patients with head and neck cancer. These results suggested that c-Met expression was a risk factor for head and neck cancer, and increased c-Met expression would be a predictor of a poorer prognosis for the patients.

Background Allograft rejection and infection are the major sources of morbidity and mortality after heart transplant. Early differential diagnosis is clinically crucial but difficult. The aim of the study was to examine serum cytokine profiles associated with each entity and whether such profiles could help to differentiate between them. Methods Heart allografts from Wistar rats were transplanted to Lewis rats as described by Yokoyama. Cardiac rejection and pulmonary bacterial infection were induced by Cyclosporine cessation and bacteria bronchus injection, and pathologically confirmed. Ninety serological cytokines profiles of the study objects were then simultaneously measured using a biotin label-based cytokine array. The fold change (FC) was used for relative cytokine concentration comparison analysis. Results Four cytokines in cardiac rejection group were significantly dysregulated as compared to health controls (β -Catenin, 0.51 FC; E-Selectin, 0.62 FC; IFN-gamma, 1.87 FC; and IL-13, 0.60 FC, respectively). In pulmonary infection animals, 11 cytokines were remarkably dysregulated in comparison with the control group (CINC-3, 0.57 FC; CNTF R alpha, 0.59 FC; E-Selectin, 0.58 FC; FSL1,0.62 FC; Hepassocin, 0.64 FC; IL-2, 0.26 FC; IL-13, 0.49 FC; NGFR, 0.57 FC; RAGE, 0.50 FC; TIMP-1, 0.49 FC; and IFN-gamma, 1.77 FC, respectively). Eleven cytokines were significantly up-regulated in cardiac rejection group comparing to the pulmonary infection animals (FSL1, 2.32FC; Fractalkine, 1.65FC; GFR alpha-1, 1.64FC; IL-2, 2.72FC; IL-5, 1.60FC; MMP-2, 1.71FC; NGFR, 2.25FC; TGF-beta1, 1.58FC; TGF-beta3, 1.58FC; Thrombospondin, 1.64FC, and TIMP-1, 1.52FC, respectively). Conclusions The current study illustrated the disease-specific serological cytokine profiles of allograft rejection and pulmonary bacterial infection after cardiac transplant. Such disease associated cytokine portraits might have the potential for early discrimination diagnosis.

Objective This study aimed to investigate the expression of long non-coding RNA (lncRNA) growth arrest-special transcript 5 (GAS5) in the serum of tuberculosis (TB) patients and discuss the mechanism of GAS5 in TB by establishing an in-vitro TB cell model. Methods Serum expressions of GAS5 and miR-18a-5p were determined by quantitative real-time PCR (qRT-PCR). The effects of GAS5 on macrophage cell viability and the inflammatory response after MTB infection were assessed by CCK-8 and ELISA. Luciferase reporter gene assay was applied to delve into the potential target gene of GAS5. Results The expression of GAS5 in TB patients was down-regulated, while miR-18a-5p was up-regulated, and the serum inflammatory factors were negatively correlated with the expression level of GAS5. MTB infection induced significant upregulation on the cell viability and inflammatory response but the acceleration effect could be rescued by GAS5-overexpression. Meanwhile, miR-18a-5p was recognized as the target gene of GAS5. Conclusion This study indicated that the expression level of GAS5 in the serum of TB patients was decreased, while in the cells infected with MTB, the down-regulated GAS5 might develop a role in facilitating the cell vitality and the inflammatory response by adsorbing miR-18a-5p in the form of molecular sponge.

Background: Diabetic cardiomyopathy has threatened the lives and health of more and more people. Growth differentiation factor 11 (GDF11) plays a crucial role within the cardiovascular system. Still, GDF11 was not clearly described in diabetic cardiomyopathy. Methods: Firstly, we used echocardiography to detect the heart function of mice. Secondly, we used qRT-PCR, western blot, CCK8 analysis, LIVE /DEAD and TUNEL analysis to evaluate cell viability and apoptosis, and then used dual-luciferase reporter assay, quantitation of m6A RNA methylation assay, RIP experiment and constructed cardiac-specific GDF11 knock-in mice to explore molecular mechanisms. Findings: Our preliminary results showed that GDF11 expression decreased in DCM mice. Exogenous GDF11 could mitigate cardiomyocyte apoptosis caused by high glucose. Mechanistically, GDF11 restrained CDR1as/Hippo signaling pathway, which was activated by high glucose. As a transcriptional factor of CDR1as, FOXO3 was identified to activate the Hippo signaling pathway. Notably, the total m6A level was downregulated in the cardiac tissue of DCM. ALKBH5 was upregulated in the cardiomyocytes of DCM mice and posttranscriptionally activated FOXO3 by m6A demethylation in an m6A-YTHDF2-dependent manner. Furthermore, we verified that GDF11 could inhibit ALKBH5-FOXO3-CDR1as/Hippo signaling by using the GDF11 cardiac-specific knock-in mice. Interpretation: In general, our results demonstrated that application of GDF11 or inhibition of ALKBH5-FOXO3-CDR1as/Hippo signaling pathway may be new strategies for use to treat DCM. Funding: This work was supported in part by the National Natural Science Foundation of China (Grants Nos.81670238 and 81970320). Declaration of Interest: The authors declare no competing interests. Ethical Approval: The Ethics Committee of Harbin Medical University approved this research.

