Search

Background. Exosomes are extracellular vesicles that play important roles in various physiological and pathological functions. Previous studies have demonstrated that exosome-derived contents are promising biomarkers to inform the pathogenesis and diagnosis of major depressive disorder and schizophrenia. Methods. We used ultraperformance liquid chromatography-tandem mass spectrometry to analyze the differentially expressed metabolites in serum exosomes of patients with bipolar disorder (BD) and evaluated the potential of exosomal metabolites as biomarkers for BD. Results. Our results showed 26 differentially expressed serum exosomal metabolites in patients with BD ( n = 32 ) when compared with healthy control (HC) subjects ( n = 40 ), and these differentially expressed metabolites were enriched in pathways related to sugar metabolism. We then utilized random forest classifier and identified 15 exosomal metabolites that can be used to classify samples from patients with BD and HC subjects with 0.838 accuracy (95% CI, 0.604–1.00) in the training set of participants. These 15 metabolites showed excellent performance in differentiating between patients with BD and HC subjects in the testing set of participants, with 0.971 accuracy (95% CI, 0.865–1.00). Importantly, the 15 exosomal metabolites also showed good to excellent performance in differentiating between BD patients and other major psychiatric diseases (major depressive disorder and schizophrenia). Conclusion. Collectively, our findings for the first time revealed a potential role of exosomal metabolite dysregulations in the onset and/or development of BD and suggested that blood exosomal metabolites are strong candidates to inform the diagnosis of BD.

Background: Group B streptococcus (GBS) is a leading cause of serious infection in infants. Understanding its regional molecular epidemiology is helpful for regulating efficient prevention practice. Methods: A retrospective study was conducted to collected data from infants and pregnant women with culture-proven GBS disease in the largest women and children's medical center in Shanxi between January 2017 and September 2019. All GBS isolates were analyzed by multi-locus sequence typing (MLST) as well as distribution of pilus island (PI) genes. Results: A total of 54 GBS isolates were obtained from 36 (66.7%) pregnant women and 18 (33.3%) infants with invasive disease. Among invasive GBS strains, the most common sequence type was ST10 (72.2%, P

To investigate the effect of open wedge tibial high osteotomy on patella position, anterior knee pain and joint function.From June 2016 to June 2021, 109 patients (111 knees) with medial knee osteoarthropathy treated by open wedge tibial high osteotomy were included according to the inclusion and exclusion criteria, including 41 males and 68 females;the age ranged from 38 to 78 years old with an average of(57.98±7.07) years;the course of disease ranged from 1 to 36 months with an average of (8.58±6.91) months. The femoral tibial angle(FTA), medial proximal tibial angle(MPTA), weight bearing line(WBL) percentage, Caton Deschamps index (CD index), lateral patella tilt angle (LPTA) and lateral patella shift (LPS) were observed and compared before and after operation. Lysholm score was used to evaluate the knee function, visual analogue scale(VAS) was used to evaluate the degree of anterior knee pain, and Kellgren Lawrence(K-L) grading system was used to evaluate the progress of patellofemoral osteoarthritis.All patients were followed up for 6 to 38 months with an average of (12.41±2.40) months. The preoperative FTA, MPTA, WBL percentage, CD index, and LPTA were significantly different from those at the last follow-up(After open wedge tibial high osteotomy, the position of patella is lowered and the patella is tilted outward, but the knee function and anterior knee pain are significantly improved. Adverse changes in patella position caused by open wedge tibial high osteotomy may not affect clinical outcomes.

Our aim was to explore the effects of dietary and behavior interventions on lipometabolism caused by an unhealthy high-fat diet and the best method to rebuild lipid homeostasis of this lifestyle. Apart from normal diet rats, 34 rats were fed with high-fat emulsion for 4 weeks and then intervened for another 4 weeks. Eight of them were classified into high-fat control group, and 9 were sorted into high-fat diet with rice vinegar group. Meanwhile, 10 were put into high-fat diet in swimming group, and 7 were just for refeeding normal diet group. Then, the data of body weight was recorded and analyzed. Indexes of serum samples were tested by kits. AMPKα, HNF1α, and CTRP6 in pancreas, liver, cardiac, and epididymis adipose tissues were detected by western blot. According to our experiments, swimming and refeeding groups reflected a better regulation on lipid homeostasis mainly by upregulating the expression of pancreas AMPKα. To be more specific, the refeeding rats showed lower T-CHO ( P < 0.001 ) and LDL-C ( P < 0.05 ), but higher weight gain ( P < 0.001 ), insulin level ( P < 0.01 ), and pancreas AMPKα ( P < 0.01 ) than high-fat control rats. Compared with rats intervened by swimming or rice vinegar, they showed higher weight gain ( P < 0.001 ), insulin level ( P < 0.01 ), and HNF1α, but lower of CTRP6. In summary, refeeding diet functioned better in regulating the lipometabolic level after high-fat diet. Whatever approach mentioned above we adopted to intervene, the best policy to keep the balance of lipid homeostasis is to maintain a healthy diet.

Increased serum uric acid (SUA) is common in type 2 diabetes mellitus (T2DM) and is associated with left ventricular (LV) myocardial dysfunction. Nonetheless the association of SUA with right ventricular (RV) function in T2DM has not been studied. This study aimed to investigate the association of SUA with biventricular myocardial function in patients with T2DM.A total of 560 patients with T2DM were enrolled and divided into four groups according to sex-specific quartiles of SUA. Transthoracic echocardiography was performed and two-dimensional speckle tracking was used to measure biventricular myocardial strain, including LV global longitudinal strain (GLS), circumferential strain (CS), radial strain (RS), and RV free wall longitudinal strain (RV-FWLS). The absolute value of all biventricular strain parameters showed a stepwise decrease across SUA quartiles (all P 0.01). In particular, LV assessment by GLS, CS and RS demonstrated that those in the 4th quartile were impaired compared with the other quartiles (all P 0.05). Similarly, RV-FWLS of the 4th quartile was significantly impaired compared with the 1st and 2nd quartiles (all P 0.05). The same reduction in biventricular strain across SUA quartiles was observed in patients with estimated glomerular filtration rate or ≥60 ml/min/1.73 mSUA was independently associated with biventricular myocardial dysfunction in asymptomatic T2DM patients, regardless of renal function or diabetic control.

Patients with Parkinson's disease (PD) have a higher incidence rate of duodenal ulcers. The mucus barrier provides the first line of defense for duodenal mucosal protection. However, it is unknown whether duodenal mucus secretion is affected in PD. In the present study, we used the rats microinjected 6-hydroxydopamine (6-OHDA) into the bilateral substantia nigra to investigate duodenal mucus secretion and potential therapeutic targets in duodenal ulcer in PD. Alcian blue-periodic acid-Schiff, transmission electron microscopy, immunofluorescence, duodenal mucosal incubation, and enzyme-linked immunosorbent assays were used. The 6-OHDA rats exhibited mucin accumulation and retention in duodenal goblet cells. Mucin granules were unable to fuse with the apical membranes of goblet cells, and the exocytosis ratio of goblet cells was significantly reduced. Moreover, decreased acetylcholine and increased muscarinic receptor 2 (M2R) levels were detected in the duodenal mucosa of 6-OHDA rats. Bilateral vagotomy rats were also characterized by defective duodenal mucus secretion and decreased acetylcholine with increased M2R levels in the duodenal mucosa. Application of the cholinomimetic drug carbachol or blocking M2R with methoctramine significantly promoted mucus secretion by goblet cells and increased MUC2 content in duodenal mucosa-incubated solutions from 6-OHDA and vagotomy rats. We conclude that the reduced acetylcholine and increased M2R contribute to the impaired duodenal mucus secretion of 6-OHDA rats. The study provides new insights into the mechanism of duodenal mucus secretion and potential therapeutic targets for the treatment of duodenal ulcers in PD patients.

Blastocystis hominis and Cystoisospora belli are considered to be common opportunistic intestinal protozoa in HIV/AIDS patients. In order to investigate the prevalence and genetic characteristics of B. hominis and C. belli in HIV/AIDS patients, a total of 285 faecal samples were individually collected from HIV/AIDS patients in Guangxi, China. B. hominis and C. belli were investigated by amplifying the barcode region of the SSU rRNA gene and the internal transcribed spacer 1 (ITS-1) region of the rRNA gene, respectively. Chi-square test or Fisher’s exact test were conducted to assess the risk factors related to B. hominis and C. belli infection. The prevalence of B. hominis and C. belli was 6.0% (17/285) and 1.1% (3/285) respectively. Four genotypes of B. hominis were detected, with ST3 (n = 8) and ST1 (n = 6) being predominant, followed by ST6 (n = 2) and ST7 (n = 1). Females had a statistically higher prevalence of B. hominis (11.6%) than males (4.2%). The statistical analysis also showed that the prevalence of B. hominis was significantly associated with age group and educational level. Our study provides convincing evidence for the genetic diversity of B. hominis, which indicates its potential zoonotic transmission and is the first report on the molecular characteristics of C. belli in HIV/AIDS patients in China.