Prophylactic antifungal therapy is widely adopted clinically for critical patients and effective in reducing the morbidity of invasive fungal infection and improves outcomes of those diagnosed patients; however, it is not associated with higher overall survival. As intestinal commensal fungi play a fundamental role in the host immune response in health and disease, we propose that antifungal therapy may eliminate intestinal fungi and aggravate another critical syndrome, sepsis. Here, with murine sepsis model, we found that antifungal therapy with fluconazole dismissed intestinal fungal burden and aggravated endotoxin-induced but no gram-positive bacteria-induced sepsis. Nevertheless, antifungal therapy did not exert its detrimental effect on germ-free mice. Moreover, colonizing more commensal fungi in the mouse intestine or administration of fungal cell wall component mannan protected the mice from endotoxin-induced sepsis. On the molecular level, we demonstrated that antifungal therapy aggravated endotoxin sepsis through promoting Gasdermin D cleavage in the distal small intestine. Intestinal colonization with commensal fungi inhibited Gasdermin D cleavage in response to lipopolysaccharide challenge. These findings show that intestinal fungi inhibit Gasdermin D-mediated pyroptosis and protect the mice from endotoxin-induced sepsis. This study demonstrates the protective role of intestinal fungi in the pathogenesis of endotoxin-induced sepsis in the laboratory. It will undoubtedly prompt us to study the relationship between antifungal therapy and sepsis in critical patients who are susceptible to endotoxin-induced sepsis in the future.

The objective of the present study was to determine whether the addition of inhaled desflurane is superior to remifentanil-propofol total intravenous anesthesia (TIVA) alone in patients undergoing laparoscopic gynecological surgery. A total of 60 patients who were scheduled to undergo laparoscopic gynecological surgery were prospectively enrolled and randomly allocated to receive either propofol-remifentanil (PR group; n=30) or combined propofol-remifentanil and low-dose desflurane (PRD group; n=30) for the maintenance of anesthesia. Hemodynamics [mean arterial pressure (MAP); heart rate (HR)], recovery parameters and complications were recorded. The results of the present study indicated that the addition of desflurane significantly reduced the amount of propofol and remifentanil that was administered in the PRD group, compared with that in the PR group. MAP and HR were significantly higher at T3 (5 min post-pneumoperitoneum), but significantly lower at T4 (removal of pneumoperitoneum needle) and T5 (post-operation immediately) in the PR group, compared with the PRD group. Moreover, MAP and HR were significantly altered at multiple time points within the PR group; however, they were relatively stable in the PRD group. There were no significant differences in the recovery parameters and complications between the two groups. In conclusion, combining low-dose desflurane with PR may represent an efficient anesthesia regimen to prevent the hemodynamic instability of TIVA in patients undergoing laparoscopic gynecological surgery.

Background To investigate the association between the CD14 –159C/T polymorphism and ischemic stroke (IS). Methods Relevant literature was searched by retrieving EMBASE, Web of Science, Chinese National Knowledge Infrastructure, and PubMed databases. R version 3.33 software was applied to calculate pooled odds ratios (ORs) and 95% confidence intervals (CIs). Results Seven qualified studies with a total of 2058 IS patients and 2123 controls were included. There was no significant association between the CD14 –159C/T polymorphism and IS risk in the total population (TT vs CC: OR = 0.84, 95% CI = 0.58–1.20; CT vs CC: OR = 0.96, 95% CI = 0.82–1.12; dominant model: OR = 1.02, 95% CI = 0.80–1.30; recessive model: OR = 0.82, 95% CI = 0.57–1.19). Similarly, subgroup analysis according to ethnicity and Hardy–Weinberg equilibrium also found no significant interrelation. Conclusion Our findings suggest that the CD14 –159C/T polymorphism does not contribute to the risk of IS. Well-designed studies with more subjects are required to further validate these results.

Gain of function LRRK2-G2019S is the most frequent mutation found in familial and sporadic Parkinson's disease. It is expected therefore that understanding the cellular function of LRRK2 will provide insight on the pathological mechanism not only of inherited Parkinson's, but also of sporadic Parkinson's, the more common form. Here, we show that constitutive LRRK2 activity controls nascent protein synthesis in rodent neurons. Specifically, pharmacological inhibition of LRRK2, Lrrk2 knockdown or Lrrk2 knockout, all lead to increased translation. In the rotenone model for sporadic Parkinson's, LRRK2 activity increases, dopaminergic neuron translation decreases, and the neurites atrophy. All are prevented by LRRK2 inhibitors. Moreover, in striatum and substantia nigra of rotenone treated rats, phosphorylation changes are observed on eIF2α-S52(↑), eIF2s2-S2(↓), and eEF2-T57(↑) in directions that signify protein synthesis arrest. Significantly, translation is reduced by 40% in fibroblasts from Parkinson's patients (G2019S and sporadic cases alike) and this is reversed upon LRRK2 inhibitor treatment. In cells from multiple system atrophy patients, translation is unchanged suggesting that repression of translation is specific to Parkinson's disease. These findings indicate that repression of translation is a proximal function of LRRK2 in Parkinson's pathology.

Background : Primary immune thrombocytopenia (ITP) is an autoimmune-mediated disorder characterized by decreased platelet count. Systemic lupus erythematosus (SLE) is also an autoimmune disease which thrombocytopenia is a common hematologic manifestation. Interleukin (IL)-1 family cytokines are major proinflammatory and immunoregulatory mediators. This study aimed to investigate the role of IL-1 cytokines in patients with ITP and SLE and the potential pathophysiologic mechanism to differentiate SLE-associated thrombocytopenia (SLE-TP) from ITP. Methods : Multiplex cytokine assay and real-time polymerase chain reaction (RT-PCR) were used to measure the IL-1 cytokines in 17 newly diagnosed ITP patients, 17 SLE-TP patients, 19 SLE patients without thrombocytopenia (SLE-NTP) and 10 healthy controls. Results : The serum levels of IL-1β, IL-18, IL-36α, IL-36β, IL-36γ and IL-33 were decreased significantly in ITP patients as compared with SLE-TP, SLE-NTP patients and healthy controls ( p

The intestinal microbiota is essential for the maintenance of the physiology of immune homeostasis. Dysbiosis has been described in some autoimmune diseases, however its role is still elusive in primary immune thrombocytopenia (ITP), which is one kind of autoimmune diseases. This study aimed to characterize the phylogenetic diversity of the fecal microbiota and its relationship with the platelet activation status in patients with ITP.The platelet activation status was assessed by 2 platelet markers, PAC-1 (antibody that recognizes the activated GPIIb/IIIa complex) and CD62p (Platelet surface P-selectin) by flow cytometry. Total DNA was extracted from fecal samples of ITP patients and healthy controls (HC). Sequencing the V4 hypervariable region of bacterial 16S rRNA genes was used to identify the changes in phylogenetic diversity and composition of the intestinal flora. The obtained sequencing reads were assigned to operational taxonomic units (OTUs, 97% sequence identity) and taxonomically classified to assess composition and diversity.The percentage of PAC-1+ platelets in ITP patients was higher than that in control group (p 0.001), The percentage of CD62p+ and PAC-1+CD62p+ platelets in ITP patients both higher than those in control group (p 0.001). At the phylum level, eight different phyla were identified in ITP individuals, with a majority of Bacteroidetes (45.96%) and Firmicutes (38.59%), followed by Proteobacteria (11.43%), Fusobacteria(1.29%), and Actinobacteria (1.22%). While in the Healthy volunteers, ten phyla were detected, with a predominance of Firmicutes (50.92%) and Bacteroidetes (34.26%), came before Proteobacteria (13.60%), and Actinobacteria (0.90%). The gut microbiota was skewed in ITP, with an increased proportion of Proteobacteria, Bacteroidetes and Bacteroidetes/Firmicutes ratio, a decreased proportion of Firmicutes compared with HC. Disease specific alterations in diversity was also identified, especially the potential markers (Anaerorhabdus, sutterella, Peptostreptococcaceae, Clostridium_XI and carnobacteriaceae, p 0.05) for ITP.The results suggested that the distinct microbiota dysbiosis in ITP characterized by alterations in biodiversity and composition, which could provide insights for diet therapy and fecal microbiota transplantation treatment to cure ITP. There might be somehow compensatory enhancement of platelet activation in ITP patients. And there is associate between platelet activation and intestinal microbiota in patients with ITP.

Peroral endoscopic myotomy (POEM) is another branch of DETT. This chapter systematically describes the indications and contraindications, standard procedures, modified POEM, complications, postoperative management and Effectiveness of POEM. In addition, the chapter presents endoscopic classifications for treatment decision, including the Ling classification, endoscopic classification of esophageal mucosal in achalasia and endoscopic classification of submucosal fibrosis.