Introduction Multiparametric magnetic resonance imaging (mpMRI) has been shown to have a good performance in predicting cancer among patients with a prostate-specific antigen (PSA) level of 4 to 10 ng/mL. However, lesion location on mpMRI has never been separately considered. Patients and Methods Patients with PSA level of 4 to 10 ng/mL were prospectively enrolled and underwent transrectal ultrasound-guided prostate biopsy. Patient information was collected, and logistic regression analysis was performed to determine the predictive factors of clinically significant prostate cancer (csPCa). Patients were grouped by lesion location to determine the Prostate Imaging Reporting and Data System (PI-RADS) v2.1 cutoff value in predicting csPCa. Results Among 222 patients, 121 were diagnosed with PCa and 92 had csPCa. Age, prostate volume, PSA density, location (peripheral zone, csPCa only), and PI-RADS v2.1 score were correlated with PCa and csPCa, and PI-RADS v2.1 score was the best predictor. A PI-RADS v2.1 score of 4 was the best cutoff value for predicting csPCa in patients with lesions only in the transitional zone with respect to the Youden index (0.5896) and negative predictive value (93.10%) with acceptable sensitivity (81.82%) and specificity (77.14%). An adjustment of the cutoff value to 3 for lesions in the peripheral zone would increase the negative predictive value (92.00%) and decrease the false negative rate (2.90%) with an acceptable sensitivity (97.10%) and specificity (30.67%). Conclusion PI-RADS v2.1 score is an effective predictor of csPCa in patients with PSA levels of 4 to 10 ng/mL. Patients with transitional zone or peripheral zone lesions should undergo biopsy if the PI-RADS v2.1 score is ≥ 4 or ≥ 3, respectively.

Dangefentong Capsules is a new traditional Chinese medicine preparation for the treatment of diabetic peripheral neuropathy. It is based on the Salviae Miltiorrhizae Radix et Rhizoma-Puerariae Lobatae Radix herb pair with salvianolic acids, tanshinones and pueraria flavonoids as main components. Studying the chemical composition in vivo of Dangefentong Capsules and its metabolites is of great significance for making clear its pharmacodynamic material basis and the action mechanism. The UHPLC-Q/Orbitrap-MS/MS was applied to rapidly analyze the metabolites and metabolic pathways of Dangefentong Capsules in Beagle dogs after gavage. Eclipse plus C_(18) column(2.1 mm×50 mm, 1.8 μm) was used, and gradient elution was performed with 0.1% formic acid aqueous solution(A)-formic acid acetonitrile solution(B). A heated electrospray ion source(HESI) was employed. The scanning mode was set as the positive and negative ion mode, and the mass scanning range was m/z 100-1 000. The plasma, urine and feces samples were collected after male Beagle dogs were administered with Dangefentong Capsules. The prototype components and metabolites were identified by UHPLC-Q/Orbitrap-MS/MS analysis combined with reference substances and references. The results showed that 107 chemical components were identified, including 58 prototype components and 49 metabolites. The identified prototype components included 42 components from Salviae Miltiorrhizae Radix et Rhizoma and 16 components from Puerariae Lobatae Radix. The metabolites consist of 21 and 28 metabolites of Salviae Miltiorrhizae Radix et Rhizoma and Puerariae Lobatae Radix, respectively. They are mainly derived from the methylation, hydroxylation, sulfation and glucuronidation of salvianolic acids, tanshinones and pueraria flavonoids. This research rapi-dly analyzes the chemical components in vivo of Beagle dogs administered with Dangefentong Capsules, laying a basis for illustrating the pharmacodynamic material basis and mechanism of Dangefentong Capsules.

Purpose: Lower grade gliomas (LGGs) are malignant brain tumors. Current therapy is associated with short- and long-term toxicity. Progression to higher tumor grade is associated with contrast enhancement on MRI. The majority of LGGs harbor mutations in the genes encoding isocitrate dehydrogenase 1 or 2 (IDH1/IDH2). Vorasidenib (AG-881) is a first-in-class, brain-penetrant, dual inhibitor of the mutant IDH1 and mutant IDH2 enzymes. Patients and Methods: We conducted a multicenter, open-label, phase I, dose-escalation study of vorasidenib in 93 patients with mutant IDH1/2 (mIDH1/2) solid tumors, including 52 patients with glioma that had recurred or progressed following standard therapy. Vorasidenib was administered orally, once daily, in 28-day cycles until progression or unacceptable toxicity. Enrollment is complete; this trial is registered with ClinicalTrials.gov, NCT02481154. Results: Vorasidenib showed a favorable safety profile in the glioma cohort. Dose-limiting toxicities of elevated transaminases occurred at doses ≥100 mg and were reversible. The protocol-defined objective response rate per Response Assessment in Neuro-Oncology criteria for LGG in patients with nonenhancing glioma was 18% (one partial response, three minor responses). The median progression-free survival was 36.8 months [95% confidence interval (CI), 11.2–40.8] for patients with nonenhancing glioma and 3.6 months (95% CI, 1.8–6.5) for patients with enhancing glioma. Exploratory evaluation of tumor volumes in patients with nonenhancing glioma showed sustained tumor shrinkage in multiple patients. Conclusions: Vorasidenib was well tolerated and showed preliminary antitumor activity in patients with recurrent or progressive nonenhancing mIDH LGG.

Introduction We evaluated 8, 12, or 24 weeks of ledipasvir/sofosbuvir in patients with hepatitis C virus and end-stage renal disease undergoing dialysis. Methods Primary efficacy end point was sustained virologic response 12 weeks after treatment. Primary safety end point was treatment discontinuation because of adverse events (AEs). Results Ninety-four percent (89/95) achieved sustained virologic response 12 weeks after treatment. Six patients died during treatment (n = 4) or before study completion (n = 2); no deaths were related to treatment. No patients discontinued treatment because of AEs. Thirteen percent had serious AEs; none were related to treatment. Discussion Treatment with ledipasvir/sofosbuvir was safe and effective in patients with end-stage renal disease undergoing dialysis.

Background The interference screw is the most popular device that fixes the graft for anterior cruciate ligament reconstruction, reducing the incidence of windshield effect and bungee effect. For the screw, either metallic, “bioresorbable,” or polyetheretherketone (PEEK) material is available. PEEK is popular and extensively used due to its stability, biocompatibility, radiolucency, and elastic modulus. Rare relevant complications were reported, but here, we report two cases of extra-articular migrations of PEEK interference screw from the tibial tunnel after anterior cruciate reconstruction. Case report An 18-year-old boy and a 56-year-old woman underwent anterior cruciate ligament reconstruction using a PEEK interference screw to fix the graft in the tibial tunnel. They suffered from screw extrusion from the tibial tunnel after 40 days and six months, respectively, with an incision rupture or palpable subcutaneous mass. They underwent a second operation and recovered well. Conclusions The exact incidence of extra-articular migrations of PEEK interference screws is unknown, but it seems to be quite low; despite this and its uncertain cause, the negative effects caused by the PEEK material need to be considered.

OBJECTIVE: To study the clinical features and gene mutation sites of children with cystic fibrosis (CF), in order to improve the understanding of CF to reduce misdiagnosis and missed diagnosis. METHODS: A retrospective analysis was performed on the medical records of 8 children with CF who were diagnosed in Hebei Children's Hospital from 2018 to 2021. RESULTS: Among the 8 children with CF, there were 5 boys and 3 girls, with an age of 3-48 months (median 8 months) at diagnosis, and the age of onset ranged from 0 to 24 months (median 2.5 months). Clinical manifestations included recurrent respiratory infection in 7 children, sinusitis in 3 children, bronchiectasis in 4 children, diarrhea in 8 children, fatty diarrhea in 3 children, suspected pancreatic insufficiency in 6 children, pancreatic cystic fibrosis in 1 child, malnutrition in 5 children, and pseudo-Bartter syndrome in 4 children. The most common respiratory pathogens were Pseudomonas aeruginosa (4 children). A total of 16 mutation sites were identified by high-throughput sequencing, multiplex ligation-dependent probe amplification, and Sanger sequencing, including 5 frameshift mutations, 4 nonsense mutations, 4 missense mutations, 2 exon deletions, and 1 splice mutation. CFTR mutations were found in all 8 children. p.G970D was the most common mutation (3 children), and F508del mutation was observed in one child. Four novel mutations were noted: deletion exon15, c.3796_3797dupGA(p.I1267Kfs*12), c.2328dupA(p.V777Sfs*2), and c.2950G>A(p.D984N). CONCLUSIONS: p.G970D is the most common mutation type in children with CF. CF should be considered for children who have recurrent respiratory infection or test positive for Pseudomonas aeruginosa, with or without digestive manifestations or pseudo-Bartter syndrome.

ObjectivesTo study the effects of psoralen on the intestinal barrier and alveolar bone loss (ABL) in rats with chronic periodontitis.MethodsFifty-two 8-week-old specific pathogen-free (SPF) male Sprague-Dawley (SD) rats were randomly divided into the following four groups: Control group (Control), Psoralen group of healthy rats (Pso), Periodontitis model group (Model), and Psoralen group of periodontitis rats (Peri+Pso). The alveolar bone resorption of maxillary molars was observed via hematoxylin-eosin staining and micro-computed tomography. The expression level of receptor activator of nuclear factor-κB ligand (RANKL) and osteoprotegerin (OPG) in periodontal tissues were evaluated by immunofluorescence staining. The changes in serum tumour necrosis factor (TNF)-α, interleukin (IL)-10, IL-6, intestinal mucosal occludin and claudin-5 were detected using enzyme-linked immunosorbent assay (ELISA). The level of intestinal mucosal NOD2 was detected using immunohistochemical methods. DNA was extracted from the intestinal contents and the 16s rRNA gene was sequenced using an Illumina Miseq platform.ResultsThe expression of NOD2 protein in the intestinal tract of periodontitis rats decreased after intragastric psoralen administration. Psoralen increased the intestinal microbiota diversity of rats. The level of serum pro-inflammatory factor TNF-α decreased and the level of anti-inflammatory factor IL-10 increased. ABL was observed to be significantly decreased in rats treated with psoralen. Psoralen decreased the RANKL/OPG ratio of periodontitis rats.ConclusionsPsoralen may affect the intestinal immune barrier and ecological barrier, mediate immune response, promote the secretion of anti-inflammatory factor IL-10, and reduce the secretion of the pro-inflammatory factor TNF-α, thus reducing ABL in experimental periodontitis in rats.

Background The clinical characteristics of Parkinson’s disease (PD) differ between men and women, and late- and early-onset patients, including motor symptoms and some nonmotor symptoms, such as cognition, anxiety, and depression. Objective To explore the features of excessive daytime sleepiness (EDS) and night-time sleep quality in PD patients of different sexes and age at onset (AAO). Methods Demographic data and clinical characteristics of 586 PD patients were collected. Epworth Sleepiness Scale (ESS) and Pittsburgh Sleep Quality Index (PSQI) were used to investigate the daytime drowsiness and nocturnal sleep. Multivariate logistic regression analysis was used to explore the risk factors of EDS and poor night-time sleep quality. Results Sleep disorders were common in PD patients. EDS was more prominent in men than in women. There was no significant difference in ESS scores between late-onset PD (LOPD) and early-onset PD. LOPD patients had a higher probability of poor night-time sleep quality. Male sex, disease duration, and depression were risk factors for EDS. In all patients of both sexes and all AAO, depression was a risk factor for poor night-time sleep. Conclusion More attention should be paid to sleep disorders of PD patients, especially male LOPD patients. Depression is a common risk factor for EDS and poor sleep quality in PD patients.

Background The optimal dose and fractionation scheme of stereotactic body radiation therapy (SBRT) for hepatocellular carcinoma (HCC) remains unclear due to different tolerated liver volumes and degrees of cirrhosis. In this study, we aimed to verify the dose-survival relationship to optimize dose selection for treatment of HCC. Methods This multicenter retrospective study included 602 patients with HCC, treated with SBRT between January 2011 and March 2017. The SBRT dosage was classified into high dose, moderate dose, and low dose levels: SaRT (BED10 ≥ 100 Gy), SbRT (EQD2 > 74 Gy to BED10 2 Results The median tumor size was 5.6 cm (interquartile range [IQR] 1.1–21.0 cm). The median follow-up time was 50.0 months (IQR 6–100 months). High radiotherapy dose correlated with better outcomes. After classifying into the SaRT, SbRT, and ScRT groups, three notably different curves were obtained for long-term post-SBRT survival and intrahepatic control. On multivariate analysis, higher radiation dose was associated with improved OS, PFS, and intrahepatic control. Conclusions If tolerated by normal tissue, we recommend SaRT (BED10 ≥ 100 Gy) as a first-line ablative dose or SbRT (EQD2 ≥ 74 Gy) as a second-line radical dose. Otherwise, ScRT (EQD2

Background Primary hyperoxaluria(PH)is a rare autosomal recessive genetic disease that contains three subtypes (PH1, PH2 and PH3). Approximately 80% of PH patients has been reported as subtype PH1, this subtype of PH has been related to a higher risk of renal failure at any age. Several genetic studies indicate that the variants in gene AGXT are responsible for the occurrence of PH1. However, the population heterogeneity of the variants in AGXT makes the genetic diagnosis of PH1 more challenging as it is hard to locate each specific variant. It is valuable to have a complete spectrum of AGXT variants from different population for early diagnosis and clinical treatments of PH1. Case presentation In this study, We performed high-throughput sequencing and genetic analysis of a 6-year-old male PH1 patient from a Chinese family. Two variants (c.346G > A: p.Gly116Arg; c.864G > A: p.Trp288X) of the gene AGXT were identified. We found a nonsense variant (c.864G > A: p.Trp288X) that comes from the proband’s mother and has never been reported previously. The other missense variant (c.346G > A: p.Gly116Arg) was inherited from his father and has been found previously in a domain of aminotransferase, which plays an important role in the function of AGT protein. Furthermore, we searched 110 pathogenic variants of AGXT that have been reported worldwide in healthy local Chinese population, none of these pathogenic variants was detected in the local genomes. Conclusions Our research provides an important diagnosis basis for PH1 on the genetic level by updating the genotype of PH1 and also develops a better understanding of the variants in AGXT by broadening the variation database of AGXT according to the Chinese reference genome.

OBJECTIVE: To compare the diagnostic efficacy of ACR TI-RADS, Kwak TI-RADS, ATA guidelines and KTA/KSThR guidelines in combination with shear wave elastography (SWE) for thyroid nodules. METHODS: The retrospective study included 566 thyroid nodules with maximum diameter≥5 mm which confirmed by FNA cytology or/and surgical pathology. The sensitivity, specificity, accuracy, Youden index of diagnosis of thyroid nodules by ACR TI-RADS, Kwak TI-RADS, ATA guidelines, KTA/KSThR guidelines and SWE were calculated. The ROC curve was drawn to determine the cut-off values of the four ultrasound classification systems and SWE Emax. The diagnostic efficacy of the four ultrasound classification systems in combination with SWE were calculated and compared with those of pre-combination. RESULTS: The ROC curves indicated that the cut-off value of ACR TI-RADS, Kwak TI-RADS, ATA guidelines, KTA/KSThR guidelines and Emax of SWE was TR5, 4c, high-suspicion, high-suspicion, and 41.7 kPa, respectively, and the area under the ROC curve (AUC) was 0.907(0.879–0.934), 0904(0.876–0.932), 0.894(0.863–0.924), 0.888(0.856–0.919), 0.886(0.859–0.913), respectively. After combination with SWE, the the sensitivities of the four ultrasound classification systems for the diagnosis of nodules were improved, and the differences were statistically significant (all P≤0.001); the specificities were decreased, but the differences were not statistically significant (all P > 0.05); the accuracies were improved, but only the difference of ACR TI-RADS was statistically significant (x2 = 4.45, P = 0.035); the differences in the AUCs were not significant (all P > 0.05). CONCLUSIONS: The four ultrasound classification systems and SWE all had high performance in the diagnosis of thyroid nodules. The four classification systems in combination with SWE were all beneficial to the differential diagnosis of nodules, and ACR TI-RADS in combination with SWE was more effective, especially for TR3 and TR4 nodules.

Background Sulfation of tyrosine, yielding O-sulfotyrosine, is a common but fixed post-translational modification in eukaryotes. Patients with increased circulating O-sulfotyrosine levels experience a faster decline in renal function with progression to end-stage renal disease (ESRD). In the present study, we measured serum O-sulfotyrosine levels in individuals with chronic kidney disease (CKD) and acute kidney injury (AKI) to explore its ability to differentiate AKI from CKD. Methods A total of 135 patients (20 with AKI and 115 with CKD) were recruited prospectively for liquid chromatography-mass spectrometry assessment of circulating O-sulfotyrosine. We also studied C57BL/6 mice with CKD after 5/6 nephrectomy (Nx). Blood samples were drawn from the tail vein on Day 1, 3, 5, 7, 14, 30, 60, and 90 after CKD. Serum separation and characterization of creatinine, blood urea nitrogen (BUN), and O-sulfotyrosine was performed. Thus, the time-concentration curves of the O-sulfotyrosine level demonstrate the variation of kidney dysfunction. Results The serum levels of O-sulfotyrosine were markedly increased in patients with CKD compared with AKI. Median O-sulfotyrosine levels in CKD patients versus AKI, respectively, were as follows:243.61 ng/mL(interquartile range [IQR] = 171.90–553.86) versus 126.55 ng/mL (IQR = 48.19–185.03, P = 0.004). In patients with CKD, O-sulfotyrosine levels were positively correlated with creatinine, BUN, and Cystatin C (r = 0.63, P P P P P = 0.002; β = 0.73, P P = 0.472; r = 0.11, P = 0.655; r = 0.09, P = 0.716, respectively). The receiver operating characteristic (ROC) analysis illustrated that the area under the curve was 0.80 (95% confidence interval [CI] 0.71–0.89; P P P Conclusion Serum O-sulfotyrosine levels were observed correlated with degrading renal function and in CKD patients substantially higher than those in AKI patients. Thus serum O-sulfotyrosine facilitated the differential diagnosis of AKI from CKD.