Aims. To assess the maresin 1 (MaR1) contents in type 2 diabetic patients with or without diabetic foot ulcer and to analyze the association of MaR1 concentrations with several metabolism-related parameters. Methods. Plasma MaR1 concentrations were analyzed in 96 subjects with normal glucose tolerant (NC, n=43), type 2 diabetes (T2DM, n=40), or diabetic foot ulcer (DFU, n=13). The intravenous glucose tolerance test (IVGTT) and biochemical parameters were measured in all participants. Results. Plasma MaR1 concentrations were significant decreased in type 2 diabetes patient with or without DFU compared with NC (both P<0.001) and were lowest in DFU patients among these 3 groups. (DFU vs. T2DM, P<0.05). Plasma MaR1 concentrations were negatively correlated with BMI, waist circumference (Wc), waist hip ratio (WHR), systolic blood pressure (SBP), diastolic blood pressure (DBP), LDL-c, FPG, 2hPG, HbA1c, and homeostasis model assessment for insulin resistance (HOMA-IR) (all P<0.05) and were positively correlated with HDL-c, acute insulin response (AIR), area under the curve of the first-phase (0-10 min) insulin secretion (AUC), and homeostasis model assessment for beta-cell function (HOMA-β) (all P<0.05). After adjusting for age and sex, Wc, WHR, TG, FPG, 2hPG, HbA1c, HOMA-IR, AIR, AUC, and HOMA-β remain statistically significant (all P<0.05). Conclusions. Plasma MaR1 concentration were decreased in T2DM with or without DFUs and were the lowest in DFU patients. The decreased plasma MaR1 strongly associated with obesity, impaired glucose and lipid metabolism, reduced first-phase of glucose-stimulated insulin secretion, and enhanced insulin resistance.

This work presents a new multi-aspect user-interest model for recommender systems to improve recommendation and prediction accuracy. We introduce the overall user satisfaction for a product to build a user-interest profile by computing the user-interest levels from multi-aspect reviews. A domain emotional dictionary is built to overcome the gap in quantity between negative and positive words for sentiment polarity analysis. A sentiment analysis model is designed to characterize the users’ sentiment polarity and strength based on uncertainty theory and the domain emotional dictionary. Accordingly, a new multi-aspect user-interest model is proposed by considering the sentiment analysis model with the user-interest profile. Then, our proposed model is applied to recommender systems and experimentally tested on five products of different categories from three e-commerce websites. Our model not only outperforms the traditional and state-of-the-art models on rating prediction tasks but also improves the recommendation accuracy in multiple domains.

Glioblastoma (GBM) is an extremely challenging malignancy to treat. Although temozolomide (TMZ) is a standard treatment regimen, many patients with GBM develop chemoresistance. The aim of this study was to identify a DNA repair-related gene signature to better stratify patients treated with TMZ.We selected 89 cases of primary GBM (pGBM) from the Chinese Glioma Genome Atlas RNA-seq dataset as the training cohort, whereas The Cancer Genome Atlas RNA-seq and Gene Set Enrichment (GSE) 16011 mRNA array sets were used as validation cohorts. Regression analysis and linear risk score assessment were performed to build a DNA repair-related signature. We used Kaplan-Meier analysis to evaluate the predictive value of the signature for overall survival (OS) in the different groups. Multivariate Cox regression analysis was used to determine whether the 5-gene signature could independently predict OS.Using our 5-gene signature panel of APEX1, APRT, PARP2, PMS2L2, and POLR2L, we divided patients with pGBM into high- and low-risk groups. Patients with a low-risk score were predicted to have favorable survival and greater benefit from TMZ therapy compared with patients from the high-risk group (P0.05). Moreover, receiver operating characteristic curves showed that the multigene signature was the most sensitive and specific model for survival prediction (P0.05).Among patients with pGBM, classification based on a risk score determined using a 5-gene panel indicated different OS and reaction to TMZ. The findings in this study demonstrate that this unique 5-gene signature could be a novel model to predict OS and provide accurate therapy for patients with pGBM.

Background/Aims: Because the prevalence of age-related cardiac impairment increases as the human lifespan increases, it is important to combat the effects of aging. Recently, the cardiac M3 muscarinic acetylcholine receptor (M3-mAChR) has been demonstrated to play important roles in cardiac development and in the pathogenesis of cardiac diseases. However, the role of M3-mAChR in aging remains largely unknown. Therefore, the aim of this study was to investigate the involvement of M3-mAChR in the progression of cardiac aging. Methods: We established a cardiac aging model in mice through subcutaneous injection with D-galactose at a dose of 100 mg/kg/day for 6 weeks. D-galactose was also used to induce aging in primary cultured neonatal mouse cardiomyocytes. The myocardium from mice was stained with hematoxylin and eosin for histological analysis. The protein expression levels of p53 and p21 were determined using western blotting. The mRNA and protein expression levels of M3-mAChR, caspase-1, and interleukin (IL)-1β were determined using real-time PCR, immunohistochemical staining, and western blotting. Results: The expression of M3-mAChR was down-regulated in the myocardium from aged mice and D-galactose-treated mice, while the expression levels of caspase-1 and its downstream molecule IL-1β were significantly increased. The M3-mAChR agonist choline reduced the increase in caspase-1 in cardiomyocytes induced by D-galactose, which was reversed by the M3-mAChR antagonist 4-DAMP. Moreover, 4-DAMP promoted D-galactose-induced cardiomyocyte aging, which was attenuated by a caspase-1 inhibitor. Conclusion: Activation of M3-mAChR delayed cardiac aging by inhibiting the caspase-1/IL-1β signaling pathway.