Management of complex left ventricular outflow tract obstruction (LVOTO) can be achieved with a Konno or Modified Konno procedure to enlarge the LVOT. We hypothesized that patients who undergo a Modified Konno procedure would have a higher rate of LVOT re-intervention compared to the Konno procedure. Patients who underwent a Konno or Modified Konno procedure for LVOTO at a single tertiary care center between 1990 and 2014 were retrospectively reviewed. The primary outcome was LVOT re-intervention post-discharge from index Konno or Modified Konno procedure. Cox regression and Kaplan–Meier estimates were used for time-to-event analysis of LVOT re-interventions, any unplanned re-interventions, and transplant-free survival. The study included 122 patients: 51 (41.8%) in the Konno group and 71 (58.2%) in the Modified Konno group. Median age at surgery was 8.2 (IQR 3–16) years in the Konno group and 3.9 (IQR 1.5–11) years in the Modified Konno group. Multiple left heart lesions were less prevalent in Modified Konno patients. There were 36 (29.5%) patients with LVOT re-interventions: 8 (16%) in the Konno group and 28 (39.4%) in the Modified Konno group (p = 0.01). Transplant-free survival at five years was 87.2% for the Konno group and 93.5% for the Modified Konno group. A higher rate of LVOT re-intervention was found in the Modified Konno group although the Konno and Modified Konno techniques were applied to different patient populations. This finding suggests that careful preoperative decision-making can direct therapy appropriately and that fundamental diagnosis affects procedure choice. Supplementary Information The online version contains supplementary material available at 10.1007/s00246-020-02522-9.

Dopamine D1 receptor (D1DR) and D2 receptor (D2DR) are closely associated with pain modulation, but their exact effects on neuropathic pain and the underlying mechanisms remain to be identified. Our research revealed that intrathecal administration of D1DR and D2DR antagonists inhibited D1–D2DR complex formation and ameliorated mechanical and thermal hypersensitivity in chronic constriction injury (CCI) rats. The D1–D2DR complex was formed in the rat spinal cord, and the antinociceptive effects of D1DR and D2DR antagonists could be reversed by D1DR, D2DR, and D1–D2DR agonists. Gαq, PLC, and IP3 inhibitors also alleviated CCI-induced neuropathic pain. D1DR, D2DR, and D1–D2DR complex agonists all increased the intracellular calcium concentration in primary cultured spinal neurons, and this increase could be reversed by D1DR, D2DR antagonists and Gαq, IP3, PLC inhibitors. D1DR and D2DR antagonists significantly reduced the expression of p-PKC γ, p-CaMKII, p-CREB, and p-MAPKs. Levo-corydalmine (l-CDL), a monomeric compound in Corydalis yanhusuo W.T. Wang, was found to obviously suppress the formation of the spinal D1–D2DR complex to alleviate neuropathic pain in CCI rats and to decrease the intracellular calcium concentration in spinal neurons. l-CDL-induced inhibition of p-PKC γ, p-MAPKs, p-CREB, and p-CaMKII was also reversed by D1DR, D2DR, and D1–D2DR complex agonists. In conclusion, these results indicate that D1DR and D2DR form a complex and in turn couple with the Gαq protein to increase neuronal excitability via PKC γ, CaMKII, MAPK, and CREB signaling in the spinal cords of CCI rats; thus, they may serve as potential drug targets for neuropathic pain therapy., Chronic pain: Cutting communication for nerve pain signals Insights into dopamine-mediated neuronal activity in the spinal cord may lead to more effective relief for some chronic pain patients. Up to 10% of adults worldwide live with some form of pain due to nerve damage (neuropathy), and few treatment options are available. The neurotransmitter dopamine is thought to regulate pain-related signaling in the spinal cord, and researchers led by Ji-Hua Liu and Bo-Yang Yu of China Pharmaceutical University, Nanjing, have identified a way to interfere with this signaling. Working with a rat neuropathic pain model, the researchers focused on a protein complex that acts as a receptor for dopamine in spinal neurons. Once activated, this complex initiates cellular processes that mediate the pain response. Chemical agents that block receptor assembly counter these processes, highlighting a promising mechanism to target in neuropathic pain patients.

Ivosidenib is a once daily (q.d.), orally available, potent mutant isocitrate dehydrogenase 1 (mIDH1) inhibitor approved for treatment of patients with relapsed or refractory (R/R) acute myeloid leukemia (AML) and intensive chemotherapy ineligible AML with a susceptible IDH1 mutation. Population pharmacokinetics (PKs; N = 253), exposure‐response (efficacy [n = 201] and safety [n = 253]), and concentration‐corrected electrocardiogram QT interval (QTc; n = 171) analyses were performed using phase I data (100 mg twice daily and 300–1200 mg q.d.). Ivosidenib disposition was well‐described by a two‐compartment PK model with first‐order absorption and elimination. Between‐subject variability was moderate for PK parameters. Intrinsic factors did not affect ivosidenib PKs. Moderate/strong CYP3A4 inhibitors increased the area under the plasma ivosidenib concentration‐time curve at steady state (AUCss) by 60%. Efficacy responders and nonresponders had similar ivosidenib exposures. Based on AUCss, there was no apparent relationship between ivosidenib exposure and efficacy or adverse events. The plasma ivosidenib concentration‐QT analysis showed a mean change in QTc using Fridericia’s method (ΔQTcF) of 17.2 msec at the approved 500 mg q.d. dose. Because of the direct association between ivosidenib exposure and QTcF, patients should have their electrocardiograms and electrolytes monitored, and comedications that increase ivosidenib exposure or prolong the QT interval should be avoided. These model‐based analyses quantitatively provide a framework to describe the relationship among ivosidenib dose, exposure, and clinical end points. With precautions for QTc prolongation, the exposure‐response analyses support the 500 mg q.d. dose in patients with AML with a susceptible IDH1 mutation.

Diets of overloaded purine-rich foods for a long time are one of the important reasons to cause renal lesions. Eucommia ulmoides is one of the traditional Chinese medicine herbs, which has been used to recover functions of the kidney. However, its mechanism remains unclear. The aim of this study was to explore the effects and protective mechanism of Eucommia ulmoides extract on renal injury caused by long-term high purine diets in rats. SD rats underwent an intragastric adenine (200 mg kg-1 d-1) administration for 9 weeks and were treated for 15 weeks. The results demonstrated that Eucommia ulmoides extract significantly reduced serum Cre and BUN levels in rats. H&E and Masson's trichrome stains showed notable lowering of the infiltration of inflammatory cells, the formation of fibrous tissues and collagen fibers, and improvement in the pathological morphology of kidneys. It also suppressed the protein and mRNA expressions of TGF-β1 and α-SMA and enhanced E-cadherin expression. Meanwhile, Eucommia ulmoides extract prominently inhibited the mRNA expression of Col I, Col III, Col IV, TIMP-1, and TIMP-2 and promoted expressions of MMP-1, MMP-2 and MMP-9. Through our study, it is the first time to prove that Eucommia ulmoides extract could ameliorate renal interstitial fibrosis and may involve in the regulation of the extracellular matrix (ECM) degradation enzyme (MMPs/TIMPs) system, promotion of the expression of E-cadherin, and suppression of expressions of TGF-β1 and α-SMA. The results provide a significant implication for the utilization of Eunomia Ulmoides extract as functional foods to enhance renal functions and improve renal injury caused by high purine diets.

Background Mechanical power (MP) refers to the energy delivered by a ventilator to the respiratory system per unit of time. MP referenced to predicted body weight (PBW) or respiratory system compliance have better predictive value for mortality than MP alone in acute respiratory distress syndrome (ARDS). Our objective was to assess the potential impact of consecutive changes of MP on hospital mortality among ARDS patients receiving extracorporeal membrane oxygenation (ECMO). Methods We performed a retrospective analysis of patients with severe ARDS receiving ECMO in a tertiary care referral center in Taiwan between May 2006 and October 2015. Serial changes of MP during ECMO were recorded. Results A total of 152 patients with severe ARDS rescued with ECMO were analyzed. Overall hospital mortality was 53.3%. There were no significant differences between survivors and nonsurvivors in terms of baseline values of MP or other ventilator settings. Cox regression models demonstrated that mean MP alone, MP referenced to PBW, and MP referenced to compliance during the first 3 days of ECMO were all independently associated with hospital mortality. Higher MP referenced to compliance (HR 2.289 [95% CI 1.214–4.314], p = 0.010) was associated with a higher risk of death than MP itself (HR 1.060 [95% CI 1.018–1.104], p = 0.005) or MP referenced to PBW (HR 1.004 [95% CI 1.002–1.007], p 14.4 J/min) during the first 3 days of ECMO was significantly higher than that of patients with low MP (≦ 14.4 J/min) (70.7% vs. 46.8%, p = 0.004), and the 90-day hospital mortality of patients with high MP referenced to compliance (> 0.53 J/min/ml/cm H2O) during the first 3 days of ECMO was significantly higher than that of patients with low MP referenced to compliance (≦ 0.53 J/min/ml/cm H2O) (63.6% vs. 29.7%, p Conclusions MP during the first 3 days of ECMO was the only ventilatory variable independently associated with 90-day hospital mortality, and MP referenced to compliance during ECMO was more predictive for mortality than was MP alone.