The human papillomavirus (HPV) vaccine plays an important role in preventing a series of diseases caused by HPV. Recent studies have shown that as a primary prevention measure, it can considerably prevent HPV infection and HPV-associated cervical cancer. However, studies on the safety, efficacy, and coverage of the HPV vaccine remain insufficient, especially in developing countries. Therefore, in this review, we outlined the recent studies of the HPV vaccine in terms of immunogenicity, safety, efficacy, latest vaccination concepts, and strategies. This review may provide a theoretical basis for use of the HPV vaccine.

The purpose of this research is to perform a systematic review and meta-analysis to compare effectiveness of premixed insulin (PM) and long-acting insulin (LA) based on cohort studies. Embase, Pubmed, Web of Science, Clinical.gov , and Opengray were searched. We included all cohort studies comparing the effectiveness of PM with LA on intermediate- or long-term outcomes. The weighted mean difference (WMD) was recorded for intermediate outcomes, and the risk ratio (RR) estimates were combined and weighted to produce pooled RR for long-term outcomes. Subgroup analysis was conducted by different insulin type and population. Eight studies involving 95,415 patients were included, in which six studies were used for quantitative analysis. Follow-up duration ranged from 6 months to 5 years. The meta-analysis indicated a comparable effect of PM and LA on the mean reduction in hemoglobin A1c (HbA1c) (WMD = − 0.03% [95% CI − 0.12–0.07]). Less fasting plasma glucose (FPG) declines were noticed with PM than LA (0.11 mmol/L [95% CI 0.03–0.18]). There was not statistically significant difference for post-prandial glucose (WMD = − 0.61 mmol/L [95% CI [− 1.49–0.27]). PM was associated with further weight gain of 0.67 kg [95% CI 0.60–0.74] and more insulin consumption (WMD = 11.72 U/day [95% CI 8.02–15.43]. The rates of hypoglycemia events were low but varied considerably. There was no significant difference in the effectiveness of PM and LA in real-world setting on HbA1c reduction, although PM was related with less FPG reductions, slight weight gain, and more insulin consumptions. Future real-world studies should concern about balanced oral hypoglycemic agents regimens between insulin cohorts and other potential confounding factors and assess relevant complications and death rate.

OBJECTIVES To assess right atrium (RA) function of patients with systemic lupus erythematosus (SLE) and pulmonary artery hypertension (PAH) by 2-dimensional speckle-tracking echocardiography. METHODS Thirty matched healthy adults were selected as group A. Then, 102 patients with SLE were divided into 3 groups according to the severity of PAH. Group B included 37 patients without PAH (pulmonary artery [PA] systolic pressure ≤ 30 mm Hg); group C included 34 patients with PAH (PA systolic pressure of 30-50 mm Hg); and group D included 31 patients with PAH (PA systolic pressure ≥ 50 mm Hg). Parameters evaluated included RA maximum volume, minimum volume, preatrial contraction volume, passive ejection fraction (EF), and active EF. The global peak longitudinal systolic strain rate and early and late diastolic strain rates of the RA were obtained by 2-dimensional speckle-tracking echocardiography. RESULTS No significant differences were found in all parameters between groups B and A (P > .05). The RA maximum volume, minimum volume, preatrial contraction volume, active EF, and late diastolic strain rate in groups C and D were significantly increased compared with those in groups A and B, and the parameters in group D were significantly higher than those in group C (P

High-fidelity two-qubit gates are essential for the realization of large-scale quantum computation and simulation. Tunable coupler design is used to reduce the problem of parasitic coupling and frequency crowding in many-qubit systems and thus thought to be advantageous. Here we design an extensible 5-qubit system in which center transmon qubit can couple to every four near-neighboring qubits via a capacitive tunable coupler and experimentally demonstrate high-fidelity controlled-phase (CZ) gate by manipulating central qubit and one near-neighboring qubit. Speckle purity benchmarking and cross entropy benchmarking are used to assess the purity fidelity and the fidelity of the CZ gate. The average purity fidelity of the CZ gate is 99.69±0.04% and the average fidelity of the CZ gate is 99.65±0.04%, which means that the control error is about 0.04%. Our work is helpful for resolving many challenges in implementation of large-scale quantum systems.

The emissions of volatile organic compounds (VOCs) from indoor furniture contribute significantly to poor indoor air quality. We have taken a typical machine learning approach using an artificial neural network (ANN), to predict the emission behaviors of VOCs from furniture. The gas-phase VOC concentrations from four kinds of furniture (solid wood furniture, panel furniture, soft leather furniture, soft cloth furniture) were measured in a 1 m3 chamber at different temperatures, relative humidity and ventilation rates. We then used these VOC concentration data as input for training. The trained ANN model could then be used to predict VOC concentrations at other emission time. We selected a back-propagation neural network, with 3 hidden layers, and a learning rate of 0.01. Pearson correlation analysis demonstrates that there is a strong correlation between the input datasets. We used relative deviation (RD) and mean absolute percentage error (MAPE) as the criteria for evaluating the performance of the ANN. For all of the tested VOCs from different types of furniture, the RDs between the predictions and experimental data at 150 h, are less than 15%. The MAPE values of the ANN model are within 10%. These indicate that the trained ANN model has excellent capability in predicting the VOC concentrations from furniture. The main merit of the ANN is that it doesn't need to solve the challenging problem of obtaining the key parameters when using physical models for prediction, and will thus be very useful for indoor source characterization, as well as for exposure assessment.

This study aims to generate recommendations for a group by weighting the preferences of each group member. We applied uncertain statistics to the preference scores of a panel of experts and a genetic algorithm (GA) to balance the weights of the group members (UGA). A group profile was then designed on the basis of the user ratings and the scores of the experts. A novel similarity measure was then developed based on uncertainty theory to refine the number of K-nearest neighbors (KNN). By integrating uncertain statistics and the novel similarity measure, group profiles were developed from the MovieLens and Gym datasets. Experiments demonstrated that the proposed approach was significantly better than two baseline approaches in generating group recommendations.

Objective To investigate the clinical outcome and endocrinological characteristics of progestin-primed ovarian stimulation (PPOS) using 4 versus 10 mg of medroxyprogesterone acetate (MPA) per day in infertile women with normal ovary reserve. Design A randomised parallel controlled trial. Setting Tertiary-care academic medical centre. Participants A cohort of 300 infertile women undergoing in vitro fertilisation (IVF)/intracytoplasmic sperm injection (ICSI) treatment. Methods Human menopausal gonadotropin (hMG; 225 iu per day) and MPA (group A, 10 mg per day; group B, 4 mg per day) were started simultaneously from cycle day 3 onwards. Ovulation was co-triggered by human chorionic gonadotropin (hCG; 1000 iu) and gonadotropin-releasing hormone agonist (GnRH agonist; 0.1 mg) when dominant follicles matured. Viable embryos were cryopreserved for later frozen embryo transfer (FET) in both groups. Main outcome measures The primary outcome measure was the number of oocytes retrieved. Secondary outcomes included the incidence of a premature surge in luteinising hormone (LH), the number of viable embryos, and clinical pregnancy outcomes. Results The number of oocytes retrieved and viable embryos were similar between two groups (9.8 ± 6.3 versus 9.6 ± 5.9; 4.2 ± 2.6 versus 3.7 ± 3.0; P > 0.05). No significant difference was found in clinical pregnancy rate (58.0 versus 48.7%) and live birth rate per participant (48.7 versus 42.0%; P > 0.05). No premature LH surge and ovarian hyperstimulation syndrome (OHSS) occurred in either group. Conclusions Progestin-primed ovarian stimulation (PPOS) using 4 or 10 mg of MPA per day was comparable in terms of the number of oocytes retrieved and pregnancy outcome after FET. The administration of 4 mg of MPA per day was sufficient to prevent an untimely LH rise in women undergoing IVF/ICSI treatment. Tweetable abstract An RCT confirmed similar pregnancy outcome in P-primed ovarian stimulation with a daily dose of 4 or 10 mg MPA.

Ethnopharmacological relevance Kai Xin San (KXS), a traditional formula of Chinese medicine, has been used to treat dementia. Aim of the study The present study aimed to investigate its ameliorating effects on Aβ 1-40 -induced cognitive impairment in rats using a series of novel reward-directed instrumental learning tasks, and to determine its possible mechanism of action. Materials and methods Rats were pretreated with KXS aqueous extract (0.72 and 1.44 g/kg, p.o.) for 10 days, and were trained to gain reward reinforcement by lever pressing at the meantime. Thereafter, rats received a bilateral microinjection of Aβ 1-40 in CA1 regions of the hippocampus. Cognitive performance was evaluated with the goal directed (higher response ratio) and habit (visual signal discrimination and extinction) learning tasks, as well as on the levels of memory-related biochemical parameters and molecules. Results Our findings first demonstrated that KXS can improve Aβ 1-40 -induced amnesia in RDIL via enhancing the comprehension of action-outcome association and the utilization of cue information to guide behavior. Then, its ameliorating effects should be attributed to the modulation of memory-related molecules in the hippocampus. Conclusion In conclusion, KXS has the potential to prevent and/or delay the deterioration of cognitive impairment in AD.

Objective: Progestin was recently used as an alternative of gonadotropin-releasing hormone (GnRH) analog for preventing premature luteinizing hormone (LH) surge with the aid of vitrification techniques, however, limited data were available about the potential of progestin in poor responders undergoing in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) treatment. We performed a randomized parallel controlled trial to investigate the difference of progestin and GnRH antagonist in poor responders.Methods: A total of 340 poor responders who met with Bologna criteria were randomly allocated into the progestin-primed ovarian stimulation (PPOS) group and GnRH antagonist group. Fresh embryo transfer was preferred in the GnRH antagonist group and freeze-all was performed in the PPOS group. The primary outcome was the incidence of premature LH surge, secondary outcomes were the number of retrieved oocytes, the number of viable embryos and the pregnancy outcomes.Results: The results showed that the incidence of premature LH surge in PPOS group was lower than that in antagonist group (0 vs. 5.88%, P < 0.05). In PPOS group, the average numbers of oocytes and viable embryos were comparable to those in GnRH antagonist group (3.7 ± 2.6 vs. 3.4 ± 2.4; 1.6 ± 1.7 vs. 1.4 ± 1.3, P > 0.05), the live birth rate was similar between the two groups (21.8 vs. 18.2%, RR 1.25 (95% confidence interval 0.73, 2.13), P > 0.05).Conclusions: The study demonstrated that PPOS had a more robust control for preventing premature LH rise than GnRH antagonist in poor responders, but PPOS in combination with freeze-all did not significantly increase the probability of pregnancy than GnRH antagonist protocol for poor responders.