OBJECTIVES: To compare the diagnostic efficacy of shear wave elastography (SWE) comnined with ACR TI-RADS categories for malignancy risk stratification of thyroid nodules with interminate FNA cytology. METHODS: The clinical data, sonographic features, ACR TI-RADS grading and shear wave elastography images of 193 patients of surgical pathologically proven thyroid nodules with interminate FNA cytology were retrospectively analyzed. The diagnostic efficacy of ACR TI-RADS categories, the maximum Young’s modulus (Emax) of SWE and the combination of the two were calculated respectively. RESULTS: The ROC curves were drawn using surgical pathology results as the gold standard. The ROC curves indicated that the cut-off value of ACR TI-RADS and Emax of SWE was TR5 and 41.2 kPa respectively, and the area under the ROC curve (AUC) was 0.864 (95% CI: 0.879–0.934) and 0.858 (95% CI: 0.796–0.920) respectively. The diagnostic sensitivity, specificity and accuracy of ACR TI-RADS was 81.4% (127/156), 84.8% (31/37), and 81.9% (158/193), respectively. That of SWE Emax was 80.8% (126/156), 78.4% (29/37), and 80.3% (155/193), respectively. After SWE combined with ACR TI-RADS, the sensitivity, specificity and accuracy was 94.2% (147/156), 75.7% (28/37), and 90.7% (175/193), respectively. CONCLUSIONS: ACR TI-RADS classification system and shear wave elastography had high diagnostic efficacy for thyroid nodules with interminate FNA cytology. The combination of the two could improve diagnostic sensitivity and accuracy, and could help to differentiate benign and malignant thyroid nodules with interminate FNA cytology.

Summary Background Vision loss is an important public health issue in China, but a detailed understanding of national and regional trends in its prevalence and causes, which could inform health policy, has not been available. This study aimed to assess the prevalence, causes, and regional distribution of vision impairment and blindness in China in 1990 and 2019. Methods Data from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019 were used to estimate the prevalence of moderate and severe vision impairment and blindness in China and compare with other Group of 20 (G20) countries. We used GBD methodology to systematically analyse all available demographic and epidemiological data at the provincial level in China. We compared the age-standardised prevalences across provinces, and the changes in proportion of vision loss attributable to various eye diseases in 1990 and 2019. We used two different counterfactual scenarios with respect to population structure and age-specific prevalence to assess the contribution of population growth and ageing to trends in vision loss. Findings In 2019, the age-standardised prevalence was 2·57% (uncertainty interval [UI] 2·28–2·86) for moderate vision impairment, 0·25% (0·22–0·29) for severe vision impairment, and 0·48% (0·43–0·54) for blindness in China, which were all below the global average, but the prevalence of moderate and severe vision impairment had increased more rapidly than in other G20 countries from 1990 to 2019. The prevalence of vision loss increased with age, and the main causes of vision loss varied across age groups. The leading causes of vision impairment in China were uncorrected refractive error, cataract, and macular degeneration in both 1990 and 2019 in the overall population. From 1990 to 2019, the number of people with moderate vision impairment increased by 133·67% (from 19·65 to 45·92 million), those with severe vision impairment increased by 147·14% (from 1·89 to 4·67 million), and those with blindness increased by 64·35% (from 5·29 to 8·69 million); in each case, 20·16% of the increase could be explained by population growth. The contributions to these changes by population ageing were 87·22% for moderate vision impairment, 116·06% for severe vision impairment, and 99·22% for blindness, and the contributions by age-specific prevalence were 26·29% for moderate vision impairment, 10·91% for severe vision impairment, and −55·04% for blindness. The prevalence and specific causes of vision loss differed across provinces. Interpretation Although a comprehensive national policy to prevent blindness is in place, public awareness of visual health needs improving, and reducing the prevalence of moderate and severe vision impairment should be prioritised in future work. Funding China National Key Research and Development Programme and Beijing Municipal Special Funds for Medical Research on Public Welfare Development and Reform.

The relationships between pre-diagnosis meat intake and ovarian cancer survival were limited and controversial. To date, no study has taken account of cooking methods. Thus, we aimed to firstly clarify these associations based on the Ovarian Cancer Follow-Up Study.

Epidemiological studies evaluating the associations between the consumption of cruciferous vegetables (CV) and diverse health outcomes have generated inconsistent findings.

To evaluate the role of the peripapillary retinal nerve fiber layer (pRNFL) and peripapillary choroidal thickness (pCT) in the development and progression of diabetic retinopathy (DR).This is a cohort study based on the baseline and 2-year follow-up data of the Guangzhou Diabetic Eye Study. Patients with type 2 diabetes mellitus between the ages of 30 and 80 years were recruited from communities in Guangzhou. DR was graded by seven-field fundus photography after dilation of the pupil. pRNFL and pCT were measured via swept-source optical coherence tomography.A total of 895 patients were included in the study; of these, 748 did not have DR at baseline and 147 had DR at baseline. During the 2-year follow-up, 80 developed DR (10.7%), and 11 experienced DR progression (7.5%). After adjusting for confounding factors, a higher risk of incident DR was strongly associated with a lower average thickness of the pRNFL (risk ratio [RR] per 1 SD, 0.55; 95% confidence interval [CI], 0.42-0.72; P0.001) and average pCT (RR per 1 SD, 0.49; 95% CI, 0.34-0.70; P0.001). Adding both metrics to the DR prediction model significantly improved the discriminant ability of the model for incidences of DR (area under the curve increased by 15.38% from 0.673 to 0.777; P0.001).Neurodegeneration shown by the thinning of pRNFL and impaired choroidal circulation shown by the thinning of pCT are independently associated with DR onset, and assessing both metrics can improve the risk assessment for DR incidences.

Background and Objectives. Genome-wide association studies (GWAS) have shown that cartilage intermediate layer protein 2 (CILP2) is associated with blood lipid levels and coronary heart disease (CHD). However, no study has reported whether CILP2 is related to atherosclerosis in humans. The purpose of the current study is to identify the associations between CILP2 and atherosclerosis in vitro and in vivo. Methods and Results. Circulating CILP2 levels (measured by ELISA) were compared to various insulin resistance- and atherosclerosis-related parameters in normal subjects and newly diagnosed CHD patients. THP-1 cells were cultured and treated with indicated stimulators. Western blots and RT-PCR were performed to examine protein and mRNA expressions. The results showed that there were significantly higher circulating CILP2 levels in CHD patients relative to healthy controls. Circulating CILP2 correlated positively with waist-hip ratio (WHR), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), HbA1c, homeostasis model assessment of insulin resistance (HOMA-IR), and Gensini scores. In an in vitro study, we found that CILP2 increased oxidatively modified LDL-stimulated lipid accumulation in THP-1 macrophages via the upregulation of CD36 expression. Inhibition of PPARγ signaling eliminated the CILP2 regulation of CD36 expression in THP-1 macrophages. CILP2 positively regulated CD36 transcription through PPARγ-mediated action on two peroxisome-proliferator-responsive elements (PPREs) binding sites of CD36 promoter, PPRE-G, and PPRE-J. Conclusions. Our findings have uncovered a novel role for CILP2 in lipid uptake and foam cell formation. This role is mediated by CD36 through the activation of PPARγ pathway.

What is known and objective The purpose of this case report is to increase the awareness of tacrolimus-induced acute pancreatitis in renal transplantation patients. Case summary We present a case of tacrolimus-induced acute pancreatitis with positive rechallenge. The 24-year-old male patient underwent kidney transplant and received immunosuppressive therapy with tacrolimus. On day 10 post-transplant, he presented with abdominal pain. A laboratory analysis showed elevated serum amylase and serum lipase levels. An abdominal computed tomography scan showed large-volume ascites and pelvic cavity effusion. These findings led to a diagnosis of acute pancreatitis. After tacrolimus was temporarily stopped and altered with cyclosporine, his symptoms decreased and he was restarted with tacrolimus. On day 61, laboratory tests again revealed significant elevations of serum amylase and serum lipase. A computed tomography scan of the abdomen showed increased pancreatic tail fluid collections. We excluded other possible causes and concluded that tacrolimus was the definite inducer of pancreatitis. The patient was switched from tacrolimus to cyclosporine again. Serum amylase and serum lipase were gradually decreased to normal, and he was discharged home with no relapse. What is new and conclusion With the consideration of the wide use of tacrolimus, it is important that healthcare providers are aware of tacrolimus-induced acute pancreatitis. Future studies are needed to confirm and quantify the risk of tacrolimus-induced acute pancreatitis.

During spaceflight, astronauts are subjected to various physical stressors including microgravity, which could cause immune dysfunction and thus potentially predispose astronauts to infections and illness. However, the mechanisms by which microgravity affects innate immunity remain largely unclear. In this study, we conducted RNA-sequencing analysis to show that simulated microgravity (SMG) suppresses the production of inflammatory cytokines including tumor necrosis factor (TNF) and interleukin-6 (IL-6) as well as the activation of the innate immune signaling pathways including the p38 mitogen-activated protein kinase (MAPK) and the Erk1/2 MAPK pathways in the Enteropathogenic escherichia coli (EPEC)-infected macrophage cells. We then adopted hindlimb-unloading (HU) mice, a model mimicking the microgravity of a spaceflight environment, to demonstrate that microgravity suppresses proinflammatory cytokine-mediated intestinal immunity to Citrobacter rodentium infection and induces the disturbance of gut microbiota, both of which phenotypes could be largely corrected by the introduction of VSL#3, a high-concentration probiotic preparation of eight live freeze-dried bacterial species. Taken together, our study provides new insights into microgravity-mediated innate immune suppression and intestinal microbiota disturbance, and suggests that probiotic VSL#3 has great potential as a dietary supplement in protecting individuals from spaceflight mission-associated infections and gut microbiota dysbiosis.

Exosomes play an important role in intercellular communication and metastatic progression of hepatocellular carcinoma (HCC). However, cellular communication between heterogeneous HCC cells with different metastatic potentials and the resultant cancer progression are not fully understood in HCC. Here, HCC cells with high-metastatic capacity (97hm and Huhm) were constructed by continually exerting selective pressure on primary HCC cells (MHCC-97H and Huh7). Through performing exosomal miRNA sequencing in HCC cells with different metastatic potentials (MHCC-97H and 97hm), many significantly different miRNA candidates were found. Among these miRNAs, miR-92a-3p was the most abundant miRNA in the exosomes of highly metastatic HCC cells. Exosomal miR92a-3p was also found enriched in the plasma of HCC patient-derived xenograft mice (PDX) model with high-metastatic potential. Exosomal miR-92a-3p promotes epithelial-mesenchymal transition (EMT) in recipient cancer cells via targeting PTEN and regulating its downstream Akt/Snail signaling. Furthermore, through mRNA sequencing in HCC cells with different metastatic potentials and predicting potential transcription factors of miR92a-3p, upregulated transcript factors E2F1 and c-Myc were found in high-metastatic HCC cells promote the expression of cellular and exosomal miR-92a-3p in HCC by directly binding the promoter of its host gene, miR17HG. Clinical data showed that a high plasma exosomal miR92a-3p level was correlated with shortened overall survival and disease-free survival, indicating poor prognosis in HCC patients. In conclusion, hepatoma-derived exosomal miR92a-3p plays a critical role in the EMT progression and promoting metastasis by inhibiting PTEN and activating Akt/Snail signaling. Exosomal miR92a-3p is a potential predictive biomarker for HCC metastasis, and this may provoke the development of novel therapeutic and preventing strategies against metastasis of HCC.

Fibroblast growth factors (FGFs) 21 and 23 are recently identified hormones regulating metabolism of glucose, lipid, phosphate and vitamin D. Here we conducted a genome-wide association study (GWAS) for circulating FGF21 and FGF23 concentrations to identify their genetic determinants. We enrolled 5,000 participants from Taiwan Biobank for this GWAS. After excluding participants with diabetes mellitus and quality control, association of single nucleotide polymorphisms (SNPs) with log-transformed FGF21 and FGF23 serum concentrations adjusted for age, sex and principal components of ancestry were analyzed. A second model additionally adjusted for body mass index (BMI) and a third model additionally adjusted for BMI and estimated glomerular filtration rate (eGFR) were used. A total of 4,201 participants underwent GWAS analysis. rs67327215, located within RGS6 (a gene involved in fatty acid synthesis), and two other SNPs (rs12565114 and rs9520257, located between PHC2-ZSCAN20 and ARGLU1-FAM155A respectively) showed suggestive associations with serum FGF21 level (P = 6.66 × 10–7, 6.00 × 10–7 and 6.11 × 10–7 respectively). The SNPs rs17111495 and rs17843626 were significantly associated with FGF23 level, with the former near PCSK9 gene and the latter near HLA-DQA1 gene (P = 1.04 × 10–10 and 1.80 × 10–8 respectively). SNP rs2798631, located within the TGFB2 gene, was suggestively associated with serum FGF23 level (P = 4.97 × 10–7). Additional adjustment for BMI yielded similar results. For FGF23, further adjustment for eGFR had similar results. We conducted the first GWAS of circulating FGF21 levels to date. Novel candidate genetic loci associated with circulating FGF21 or FGF23 levels were found. Further replication and functional studies are needed to support our findings.

OBJECTIVE: Abnormal liver function is a common form of extra-pulmonary organ damage in patients with coronavirus disease 2019 (COVID-19). Patients with severe COVID-19 have a higher probability and progression of liver injury than those without severe disease. We aimed to evaluate the prognosis of liver injury in patients with COVID-19. METHODS: We retrospectively included 502 patients with laboratory-confirmed SARS-CoV-2 infection. Clinical features and survival of patients with and without liver injury were compared. Cox proportional hazards models were used to determine the variables that might have an effect on survival. RESULTS: Among the 502 patients enrolled, 301 patients had abnormal liver function with increased neutrophil count, C-reactive protein, creatinine, troponin I (TnI), D-dimer, lactose dehydrogenase and creatine kinase. Patients with abnormal liver functions had a higher mortality rate (28.9% vs 9.0%, P < 0.001), a higher ratio of male sex (65.1% vs 40.8%, P < 0.001) and a higher chance of developing systemic inflammatory response syndrome (53.5% vs 41.3%, P = 0.007). Among patients with abnormal liver functions, patients with grade 2 liver damage (with both abnormal alanine aminotransferase or aspartate aminotransferase levels and abnormal alkaline phosphatase or gamma-glutamyl transpeptidase levels) had a higher ratio of male patients, elevated neutrophil count, procalcitonin, D-dimer levels and mortality rate. Multivariate Cox regression analyses suggested that the grade of liver damage (hazard ratio: 1.377, 95% confidence interval: 1.000-1.896, P = 0.049) was an independent predictor of death. CONCLUSIONS: Patients with COVID-19 and abnormal liver functions have a higher mortality than those with normal liver functions. Liver damage is an independent prognostic factor of COVID-19.

Aims: Dexmedetomidine (Dex) as a highly selective α2-adrenoceptor agonist, was widely used anesthetic in perioperative settings, whether Dex induces cardiac hypertrophy during perioperative administration is unknown. Methods: The effects of Dex on cardiac hypertrophy were explored using the transverse aortic constriction model and neonatal rat cardiomyocytes. Results: We reported that Dex induces cardiomyocyte hypertrophy with activated ERK, AKT, PKC and inactivated AMPK in both wild-type mice and primary cultured rat cardiomyocytes. Additionally, pre-administration of Dex protects against transverse aortic constriction induced-heart failure in mice. We found that Dex up-regulates the activation of ERK, AKT, and PKC via suppression of AMPK activation in rat cardiomyocytes. However, suppression of mitochondrial coupling efficiency and membrane potential by FCCP blocks Dex induced AMPK inactivation as well as ERK, AKT, and PKC activation. All of these effects are blocked by the α2-adrenoceptor antagonist atipamezole. Conclusion: The present study demonstrates Dex preconditioning induces cardiac hypertrophy that protects against heart failure through mitochondria-AMPK pathway in perioperative settings.