Obstructive sleep apnea (OSA) has been reproducibly identified as a risk factor for initiation and progression of atrial fibrillation (AF) and reduces the efficacy of antiarrhythmic drugs, electrical cardioversion, and catheter ablation in AF. It is still controversial whether continuous positive airway pressure ventilation (CPAP) could improve the successful rate of AF treatment in OSA patients. Besides, CPAP has shown relative low compliance in patients with OSA. Therefore, novel optional therapies might be needed to improve the control of AF associated with OSA. A growing body of evidence suggests that autonomic activation contributes to the pathogenesis of AF in OSA. Acute apneic episodes result in sympathovagal co-activation, shortening atrial refractoriness and promoting the initiation of AF. Chronic OSA-induced sympathetic activation plays a crucial role in atrial autonomic, structural, and electrical remodeling, thus providing substrates for AF maintenance and recurrence. Therefore, the autonomic nervous system may be a promising therapeutic target for OSA and AF. Autonomic modulation as a treatment for OSA-associated AF has been well established in several preclinical studies. Further clinical studies are needed to provide a more precise definition of the role of autonomic modulation in the treatment of AF in OSA.

Background. Th17/Treg balance skews towards Th17 in ITP patient. IRF4 has been highlighted for its close relationship to the immunosuppressive function of Treg cells and the IL-17 synthesis in CD4+ T cells. This study was aimed at examining the effects of IRF4 to the Th17/Treg cells in patients with ITP. Methods. Treg and Teff cells were isolated from PBMCs of newly diagnosed ITP patients. The percentages of CD4+CD25hiFoxp3+Treg cells and the CD3+CD4+IL-17+Th17 cells were detected by flow cytometry. After being cultured, the supernatants of Tregs were collected for IL-10 concentration test. The IRF4 levels of Tregs were measured. Teffs were cultured alone or with Tregs for 24 hours. Then the supernatants were collected for IL-17 concentration test. The binding intensity of IRF4 to the gene IL-10 in Treg cells was detected by ChIP-qPCR. Metabolic assays for Teffs and Tregs were performed with Agilent Seahorse XF96 Analyzer. Results. The secretion of IL-10 by Tregs was decreased in ITP patients. The intensity of IRF4 binding to IL-10 DNA of Tregs in patients was higher than that of normal controls and Teffs in ITP patients. The expressions of IRF4 of Tregs in ITP patients were remarkably lower than that of healthy controls. The percentage of Th17 cells in healthy controls was significantly increased after IRF4 mRNA silencing. Abnormal metabolism of Treg and Teff cells was found in ITP patients. Conclusion. The skewed ratio of Th17/Treg cells and dysfunction of Treg cells in newly diagnosed ITP patients was at least partly caused by IRF4 dysfunction. The underlying mechanism might be the impact of IRF4 on the metabolism of Treg and Teff cells.