Gastric cancer (GC) is one of the most leading malignancies. Long noncoding RNA is related to GC. In this study, 11 miRNAs in the exosomes and six lncRNAs in the tissues was examined by qRT-PCR. Correlation analysis was used to analyze the relationship between miRNAs in exosome and lncRNAs in the tissues. Four miRNAs level in GC tissues were examined by qRT-PCR. MTT was used to determine cell viability. Flow cytometry was used to quantify the apoptotic cells. Transwell assay was used to examine the migration and invasion capacity. Dual-luciferase assay was used to examine the interaction between HOTAIR and miR-30a or -b. Capillary formation was used to determine the capillary formation capacity. Weak negative correlations were found between HOTAIR and miR-30a or -b in GC tissue samples. Interestingly, strong negative correlations were identified between the HOTAIR level in GC tissue samples and the miR-30a or -b levels in plasma exosomes. HOTAIR knockdown GC cells exhibited decreased migration, invasion, proliferation, and upregulated apoptosis, which released more miR-30a and -b into the exosomes. KRAS was upregulated when co-cultured with exosomes from HOTAIR overexpressed cells, and promoted GC cells proliferation, migration, and invasion. Meanwhile, HUVEC cells expressed increased VEGF-A and formatted more capillaries. Subsequently, we identified a 10mer target site of miR-30a or -b in HOTAIR sequence, and the overexpression of HOTAIR induced the degradation of miR-30a or -b, indicating a ceRNA role of HOTAIR. We report the negative correlation between the plasma miRNAs level and GC tissue HOTAIR expression for the first time and unveiled the ceRNA role of HOTAIR in GC. HOTAIR functions as an onco-lncRNA regulating the level of miR-30a and -b in both GC cells and exosomes. These findings may give insight into understanding the mechanism of GC pathogenesis and provide new biomarkers for clinical diagnosis.

Objectives Renal function may improve after left ventricular assist device (LVAD) implant, however, some patients develop postoperative acute kidney injury (AKI). Randomized trials showed benefit for early renal replacement therapy (RRT) in critically ill patients with AKI, but this practice has not been studied in LVAD patients. Methods We performed a single-center, retrospective cohort study of all adults (>18 years) who underwent LVAD placement from 1/2010 to 12/2018. We collected preoperative, hemodynamic, echocardiographic, intraoperative, and postoperative data. AKI was defined according to Kidney Disease: Improving Global Outcomes definition. Early (E) RRT was considered treatment at AKI stage II or below. Standard (S) RRT was considered treatment at AKI stage III. Outcomes and Kaplan-Meier analysis were compared between groups. Results A total of 184 patients were included (mean age 56.10 years, 81% males, 30.4% African-American race). A total of 71 (38.6%) developed AKI and 17 (9.24%) needed RRT (11 E vs 6 S). A total of 11 remained hemodialysis-dependent at discharge (5 [45.5%] in E vs 6 [100%] in S, P = .043). There was a trend toward shorter intensive care unit stay and ventilation time in E group, and overall hospital stay was significantly less in the E group (48.18 ± 25.95 vs 94.00 ± 53.07 days, P = .028). Thirty-day mortality was similar between groups (E 18% vs S 16%, P = .9), but there was a trend toward improved overall survival in the E group. Conclusion This is the first study to examine early initiation of RRT after LVAD implant. Early RRT was associated with shorter hospital stay, lower need for permanent RRT, and a trend toward improved survival. This practice may provide significant cost savings and should be examined further.

Objective Spinocerebellar ataxia type 3 (SCA3) is one of the most common hereditary neurodegenerative diseases, with balance instability as main symptom. Balance quantification is crucial for evaluating the efficacy of therapeutic interventions. However, balance evaluation in SCA3 is often subject to bias. Here, we aimed to quantitatively evaluate postural instability and investigate the relationship between postural instability and clinical characteristics in SCA3 patients. Methods Sixty‐two SCA3 patients and 62 normal controls were recruited, and their postural balance was measured using a posturographic platform. Principal component analysis was performed as data reduction to identify postural instability factors. Multivariable linear regression was used to investigate potential risk factors for postural instability and to explore whether postural instability predicts the severity and progression of ataxia in SCA3 patients. Results We found SCA3 patients experience postural instability characterized by significant impairment in static and dynamic stability. The condition without visual feedback was the most sensitive measure in differentiating SCA3 from controls. Regression analyses revealed that ataxia severity predicted both static (P = 0.014) and dynamic stability (P = 0.001). Likewise, along with expanded CAG repeats (P

Background/purpose: Treatment of chronic hepatitis C (CHC) has entered a new era since the introduction of direct-acting antiviral agents (DAAs). Numerous clinical trials have shown that treatment response as well as tolerability of DAAs are superior to those of conventional therapy with pegylated interferon and ribavirin. However, the results of clinical trials may not be directly applied to real-world practice. Therefore our study tried to investigate the effectiveness of various DAA regimens in Taiwanese patients with chronic hepatitis C. Methods: We performed a retrospective study on 400 CHC patients. The primary endpoint was undetectable HCV RNA (an HCV RNA level of

Due to the discomfort and incidence of complications increases with the increasing number of biopsy cores, the protocol of prostate biopsy has been promoted from systematic biopsy (SB) to targeted biopsy (TB) in many studies. However, the optimal prostate sampling scheme to balance the incidence of biopsy complications and accuracy of biopsy remains controversial. Our objective is to explore an optimal prostate cancer (PCa) sampling scheme with fewer SB cores. Patients with at least one lesion of Prostate Imaging Reporting and Data System ≥3 were prospectively enrolled. TB and SB were performed for each patient as reference. The hypothetical biopsy sampling schemes were TB only, SB only, and TB followed by SB of the nontargeted sector (TB+nSB). The PCa and clinically significant PCa (csPCa) detection rates and cores of the three hypothetical biopsy schemes were compared with TB+SB. Among 165 patients, 107 (64.8%) were diagnosed with PCa and 91 (55.2%) with csPCa via TB+SB. There were 54 (50.5%) and 42 (46.2%) magnetic resonance imaging (MRI) true negative cases and 53 (49.5%) and 49 (53.8%) false negative cases of nontargeted sectors among PCa and csPCa patients, respectively. The maximal cancer proportion in positive biopsy cases differed significantly between the true and false groups of these cohorts. There was no difference between TB+nSB and TB+SB for PCa or csPCa detection. The optimal sampling scheme TB+nSB with fewer SB cores showed same PCa and csPCa detection rates as that of standard TB+SB with MRI/ultrasound fusion biopsy.

Sepsis-induced diaphragm dysfunction (SIDD) which is mainly characterized by decrease in diaphragmatic contractility has been identified to cause great harms to patients. Therefore, there is an important and pressing need to find effective treatments for improving SIDD. In addition, acetylcholinesterase (AChE) activity is a vital property of the diaphragm, so we evaluated both diaphragmatic contractility and AChE activity. Though neuregulin-1β (NRG-1β) is known to exert organ-protective effects in some inflammatory diseases, little is known about the potential of NRG-1β therapy in the diaphragm during sepsis. Our study was aimed at exploring the effects of NRG-1β application on diaphragmatic contractility and AChE activity during sepsis. Proinflammatory cytokines, muscle injury biomarkers in serum, contractile force, AChE activity, proinflammatory cytokines, oxidative parameters, histological condition, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining, and expression of phosphoinositide 3-kinase (PI3K)/protein kinase B (PKB/Akt) signaling proteins in the diaphragm were measured and compared between nonseptic and septic groups with or without NRG-1β treatment. In vitro, the effects of NRG-1β on reactive oxygen species (ROS) production in the lipopolysaccharide- (LPS-) stimulated L6 rat muscle skeletal cells with or without the Akt inhibitor MK-2206 were detected. NRG-1β inhibited proinflammatory cytokine release and muscle injury biomarkers soaring in serum and improved the sepsis-induced diaphragm dysfunction and AChE activity decrease significantly during sepsis. Meanwhile, the inflammatory response, oxidative stress, pathological impairment, and cell apoptosis in the diaphragm were mitigated by NRG-1β. And NRG-1β activated the PI3K/Akt signaling in the diaphragm of septic rats. Elevated ROS production in the LPS-stimulated L6 rat skeletal muscle cells was reduced after treatment with NRG-1β, while MK-2206 blocked these effects of NRG-1β. In conclusion, our findings underlined that NRG-1β could reduce circulating levels of proinflammatory cytokines in rats with sepsis, adjust diaphragmatic proinflammatory cytokine level, mitigate diaphragmatic oxidative injury, and lessen diaphragm cell apoptosis, thereby improving diaphragmatic function, and play a role in diaphragmatic protection by activating PI3K/Akt signaling.

Recalcitrant bladder neck contracture (BNC) is a common complication after transurethral resection of the prostate. Our aim was to show the outcomes of a modified cystoscopy-assisted laparoscopic Y-V plasty for BNC treatments.We retrospectively evaluated a series of 27 patients who underwent a modified cystoscopy-assisted laparoscopic Y-V plasty for recalcitrant BNC from January 2017 to September 2019. Urinary flow rate, international prostate symptom score (IPSS), international index of erectile function-5 (IIEF-5) and bladder urethral examination by cystoscopy were performed preoperatively and postoperatively, respectively.All patients underwent the procedure successfully and no serious complication occurred. The median surgery time was 68.6 min without massive bleeding. The median follow-up time was 14.2 months and no patients had urinary incontinence. The maximum urine flow rate 3 months after surgery was significantly higher than prior to surgery (17.7 ± 2.1 ml/s vs. 8.2 ± 1.2 ml/s,The modified cystoscopy-assisted laparoscopic Y-V plasty is a feasible and effective technique for recalcitrant BNC treatment.

Background Percutaneous nephrolithotomy is traditionally performed in the prone or supine position. We report the first case of percutaneous nephrolithotomy in sit position under local infiltration anesthesia. Case summary A 69-year-old male presented with left flank pain. Kidney B ultrasound and computed tomography scan showed multiple left renal calculi and hydronephrosis. He had a long history of chronic obstructive pulmonary disease, with severe ventilatory and cardiac dysfunction, and cannot tolerate the prone or supine position. The patient received the surgery in sit position under local infiltration anesthesia. The operative time was 1 h. The visual analogue scale score during the surgery was 3. The patient had no intraoperative and postoperative complications. The postoperative plain radiography showed no residual stone fragments. Conclusions We believe that in high-risk patients who need to undergo PCNL, a combination of sit position and local infiltration anesthesia is an alternative method.

Data regarding the efficacy and tolerability of elbasvir/grazoprevir (EBR/GZR) for East-Asian hepatitis C virus genotype 1b (HCV GT1b) patients receiving hemodialysis were limited. We prospectively recruited 40 HCV GT1b hemodialysis patients who received EBR/GZR for 12 weeks at 6 academic centers in Taiwan. The efficacy endpoints were sustained virologic response 12 weeks off-therapy (SVR12) by intention-to-treat (ITT) modified ITT (mITT) analyses. Patients’ baseline characteristics, early viral kinetics and HCV resistance-associated substitutions (RASs) at HCV non-structural 3 and 5 A (NS3 and NS5A) regions potentially affecting SVR12 were analyzed. The tolerability for EBR/GZR was also assessed. The SVR12 rates by ITT and mITT analyses were 95% (38 of 40 patients; 95% confidence interval (CI): 83.5–98.6%) and 100% (38 of 38 patients; 95% CI: 90.8–100%), respectively. Patients’ baseline characteristics, on-treatment viral decline, and baseline HCV RASs did not affect SVR12. All patients tolerated treatment well. Among 5 patients who had serious adverse events (AEs) including one death due to on-treatment suicide and the other death due to off-therapy acute myocardial infarction, none of these events were judged related to EBR/GZR. The common AEs included upper respiratory tract infection (7.5%), fatigue (5.0%) and anorexia (5.0%). Nine (22.5%) and 8 (20.0%) patients had on-treatment hemoglobin levels of 9.0–10.0 g/dL and 7.0–9.0 g/dL. Three (7.5%) patients had on-treatment elevated alanine aminotransferase (ALT) quotient > 2.5, in whom one (2.5%) had EBR/GZR-induced late ALT elevation. No patients developed hyperbilirubinemia or hepatic decompensation. In conclusion, treatment with EBR/GZR is effective and well-tolerated for East-Asian HCV GT1b patients receiving hemodialysis.

Background & Aims Acute HEV infection causes varying degrees of liver damage. Although liver-related death due to HEV infection alone is rare in healthy individuals, it is unclear whether HEV superinfection is associated with worse outcomes in patients with chronic HBV infection. Thus, we explored whether HEV superinfection was associated with increased incidence of liver-related death, cirrhosis, and hepatocellular carcinoma (HCC). Methods Serum and data were collected from 2 independent retrospective cohorts of patients with chronic HBV infection, comprising 2,123 patients without cirrhosis and 414 with cirrhosis at baseline, respectively. All the patients were negative for HEV-IgG at enrolment and HEV superinfection was defined by the presence of HEV-IgG seroconversion. Results In the non-cirrhotic cohort, 46 of 2,123 patients developed HEV superinfection. Though HEV superinfection was only associated with increased incidence of liver-related death in the overall cohort, it was a risk factor for all 3 endpoints (liver-related death, cirrhosis, and HCC) in a subgroup of 723 HBeAg-negative patients with chronic HBV infection. In addition, the 1-year mortality rate after HEV superinfection was higher in 4 patients who developed cirrhosis during the follow-up than in those who did not (50% vs. 2.4%, p = 0.001). To elucidate the perceived relationship between HEV superinfection and risk of mortality, an independent cohort of cirrhotic patients (n = 414) was further analyzed to control for the inherent increase in mortality risk due to cirrhosis. The 10 cirrhotic patients with HEV superinfection had a higher 1-year mortality rate than those without (30% vs. 0%, p Conclusions In both cohorts of patients with chronic HBV infection, acute HEV superinfection increases the risk of liver-related death, especially in those with cirrhosis. Lay summary The mortality caused by acute hepatitis E virus infection is usually low in the healthy population, but it is unclear how it affects patients with chronic hepatitis B virus infection, as they already have compromised liver function. Our data show that the 1-year mortality rate is 35.7% in patients with hepatitis B-related cirrhosis who contract hepatitis E virus. Hepatitis E may accelerate disease progression in patients with chronic hepatitis B.

Latifolin, one of the major flavonoids extracted from lignum dalbergiae odoriferae, has been documented to protect the heart from acute myocardial ischemia induced by pituitrin and isoproterenol in rats and has also been found to inhibit inflammation. In this study, we aimed to investigate whether latifolin could protect the heart from doxorubicin (DOX)-induced cardiotoxicity and elucidate its underlying mechanisms. Male mice were treated with an intraperitoneal dose of DOX (20 mg/kg) plus oral latifolin at a dose of 50 or 100 mg/kg for 12 days. After exposure, we assessed cardiac function, myocardial injury, and macrophage polarization in excised cardiac tissue. Our results demonstrated that latifolin prevented DOX-induced cardiac dysfunction and produced macrophage polarization in mice challenged with latifolin. In cultured peritoneal macrophages, latifolin significantly reduced inflammatory cytokines (P < 0.05). Furthermore, latifolin remarkably decreased the percentage of macrophage M1/M2 polarization (P < 0.05). The results from the present study highlight the benefits of treatment with latifolin in DOX-induced cardiotoxicity, and the mechanism involved in mediating the polarization phenotype change of M1/M2 macrophages.

The objective of this project was to find a bronchodilatory compound from herbs and clarify the mechanism. We found that the ethanol extract of Folium Sennae (EEFS) can relax airway smooth muscle (ASM). EEFS inhibited ASM contraction, induced by acetylcholine, in mouse tracheal rings and lung slices. High-performance liquid chromatography assay showed that EEFS contained emodin. Emodin had a similar reversal action. Acetylcholine-evoked contraction was also partially reduced by nifedipine (a selective inhibitor of L-type voltage-dependent Ca2+ channels, LVDCCs), YM-58483 (a selective inhibitor of store-operated Ca2+ entry, SOCE), as well as Y-27632 (an inhibitor of Rho-associated protein kinase). In addition, LVDCC- and SOCE-mediated currents and cytosolic Ca2+ elevations were inhibited by emodin. Emodin reversed acetylcholine-caused increases in phosphorylation of myosin phosphatase target subunit 1. Furthermore, emodin, in vivo, inhibited acetylcholine-induced respiratory system resistance in mice. These results indicate that EEFS-induced relaxation results from emodin inhibiting LVDCC, SOCE, and Ca2+ sensitization. These findings suggest that Folium Sennae and emodin may be new sources of bronchodilators.

Long non-coding RNA (lncRNA) LINC00473 plays a carcinogenic role in a variety of different tumor types. Nevertheless, the mechanisms through which LINC00473 regulates the radiosensitivity of esophageal squamous cell carcinoma (ESCC) cells remains elusive. In the present study, reverse transcription-quantitative PCR was used to quantify the expression of LINC00473, microRNA (miRNA/miR)-497-5p and cell division cycle 25A (CDC25A) in ESCC tissues. The association between LINC00473 expression and the clinicopathological characteristics of patients with ESCC was also assessed. Furthermore, Cell Counting kit-8 and colony formation assays were carried out to monitor the proliferation of ESCC cells exposed to X-ray radiation. A dual-luciferase reporter assay was also conducted to analyze the interaction between LINC00473 and miR-497-5p, as well as the interaction between CDC25A and miR-497-5p. The findings of the present study demonstrated that in ESCC tissues and cells, the expression levels of LINC00473 and CDC25A were significantly upregulated, while the expression of miR-497-5p was downregulated. The high expression level of LINC00473 was associated with a higher T stage, lymph node metastasis stage and a lower tumor differentiation grade in patients with ESCC. Following irradiation, transfection with miR-497-5p mimics reduced the promoting effect of LINC00473 overexpression on ESCC cell proliferation, and partially impeded the resistance of ESCC cells to X-ray radiation induced by LINC00473 overexpression. Moreover, transfection with miR-497-5p inhibitors partially alleviated the inhibitory effects of LINC00473 knockdown on cellular proliferation, and partly reversed the sensitivity of cells to X-ray irradiation induced by LINC00473 knockdown. Furthermore, it was confirmed that miR-497-5p was able to bind LINC00473 and the 3′-untranslated region of CDC25A. On the whole, the findings of the present study demonstrate that LINC00473 reduces the radiosensitivity of ESCC cells by modulating the miR-497-5p/CDC25A axis.