Background: Platelets are important in the initiation of thrombosis, and their morphological and functional changes are closely related with the occurrence and development of coronary artery thrombosis. Platelet parameters might be valuable in distinguishing between acute myocardial infarction (AMI) and stable coronary artery disease (SCAD). Objective: This study was designed to detect and compare changes in platelet parameters, such as mean platelet volume (MPV) in patients with acute myocardial infarction (AMI) and stable coronary artery disease (SCAD) and to investigate their roles in these diseases. Methods: Specimen collection: Between January 2011 and December 2013, 2 mL of elbow vein blood was drawn from each of 31 patients primarily diagnosed with AMI, 34 SCAD patients and 50 healthy subjects; and placed in EDTA-K2 anticoagulant tubes. Platelet count (PLT), MPV, plateletcrit (PCT), platelet distribution width (PDW), white blood cell (WBC) and neutrophil (NEU) counts were determined using an STKS automated hematology analyzer (Beckman Courter). Results: Compared with the control group, MPV levels were significantly higher in the AMI and SCAD groups (p < 0.05), while PLT was significantly lower (p < 0.05). Conclusion: These results suggest that MPV and other related parameters have a certain value in the diagnosis of SCAD and AMI. Resumo Fundamento: As plaquetas são importantes no início da trombose e suas alterações morfológicas e funcionais estão intimamente relacionadas com a ocorrência e o desenvolvimento de trombose da artéria coronária. Os parâmetros plaquetários podem ser valiosos na distinção entre infarto agudo do miocárdio (IAM) e doença arterial coronariana estável (DACE). Objetivo: O objetivo desse estudo foi detectar e comparar alterações nos parâmetros plaquetários, como o volume plaquetário médio (VPM) em pacientes com infarto agudo do miocárdio (IAM) e doença arterial coronariana estável (DACE) e investigar seu papel nessas doenças. Métodos: Coleta de amostras: Entre janeiro de 2011 e dezembro de 2013, foram retirados 2 mL de sangue da veia do antebraço de cada um dos 31 pacientes diagnosticados principalmente com IAM, 34 pacientes com DACE e 50 indivíduos saudáveis; e colocado em tubos com anticoagulante EDTA-K2. As contagens de plaquetas (PQT), VPM, massa total de plaquetas (MTP), Amplitude de Distribuição de Plaquetas (PDW, do inglês platelet distribution width), contagem de glóbulos brancos (WBC, do inglês white blood cells) e neutrófilos (NEU) foram determinadas utilizando-se um analisador de hematologia automatizado STKS (Beckman Courter). Resultados: Comparado com o grupo controle, os níveis de VPM foram significativamente maiores nos grupos IAM e DACE (p < 0,05), enquanto os níveis de PQT foram significativamente menores (p < 0,05). Conclusão: Esses resultados sugerem que o VPM e outros parâmetros associados têm um certo valor no diagnóstico de DACE e IAM.

Background Primary immune thrombocytopenia (ITP) is an autoimmune heterogeneous disorder of which Treg cells are numerically or functionally deficient. It is known that human FoxP3 + CD4 + T cells were composed of 3 phenotypically and functionally distinct subpopulations (resting Treg, rTreg; activated Treg, aTreg; and non-suppressive Treg, n-sTreg). The current study was aimed to determine whether these Treg subtypes are altered in ITP patients and the related potential clinical applications. Method Normal control volunteers and newly diagnosed ITP patients were enrolled in the study. The percentage of Treg cells' subtypes in peripheral blood was examined by flow cytometry before and after the glucocorticoid treatment. The IL-10 production by Treg subtypes was also examined. Results Treg cell subtypes of aTreg increased, rTreg decreased, and n-s Treg increased in newly diagnosed ITP patients' peripheral blood. The IL-10 production by respective Treg subtype didn't change after the treatment, and aTreg cells had the highest IL-10 yield. Patients who gained remission during follow-up had a higher aTreg cells' percentage than those who did not at the disease diagnosis. Conclusion Tregs cell subtypes percentage was altered when ITP occurred. The increased aTreg cells at disease diagnosis might predict a better glucocorticoid treatment efficacy.

Evidence from a neuropsychological test revealed that interictal epileptiform discharges (IEDs) may have significant impact on cognitive performance. Sometimes, neuropsychological tests may not be sensitive to detection of mild cognitive changes. We applied P300 and mismatch negativity (MMN) to detect mild cognitive changes caused by small amount of IEDs. Sixty-seven adult epilepsy patients and participants were divided into six groups according to different IEDs index. The patients with IED index greater than 7.5% showed longer latency and lower amplitude in the test of P300 and MMN than patients with IED index less than 7.5%, which indicated mild impaired cognitive function. The negative effect of IED index greater than 10% on cognitive has been found by neuropsychological test, whereas the mild negative effect of IED index greater than 7.5% has only been found by P300 and MMN. So, P300 and MMN may be more sensitive than neuropsychological tests to detect mild cognitive impairment caused by IEDs.

OBJECTIVE To assess left atrial function in type 2 diabetes mellitus (T2DM) patients with nonalcoholic fatty liver disease (NAFLD) by two-dimensional speckle tracking echocardiography (2D-STE). METHODS We classified 97 patients with T2DM into three groups according to the results of liver ultrasonography: group A (without NAFLD), group B (mild fatty liver), and group C (moderate to severe fatty liver). Conventional echocardiography parameters included left atrial end-systolic diameter (LAD), left ventricular end-systolic and end-diastolic diameter (LVDs, LVDd), end-diastolic thickness of ventricular septumi and LV posterior wall (IVSTd, LVPWTd), peak E and A of mitralis (E, A), septal and lateral early (e') mitral annular diastolic tissue velocities, then calculated E/A and E/mean e'. We measured LV ejection fraction (LVEF) and left atrial (LA) volumes (max, min, and preatrial contraction volume) by Simpson's rule, then calculated LA passive and active ejection fraction (LAPEF, LAAEF), left atrial maximum volume index (LAVImax). The global peak longitudinal systolic strain (LASRs), early diastolic strain (LASRe), and late diastolic strain (LASRa) rates of the LA were obtained by 2D-STE. RESULTS No differences were found between groups A and B (all P > 0.05). In group C, LAAEF and LASRa were obviously higher, while LAPEF, LASRe, and LASRs were obviously decreased compared with those values in groups A and B (all P